1 Title Page
Not populated in this demonstration. E3 lists 14 required title-page fields, including study title, protocol identifier, indication, a brief statement of design, investigational product, study phase, study initiation/completion dates, sponsor and responsible medical officer, and a statement of GCP compliance.
2 Synopsis
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3 Table of Contents for the Individual Clinical Study Report
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4 List of Abbreviations and Definition of Terms
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5 Ethics
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5.1 Independent Ethics Committee (IEC) or Institutional Review Board (IRB)
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5.2 Ethical Conduct of the Study
This study was conducted in accordance with the ethical principles that have their origin in the Declaration of Helsinki, and that are consistent with the International Council for Harmonisation Guideline for Good Clinical Practice (ICH E6) and the applicable regulatory requirements of the jurisdictions in which the study was conducted.
The protocol, the protocol amendments, the patient information sheet and the informed consent form were reviewed and approved by the responsible independent ethics committee or institutional review board at each participating centre before any patient was screened. Substantial amendments were submitted for review and approved before implementation, except where an immediate change was necessary to eliminate a hazard to patients.
TXT-E3-0502 · boilerplate
5.3 Patient Information and Consent
Written informed consent was obtained from every patient, or from the patient's legally acceptable representative where the patient was not competent to consent, before any study-specific procedure was performed. Because the study enrolled patients with mild to moderate Alzheimer's disease, the consent process explicitly provided for assessment of decisional capacity and, where capacity was impaired, for consent by a legally acceptable representative together with the assent of the patient.
Patients and their representatives were informed of the objectives of the study, of the investigational nature of the treatment, of the reasonably foreseeable risks and inconveniences, and of their right to withdraw from the study at any time without penalty or loss of benefits to which they were otherwise entitled. A copy of the signed consent form was provided to each patient or representative. The patient information sheet and the sample consent form are provided in Section 16.1.3.
TXT-E3-0503 · boilerplate
6 Investigators and Study Administrative Structure
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7 Introduction
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8 Study Objectives
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9 Investigational Plan
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9.1 Overall Study Design and Plan: Description
This was a randomised, double-blind, placebo-controlled, parallel-group study of the Xanomeline Transdermal Therapeutic System (TTS) in patients with mild to moderate Alzheimer's disease. Patients who satisfied all entry criteria at screening were randomised in equal allocation to one of three treatment groups — placebo, xanomeline low dose, or xanomeline high dose — and treated for the planned treatment period defined in the protocol, followed by an end-of-study evaluation.
A total of 254 patients were randomised and treated: 86 to placebo, 84 to xanomeline low dose and 84 to xanomeline high dose. Patients who were screened but not randomised are excluded from all analyses presented in this report; the derivation of the analysis populations is described in Section 11.1.
Study drug was supplied as a transdermal patch applied once daily. The blind was maintained by supplying placebo and active patches of identical appearance, and by withholding the randomisation code from investigators, patients and study personnel involved in the conduct of the study until database lock. The randomisation scheme and codes are provided in Section 16.1.7.
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9.2 Discussion of Study Design, Including the Choice of Control Groups
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9.3 Selection of Study Population
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9.3.1 Inclusion Criteria
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9.3.2 Exclusion Criteria
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9.3.3 Removal of Patients from Therapy or Assessment
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9.4 Treatments
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9.4.1 Treatments Administered
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9.4.2 Identity of Investigational Product(s)
Not populated in this demonstration. Batch listing, where more than one batch was used, goes to 16.1.6.
9.4.3 Method of Assigning Patients to Treatment Groups
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9.4.4 Selection of Doses in the Study
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9.4.5 Selection and Timing of Dose for Each Patient
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9.4.6 Blinding
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9.4.7 Prior and Concomitant Therapy
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9.4.8 Treatment Compliance
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9.5 Efficacy and Safety Variables
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9.5.1 Efficacy and Safety Measurements Assessed and Flow Chart
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9.5.2 Appropriateness of Measurements
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9.5.3 Primary Efficacy Variable(s)
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9.5.4 Drug Concentration Measurements
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9.6 Data Quality Assurance
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9.7 Statistical Methods Planned in the Protocol and Determination of Sample Size
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9.7.1 Statistical and Analytical Plans
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9.7.2 Determination of Sample Size
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9.8 Changes in the Conduct of the Study or Planned Analyses
No changes were made to the conduct of the study after the first patient was randomised, other than those recorded in the protocol amendments provided in Section 16.1.1.
The analyses presented in this report follow the statistical analysis plan. Every analysis was executed from version-controlled specifications, and each regeneration of a display is recorded as a numbered iteration with the specification hash, the input dataset hashes and the software environment that produced it. Any analysis performed after the statistical analysis plan was finalised is identified as post hoc where it appears. The complete documentation of statistical methods, including the specification and environment provenance for every display in this report, is provided in Section 16.1.9.
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10 Study Patients
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10.1 Disposition of Patients
Of the 254 patients randomised and treated, 110 (43.3%) completed the study and 144 (56.7%) discontinued prematurely.
Completion was substantially lower in both xanomeline groups than in the placebo group. 58 of the 86 patients randomised to placebo (67.4%) completed the study, compared with 25 of 84 (29.8%) in the xanomeline low dose group and 27 of 84 (32.1%) in the xanomeline high dose group. Premature discontinuation was therefore about twice as frequent in the xanomeline groups as in the placebo group, and this imbalance is the dominant feature of study conduct.
Death was recorded as the reason for discontinuation in 3 patients: 2 receiving placebo, 1 receiving xanomeline low dose and 0 receiving xanomeline high dose. The remaining 141 discontinuations are recorded in the analysis dataset as other or not specified, so no further breakdown of discontinuation reason is available from these data; the adverse event profile that plausibly accounts for the imbalance is described in Section 12.2.
Patient disposition is summarised in 14.1.1. Individual discontinued patients, with the date and the recorded reason for discontinuation, are listed in Section 16.2.1.
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| Subject Disposition (Summary) | ||||
| Study CDISCPILOT01 — Intent-to-Treat Analysis Set | ||||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | Total (N=254) | |
|---|---|---|---|---|
| Disposition, n (%) | ||||
| Subjects randomised | ||||
| Subjects treated | ||||
| Completed the study | ||||
| Discontinued the study | ||||
| Reason for discontinuation, n (%) | ||||
| Death | ||||
| Other / not specified | ||||
| Deaths, n (%) | ||||
| Died on study | ||||
| Percentages are based on the number of randomised subjects in each treatment group. | ||||
| The ADSL shipped in pharmaverseadam carries no DCSREAS/DCDECOD, so the reason for discontinuation is derived: 'Death' where DTHFL = 'Y', otherwise 'Other / not specified'. | ||||
| 52 screen failures are excluded from every analysis dataset. | ||||
| Source: adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | ||||
| open.csr display t-disposition (in_text variant); generated from the committed ARD. | ||||
| Subject Disposition | |
| Study CDISCPILOT01 — All Subjects | |
| All Subjects | |
|---|---|
| Subjects screened | |
| Screen failures | |
| Randomised, entered treatment phase | |
| Completed Week 24 | |
| Completed study through Week 26 | |
| Subjects screened are every subject in the study's SDTM DM domain; screen failures are those DM labels as such. Randomised subjects are every subject in ADSL; completed Week 24 is COMP24FL, and completed the study through Week 26 is the complement of DISCONFL — the definition Table 14-1.01 states for Complete Study. | |
| Drawn as the reference report's Figure 10-1: 306 screened, of whom 52 screen failures and 254 randomised; of those, 118 completed Week 24 and 110 completed the study. | |
| Source: dm (the study's SDTM demographics domain) and adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | |
| open.csr display f-disposition (in_text variant); generated from the committed ARD. | |
10.2 Protocol Deviations
Not populated in this demonstration. Individual deviations are listed in 16.2.2.
11 Efficacy Evaluation
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11.1 Data Sets Analysed
The safety analysis set comprised all patients who were randomised and received at least one dose of study medication. It included 254 patients: 86 in the placebo group, 84 in the xanomeline low dose group and 84 in the xanomeline high dose group. All safety analyses in this report, and every display referenced from Section 12, are based on this analysis set, and each display identifies its analysis set in the header in accordance with ICH E3.
Patients who were screened but not randomised are excluded from every analysis set. Analysis-set membership is derived in a documented, version-controlled data preparation step rather than assumed from the source data; that derivation, and the environment that executed it, are recorded in Section 16.1.9.
The efficacy analysis set comprised all randomised patients who took at least one dose of study medication and had at least one post-baseline assessment of both the ADAS-Cog and the CIBIC+, as the study's own analysis data flag it (EFFFL). It included 234 patients: 79 in the placebo group, 81 in the xanomeline low dose group and 74 in the xanomeline high dose group. The efficacy analyses and the post-text efficacy displays are based on this analysis set. The intent-to-treat population, every randomised patient, is 254 patients and is the population of the disposition displays. Patients excluded from any analysis population would be listed in Section 16.2.3.
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11.2 Demographic and Other Baseline Characteristics
Demographic and baseline characteristics were comparable across the three treatment groups in the safety analysis set of 254 patients.
The study population was elderly, as expected for a mild to moderate Alzheimer's disease population. Mean age overall was 75.1 years (SD 8.25), with a median of 77 years and a range of 51 to 89 years. Mean age was 75.2 years in the placebo group, 75.7 years in the xanomeline low dose group and 74.4 years in the xanomeline high dose group.
Women accounted for 143 patients (56.3%) overall, and the proportion of women ranged from 47.6% in the xanomeline high dose group to 61.6% in the placebo group. The population was predominantly white (230 patients, 90.6%), with 23 patients reported as Black or African American. The limited racial diversity of the population should be considered when generalising the findings of this study.
Demographic and baseline characteristics are summarised in 14.1.2; individual demographic data are listed in Section 16.2.4.
TXT-E3-1102 · parameterized
| Demographic Characteristics | ||||
| Study CDISCPILOT01 — Intent-to-Treat | ||||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | Total (N=254) | |
|---|---|---|---|---|
| Age (years), mean (range) | ||||
| Gender (%) | ||||
| Male | ||||
| Female | ||||
| Race (%) | ||||
| White/Caucasian | ||||
| Other | ||||
| Education (years), mean (range) | ||||
| [1] P-values are results of ANOVA treatment group comparison for continuous variables and Pearson's chi-square test for categorical variables, as the reference report (Table 14-2.01) states; each block carries one test across the three treatment groups. | ||||
| Race (Origin) is the reference report's classification, with Hispanic as a category. The study's ADaM carries race and ethnicity separately (230 White, 23 Black or African American, 1 American Indian or Alaska Native; 12 Hispanic or Latino, all of them White by race). The recode is ethnicity first, then race: 218 Caucasian, 23 African Descent, 12 Hispanic, 1 Other. It is a coding convention, not a disagreement between the data and the report. | ||||
| Duration of disease is DURDIS, months from onset of the first definite symptoms of Alzheimer's disease to enrolment, as the study's ADaM carries it. Years of education is EDUCLVL. MMSE is MMSETOT. | ||||
| n is the number of subjects with a value; one subject on low dose has no baseline weight or BMI. Percentages are based on the number of subjects in the intent-to-treat population for each treatment group; the Total column pools the three groups. Treatment groups are planned treatment, TRT01P, which agrees with actual treatment for every subject in this study. | ||||
| Source: adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | ||||
| open.csr display t-demographics (in_text variant); generated from the committed ARD. | ||||
11.3 Measurements of Treatment Compliance
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11.4 Efficacy Results and Tabulations of Individual Patient Data
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11.4.1 Analysis of Efficacy
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11.4.2 Statistical/Analytical Issues
Not populated in this demonstration. E3 enumerates eight statistical issues; each is a reusable prose block in the Text Library.
11.4.2.1 Adjustments for Covariates
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11.4.2.2 Handling of Dropouts or Missing Data
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11.4.2.3 Interim Analyses and Data Monitoring
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11.4.2.4 Multicentre Studies
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11.4.2.5 Multiple Comparison/Multiplicity
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11.4.2.6 Use of an "Efficacy Subset" of Patients
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11.4.2.7 Active-Control Studies Intended to Show Equivalence
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11.4.2.8 Examination of Subgroups
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11.4.3 Tabulation of Individual Response Data
Not populated in this demonstration. Cross-references the listings in 16.2.6.
11.4.4 Drug Dose, Drug Concentration, and Relationships to Response
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11.4.5 Drug-Drug and Drug-Disease Interactions
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11.4.6 By-Patient Displays
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11.4.7 Efficacy Conclusions
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12 Safety Evaluation
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12.1 Extent of Exposure
Exposure to study drug was longest in the placebo group and shortest in the xanomeline low dose group, a direct consequence of the discontinuation pattern described in Section 10.1. The imbalance must be taken into account when interpreting crude adverse event frequencies.
Mean duration of exposure was 149.1 days (SD 60.30) in the placebo group, 99.0 days (SD 68.15) in the xanomeline low dose group and 99.4 days (SD 70.64) in the xanomeline high dose group. The corresponding medians were 182.0, 82.5 and 76.5 days. Individual exposure ranged from 1 to 212 days across the safety analysis set.
Cumulative exposure thresholds show the same pattern. At least 30 days of exposure was achieved by 79 patients (91.9%) receiving placebo, 66 (78.6%) receiving xanomeline low dose and 69 (82.1%) receiving xanomeline high dose. Long-term exposure of at least 180 days was reached by 55 patients (64.0%) in the placebo group, against 25 (29.8%) and 26 (31.0%) in the low and high dose groups respectively — so fewer than half as many xanomeline patients as placebo patients reached the long-term exposure threshold.
Extent of exposure, including total and average daily dose, is summarised in 14.3.1.1.
