Assembled document

Study Synopsis

The ICH E3 Annex I Study Synopsis document model, filled from the text library and the display library. Every bound number and every display is clickable: the trace panel answers which dataset, which spec, which ARD row, which display, which sentence.

Draft prose — not reviewed by anyone. All 18 prose blocks in this document are unapproved drafts: no human has read or signed off on the words below. They are published to exercise the assembler against a second document model, not to be read as a statement about this study. The numbers are bound to the same committed ARDs as every other document here and are gated the same way; the sentences around them are not.

1 Administrative Information

Not populated in this demonstration. Annex I's header block. E3 prints these as labelled cells rather than as numbered sections; open.csr numbers them so each field is separately addressable by an assembly, a text block and a cross-reference.

This synopsis is an open.csr demonstration report. It carries no sponsor: the underlying data are the CDISC pilot study ADaM datasets published in the pharmaverseadam package under the Apache License, and the report around them was assembled by the open.csr framework to exercise its own machinery end to end.

The finished product studied is the Xanomeline Transdermal Therapeutic System (TTS). The active ingredient is xanomeline.

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1.2 Title of Study

Safety and Efficacy of the Xanomeline Transdermal Therapeutic System (TTS) in Patients with Mild to Moderate Alzheimer's Disease.

The protocol identifier is CDISCPILOT01.

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1.3 Investigators and Study Centres

The study was conducted at multiple centres. Individual investigator and centre identities are not carried in the ADaM extract this demonstration is built from, so no coordinating investigator is named here.

In a real report this field cross-references the list of investigators in the appendices, and the by-site enrolment summary that accompanies it.

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1.4 Publication (Reference)

None. The CDISC pilot study is a teaching dataset distributed for standards work and is not a published clinical trial.

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1.5 Studied Period

Dates of first enrolment and last completed visit are not carried in the ADaM extract this demonstration is built from and are therefore not reported.

All analyses in this synopsis and in the accompanying clinical study report were produced against a single data cutoff of 2014-07-01, and every number in both documents resolves to the same committed analysis results datasets taken at that cutoff.

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1.6 Phase of Development

Phase 2.

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2 Objectives

The stated objectives of the CDISC pilot study were to evaluate the efficacy and safety of transdermal xanomeline in patients with mild to moderate Alzheimer's disease.

The objective of this report is narrower and should not be mistaken for the study's: it is to demonstrate that a clinical study report and its synopsis can be assembled mechanically from analysis results datasets, a library of text blocks and a library of named values, such that every number in the prose is traceable to the row of the analysis dataset it came from. Efficacy is therefore out of scope here (see the efficacy sections, which are deliberately left unpopulated), and the demonstration is confined to safety.

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3 Methodology

Randomised, double-blind, placebo-controlled, parallel-group.

Patients were assigned to one of three arms: placebo, xanomeline low dose, or xanomeline high dose.

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4 Number of Patients (Planned and Analysed)

The planned sample size is not carried in the ADaM extract this demonstration is built from. Of the patients actually enrolled, {{value:randomised-n}} were randomised and {{value:treated-n}} were treated and form the safety analysis set, which is the population analysed throughout this synopsis.

{{value:completed-n}} patients ({{value:completed-pct}}%) completed the study and {{value:discontinued-n}} discontinued prematurely. Disposition by treatment group is given in 13.1.

Every figure in this paragraph is a binding into the named values store, not a typed number. The same store supplies the same figures to the disposition section of the full clinical study report, so the two documents cannot disagree: if the underlying analysis results dataset changes, both change together, and if a value in the store no longer re-derives from the committed dataset the build fails before either document is written.

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13.1 Subject Dispositionin_text

t-disposition · in_text variant · study CDISCPILOT01 · data cut-off 2014-07-01

Subject Disposition (Summary)
Study CDISCPILOT01 — Intent-to-Treat Analysis Set
Placebo (N=86) Xanomeline Low Dose (N=96) Xanomeline High Dose (N=72) Total (N=254)
Disposition, n (%)
   Subjects randomised 86 (100.0%) 96 (100.0%) 72 (100.0%) 254 (100.0%)
   Subjects treated 86 (100.0%) 96 (100.0%) 72 (100.0%) 254 (100.0%)
   Completed the study 58 (67.4%) 25 (26.0%) 27 (37.5%) 110 (43.3%)
   Discontinued the study 28 (32.6%) 71 (74.0%) 45 (62.5%) 144 (56.7%)
Reason for discontinuation, n (%)
   Death 2 (2.3%) 1 (1.0%) 0 (0.0%) 3 (1.2%)
   Other / not specified 26 (30.2%) 70 (72.9%) 45 (62.5%) 141 (55.5%)
Deaths, n (%)
   Died on study 2 (2.3%) 1 (1.0%) 0