TXT-E3-1201 · parameterized
| Extent of Exposure (Summary) | ||||
| Study CDISCPILOT01 — Safety Analysis Set | ||||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | Total (N=254) | |
|---|---|---|---|---|
| Safety population | ||||
| Average daily dose (mg) | ||||
| n | ||||
| Mean | ||||
| SD | ||||
| Median | ||||
| Min | ||||
| Max | ||||
| Cumulative dose at end of study (mg) | ||||
| n | ||||
| Mean | ||||
| SD | ||||
| Median | ||||
| Min | ||||
| Max | ||||
| Completers at Week 24 | ||||
| Average daily dose (mg) | ||||
| n | ||||
| Mean | ||||
| SD | ||||
| Median | ||||
| Min | ||||
| Max | ||||
| Cumulative dose at end of study (mg) | ||||
| n | ||||
| Mean | ||||
| SD | ||||
| Median | ||||
| Min | ||||
| Max | ||||
| Duration of treatment (days) — not in the reference table | ||||
| n | ||||
| Mean | ||||
| SD | ||||
| Median | ||||
| Min | ||||
| Max | ||||
| Cumulative exposure, n (%) — not in the reference table | ||||
| ≥ 1 day | ||||
| ≥ 30 days | ||||
| ≥ 90 days | ||||
| ≥ 180 days | ||||
| Average daily dose and cumulative dose are the subject-level AVGDD and CUMDOSE the study's own ADaM package carries; no exposure (ADEX) dataset is used. End of study is Week 26 or early termination. | ||||
| The reference report (Table 14-4.01) presents completers at Week 24 and the safety population as two column groups. This display presents the same statistics with the two populations as row blocks under one set of treatment columns; no number differs. | ||||
| Completers at Week 24 are the subjects flagged COMP24FL = 'Y' in the safety analysis set: 60, 28 and 30 subjects. | ||||
| Duration of treatment (ADSL TRTDUR, days from first to last dose inclusive) and the cumulative exposure categories over it are not part of the reference table; they are carried here because the narrative in Section 12.1 quotes them. A subject treated for 200 days is counted in every category up to 180 days. | ||||
| Placebo subjects have a planned dose of zero, so every placebo dose statistic is 0. The Total column pools the three treatment groups. | ||||
| Source: adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | ||||
| open.csr display t-exposure (in_text variant); generated from the committed ARD. | ||||
12.2 Adverse Events (AEs)
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12.2.1 Brief Summary of Adverse Events
Treatment-emergent adverse events were reported by 218 of the 254 patients in the safety analysis set (85.8%), covering 1126 individual adverse event records.
The proportion of patients reporting at least one treatment-emergent adverse event rose with dose: 75.6% of patients receiving placebo, 91.7% receiving xanomeline low dose and 90.5% receiving xanomeline high dose. The same gradient was present, and more pronounced, for adverse events assessed by the investigator as related to study drug, reported by 43 patients (50.0%), 72 patients (85.7%) and 70 patients (83.3%) respectively.
Most events were of mild or moderate maximum severity. Severe events were reported by 5 patients (5.8%) receiving placebo, 16 patients (19.0%) receiving xanomeline low dose and 8 patients (9.5%) receiving xanomeline high dose; moderate events were reported by 130 patients (51.2%) overall.
Serious adverse events were uncommon in this study. They were reported by 3 patients (1.2%) overall: 0 receiving placebo, 1 receiving xanomeline low dose and 2 receiving xanomeline high dose. Adverse events with a fatal outcome were recorded for 3 patients, of whom 2 were receiving placebo. Deaths and serious adverse events are described in Section 12.3.
An overview of treatment-emergent adverse events is presented in 14.3.1.2. Because exposure differed substantially between the groups (Section 12.1), the crude proportions above should be read alongside the exposure summary.
TXT-E3-1221 · parameterized
| Overview of Treatment-Emergent Adverse Events (Summary) | ||||
| Study CDISCPILOT01 — Safety Analysis Set | ||||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | Total (N=254) | |
|---|---|---|---|---|
| Adverse events | ||||
| Number of events | ||||
| Subjects with ≥1 adverse event | ||||
| Subjects with a serious adverse event | ||||
| Subjects with a fatal adverse event | ||||
| Subjects with a related adverse event | ||||
| Subjects by severity, n (%) | ||||
| Mild | ||||
| Moderate | ||||
| Severe | ||||
| A treatment-emergent adverse event is an event with TRTEMFL = 'Y'. | ||||
| Percentages are based on the number of subjects in the safety analysis set for each treatment group. | ||||
| Subjects reporting more than one event are counted once in each row they qualify for; severity rows count subjects with at least one event of that severity and therefore do not sum to the number of subjects with any event. | ||||
| Source: adae, adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | ||||
| open.csr display t-ae-overview (in_text variant); generated from the committed ARD. | ||||
12.2.2 Display of Adverse Events
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| Common Treatment-Emergent Adverse Events (≥5% in any treatment group) | ||||
| Study CDISCPILOT01 — Safety Analysis Set | ||||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | Total (N=254) | |
|---|---|---|---|---|
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS | ||||
| APPLICATION SITE PRURITUS | ||||
| APPLICATION SITE ERYTHEMA | ||||
| APPLICATION SITE DERMATITIS | ||||
| APPLICATION SITE IRRITATION | ||||
| APPLICATION SITE VESICLES | ||||
| FATIGUE | ||||
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS | ||||
| PRURITUS | ||||
| ERYTHEMA | ||||
| RASH | ||||
| HYPERHIDROSIS | ||||
| SKIN IRRITATION | ||||
| BLISTER | ||||
| NERVOUS SYSTEM DISORDERS | ||||
| DIZZINESS | ||||
| HEADACHE | ||||
| GASTROINTESTINAL DISORDERS | ||||
| DIARRHOEA | ||||
| VOMITING | ||||
| NAUSEA | ||||
| CARDIAC DISORDERS | ||||
| SINUS BRADYCARDIA | ||||
| INFECTIONS AND INFESTATIONS | ||||
| NASOPHARYNGITIS | ||||
| UPPER RESPIRATORY TRACT INFECTION | ||||
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS | ||||
| COUGH | ||||
| Reduced variant: only preferred terms reported by at least 5% of subjects in at least one treatment group are shown. The full display is Section 14. | ||||
| Subjects are counted once per system organ class and once per preferred term, regardless of how many events they reported. | ||||
| Percentages are based on the number of subjects in the safety analysis set for each treatment group. | ||||
| System organ classes and preferred terms are sorted by descending subject count. | ||||
| The Total column pools all treatment groups; the 5% threshold applied to the in-text variant is evaluated on the treatment columns only, never on Total. | ||||
| Source: adae, adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | ||||
| open.csr display t-ae-common (in_text variant); generated from the committed ARD. | ||||
12.2.3 Analysis of Adverse Events
| Most Common AE's (5% Subjects in any Treatment Group) | |||
| Study CDISCPILOT01 — Safety Analysis Set | |||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | |
|---|---|---|---|
| Sinus Bradycardia | |||
| Vomiting | |||
| Nausea | |||
| Diarrhoea | |||
| Application Site Pruritus | |||
| Application Site Erythema | |||
| Application Site Irritation | |||
| Application Site Dermatitis | |||
| Application Site Vesicles | |||
| Fatigue | |||
| Nasopharyngitis | |||
| Upper Respiratory Tract Infection | |||
| Dizziness | |||
| Headache | |||
| Cough | |||
| Pruritus | |||
| Erythema | |||
| Rash | |||
| Hyperhidrosis | |||
| Skin Irritation | |||
| Blister | |||
| Preferred terms reported by at least 5% of subjects in at least one treatment group, as the reference report's Table 12-1; an asterisk marks an active-arm incidence whose Fisher's exact comparison with placebo has p < 0.15. The full display, by system organ class, is Section 14. | |||
| Treatment-emergent events are those flagged TRTEMFL = 'Y' in the study's ADAE: events that start on or after the start of treatment, as the reference report (Table 14-5.01) defines them. Adverse events are coded using MedDRA. | |||
| Subjects are counted once per system organ class and once per preferred term; percentages are based on the number of subjects in the safety population within each treatment group. The bracketed figure is the total number of times an event was recorded. | |||
| P-values are Fisher's exact test comparing placebo with each active treatment group on the number of subjects with the event. An asterisk is appended to p-values below 0.15, as in the reference report; a p-value that rounds to 1 prints as >0.99; where neither arm has a subject with the event there is no test and the cell is blank. | |||
| System organ classes are in alphabetical order; preferred terms within a class are in descending order of high-dose subjects, then alphabetical — the order the reference report prints. | |||
| Four of the 227 p-values the reference report prints differ from this display at the third decimal, each by one thousandth: vomiting (placebo vs high dose, 0.208 here, 0.209 there), salivary hypersecretion (0.057 here, 0.058 there), application site erythema (0.002 here, 0.003 there) and syncope (placebo vs low dose, 0.057 here, 0.058 there). The subject counts agree; R's exact two-sided test gives 0.2085, 0.0575, 0.0025 and 0.0575, and the 2006 program rounded each up. They are recorded and tracked in quality/data/reference-report-agreement.json. | |||
| Source: adae, adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | |||
| open.csr display t-ae-incidence (in_text variant); generated from the committed ARD. | |||
12.2.4 Listing of Adverse Events by Patient
All treatment-emergent adverse events recorded during the study are listed by patient in Section 16.2.7. The listing gives, for each event, the patient identifier, treatment group, verbatim term, preferred term and system organ class, onset and resolution dates, maximum severity, seriousness, the investigator's assessment of relationship to study drug, the action taken with study drug and the outcome.
Serious adverse events, adverse events with a fatal outcome and adverse events leading to withdrawal of study drug are additionally presented in 14.3.2.1.
Every listing carries the study number, the analysis set and the data cut-off date in its header, and identifies derived values in a conspicuous fashion, as required by ICH E3. Patient identifiers in listings intended for public disclosure are subject to the anonymisation approach described in the study's disclosure plan.
TXT-E3-1224 · boilerplate
12.3 Deaths, Other Serious Adverse Events, and Other Significant Adverse Events
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12.3.1 Listing of Deaths, Other Serious Adverse Events and Other Significant Adverse Events
TXT-E3-1231 is excluded from the assembled document: generated-tier block is draft; excluded from assembly pending human approval.
| USUBJID | TRT01A | AGE | SEX | AEBODSYS | AEDECOD | AESEV | AEREL | ASTDY | AENDY | AEOUT |
|---|---|---|---|---|---|---|---|---|---|---|
| 01-709-1424 | Xanomeline High Dose | 77 | M | NERVOUS SYSTEM DISORDERS | SYNCOPE | MODERATE | POSSIBLE | 5 | 5 | RECOVERED/RESOLVED |
| 01-718-1170 | Xanomeline Low Dose | 80 | F | NERVOUS SYSTEM DISORDERS | SYNCOPE | SEVERE | PROBABLE | 27 | 28 | RECOVERED/RESOLVED |
| 01-718-1371 | Xanomeline High Dose | 69 | F | NERVOUS SYSTEM DISORDERS | PARTIAL SEIZURES WITH SECONDARY GENERALISATION | SEVERE | NONE | 38 | 41 | RECOVERED/RESOLVED |
12.3.1.1 Deaths
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12.3.1.2 Other Serious Adverse Events
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12.3.1.3 Other Significant Adverse Events
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12.3.2 Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events
Not populated in this demonstration. Prose, not a table — but E3 also reserves 14.3.3 for the narratives. The narratives are a Text Library product built from the same ADaM spine as the AE displays.
12.3.3 Analysis and Discussion of Deaths, Other Serious and Other Significant Adverse Events
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12.4 Clinical Laboratory Evaluation
Not populated in this demonstration.
12.4.1 Listing of Individual Laboratory Measurements by Patient and Each Abnormal Laboratory Value
Not populated in this demonstration. Listings appear in 16.2.8; abnormal values also in 14.3.4.
12.4.2 Evaluation of Each Laboratory Parameter
Not populated in this demonstration.
12.4.2.1 Laboratory Values Over Time
Not populated in this demonstration.
12.4.2.2 Individual Patient Changes
Not populated in this demonstration.
12.4.2.3 Individual Clinically Significant Abnormalities
Not populated in this demonstration.
12.5 Vital Signs, Physical Findings and Other Observations Related to Safety
| Summary of Change from Baseline in Weight | ||||||
| Study CDISCPILOT01 — Safety Analysis Set | ||||||
| Placebo n (N=86) | Placebo Mean (N=86) | Low Dose n (N=84) | Low Dose Mean (N=84) | High Dose n (N=84) | High Dose Mean (N=84) | |
|---|---|---|---|---|---|---|
| Weight (kg) | ||||||
| Baseline | ||||||
| Change at Week 24 | ||||||
| Change at End of Treatment | ||||||
| Treatment groups are PLANNED treatment (TRT01P). Twelve subjects in this study received a treatment other than the one they were randomised to; grouping by actual treatment (TRT01A) would give column sizes of 86, 96 and 72. | ||||||
| Baseline is the subject's observed Week 0 weight. Change from baseline is that subject's value minus that baseline, so a subject with no Week 0 weight contributes to the weight rows but not to the change rows. | ||||||
| End of treatment is the last observed weight at a planned visit after Week 0 up to and including Week 24. Unscheduled visits, the Week 26 follow-up visit and records derived by averaging or carry-forward are never selected. | ||||||
| n is the number of subjects contributing a measurement; N in the column header is the number of subjects in the safety analysis set. | ||||||
| Source: advs, adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | ||||||
| open.csr display t-weight (in_text variant); generated from the committed ARD. | ||||||
12.6 Safety Conclusions
TXT-E3-1206 is excluded from the assembled document: generated-tier block is draft; excluded from assembly pending human approval.
13 Discussion and Overall Conclusions
TXT-E3-1300 is excluded from the assembled document: generated-tier block is draft; excluded from assembly pending human approval.
14 Tables, Figures and Graphs Referred to but not Included in the Text
Not populated in this demonstration. E3's three-level rule: overall summaries may sit in the text, other summary tables/figures/listings belong here, individual patient data go to 16.2, and all individual data (US archival) to 16.4.
14.1 Demographic Data
| Subject Disposition | ||||
| Study CDISCPILOT01 — Intent-to-Treat Analysis Set | ||||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | Total (N=254) | |
|---|---|---|---|---|
| Disposition, n (%) | ||||
| Subjects randomised | ||||
| Subjects treated | ||||
| Completed the study | ||||
| Discontinued the study | ||||
| Reason for discontinuation, n (%) | ||||
| Death | ||||
| Other / not specified | ||||
| Deaths, n (%) | ||||
| Died on study | ||||
| Percentages are based on the number of randomised subjects in each treatment group. | ||||
| The ADSL shipped in pharmaverseadam carries no DCSREAS/DCDECOD, so the reason for discontinuation is derived: 'Death' where DTHFL = 'Y', otherwise 'Other / not specified'. | ||||
| 52 screen failures are excluded from every analysis dataset. | ||||
| Source: adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | ||||
| open.csr display t-disposition (post_text variant); generated from the committed ARD. | ||||
| Summary of Demographic and Baseline Characteristics | |||||
| Study CDISCPILOT01 — Intent-to-Treat | |||||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | Total (N=254) | p-value | |
|---|---|---|---|---|---|
| Age (y) | |||||
| n | |||||
| Mean | |||||
| SD | |||||
| Median | |||||
| Min | |||||
| Max | |||||
| <65 yrs | |||||
| 65-80 yrs | |||||
| >80 yrs | |||||
| Sex | |||||
| n | |||||
| Male | |||||
| Female | |||||
| Race (Origin) | |||||
| n | |||||
| Caucasian | |||||
| African Descent | |||||
| Hispanic | |||||
| Other | |||||
| MMSE | |||||
| n | |||||
| Mean | |||||
| SD | |||||
| Median | |||||
| Min | |||||
| Max | |||||
| Duration of disease | |||||
| n | |||||
| Mean | |||||
| SD | |||||
| Median | |||||
| Min | |||||
| Max | |||||
| <12 months | |||||
| >=12 months | |||||
| Years of education | |||||
| n | |||||
| Mean | |||||
| SD | |||||
| Median | |||||
| Min | |||||
| Max | |||||
| Baseline weight(kg) | |||||
| n | |||||
| Mean | |||||
| SD | |||||
| Median | |||||
| Min | |||||
| Max | |||||
| Baseline height(cm) | |||||
| n | |||||
| Mean | |||||
| SD | |||||
| Median | |||||
| Min | |||||
| Max | |||||
| Baseline BMI | |||||
| n | |||||
| Mean | |||||
| SD | |||||
| Median | |||||
| Min | |||||
| Max | |||||
| <25 | |||||
| 25-<30 | |||||
| >=30 | |||||
| [1] P-values are results of ANOVA treatment group comparison for continuous variables and Pearson's chi-square test for categorical variables, as the reference report (Table 14-2.01) states; each block carries one test across the three treatment groups. | |||||
| Race (Origin) is the reference report's classification, with Hispanic as a category. The study's ADaM carries race and ethnicity separately (230 White, 23 Black or African American, 1 American Indian or Alaska Native; 12 Hispanic or Latino, all of them White by race). The recode is ethnicity first, then race: 218 Caucasian, 23 African Descent, 12 Hispanic, 1 Other. It is a coding convention, not a disagreement between the data and the report. | |||||
| Duration of disease is DURDIS, months from onset of the first definite symptoms of Alzheimer's disease to enrolment, as the study's ADaM carries it. Years of education is EDUCLVL. MMSE is MMSETOT. | |||||
| n is the number of subjects with a value; one subject on low dose has no baseline weight or BMI. Percentages are based on the number of subjects in the intent-to-treat population for each treatment group; the Total column pools the three groups. Treatment groups are planned treatment, TRT01P, which agrees with actual treatment for every subject in this study. | |||||
| Source: adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | |||||
| open.csr display t-demographics (post_text variant); generated from the committed ARD. | |||||
| Summary of Populations | ||||
| Study CDISCPILOT01 — All Subjects | ||||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | Total (N=254) | |
|---|---|---|---|---|
| Intent-To-Treat (ITT) | ||||
| Safety | ||||
| Efficacy | ||||
| Complete Week 24 | ||||
| Complete Study | ||||
| N in the column headers is the number of subjects randomised to that treatment group; percentages are based on it. The reference report's note calls this the number of subjects "entered in study (i.e., signed informed consent)". This display does not repeat that wording: 306 subjects were screened and 254 randomised, and it is the 254 that N counts. | ||||
| The ITT population includes all subjects randomised. The Safety population includes all randomised subjects known to have taken at least one dose of randomised study drug. The Efficacy population includes all subjects in the safety population who also have at least one post-baseline ADAS-Cog and CIBIC+ assessment. | ||||
| Treatment groups are planned (randomised) treatment, TRT01P. In this ADSL planned and actual treatment agree for all 254 subjects. | ||||
| The population line above reads All Subjects because that is what the reference report prints above this table. In this study it selects the same 254 subjects as the Intent-To-Treat row below, since the analysis dataset contains only randomised subjects and every one of them carries ITTFL = Y. | ||||
| Complete Week 24 is the study's own COMP24FL. Complete Study is not a variable the study ships: the reference report prints the row but states no definition for it, so this display derives it as the complement of the study's own DISCONFL — a subject who did not discontinue. That derivation is open.csr's, not the study's, and the evidence for it is that it reproduces all four printed figures (58, 25, 27, 110) and the report's own narrative that 110 subjects completed the study through Week 26. | ||||
| The cut-off shown is the latest subject end date (RFENDT) recorded in the vendored ADSL. The CDISC pilot package states no separate database-lock date. | ||||
| Source: adsl (phuse-org/phuse-scripts, data/adam/cdisc — the CDISC pilot submission's own ADaM package). Data cut-off: 2015-03-05. | ||||
| open.csr display t-populations (post_text variant); generated from the committed ARD. | ||||
| Summary of End of Study Data | |||||
| Study CDISCPILOT01 — Intent-to-Treat | |||||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | Total (N=254) | p-value | |
|---|---|---|---|---|---|
| Completion Status: | |||||
| Completed Week 24 [1] | |||||
| Early Termination (prior to Week 24) | |||||
| Missing | |||||
| Reason for Early Termination (prior to Week 24): | |||||
| Adverse Event [1] | |||||
| Death | |||||
| Lack of Efficacy [1][2] | |||||
| Lost to Follow-up | |||||
| Subject decided to withdraw | |||||
| Physician decided to withdraw subject | |||||
| Protocol criteria not met | |||||
| Protocol violation | |||||
| Sponsor decision | |||||
| Missing | |||||
| [1] Fisher's exact test, comparing the row against the rest of the treatment group across all three groups at once. The statistical analysis plan (section 9.7.1.2) specifies this test for protocol completion, lack of efficacy and adverse event only; the other rows are descriptive and carry no p-value. | |||||
| [2] Lack of efficacy is based on either patient/caregiver perception or physician perception. | |||||
| N in the column headers is the number of subjects randomised to that treatment group; every percentage on this table, including the reasons for early termination, is based on it rather than on the number of early terminations — as the reference report does. The reference's own note calls N the number of subjects "entered in study (i.e., signed informed consent)"; this display does not repeat that wording, because 306 subjects were screened and 254 randomised, and it is the 254 that N counts. | |||||
| The population line above reads Intent-to-Treat because that is what the reference report prints above this table. In this study it selects the same 254 subjects as the whole analysis dataset, since every subject in it carries ITTFL = Y. | |||||
| Completion status is the study's own COMP24FL and the reason is its DCREASCD. Both are collected fields carried in the CDISC pilot's ADSL; neither exists in the pharmaverse re-derivation of this study, so this display reads the pilot package directly. | |||||
| Treatment groups are planned (randomised) treatment, TRT01P. In this ADSL planned and actual treatment agree for all 254 subjects. | |||||
| 144 subjects discontinued the study in total; the 136 counted here are those who did so before Week 24. The remaining 8 discontinued after completing Week 24. | |||||
| The cut-off shown is the latest subject end date (RFENDT) recorded in the vendored ADSL. The CDISC pilot package states no separate database-lock date. | |||||
| Source: adsl (phuse-org/phuse-scripts, data/adam/cdisc — the CDISC pilot submission's own ADaM package). Data cut-off: 2015-03-05. | |||||
| open.csr display t-end-of-study (post_text variant); generated from the committed ARD. | |||||
| Summary of Number of Subjects By Site | ||||||||||||
| Study CDISCPILOT01 — All Subjects | ||||||||||||
| Placebo ITT (N=86) | Placebo Eff (N=79) | Placebo Com (N=60) | Low Dose ITT (N=84) | Low Dose Eff (N=81) | Low Dose Com (N=28) | High Dose ITT (N=84) | High Dose Eff (N=74) | High Dose Com (N=30) | Total ITT (N=254) | Total Eff (N=234) | Total Com (N=118) | |
|---|---|---|---|---|---|---|---|---|---|---|---|---|
| 701 / 701 | ||||||||||||
| 703 / 703 | ||||||||||||
| 704 / 704 | ||||||||||||
| 705 / 705 | ||||||||||||
| 708 / 708 | ||||||||||||
| 709 / 709 | ||||||||||||
| 710 / 710 | ||||||||||||
| 713 / 713 | ||||||||||||
| 716 / 716 | ||||||||||||
| 718 / 718 | ||||||||||||
| 900 / 702 | ||||||||||||
| 900 / 706 | ||||||||||||
| 900 / 707 | ||||||||||||
| 900 / 711 | ||||||||||||
| 900 / 714 | ||||||||||||
| 900 / 715 | ||||||||||||
| 900 / 717 | ||||||||||||
| TOTAL | ||||||||||||
| ITT is the intent-to-treat population (ITTFL), Eff the efficacy population (EFFFL) and Com the subjects who completed Week 24 (COMP24FL), as the study's ADaM carries them and the reference report (Table 14-1.03) prints them. | ||||||||||||
| Each row is one site, labelled with its pooled site id and its own id. Seven sites met the pre-specified criterion for small sample sizes and are pooled under id 900 for analyses that include site as a covariate; every site is listed on its own line, as in the reference. | ||||||||||||
| Treatment groups are planned treatment, TRT01P, which agrees with actual treatment for every subject in this study. The Total column pools the three groups. | ||||||||||||
| Source: adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | ||||||||||||
| open.csr display t-subjects-by-site (post_text variant); generated from the committed ARD. | ||||||||||||
| Subject Disposition | |
| Study CDISCPILOT01 — All Subjects | |
| All Subjects | |
|---|---|
| Subjects screened | |
| Screen failures | |
| Randomised, entered treatment phase | |
| Completed Week 24 | |
| Completed study through Week 26 | |
| Subjects screened are every subject in the study's SDTM DM domain; screen failures are those DM labels as such. Randomised subjects are every subject in ADSL; completed Week 24 is COMP24FL, and completed the study through Week 26 is the complement of DISCONFL — the definition Table 14-1.01 states for Complete Study. | |
| Drawn as the reference report's Figure 10-1: 306 screened, of whom 52 screen failures and 254 randomised; of those, 118 completed Week 24 and 110 completed the study. | |
| Source: dm (the study's SDTM demographics domain) and adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | |
| open.csr display f-disposition (post_text variant); generated from the committed ARD. | |
14.2 Efficacy Data
| Primary Endpoint Analysis: ADAS-Cog (11) - Change from Baseline to Week 24 - LOCF | |||
| Study CDISCPILOT01 — Efficacy Analysis Set | |||
| Placebo (N=79) | Xanomeline Low Dose (N=81) | Xanomeline High Dose (N=74) | |
|---|---|---|---|
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Change from baseline | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Statistical comparison of the change from baseline | |||
| p-value (dose response) [1][2] | |||
| p-value (Xanomeline - Placebo) [1][3] | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| p-value (Xanomeline High - Xanomeline Low) [1][3] | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| [1] Based on an analysis of covariance (ANCOVA) model with treatment and site group as factors and the baseline score as a covariate. | |||
| [2] Test for a non-zero coefficient for treatment (dose) as a continuous variable. | |||
| [3] Pairwise comparison with treatment as a categorical variable; p-values are not adjusted for multiple comparisons. | |||
| Missing post-baseline values are imputed by last observation carried forward, over assessments assigned to visit windows (CDISCPILOT01 statistical analysis plan, sections 8.1 and 8.2). | |||
| Treatment columns are planned treatment (TRTP), which is how the CDISCPILOT01 reference report presents them. | |||
| CDISCPILOT01 states no data cut-off date. The date shown is the latest ADAS-Cog assessment date present in the vendored ADaM package. | |||
| Source: adqsadas (ADAS-Cog (11) total score, PARAMCD ACTOT) and adsl, from the CDISC pilot's own ADaM package (phuse-org/phuse-scripts, MIT). Analysis as specified in the CDISCPILOT01 statistical analysis plan, section 10.1.1. Reference report display: Table 14-3.01. Data cut-off: 2015-02-17. | |||
| open.csr display t-eff-adas-wk24 (post_text variant); generated from the committed ARD. | |||
| Primary Endpoint Analysis: CIBIC+ — Summary at Week 24 — LOCF | |||
| Study CDISCPILOT01 — Efficacy Analysis Set | |||
| Placebo (N=79) | Xanomeline Low Dose (N=81) | Xanomeline High Dose (N=74) | |
|---|---|---|---|
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Analysis of covariance | |||
| p-value (dose response) | |||
| p-value (Xanomeline − Placebo) | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| p-value (Xanomeline High − Xanomeline Low) | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| The Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+) is scored 1 (marked improvement) to 7 (marked worsening); 4 is no change. A higher score is a worse outcome. | |||
| Values are last observation carried forward within the analysis window (ADQSCIBC ANL01FL = 'Y'). | |||
| Column headings are the size of the efficacy analysis set; n is the number of subjects with a value at this visit. | |||
| Model: analysis of covariance with treatment and site group as factors. The dose-response p-value tests a non-zero coefficient for treatment entered as randomised dose (0, 54 or 81 mg), and is a single model-level result, printed once. | |||
| Pairwise comparisons treat treatment as a categorical variable and are not adjusted for multiplicity. The study's analysis plan directs that they not be interpreted unless the dose-response test is significant. | |||
| Source: adqscibc, adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | |||
| open.csr display t-cibic-week24 (post_text variant); generated from the committed ARD. | |||
| ADAS-Cog (11) - Change from Baseline to Week 8 - LOCF | |||
| Study CDISCPILOT01 — Efficacy Analysis Set | |||
| Placebo (N=79) | Xanomeline Low Dose (N=81) | Xanomeline High Dose (N=74) | |
|---|---|---|---|
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Week 8 | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Change from baseline | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Statistical comparison of the change from baseline | |||
| p-value (dose response) [1][2] | |||
| p-value (Xanomeline - Placebo) [1][3] | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| p-value (Xanomeline High - Xanomeline Low) [1][3] | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| [1] Based on an analysis of covariance (ANCOVA) model with treatment and site group as factors and the baseline score as a covariate. | |||
| [2] Test for a non-zero coefficient for treatment (dose) as a continuous variable. | |||
| [3] Pairwise comparison with treatment as a categorical variable; p-values are not adjusted for multiple comparisons. | |||
| Missing post-baseline values are imputed by last observation carried forward, over assessments assigned to visit windows (CDISCPILOT01 statistical analysis plan, sections 8.1 and 8.2). | |||
| Treatment columns are planned treatment (TRTP), which is how the CDISCPILOT01 reference report presents them. | |||
| CDISCPILOT01 states no data cut-off date. The date shown is the latest ADAS-Cog assessment date present in the vendored ADaM package. | |||
| Source: adqsadas (ADAS-Cog (11) total score, PARAMCD ACTOT) and adsl, from the CDISC pilot's own ADaM package (phuse-org/phuse-scripts, MIT). Analysis as specified in the CDISCPILOT01 statistical analysis plan, section 10.1.1. Reference report display: Table 14-3.03. Data cut-off: 2015-02-17. | |||
| open.csr display t-eff-adas-wk8 (post_text variant); generated from the committed ARD. | |||
| CIBIC+ — Summary at Week 8 — LOCF | |||
| Study CDISCPILOT01 — Efficacy Analysis Set | |||
| Placebo (N=79) | Xanomeline Low Dose (N=81) | Xanomeline High Dose (N=74) | |
|---|---|---|---|
| Week 8 | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Analysis of covariance | |||
| p-value (dose response) | |||
| p-value (Xanomeline − Placebo) | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| p-value (Xanomeline High − Xanomeline Low) | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| A supporting analysis at an earlier time point. The primary endpoint is CIBIC+ at Week 24. | |||
| The Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+) is scored 1 (marked improvement) to 7 (marked worsening); 4 is no change. A higher score is a worse outcome. | |||
| Values are last observation carried forward within the analysis window (ADQSCIBC ANL01FL = 'Y'). | |||
| Column headings are the size of the efficacy analysis set; n is the number of subjects with a value at this visit. | |||
| Model: analysis of covariance with treatment and site group as factors. The dose-response p-value tests a non-zero coefficient for treatment entered as randomised dose (0, 54 or 81 mg), and is a single model-level result, printed once. | |||
| Pairwise comparisons treat treatment as a categorical variable and are not adjusted for multiplicity. The study's analysis plan directs that they not be interpreted unless the dose-response test is significant. | |||
| Source: adqscibc, adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | |||
| open.csr display t-cibic-week8 (post_text variant); generated from the committed ARD. | |||
| ADAS-Cog (11) - Change from Baseline to Week 16 - LOCF | |||
| Study CDISCPILOT01 — Efficacy Analysis Set | |||
| Placebo (N=79) | Xanomeline Low Dose (N=81) | Xanomeline High Dose (N=74) | |
|---|---|---|---|
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Week 16 | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Change from baseline | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Statistical comparison of the change from baseline | |||
| p-value (dose response) [1][2] | |||
| p-value (Xanomeline - Placebo) [1][3] | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| p-value (Xanomeline High - Xanomeline Low) [1][3] | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| [1] Based on an analysis of covariance (ANCOVA) model with treatment and site group as factors and the baseline score as a covariate. | |||
| [2] Test for a non-zero coefficient for treatment (dose) as a continuous variable. | |||
| [3] Pairwise comparison with treatment as a categorical variable; p-values are not adjusted for multiple comparisons. | |||
| Missing post-baseline values are imputed by last observation carried forward, over assessments assigned to visit windows (CDISCPILOT01 statistical analysis plan, sections 8.1 and 8.2). | |||
| Treatment columns are planned treatment (TRTP), which is how the CDISCPILOT01 reference report presents them. | |||
| CDISCPILOT01 states no data cut-off date. The date shown is the latest ADAS-Cog assessment date present in the vendored ADaM package. | |||
| Source: adqsadas (ADAS-Cog (11) total score, PARAMCD ACTOT) and adsl, from the CDISC pilot's own ADaM package (phuse-org/phuse-scripts, MIT). Analysis as specified in the CDISCPILOT01 statistical analysis plan, section 10.1.1. Reference report display: Table 14-3.05. Data cut-off: 2015-02-17. | |||
| open.csr display t-eff-adas-wk16 (post_text variant); generated from the committed ARD. | |||
| CIBIC+ — Summary at Week 16 — LOCF | |||
| Study CDISCPILOT01 — Efficacy Analysis Set | |||
| Placebo (N=79) | Xanomeline Low Dose (N=81) | Xanomeline High Dose (N=74) | |
|---|---|---|---|
| Week 16 | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Analysis of covariance | |||
| p-value (dose response) | |||
| p-value (Xanomeline − Placebo) | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| p-value (Xanomeline High − Xanomeline Low) | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| A supporting analysis at an earlier time point. The primary endpoint is CIBIC+ at Week 24. | |||
| The Clinician's Interview-Based Impression of Change plus caregiver input (CIBIC+) is scored 1 (marked improvement) to 7 (marked worsening); 4 is no change. A higher score is a worse outcome. | |||
| Values are last observation carried forward within the analysis window (ADQSCIBC ANL01FL = 'Y'). | |||
| Column headings are the size of the efficacy analysis set; n is the number of subjects with a value at this visit. | |||
| Model: analysis of covariance with treatment and site group as factors. The dose-response p-value tests a non-zero coefficient for treatment entered as randomised dose (0, 54 or 81 mg), and is a single model-level result, printed once. | |||
| Pairwise comparisons treat treatment as a categorical variable and are not adjusted for multiplicity. The study's analysis plan directs that they not be interpreted unless the dose-response test is significant. | |||
| Source: adqscibc, adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | |||
| open.csr display t-cibic-week16 (post_text variant); generated from the committed ARD. | |||
| ADAS-Cog (11) - Change from Baseline to Week 24 - Completers at Week 24, Observed Cases, Windowed | |||
| Study CDISCPILOT01 — Efficacy Analysis Set, Week 24 completers | |||
| Placebo (N=60) | Xanomeline Low Dose (N=28) | Xanomeline High Dose (N=30) | |
|---|---|---|---|
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Change from baseline | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Statistical comparison of the change from baseline | |||
| p-value (dose response) [1][2] | |||
| p-value (Xanomeline - Placebo) [1][3] | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| p-value (Xanomeline High - Xanomeline Low) [1][3] | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| [1] Based on an analysis of covariance (ANCOVA) model with treatment and site group as factors and the baseline score as a covariate. | |||
| [2] Test for a non-zero coefficient for treatment (dose) as a continuous variable. | |||
| [3] Pairwise comparison with treatment as a categorical variable; p-values are not adjusted for multiple comparisons. | |||
| Only assessments falling within the Week 24 assessment window are included, and no value is imputed. | |||
| Baseline, on-treatment and change statistics are summarised over one record per subject at the analysis visit, so a subject with no assessment in that window contributes to none of the three and n is smaller than the column N. | |||
| Treatment columns are planned treatment (TRTP), which is how the CDISCPILOT01 reference report presents them. | |||
| CDISCPILOT01 states no data cut-off date. The date shown is the latest ADAS-Cog assessment date present in the vendored ADaM package. | |||
| Source: adqsadas (ADAS-Cog (11) total score, PARAMCD ACTOT) and adsl, from the CDISC pilot's own ADaM package (phuse-org/phuse-scripts, MIT). Analysis as specified in the CDISCPILOT01 statistical analysis plan, section 10.1.1. Reference report display: Table 14-3.07. Data cut-off: 2015-02-17. | |||
| open.csr display t-eff-adas-wk24-completers (post_text variant); generated from the committed ARD. | |||
| ADAS-Cog (11) - Change from Baseline to Week 24 in Male Subjects - LOCF | |||
| Study CDISCPILOT01 — Efficacy Analysis Set, male subjects | |||
| Placebo (N=33) | Xanomeline Low Dose (N=34) | Xanomeline High Dose (N=39) | |
|---|---|---|---|
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Change from baseline | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Statistical comparison of the change from baseline | |||
| p-value (dose response) [1][2] | |||
| p-value (Xanomeline - Placebo) [1][3] | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| p-value (Xanomeline High - Xanomeline Low) [1][3] | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| [1] Based on an analysis of covariance (ANCOVA) model with treatment and site group as factors and the baseline score as a covariate. | |||
| [2] Test for a non-zero coefficient for treatment (dose) as a continuous variable. | |||
| [3] Pairwise comparison with treatment as a categorical variable; p-values are not adjusted for multiple comparisons. | |||
| Missing post-baseline values are imputed by last observation carried forward, over assessments assigned to visit windows (CDISCPILOT01 statistical analysis plan, sections 8.1 and 8.2). | |||
| Treatment columns are planned treatment (TRTP), which is how the CDISCPILOT01 reference report presents them. | |||
| CDISCPILOT01 states no data cut-off date. The date shown is the latest ADAS-Cog assessment date present in the vendored ADaM package. | |||
| Source: adqsadas (ADAS-Cog (11) total score, PARAMCD ACTOT) and adsl, from the CDISC pilot's own ADaM package (phuse-org/phuse-scripts, MIT). Analysis as specified in the CDISCPILOT01 statistical analysis plan, section 10.1.1. Reference report display: Table 14-3.08. Data cut-off: 2015-02-17. | |||
| open.csr display t-eff-adas-wk24-male (post_text variant); generated from the committed ARD. | |||
| ADAS-Cog (11) - Change from Baseline to Week 24 in Female Subjects - LOCF | |||
| Study CDISCPILOT01 — Efficacy Analysis Set, female subjects | |||
| Placebo (N=46) | Xanomeline Low Dose (N=47) | Xanomeline High Dose (N=35) | |
|---|---|---|---|
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Change from baseline | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Statistical comparison of the change from baseline | |||
| p-value (dose response) [1][2] | |||
| p-value (Xanomeline - Placebo) [1][3] | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| p-value (Xanomeline High - Xanomeline Low) [1][3] | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| [1] Based on an analysis of covariance (ANCOVA) model with treatment and site group as factors and the baseline score as a covariate. | |||
| [2] Test for a non-zero coefficient for treatment (dose) as a continuous variable. | |||
| [3] Pairwise comparison with treatment as a categorical variable; p-values are not adjusted for multiple comparisons. | |||
| Missing post-baseline values are imputed by last observation carried forward, over assessments assigned to visit windows (CDISCPILOT01 statistical analysis plan, sections 8.1 and 8.2). | |||
| Treatment columns are planned treatment (TRTP), which is how the CDISCPILOT01 reference report presents them. | |||
| CDISCPILOT01 states no data cut-off date. The date shown is the latest ADAS-Cog assessment date present in the vendored ADaM package. | |||
| Source: adqsadas (ADAS-Cog (11) total score, PARAMCD ACTOT) and adsl, from the CDISC pilot's own ADaM package (phuse-org/phuse-scripts, MIT). Analysis as specified in the CDISCPILOT01 statistical analysis plan, section 10.1.1. Reference report display: Table 14-3.09. Data cut-off: 2015-02-17. | |||
| open.csr display t-eff-adas-wk24-female (post_text variant); generated from the committed ARD. | |||
| ADAS-Cog (11) - Mean and Mean Change from Baseline over Time | |||
| Study CDISCPILOT01 — Efficacy Analysis Set | |||
| Placebo (N=79) | Xanomeline Low Dose (N=81) | Xanomeline High Dose (N=74) | |
|---|---|---|---|
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Week 8 (windowed) | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Baseline of these subjects, mean (SD) | |||
| Change from baseline, mean (SD) | |||
| Change from baseline, median (Range) | |||
| Week 16 (windowed) | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Baseline of these subjects, mean (SD) | |||
| Change from baseline, mean (SD) | |||
| Change from baseline, median (Range) | |||
| Week 24 (windowed) | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Baseline of these subjects, mean (SD) | |||
| Change from baseline, mean (SD) | |||
| Change from baseline, median (Range) | |||
| Week 8 (LOCF) | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Baseline of these subjects, mean (SD) | |||
| Change from baseline, mean (SD) | |||
| Change from baseline, median (Range) | |||
| Week 16 (LOCF) | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Baseline of these subjects, mean (SD) | |||
| Change from baseline, mean (SD) | |||
| Change from baseline, median (Range) | |||
| Week 24 (LOCF) | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Baseline of these subjects, mean (SD) | |||
| Change from baseline, mean (SD) | |||
| Change from baseline, median (Range) | |||
| Windowed rows include only assessments that fell inside the visit's assessment window, and impute nothing; a subject with no assessment in that window contributes to none of the statistics for that row, so n is below the column N. LOCF rows carry the last observation forward, so every subject contributes at every visit and n equals the column N. | |||
| The baseline row of each visit is the mean baseline score of the subjects contributing to that visit, not the baseline of the whole column. The two differ wherever a visit is missing for some subjects, which is why the windowed rows are the ones that move. | |||
| ORIENTED HERE, NOT INHERITED: the reference report lays this table out with treatment as row groups and thirteen statistic columns. It is presented here with treatment in the columns, as every other display in this library does, and the statistics as rows. No number, no record selection and no rounding differs; only the axis the reader scans. The reference orientation is recoverable from the same ARD without recomputation. | |||
| Assessments are selected by AVISITN rather than the AVISIT label throughout. | |||
| Treatment columns are planned treatment (TRTP), which is how the CDISCPILOT01 reference report presents them. | |||
| CDISCPILOT01 states no data cut-off date. The date shown is the latest ADAS-Cog assessment date present in the vendored ADaM package. | |||
| Source: adqsadas (ADAS-Cog (11) total score, PARAMCD ACTOT) and adsl, from the CDISC pilot's own ADaM package (phuse-org/phuse-scripts, MIT). Analysis as specified in the CDISCPILOT01 statistical analysis plan, sections 8.1, 8.2 and 10.1.1, and its display specification Template 9. Reference report display: Table 14-3.10. Data cut-off: 2015-02-17. | |||
| open.csr display t-eff-adas-overtime (post_text variant); generated from the committed ARD. | |||
| ADAS-Cog (11) - Repeated Measures Analysis of Change from Baseline to Week 24 | |||
| Study CDISCPILOT01 — Efficacy Analysis Set | |||
| Placebo (N=79) | Xanomeline Low Dose (N=81) | Xanomeline High Dose (N=74) | |
|---|---|---|---|
| LS means (SE) [1] | |||
| Comparison of least-squares means | |||
| p-value (Xanomeline - Placebo) [1][2] | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| p-value (Xanomeline High - Xanomeline Low) [1][2] | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| Kenward-Roger was tried (qc/mmrm-kenward-roger.R, 2 September 2026, mmrm 0.3.15): the refit reproduces the reference REML criterion to every printed digit and moves one of the five cells — the lower confidence limit of high dose against placebo prints -1.9 as the report does — but not the other four, so the model-based fit is kept and the four are stated here. | |||
| [1] Mixed model for repeated measures of the change from baseline, fitted by restricted maximum likelihood with an unstructured within-subject covariance matrix. Fixed effects: treatment, site group, visit, treatment by visit, the baseline score, and the baseline score by visit. | |||
| [2] Pairwise comparison of least-squares means; p-values are not adjusted for multiple comparisons. | |||
| Observed cases only: 539 assessments from 234 subjects at Weeks 8, 16 and 24. The model accounts for a missing visit through the covariance structure, so no value is carried forward. | |||
| WHAT THE LEAST-SQUARES MEANS ESTIMATE: they are the treatment main effect — the model's prediction averaged over all three post-baseline visits and over the eleven site groups equally, with the baseline score held at its mean. They are not the Week-24 visit conditioned on, which the title might suggest and which is a different and less precise quantity (for placebo, 2.3 with a standard error of 0.69 rather than 1.6 with 0.49). This display reproduces what the reference report computed; the distinction is stated here because the number cannot state it itself. | |||
| MEASURED, NOT ASSUMED: the fit reproduces the reference report's own PROC MIXED output to six significant figures on all six unstructured covariance parameters, and its REML criterion of 3087.84303515 to ten. It uses the same 539 observations from the same 234 subjects. Two programs can agree on a rounded least-squares mean by accident; they cannot agree on that by accident, so the model is identified far more sharply than the rounded cells above can show. | |||
| DIFFERS FROM THE REFERENCE, DELIBERATELY: standard errors and degrees of freedom here are the model-based ones, on 517 residual degrees of freedom. The reference used Kenward-Roger degrees of freedom with Prasad-Rao-Jeske-Kackar-Harville standard errors, which inflate both by roughly one per cent to allow for the covariance parameters having been estimated rather than known. That adjustment is not implemented here. Of the twelve cells above, seven are identical to the reference and five differ at the last digit shown: the three p-values, each 0.001 lower (0.954, 0.555 and 0.605 against 0.955, 0.556 and 0.606); the high-dose least-squares mean standard error (0.55 against 0.56); and one confidence-interval bound (-1.8 against -1.9). Every point estimate agrees. The difference is measured and recorded in quality/data/efficacy-agreement.json. | |||
| Treatment columns are planned treatment (TRTP), which is how the CDISCPILOT01 reference report presents them. | |||
| CDISCPILOT01 states no data cut-off date. The date shown is the latest ADAS-Cog assessment date present in the vendored ADaM package. | |||
| Source: adqsadas (ADAS-Cog (11) total score, PARAMCD ACTOT) and adsl, from the CDISC pilot's own ADaM package (phuse-org/phuse-scripts, MIT). Supportive analysis as specified in the CDISCPILOT01 statistical analysis plan, section 10.1.1. Reference report display: Table 14-3.11. Data cut-off: 2015-02-17. | |||
| open.csr display t-eff-adas-mmrm (post_text variant); generated from the committed ARD. | |||
| Mean NPI-X Total Score from Week 4 through Week 24 - Windowed | |||
| Study CDISCPILOT01 — Efficacy Analysis Set | |||
| Placebo (N=79) | Xanomeline Low Dose (N=81) | Xanomeline High Dose (N=74) | |
|---|---|---|---|
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Mean of Weeks 4-24 | |||
| n | |||
| Mean (SD) | |||
| Median (Range) | |||
| Statistical comparison of the mean over Weeks 4 to 24 | |||
| p-value (dose response) [1][2] | |||
| p-value (Xanomeline - Placebo) [1][3] | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| p-value (Xanomeline High - Xanomeline Low) [1][3] | |||
| Difference of LS means (SE) | |||
| 95% CI | |||
| [1] Based on an analysis of covariance (ANCOVA) model with treatment and site group as factors and the baseline score as a covariate. | |||
| [2] Test for a non-zero coefficient for treatment (dose) as a continuous variable. | |||
| [3] Pairwise comparison with treatment as a categorical variable; p-values are not adjusted for multiple comparisons. | |||
| The Week 4 to Week 24 endpoint is the mean of a subject's available NPI-X (9) total scores over the Week 4 to Week 24 assessment windows, as the statistical analysis plan defines it in section 10.2.1. A subject contributes one value however many assessments it averages, and a subject with no assessment in that span contributes none, so n is smaller than the column N. | |||
| DEFINED HERE, NOT INHERITED: this endpoint is derived from the per-visit NPTOT records rather than read from the study's own NPTOTMN parameter, because the study's two authoritative statements about this table disagree. Its analysis results metadata (define.xml, Table_14-3.12) selects PARAMCD NPTOTMN, which covers 210 of the 222 efficacy subjects who have an assessment in the Week 4 to Week 24 span: it omits 12 — eleven contributing a single assessment and one contributing two — and adds none. Selecting it reports n = 76, 69, 65. Its own reference report reports n = 78, 75, 69, which is every subject with an assessment in the span, and which the analysis plan's wording ('the mean of all available total scores between Weeks 4 and 24, inclusive') describes. The derivation used here follows the analysis plan and reproduces the reference report to every cell, including the ANCOVA. The divergence is measured and recorded in quality/data/efficacy-agreement.json. | |||
| Assessments are selected by AVISITN, not AVISIT: adqsnpix ships AVISIT right-aligned in a 16-character field, so a comparison against the visible label silently selects no records. | |||
| Treatment columns are planned treatment (TRTP), which is how the CDISCPILOT01 reference report presents them. | |||
| CDISCPILOT01 states no data cut-off date. The date shown is the latest assessment date present in the vendored ADaM package. | |||
| Source: adqsnpix (NPI-X (9) total score, PARAMCD NPTOT) and adsl, from the CDISC pilot's own ADaM package (phuse-org/phuse-scripts, MIT). Analysis as specified in the CDISCPILOT01 statistical analysis plan, section 10.2.1. Reference report display: Table 14-3.12. Data cut-off: 2015-02-17. | |||
| open.csr display t-eff-npix-mean (post_text variant); generated from the committed ARD. | |||
| CIBIC+ — Categorical Analysis — LOCF | |||
| Study CDISCPILOT01 — Efficacy Analysis Set | |||
| Placebo (N=79) | Xanomeline Low Dose (N=81) | Xanomeline High Dose (N=74) | |
|---|---|---|---|
| Week 8 | |||
| n | |||
| Marked improvement | |||
| Moderate improvement | |||
| Minimal improvement | |||
| No change | |||
| Minimal worsening | |||
| Moderate worsening | |||
| Marked worsening | |||
| p-value | |||
| Week 16 | |||
| n | |||
| Marked improvement | |||
| Moderate improvement | |||
| Minimal improvement | |||
| No change | |||
| Minimal worsening | |||
| Moderate worsening | |||
| Marked worsening | |||
| p-value | |||
| Week 24 | |||
| n | |||
| Marked improvement | |||
| Moderate improvement | |||
| Minimal improvement | |||
| No change | |||
| Minimal worsening | |||
| Moderate worsening | |||
| Marked worsening | |||
| p-value | |||
| An analysis not specified in the protocol, treating the CIBIC+ score as a categorical rather than a continuous variable. | |||
| The seven categories are the CIBIC+ scale as the study's statistical analysis plan defines it (Appendix 1, section 14.1.2): 1 = marked improvement through 7 = marked worsening, with 4 = no change. Every category is reported at every visit, including those no subject was scored in. | |||
| Values are last observation carried forward within the analysis window (ADQSCIBC ANL01FL = 'Y'). | |||
| Column headings are the size of the efficacy analysis set; n is the number of subjects with a value at the visit, and percentages are of that n. | |||
| The p-value is an overall comparison of the three treatment groups by the Cochran-Mantel-Haenszel row-mean-scores statistic on 2 degrees of freedom, stratified by site group. It is a single test per visit, printed once. | |||
| Source: adqscibc, adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | |||
| open.csr display t-cibic-categorical (post_text variant); generated from the committed ARD. | |||
| Time to Dermatologic Event by Treatment Group | |||
| Study CDISCPILOT01 — Safety Analysis Set | |||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | |
|---|---|---|---|
| Subjects with a dermatologic event, n (%) | |||
| Censored, n (%) | |||
| Median time to event, days (95% CI) | |||
| Dermatologic events are the adverse events the study flagged as its first customised query, CQ01NAM = 'DERMATOLOGIC EVENTS'; ADTTE carries one record per subject for the first such treatment-emergent event. | |||
| Subjects without a dermatologic event are censored at their study completion date (CNSR = 1); the event time is the day of the first event (CNSR = 0). | |||
| Survival probability is the Kaplan-Meier product-limit estimate of remaining free of a dermatologic event. Tick marks on a curve are censored subjects, and the counts beneath it are the subjects still at risk at each of those days. | |||
| The median and its 95% confidence limits use the linear transformation, reproducing the limits in the reference report; NE means the curve never reached 0.5 and the median is not estimable. | |||
| The test annotated on the figure is the log-rank test of equality across the three treatment groups. Its chi-square and degrees of freedom are stated alongside the p-value so the p-value can be checked rather than taken on trust; the reference report states only that the difference was significant. A p-value smaller than the precision this display declares is reported at that boundary — '<0.0001' — rather than rounded to '0.0000', which would assert a probability of zero. The unrounded value is retained in the analysis results dataset. | |||
| The curve, the tick marks, the numbers at risk and the annotated test are drawn from the same committed analysis results dataset as the table beneath them, so no number on this page is a second calculation of another. | |||
| Source: adtte, adsl (CDISC pilot ADaM package, vendored from phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | |||
| open.csr display f-derm-time-to-event (post_text variant); generated from the committed ARD. | |||
14.3 Safety Data
Not populated in this demonstration.
14.3.1 Displays of Adverse Events
| Summary of Planned Exposure to Study Drug, as of End of Study | ||||
| Study CDISCPILOT01 — Safety Analysis Set | ||||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | Total (N=254) | |
|---|---|---|---|---|
| Safety population | ||||
| Average daily dose (mg) | ||||
| n | ||||
| Mean | ||||
| SD | ||||
| Median | ||||
| Min | ||||
| Max | ||||
| Cumulative dose at end of study (mg) | ||||
| n | ||||
| Mean | ||||
| SD | ||||
| Median | ||||
| Min | ||||
| Max | ||||
| Completers at Week 24 | ||||
| Average daily dose (mg) | ||||
| n | ||||
| Mean | ||||
| SD | ||||
| Median | ||||
| Min | ||||
| Max | ||||
| Cumulative dose at end of study (mg) | ||||
| n | ||||
| Mean | ||||
| SD | ||||
| Median | ||||
| Min | ||||
| Max | ||||
| Duration of treatment (days) — not in the reference table | ||||
| n | ||||
| Mean | ||||
| SD | ||||
| Median | ||||
| Min | ||||
| Max | ||||
| Cumulative exposure, n (%) — not in the reference table | ||||
| ≥ 1 day | ||||
| ≥ 30 days | ||||
| ≥ 90 days | ||||
| ≥ 180 days | ||||
| Average daily dose and cumulative dose are the subject-level AVGDD and CUMDOSE the study's own ADaM package carries; no exposure (ADEX) dataset is used. End of study is Week 26 or early termination. | ||||
| The reference report (Table 14-4.01) presents completers at Week 24 and the safety population as two column groups. This display presents the same statistics with the two populations as row blocks under one set of treatment columns; no number differs. | ||||
| Completers at Week 24 are the subjects flagged COMP24FL = 'Y' in the safety analysis set: 60, 28 and 30 subjects. | ||||
| Duration of treatment (ADSL TRTDUR, days from first to last dose inclusive) and the cumulative exposure categories over it are not part of the reference table; they are carried here because the narrative in Section 12.1 quotes them. A subject treated for 200 days is counted in every category up to 180 days. | ||||
| Placebo subjects have a planned dose of zero, so every placebo dose statistic is 0. The Total column pools the three treatment groups. | ||||
| Source: adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | ||||
| open.csr display t-exposure (post_text variant); generated from the committed ARD. | ||||
| Overview of Treatment-Emergent Adverse Events | ||||
| Study CDISCPILOT01 — Safety Analysis Set | ||||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | Total (N=254) | |
|---|---|---|---|---|
| Adverse events | ||||
| Number of events | ||||
| Subjects with ≥1 adverse event | ||||
| Subjects with a serious adverse event | ||||
| Subjects with a fatal adverse event | ||||
| Subjects with a related adverse event | ||||
| Subjects by severity, n (%) | ||||
| Mild | ||||
| Moderate | ||||
| Severe | ||||
| A treatment-emergent adverse event is an event with TRTEMFL = 'Y'. | ||||
| Percentages are based on the number of subjects in the safety analysis set for each treatment group. | ||||
| Subjects reporting more than one event are counted once in each row they qualify for; severity rows count subjects with at least one event of that severity and therefore do not sum to the number of subjects with any event. | ||||
| Source: adae, adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | ||||
| open.csr display t-ae-overview (post_text variant); generated from the committed ARD. | ||||
| Treatment-Emergent Adverse Events by System Organ Class and Preferred Term | ||||
| Study CDISCPILOT01 — Safety Analysis Set | ||||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | Total (N=254) | |
|---|---|---|---|---|
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS | ||||
| APPLICATION SITE PRURITUS | ||||
| APPLICATION SITE ERYTHEMA | ||||
| APPLICATION SITE DERMATITIS | ||||
| APPLICATION SITE IRRITATION | ||||
| APPLICATION SITE VESICLES | ||||
| FATIGUE | ||||
| OEDEMA PERIPHERAL | ||||
| APPLICATION SITE SWELLING | ||||
| APPLICATION SITE URTICARIA | ||||
| CHILLS | ||||
| MALAISE | ||||
| PYREXIA | ||||
| APPLICATION SITE PAIN | ||||
| APPLICATION SITE PERSPIRATION | ||||
| APPLICATION SITE REACTION | ||||
| ASTHENIA | ||||
| CHEST DISCOMFORT | ||||
| CHEST PAIN | ||||
| OEDEMA | ||||
| PAIN | ||||
| APPLICATION SITE BLEEDING | ||||
| APPLICATION SITE DESQUAMATION | ||||
| APPLICATION SITE DISCHARGE | ||||
| APPLICATION SITE DISCOLOURATION | ||||
| APPLICATION SITE INDURATION | ||||
| APPLICATION SITE WARMTH | ||||
| FEELING ABNORMAL | ||||
| FEELING COLD | ||||
| INFLAMMATION | ||||
| SECRETION DISCHARGE | ||||
| SUDDEN DEATH | ||||
| SWELLING | ||||
| ULCER | ||||
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS | ||||
| PRURITUS | ||||
| ERYTHEMA | ||||
| RASH | ||||
| HYPERHIDROSIS | ||||
| SKIN IRRITATION | ||||
| BLISTER | ||||
| RASH PRURITIC | ||||
| PRURITUS GENERALISED | ||||
| URTICARIA | ||||
| ACTINIC KERATOSIS | ||||
| ALOPECIA | ||||
| COLD SWEAT | ||||
| DERMATITIS CONTACT | ||||
| DRUG ERUPTION | ||||
| RASH ERYTHEMATOUS | ||||
| RASH MACULO-PAPULAR | ||||
| SKIN EXFOLIATION | ||||
| SKIN ODOUR ABNORMAL | ||||
| SKIN ULCER | ||||
| NERVOUS SYSTEM DISORDERS | ||||
| DIZZINESS | ||||
| HEADACHE | ||||
| SYNCOPE | ||||
| SOMNOLENCE | ||||
| TRANSIENT ISCHAEMIC ATTACK | ||||
| BURNING SENSATION | ||||
| LETHARGY | ||||
| AMNESIA | ||||
| BALANCE DISORDER | ||||
| COGNITIVE DISORDER | ||||
| COMPLEX PARTIAL SEIZURES | ||||
| COORDINATION ABNORMAL | ||||
| HEMIANOPIA HOMONYMOUS | ||||
| HYPERSOMNIA | ||||
| PARAESTHESIA | ||||
| PARAESTHESIA ORAL | ||||
| PARKINSON'S DISEASE | ||||
| PAROSMIA | ||||
| PARTIAL SEIZURES WITH SECONDARY GENERALISATION | ||||
| PSYCHOMOTOR HYPERACTIVITY | ||||
| STUPOR | ||||
| SYNCOPE VASOVAGAL | ||||
| GASTROINTESTINAL DISORDERS | ||||
| DIARRHOEA | ||||
| VOMITING | ||||
| NAUSEA | ||||
| ABDOMINAL PAIN | ||||
| SALIVARY HYPERSECRETION | ||||
| DYSPEPSIA | ||||
| ABDOMINAL DISCOMFORT | ||||
| CONSTIPATION | ||||
| DYSPHAGIA | ||||
| FLATULENCE | ||||
| GASTROINTESTINAL HAEMORRHAGE | ||||
| GASTROOESOPHAGEAL REFLUX DISEASE | ||||
| GLOSSITIS | ||||
| HIATUS HERNIA | ||||
| RECTAL HAEMORRHAGE | ||||
| STOMACH DISCOMFORT | ||||
| CARDIAC DISORDERS | ||||
| SINUS BRADYCARDIA | ||||
| MYOCARDIAL INFARCTION | ||||
| ATRIAL FIBRILLATION | ||||
| SUPRAVENTRICULAR EXTRASYSTOLES | ||||
| VENTRICULAR EXTRASYSTOLES | ||||
| ATRIAL FLUTTER | ||||
| ATRIOVENTRICULAR BLOCK FIRST DEGREE | ||||
| BUNDLE BRANCH BLOCK RIGHT | ||||
| PALPITATIONS | ||||
| ATRIAL HYPERTROPHY | ||||
| ATRIOVENTRICULAR BLOCK SECOND DEGREE | ||||
| BRADYCARDIA | ||||
| BUNDLE BRANCH BLOCK LEFT | ||||
| CARDIAC DISORDER | ||||
| CARDIAC FAILURE CONGESTIVE | ||||
| SINUS ARRHYTHMIA | ||||
| SUPRAVENTRICULAR TACHYCARDIA | ||||
| TACHYCARDIA | ||||
| VENTRICULAR HYPERTROPHY | ||||
| WOLFF-PARKINSON-WHITE SYNDROME | ||||
| INFECTIONS AND INFESTATIONS | ||||
| NASOPHARYNGITIS | ||||
| UPPER RESPIRATORY TRACT INFECTION | ||||
| INFLUENZA | ||||
| URINARY TRACT INFECTION | ||||
| CYSTITIS | ||||
| EAR INFECTION | ||||
| BRONCHITIS | ||||
| CELLULITIS | ||||
| CERVICITIS | ||||
| GASTROENTERITIS VIRAL | ||||
| HORDEOLUM | ||||
| LOCALISED INFECTION | ||||
| LOWER RESPIRATORY TRACT INFECTION | ||||
| PNEUMONIA | ||||
| RHINITIS | ||||
| VAGINAL MYCOSIS | ||||
| VIRAL INFECTION | ||||
| PSYCHIATRIC DISORDERS | ||||
| CONFUSIONAL STATE | ||||
| AGITATION | ||||
| INSOMNIA | ||||
| ANXIETY | ||||
| DELUSION | ||||
| IRRITABILITY | ||||
| COMPLETED SUICIDE | ||||
| DELIRIUM | ||||
| DEPRESSED MOOD | ||||
| DISORIENTATION | ||||
| HALLUCINATION | ||||
| HALLUCINATION, VISUAL | ||||
| LIBIDO DECREASED | ||||
| LISTLESS | ||||
| NIGHTMARE | ||||
| RESTLESSNESS | ||||
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS | ||||
| COUGH | ||||
| NASAL CONGESTION | ||||
| DYSPNOEA | ||||
| EPISTAXIS | ||||
| PHARYNGOLARYNGEAL PAIN | ||||
| RHINORRHOEA | ||||
| ALLERGIC GRANULOMATOUS ANGIITIS | ||||
| DYSPHONIA | ||||
| EMPHYSEMA | ||||
| HAEMOPTYSIS | ||||
| PHARYNGEAL ERYTHEMA | ||||
| POSTNASAL DRIP | ||||
| PRODUCTIVE COUGH | ||||
| RALES | ||||
| RESPIRATORY TRACT CONGESTION | ||||
| INVESTIGATIONS | ||||
| ELECTROCARDIOGRAM ST SEGMENT DEPRESSION | ||||
| ELECTROCARDIOGRAM T WAVE INVERSION | ||||
| BLOOD GLUCOSE INCREASED | ||||
| ELECTROCARDIOGRAM T WAVE AMPLITUDE DECREASED | ||||
| BIOPSY | ||||
| BIOPSY PROSTATE | ||||
| BLOOD ALKALINE PHOSPHATASE INCREASED | ||||
| BLOOD CHOLESTEROL INCREASED | ||||
| BLOOD CREATINE PHOSPHOKINASE INCREASED | ||||
| BLOOD URINE PRESENT | ||||
| BODY TEMPERATURE INCREASED | ||||
| CYSTOSCOPY | ||||
| HEART RATE INCREASED | ||||
| HEART RATE IRREGULAR | ||||
| NASAL MUCOSA BIOPSY | ||||
| WEIGHT DECREASED | ||||
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS | ||||
| BACK PAIN | ||||
| ARTHRALGIA | ||||
| SHOULDER PAIN | ||||
| MUSCLE SPASMS | ||||
| ARTHRITIS | ||||
| FLANK PAIN | ||||
| MUSCULAR WEAKNESS | ||||
| MYALGIA | ||||
| PAIN IN EXTREMITY | ||||
| INJURY, POISONING AND PROCEDURAL COMPLICATIONS | ||||
| CONTUSION | ||||
| EXCORIATION | ||||
| FALL | ||||
| HIP FRACTURE | ||||
| SKIN LACERATION | ||||
| FACIAL BONES FRACTURE | ||||
| JOINT DISLOCATION | ||||
| WOUND | ||||
| RENAL AND URINARY DISORDERS | ||||
| MICTURITION URGENCY | ||||
| DYSURIA | ||||
| NEPHROLITHIASIS | ||||
| CALCULUS URETHRAL | ||||
| INCONTINENCE | ||||
| POLLAKIURIA | ||||
| METABOLISM AND NUTRITION DISORDERS | ||||
| DECREASED APPETITE | ||||
| FOOD CRAVING | ||||
| INCREASED APPETITE | ||||
| DEHYDRATION | ||||
| DIABETES MELLITUS | ||||
| HYPONATRAEMIA | ||||
| VASCULAR DISORDERS | ||||
| HYPOTENSION | ||||
| HYPERTENSION | ||||
| HOT FLUSH | ||||
| ORTHOSTATIC HYPOTENSION | ||||
| WOUND HAEMORRHAGE | ||||
| EYE DISORDERS | ||||
| VISION BLURRED | ||||
| CONJUNCTIVAL HAEMORRHAGE | ||||
| CONJUNCTIVITIS | ||||
| EYE ALLERGY | ||||
| EYE PRURITUS | ||||
| EYE SWELLING | ||||
| SURGICAL AND MEDICAL PROCEDURES | ||||
| CATARACT OPERATION | ||||
| ACROCHORDON EXCISION | ||||
| EYE LASER SURGERY | ||||
| SKIN LESION EXCISION | ||||
| EAR AND LABYRINTH DISORDERS | ||||
| VERTIGO | ||||
| CERUMEN IMPACTION | ||||
| EAR PAIN | ||||
| CONGENITAL, FAMILIAL AND GENETIC DISORDERS | ||||
| VENTRICULAR SEPTAL DEFECT | ||||
| NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) | ||||
| COLON CANCER | ||||
| MALIGNANT FIBROUS HISTIOCYTOMA | ||||
| PROSTATE CANCER | ||||
| REPRODUCTIVE SYSTEM AND BREAST DISORDERS | ||||
| BENIGN PROSTATIC HYPERPLASIA | ||||
| PELVIC PAIN | ||||
| HEPATOBILIARY DISORDERS | ||||
| HYPERBILIRUBINAEMIA | ||||
| IMMUNE SYSTEM DISORDERS | ||||
| HYPERSENSITIVITY | ||||
| SOCIAL CIRCUMSTANCES | ||||
| ALCOHOL USE | ||||
| Subjects are counted once per system organ class and once per preferred term, regardless of how many events they reported. | ||||
| Percentages are based on the number of subjects in the safety analysis set for each treatment group. | ||||
| System organ classes and preferred terms are sorted by descending subject count. | ||||
| The Total column pools all treatment groups; the 5% threshold applied to the in-text variant is evaluated on the treatment columns only, never on Total. | ||||
| Source: adae, adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | ||||
| open.csr display t-ae-common (post_text variant); generated from the committed ARD. | ||||
| Incidence of Treatment Emergent Adverse Events by Treatment Group | |||||
| Study CDISCPILOT01 — Safety Analysis Set | |||||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | Placebo vs. Low Dose | Placebo vs. High Dose | |
|---|---|---|---|---|---|
| ANY BODY SYSTEM | |||||
| CARDIAC DISORDERS | |||||
| SINUS BRADYCARDIA | |||||
| MYOCARDIAL INFARCTION | |||||
| ATRIAL FIBRILLATION | |||||
| ATRIAL FLUTTER | |||||
| CARDIAC DISORDER | |||||
| SUPRAVENTRICULAR EXTRASYSTOLES | |||||
| VENTRICULAR EXTRASYSTOLES | |||||
| ATRIAL HYPERTROPHY | |||||
| ATRIOVENTRICULAR BLOCK FIRST DEGREE | |||||
| ATRIOVENTRICULAR BLOCK SECOND DEGREE | |||||
| BRADYCARDIA | |||||
| BUNDLE BRANCH BLOCK LEFT | |||||
| BUNDLE BRANCH BLOCK RIGHT | |||||
| CARDIAC FAILURE CONGESTIVE | |||||
| PALPITATIONS | |||||
| SINUS ARRHYTHMIA | |||||
| SUPRAVENTRICULAR TACHYCARDIA | |||||
| TACHYCARDIA | |||||
| VENTRICULAR HYPERTROPHY | |||||
| WOLFF-PARKINSON-WHITE SYNDROME | |||||
| CONGENITAL, FAMILIAL AND GENETIC DISORDERS | |||||
| VENTRICULAR SEPTAL DEFECT | |||||
| EAR AND LABYRINTH DISORDERS | |||||
| VERTIGO | |||||
| CERUMEN IMPACTION | |||||
| EAR PAIN | |||||
| EYE DISORDERS | |||||
| VISION BLURRED | |||||
| CONJUNCTIVAL HAEMORRHAGE | |||||
| CONJUNCTIVITIS | |||||
| EYE ALLERGY | |||||
| EYE PRURITUS | |||||
| EYE SWELLING | |||||
| GASTROINTESTINAL DISORDERS | |||||
| VOMITING | |||||
| NAUSEA | |||||
| DIARRHOEA | |||||
| SALIVARY HYPERSECRETION | |||||
| ABDOMINAL DISCOMFORT | |||||
| ABDOMINAL PAIN | |||||
| GASTROINTESTINAL HAEMORRHAGE | |||||
| STOMACH DISCOMFORT | |||||
| CONSTIPATION | |||||
| DYSPEPSIA | |||||
| DYSPHAGIA | |||||
| FLATULENCE | |||||
| GASTROOESOPHAGEAL REFLUX DISEASE | |||||
| GLOSSITIS | |||||
| HIATUS HERNIA | |||||
| RECTAL HAEMORRHAGE | |||||
| GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS | |||||
| APPLICATION SITE PRURITUS | |||||
| APPLICATION SITE ERYTHEMA | |||||
| APPLICATION SITE IRRITATION | |||||
| APPLICATION SITE DERMATITIS | |||||
| APPLICATION SITE VESICLES | |||||
| FATIGUE | |||||
| APPLICATION SITE PAIN | |||||
| APPLICATION SITE PERSPIRATION | |||||
| APPLICATION SITE SWELLING | |||||
| CHEST DISCOMFORT | |||||
| CHEST PAIN | |||||
| MALAISE | |||||
| OEDEMA PERIPHERAL | |||||
| APPLICATION SITE DISCHARGE | |||||
| APPLICATION SITE REACTION | |||||
| APPLICATION SITE URTICARIA | |||||
| ASTHENIA | |||||
| CHILLS | |||||
| FEELING ABNORMAL | |||||
| FEELING COLD | |||||
| PAIN | |||||
| PYREXIA | |||||
| APPLICATION SITE BLEEDING | |||||
| APPLICATION SITE DESQUAMATION | |||||
| APPLICATION SITE DISCOLOURATION | |||||
| APPLICATION SITE INDURATION | |||||
| APPLICATION SITE WARMTH | |||||
| INFLAMMATION | |||||
| OEDEMA | |||||
| SECRETION DISCHARGE | |||||
| SUDDEN DEATH | |||||
| SWELLING | |||||
| ULCER | |||||
| HEPATOBILIARY DISORDERS | |||||
| HYPERBILIRUBINAEMIA | |||||
| IMMUNE SYSTEM DISORDERS | |||||
| HYPERSENSITIVITY | |||||
| INFECTIONS AND INFESTATIONS | |||||
| NASOPHARYNGITIS | |||||
| UPPER RESPIRATORY TRACT INFECTION | |||||
| CYSTITIS | |||||
| HORDEOLUM | |||||
| INFLUENZA | |||||
| LOWER RESPIRATORY TRACT INFECTION | |||||
| RHINITIS | |||||
| URINARY TRACT INFECTION | |||||
| BRONCHITIS | |||||
| CELLULITIS | |||||
| CERVICITIS | |||||
| EAR INFECTION | |||||
| GASTROENTERITIS VIRAL | |||||
| LOCALISED INFECTION | |||||
| PNEUMONIA | |||||
| VAGINAL MYCOSIS | |||||
| VIRAL INFECTION | |||||
| INJURY, POISONING AND PROCEDURAL COMPLICATIONS | |||||
| CONTUSION | |||||
| HIP FRACTURE | |||||
| EXCORIATION | |||||
| FACIAL BONES FRACTURE | |||||
| FALL | |||||
| JOINT DISLOCATION | |||||
| SKIN LACERATION | |||||
| WOUND | |||||
| INVESTIGATIONS | |||||
| BIOPSY | |||||
| BIOPSY PROSTATE | |||||
| BLOOD CHOLESTEROL INCREASED | |||||
| BLOOD GLUCOSE INCREASED | |||||
| ELECTROCARDIOGRAM T WAVE INVERSION | |||||
| WEIGHT DECREASED | |||||
| BLOOD ALKALINE PHOSPHATASE INCREASED | |||||
| BLOOD CREATINE PHOSPHOKINASE INCREASED | |||||
| BLOOD URINE PRESENT | |||||
| BODY TEMPERATURE INCREASED | |||||
| CYSTOSCOPY | |||||
| ELECTROCARDIOGRAM ST SEGMENT DEPRESSION | |||||
| ELECTROCARDIOGRAM T WAVE AMPLITUDE DECREASED | |||||
| HEART RATE INCREASED | |||||
| HEART RATE IRREGULAR | |||||
| NASAL MUCOSA BIOPSY | |||||
| METABOLISM AND NUTRITION DISORDERS | |||||
| DECREASED APPETITE | |||||
| INCREASED APPETITE | |||||
| DEHYDRATION | |||||
| DIABETES MELLITUS | |||||
| FOOD CRAVING | |||||
| HYPONATRAEMIA | |||||
| MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS | |||||
| BACK PAIN | |||||
| ARTHRALGIA | |||||
| ARTHRITIS | |||||
| FLANK PAIN | |||||
| MUSCLE SPASMS | |||||
| MYALGIA | |||||
| MUSCULAR WEAKNESS | |||||
| PAIN IN EXTREMITY | |||||
| SHOULDER PAIN | |||||
| NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) | |||||
| PROSTATE CANCER | |||||
| COLON CANCER | |||||
| MALIGNANT FIBROUS HISTIOCYTOMA | |||||
| NERVOUS SYSTEM DISORDERS | |||||
| DIZZINESS | |||||
| HEADACHE | |||||
| SYNCOPE | |||||
| BURNING SENSATION | |||||
| AMNESIA | |||||
| COGNITIVE DISORDER | |||||
| HYPERSOMNIA | |||||
| LETHARGY | |||||
| PARAESTHESIA | |||||
| PAROSMIA | |||||
| PARTIAL SEIZURES WITH SECONDARY GENERALISATION | |||||
| SOMNOLENCE | |||||
| SYNCOPE VASOVAGAL | |||||
| TRANSIENT ISCHAEMIC ATTACK | |||||
| BALANCE DISORDER | |||||
| COMPLEX PARTIAL SEIZURES | |||||
| COORDINATION ABNORMAL | |||||
| HEMIANOPIA HOMONYMOUS | |||||
| PARAESTHESIA ORAL | |||||
| PARKINSON'S DISEASE | |||||
| PSYCHOMOTOR HYPERACTIVITY | |||||
| STUPOR | |||||
| PSYCHIATRIC DISORDERS | |||||
| INSOMNIA | |||||
| AGITATION | |||||
| CONFUSIONAL STATE | |||||
| DELIRIUM | |||||
| DELUSION | |||||
| HALLUCINATION | |||||
| HALLUCINATION, VISUAL | |||||
| LIBIDO DECREASED | |||||
| LISTLESS | |||||
| NIGHTMARE | |||||
| ANXIETY | |||||
| COMPLETED SUICIDE | |||||
| DEPRESSED MOOD | |||||
| DISORIENTATION | |||||
| IRRITABILITY | |||||
| RESTLESSNESS | |||||
| RENAL AND URINARY DISORDERS | |||||
| CALCULUS URETHRAL | |||||
| MICTURITION URGENCY | |||||
| NEPHROLITHIASIS | |||||
| DYSURIA | |||||
| INCONTINENCE | |||||
| POLLAKIURIA | |||||
| REPRODUCTIVE SYSTEM AND BREAST DISORDERS | |||||
| BENIGN PROSTATIC HYPERPLASIA | |||||
| PELVIC PAIN | |||||
| RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS | |||||
| COUGH | |||||
| NASAL CONGESTION | |||||
| EPISTAXIS | |||||
| ALLERGIC GRANULOMATOUS ANGIITIS | |||||
| DYSPNOEA | |||||
| PHARYNGEAL ERYTHEMA | |||||
| PHARYNGOLARYNGEAL PAIN | |||||
| PRODUCTIVE COUGH | |||||
| RESPIRATORY TRACT CONGESTION | |||||
| RHINORRHOEA | |||||
| DYSPHONIA | |||||
| EMPHYSEMA | |||||
| HAEMOPTYSIS | |||||
| POSTNASAL DRIP | |||||
| RALES | |||||
| SKIN AND SUBCUTANEOUS TISSUE DISORDERS | |||||
| PRURITUS | |||||
| ERYTHEMA | |||||
| RASH | |||||
| HYPERHIDROSIS | |||||
| SKIN IRRITATION | |||||
| RASH PRURITIC | |||||
| ACTINIC KERATOSIS | |||||
| BLISTER | |||||
| PRURITUS GENERALISED | |||||
| RASH MACULO-PAPULAR | |||||
| SKIN ODOUR ABNORMAL | |||||
| URTICARIA | |||||
| ALOPECIA | |||||
| COLD SWEAT | |||||
| DERMATITIS CONTACT | |||||
| DRUG ERUPTION | |||||
| RASH ERYTHEMATOUS | |||||
| SKIN EXFOLIATION | |||||
| SKIN ULCER | |||||
| SOCIAL CIRCUMSTANCES | |||||
| ALCOHOL USE | |||||
| SURGICAL AND MEDICAL PROCEDURES | |||||
| ACROCHORDON EXCISION | |||||
| SKIN LESION EXCISION | |||||
| CATARACT OPERATION | |||||
| EYE LASER SURGERY | |||||
| VASCULAR DISORDERS | |||||
| WOUND HAEMORRHAGE | |||||
| HOT FLUSH | |||||
| HYPERTENSION | |||||
| HYPOTENSION | |||||
| ORTHOSTATIC HYPOTENSION | |||||
| Treatment-emergent events are those flagged TRTEMFL = 'Y' in the study's ADAE: events that start on or after the start of treatment, as the reference report (Table 14-5.01) defines them. Adverse events are coded using MedDRA. | |||||
| Subjects are counted once per system organ class and once per preferred term; percentages are based on the number of subjects in the safety population within each treatment group. The bracketed figure is the total number of times an event was recorded. | |||||
| P-values are Fisher's exact test comparing placebo with each active treatment group on the number of subjects with the event. An asterisk is appended to p-values below 0.15, as in the reference report; a p-value that rounds to 1 prints as >0.99; where neither arm has a subject with the event there is no test and the cell is blank. | |||||
| System organ classes are in alphabetical order; preferred terms within a class are in descending order of high-dose subjects, then alphabetical — the order the reference report prints. | |||||
| Four of the 227 p-values the reference report prints differ from this display at the third decimal, each by one thousandth: vomiting (placebo vs high dose, 0.208 here, 0.209 there), salivary hypersecretion (0.057 here, 0.058 there), application site erythema (0.002 here, 0.003 there) and syncope (placebo vs low dose, 0.057 here, 0.058 there). The subject counts agree; R's exact two-sided test gives 0.2085, 0.0575, 0.0025 and 0.0575, and the 2006 program rounded each up. They are recorded and tracked in quality/data/reference-report-agreement.json. | |||||
| Source: adae, adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | |||||
| open.csr display t-ae-incidence (post_text variant); generated from the committed ARD. | |||||
14.3.2 Listings of Deaths, Other Serious and Significant Adverse Events
| Listing of Serious Adverse Events | |||||||||||
| Study CDISCPILOT01 — Safety Analysis Set | |||||||||||
| Subject | Treatment | Age | Sex | System organ class | Preferred term | Severity | Relationship | Start day | End day | Outcome | |
|---|---|---|---|---|---|---|---|---|---|---|---|
| 1 | |||||||||||
| 2 | |||||||||||
| 3 | |||||||||||
| One row per serious adverse event record (AESER = 'Y'). | |||||||||||
| Study day is relative to the first dose of study drug. | |||||||||||
| Source: adae (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | |||||||||||
| open.csr display l-ae-serious (post_text variant); generated from the committed ARD. | |||||||||||
| Incidence of Treatment Emergent Serious Adverse Events by Treatment Group | |||||
| Study CDISCPILOT01 — Safety Analysis Set | |||||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | Placebo vs. Low Dose | Placebo vs. High Dose | |
|---|---|---|---|---|---|
| ANY BODY SYSTEM | |||||
| NERVOUS SYSTEM DISORDERS | |||||
| SYNCOPE | |||||
| PARTIAL SEIZURES WITH SECONDARY GENERALISATION | |||||
| Serious treatment-emergent events are those flagged AESER = 'Y' and TRTEMFL = 'Y' in the study's ADAE, as the reference report (Table 14-5.02) counts them. Adverse events are coded using MedDRA. | |||||
| Subjects are counted once per system organ class and once per preferred term; percentages are based on the number of subjects in the safety population within each treatment group. The bracketed figure is the total number of times an event was recorded. | |||||
| P-values are Fisher's exact test comparing placebo with each active treatment group on the number of subjects with the event. An asterisk is appended to p-values below 0.15, as in the reference report; a p-value that rounds to 1 prints as >0.99; where neither arm has a subject with the event there is no test and the cell is blank. | |||||
| System organ classes are in alphabetical order; preferred terms within a class are in descending order of subjects across the three groups, then alphabetical — the order the reference report's serious-events program prints, which differs from its full incidence table. | |||||
| Source: adae, adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | |||||
| open.csr display t-sae-incidence (post_text variant); generated from the committed ARD. | |||||
14.3.3 Narratives of Deaths, Other Serious and Certain Other Significant Adverse Events
Not populated in this demonstration. Prose block inside the TFL section — the Text Library/TFL Library seam.
14.3.4 Abnormal Laboratory Value Listing (Each Patient)
Not populated in this demonstration.
14.3.5 Displays of Vital Signs, Weight and Concomitant Medications
| Summary of Vital Signs at Baseline and End of Treatment | |||
| Study CDISCPILOT01 — Safety Analysis Set | |||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | |
|---|---|---|---|
| Systolic Blood Pressure (mmHg) | |||
| After lying down for 5 minutes | |||
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| After standing for 1 minute | |||
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| After standing for 3 minutes | |||
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Diastolic Blood Pressure (mmHg) | |||
| After lying down for 5 minutes | |||
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| After standing for 1 minute | |||
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| After standing for 3 minutes | |||
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Pulse (beats/min) | |||
| After lying down for 5 minutes | |||
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| After standing for 1 minute | |||
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| After standing for 3 minutes | |||
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Treatment groups are PLANNED treatment (TRT01P). Twelve subjects in this study received a treatment other than the one they were randomised to; grouping by actual treatment (TRT01A) would give column sizes of 86, 96 and 72. | |||
| Blood pressure and pulse are measured in three positions and each position is summarised as its own series: a subject's baseline after standing for three minutes is not the baseline for their supine measurement. | |||
| End of treatment is the last observed measurement of that parameter in that position, at a planned visit after Week 0 up to and including Week 24. Unscheduled visits, the Week 26 follow-up visit and records derived by averaging or carry-forward are never selected. | |||
| n is the number of subjects contributing a measurement; N in the column header is the number of subjects in the safety analysis set. | |||
| Source: advs, adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | |||
| open.csr display t-vitals (post_text variant); generated from the committed ARD. | |||
| Summary of Vital Signs Change from Baseline at End of Treatment | |||
| Study CDISCPILOT01 — Safety Analysis Set | |||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | |
|---|---|---|---|
| Systolic Blood Pressure (mmHg) | |||
| After lying down for 5 minutes | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| After standing for 1 minute | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| After standing for 3 minutes | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Diastolic Blood Pressure (mmHg) | |||
| After lying down for 5 minutes | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| After standing for 1 minute | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| After standing for 3 minutes | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Pulse (beats/min) | |||
| After lying down for 5 minutes | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| After standing for 1 minute | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| After standing for 3 minutes | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Treatment groups are PLANNED treatment (TRT01P). Twelve subjects in this study received a treatment other than the one they were randomised to; grouping by actual treatment (TRT01A) would give column sizes of 86, 96 and 72. | |||
| Blood pressure and pulse are measured in three positions and each position is summarised as its own series: a subject's baseline after standing for three minutes is not the baseline for their supine measurement. | |||
| End of treatment is the last observed measurement of that parameter in that position, at a planned visit after Week 0 up to and including Week 24. Unscheduled visits, the Week 26 follow-up visit and records derived by averaging or carry-forward are never selected. | |||
| Change from baseline is the subject's value minus that subject's own observed Week 0 value in the same position. A subject with no Week 0 measurement contributes to no row here, so n can be one below the corresponding n in the vital signs summary. | |||
| n is the number of subjects contributing a change; N in the column header is the number of subjects in the safety analysis set. | |||
| Source: advs, adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | |||
| open.csr display t-vitals-change (post_text variant); generated from the committed ARD. | |||
| Summary of Weight and Weight Change from Baseline at End of Treatment | |||
| Study CDISCPILOT01 — Safety Analysis Set | |||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | |
|---|---|---|---|
| Weight (kg) | |||
| Baseline | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Weight change from baseline (kg) | |||
| Week 24 | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| End of treatment | |||
| n | |||
| Mean (SD) | |||
| Median | |||
| Min, Max | |||
| Treatment groups are PLANNED treatment (TRT01P). Twelve subjects in this study received a treatment other than the one they were randomised to; grouping by actual treatment (TRT01A) would give column sizes of 86, 96 and 72. | |||
| Baseline is the subject's observed Week 0 weight. Change from baseline is that subject's value minus that baseline, so a subject with no Week 0 weight contributes to the weight rows but not to the change rows. | |||
| End of treatment is the last observed weight at a planned visit after Week 0 up to and including Week 24. Unscheduled visits, the Week 26 follow-up visit and records derived by averaging or carry-forward are never selected. | |||
| n is the number of subjects contributing a measurement; N in the column header is the number of subjects in the safety analysis set. | |||
| Source: advs, adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | |||
| open.csr display t-weight (post_text variant); generated from the committed ARD. | |||
| Summary of Concomitant Medications (Number of Subjects) | |||
| Study CDISCPILOT01 — Safety Analysis Set | |||
| Placebo (N=86) | Xanomeline Low Dose (N=84) | Xanomeline High Dose (N=84) | |
|---|---|---|---|
| Subjects receiving at least one concomitant medication | |||
| Therapeutic class and coded medication, n (%) | |||
| UNCODED | |||
| UNCODED | |||
| NERVOUS SYSTEM | |||
| ACETYLSALICYLIC ACID | |||
| DONEPEZIL HYDROCHLORIDE | |||
| ALPRAZOLAM | |||
| HALOPERIDOL | |||
| PAROXETINE HYDROCHLORIDE | |||
| SUMATRIPTAN | |||
| SYSTEMIC HORMONAL PREPARATIONS, EXCL. | |||
| HYDROCORTISONE | |||
| ALIMENTARY TRACT AND METABOLISM | |||
| CALCIUM | |||
| NIZATIDINE | |||
| ALGELDRATE | |||
| SIMETICONE | |||
| CALCIUM CARBONATE | |||
| CIMETIDINE | |||
| LOPERAMIDE HYDROCHLORIDE | |||
| METFORMIN HYDROCHLORIDE | |||
| CARDIOVASCULAR SYSTEM | |||
| AMLODIPINE | |||
| DIGOXIN | |||
| DOXAZOSIN MESILATE | |||
| FLUVASTATIN | |||
| FUROSEMIDE | |||
| LOSARTAN POTASSIUM | |||
| NIFEDIPINE | |||
| DILTIAZEM HYDROCHLORIDE | |||
| FELODIPINE | |||
| GENITO URINARY SYSTEM AND SEX HORMONES | |||
| ESTROGENS CONJUGATED | |||
| RESPIRATORY SYSTEM | |||
| NAPROXEN SODIUM | |||
| SALBUTAMOL SULFATE | |||
| BUDESONIDE | |||
| GUAIFENESIN | |||
| IPRATROPIUM BROMIDE | |||
| ANTINEOPLASTIC AND IMMUNOMODULATING AGENTS | |||
| LEUPRORELIN ACETATE | |||
| BLOOD AND BLOOD FORMING ORGANS | |||
| FERROUS SULFATE | |||
| DERMATOLOGICALS | |||
| CLOBETASOL PROPIONATE | |||
| Treatment groups are PLANNED treatment (TRT01P). Twelve subjects in this study received a treatment other than the one they were randomised to; grouping by actual treatment (TRT01A) would give column sizes of 86, 96 and 72. | |||
| A subject is counted once per therapeutic class and once per coded medication, however many records they have. Class counts are therefore not the sum of the medication counts beneath them. | |||
| Every recorded medication counts, whether it was taken before, during or after treatment. Restricting to medications taken on treatment (ONTRTFL = 'Y') would count a much smaller set of records. | |||
| UNCODED is not a therapeutic class. It is how this study's data records a medication that was never coded to a dictionary term, and it is reported rather than dropped. | |||
| Classes, and the medications within a class, are ordered by the largest subject count in any treatment group, ties alphabetically. The reference document this display targets ordered them alphabetically by class instead. | |||
| Percentages are based on the number of subjects in the safety analysis set for each treatment group. | |||
| Source: adcm, adsl (CDISCPILOT01 ADaM package, phuse-org/phuse-scripts). Data cut-off: 2014-07-01. | |||
| open.csr display t-conmeds (post_text variant); generated from the committed ARD. | |||
15 Reference List
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16 Appendices
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16.1 Study Information
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16.1.1 Protocol and Protocol Amendments
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16.1.2 Sample Case Report Form (unique pages only)
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16.1.3 List of IEC or IRB and Representative Written Information for Patient and Sample Consent Forms
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16.1.4 List and Description of Investigators and Other Important Participants in the Study, Including Brief CVs or Equivalent Summaries of Training and Experience
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16.1.5 Signatures of Principal or Coordinating Investigator(s) or Sponsor's Responsible Medical Officer
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16.1.6 Listing of Patients Receiving Test Drug(s)/Investigational Product(s) from Specific Batches, Where More Than One Batch Was Used
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16.1.7 Randomisation Scheme and Codes (patient identification and treatment assigned)
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16.1.8 Audit Certificates (if available)
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16.1.9 Documentation of Statistical Methods
| Display | Title | Spec / display | Input data | Environment | Commit |
|---|---|---|---|---|---|
| t-disposition 14.1.1 | Subject Disposition | 8c432e5 c00f247 | adsl 254 rows · 70c7278 | R 4.3.3 | uncommitted 2026-09-02 |
| t-demographics 14.1.2 | Summary of Demographic and Baseline Characteristics | bc60600 c2a1f17 | adsl 254 rows · b022f78 | R 4.3.3 | uncommitted 2026-09-02 |
| t-populations 14.1.3 | Summary of Populations | c8dbaff 9ac815d | adsl 254 rows · 70c7278 | R 4.3.3 | uncommitted 2026-09-02 |
| t-end-of-study 14.1.4 | Summary of End of Study Data | d39450d 6a7d3f3 | adsl 254 rows · 70c7278 | R 4.3.3 | uncommitted 2026-09-02 |
| t-subjects-by-site 14.1.5 | Summary of Number of Subjects By Site | 9b145f6 3087fc5 | adsl 254 rows · 1f6fa03 | R 4.3.3 | uncommitted 2026-09-02 |
| f-disposition 14.1.6 | Subject Disposition | abf4fa1 334133a | adsl 254 rows · 3139478 dm 306 rows · 6f25948 | R 4.3.3 | uncommitted 2026-09-02 |
| t-eff-adas-wk24 14.2.1 | Primary Endpoint Analysis: ADAS-Cog (11) - Change from Baseline to Week 24 - LOCF | b129304 e51fda2 | adsl 254 rows · 70c7278 adqsadas 12463 rows · d6ee9a3 | R 4.3.3 | uncommitted 2026-09-02 |
| t-eff-adas-overtime 14.2.10 | ADAS-Cog (11) - Mean and Mean Change from Baseline over Time | 37f6ffa cc82b9a | adsl 254 rows · 70c7278 adqsadas 12463 rows · d6ee9a3 | R 4.3.3 | uncommitted 2026-09-02 |
| t-eff-adas-mmrm 14.2.11 | ADAS-Cog (11) - Repeated Measures Analysis of Change from Baseline to Week 24 | 3070e2a 2b6b835 | adsl 254 rows · 1f6fa03 adqsadas 12463 rows · d6ee9a3 | R 4.3.3 | uncommitted 2026-09-02 |
| t-eff-npix-mean 14.2.12 | Mean NPI-X Total Score from Week 4 through Week 24 - Windowed | 80f5f0c c321095 | adsl 254 rows · 70c7278 adqsnpix 31140 rows · a8db42f | R 4.3.3 | uncommitted 2026-09-02 |
| t-cibic-categorical 14.2.13 | CIBIC+ — Categorical Analysis — LOCF | f6675d7 3e86f7c | adsl 254 rows · 70c7278 adqscibc 730 rows · f6461f4 | R 4.3.3 | uncommitted 2026-09-02 |
| f-derm-time-to-event 14.2.14 | Time to Dermatologic Event by Treatment Group | dd67fc1 a900fd7 | adsl 254 rows · 70c7278 adtte 254 rows · 82a036b | R 4.3.3 | uncommitted 2026-09-02 |
| t-cibic-week24 14.2.2 | Primary Endpoint Analysis: CIBIC+ — Summary at Week 24 — LOCF | 190d176 c326ce8 | adsl 254 rows · 70c7278 adqscibc 730 rows · f6461f4 | R 4.3.3 | uncommitted 2026-09-02 |
| t-eff-adas-wk8 14.2.3 | ADAS-Cog (11) - Change from Baseline to Week 8 - LOCF | 6508cc4 675584e | adsl 254 rows · 70c7278 adqsadas 12463 rows · d6ee9a3 | R 4.3.3 | uncommitted 2026-09-02 |
| t-cibic-week8 14.2.4 | CIBIC+ — Summary at Week 8 — LOCF | d243537 9e6e7dd | adsl 254 rows · 70c7278 adqscibc 730 rows · f6461f4 | R 4.3.3 | uncommitted 2026-09-02 |
| t-eff-adas-wk16 14.2.5 | ADAS-Cog (11) - Change from Baseline to Week 16 - LOCF | 304b616 6bbf55b | adsl 254 rows · 70c7278 adqsadas 12463 rows · d6ee9a3 | R 4.3.3 | uncommitted 2026-09-02 |
| t-cibic-week16 14.2.6 | CIBIC+ — Summary at Week 16 — LOCF | 00a39ba ddcd203 | adsl 254 rows · 70c7278 adqscibc 730 rows · f6461f4 | R 4.3.3 | uncommitted 2026-09-02 |
| t-eff-adas-wk24-completers 14.2.7 | ADAS-Cog (11) - Change from Baseline to Week 24 - Completers at Week 24, Observed Cases, Windowed | 09b7453 4cf74d8 | adsl 254 rows · 70c7278 adqsadas 12463 rows · d6ee9a3 | R 4.3.3 | uncommitted 2026-09-02 |
| t-eff-adas-wk24-male 14.2.8 | ADAS-Cog (11) - Change from Baseline to Week 24 in Male Subjects - LOCF | f08b78f cc16d83 | adsl 254 rows · 70c7278 adqsadas 12463 rows · d6ee9a3 | R 4.3.3 | uncommitted 2026-09-02 |
| t-eff-adas-wk24-female 14.2.9 | ADAS-Cog (11) - Change from Baseline to Week 24 in Female Subjects - LOCF | 9b0ea9b 97fcb12 | adsl 254 rows · 70c7278 adqsadas 12463 rows · d6ee9a3 | R 4.3.3 | uncommitted 2026-09-02 |
| t-exposure 14.3.1.1 | Summary of Planned Exposure to Study Drug, as of End of Study | 065027f d4dbe63 | adsl 254 rows · 70c7278 | R 4.3.3 | uncommitted 2026-09-02 |
| t-ae-overview 14.3.1.2 | Overview of Treatment-Emergent Adverse Events | 6b0ba69 ea18faf | adsl 254 rows · 70c7278 adae 1191 rows · 4ffe4e4 | R 4.3.3 | uncommitted 2026-09-02 |
| t-ae-common 14.3.1.3 | Treatment-Emergent Adverse Events by System Organ Class and Preferred Term | a45e3a1 3027c71 | adsl 254 rows · 70c7278 adae 1191 rows · 4ffe4e4 | R 4.3.3 | uncommitted 2026-09-02 |
| t-ae-incidence 14.3.1.4 | Incidence of Treatment Emergent Adverse Events by Treatment Group | a94b85b 0511d99 | adsl 254 rows · b022f78 adae 1191 rows · 4ffe4e4 | R 4.3.3 | uncommitted 2026-09-02 |
| l-ae-serious 14.3.2.1 | Listing of Serious Adverse Events | a046fb1 11a00d0 | adsl 254 rows · 70c7278 adae 1191 rows · 4ffe4e4 | R 4.3.3 | uncommitted 2026-09-02 |
| t-sae-incidence 14.3.2.2 | Incidence of Treatment Emergent Serious Adverse Events by Treatment Group | 065d87f 2e8296c | adsl 254 rows · 3139478 adae 1191 rows · 4ffe4e4 | R 4.3.3 | uncommitted 2026-09-02 |
| t-vitals 14.3.5.1 | Summary of Vital Signs at Baseline and End of Treatment | 2aeb258 eb31735 | adsl 254 rows · 70c7278 advs 32139 rows · ccc9f70 | R 4.3.3 | uncommitted 2026-09-02 |
| t-vitals-change 14.3.5.2 | Summary of Vital Signs Change from Baseline at End of Treatment | 0d204e9 840b226 | adsl 254 rows · 70c7278 advs 32139 rows · ccc9f70 | R 4.3.3 | uncommitted 2026-09-02 |
| t-weight 14.3.5.3 | Summary of Weight and Weight Change from Baseline at End of Treatment | 14be68b e1621d7 | adsl 254 rows · b022f78 advs 32139 rows · ccc9f70 | R 4.3.3 | uncommitted 2026-09-02 |
| t-conmeds 14.3.5.4 | Summary of Concomitant Medications (Number of Subjects) | 5b8045e a79342e | adsl 254 rows · 3139478 adcm 7510 rows · 78178a0 | R 4.3.3 | uncommitted 2026-09-02 |
16.1.10 Documentation of Inter-laboratory Standardisation Methods and Quality Assurance Procedures if Used
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16.1.11 Publications Based on the Study
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16.1.12 Important Publications Referenced in the Report
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16.2 Patient Data Listings
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16.2.1 Discontinued Patients
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16.2.2 Protocol Deviations
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16.2.3 Patients Excluded from the Efficacy Analysis
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16.2.4 Demographic Data
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16.2.5 Compliance and/or Drug Concentration Data (if available)
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16.2.6 Individual Efficacy Response Data
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16.2.7 Adverse Event Listings (each patient)
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16.2.8 Listing of Individual Laboratory Measurements by Patient, When Required by Regulatory Authorities
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16.3 Case Report Forms
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16.3.1 CRFs for Deaths, Other Serious Adverse Events and Withdrawals for AE
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16.3.2 Other CRFs Submitted
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16.4 Individual Patient Data Listings (US Archival Listings)
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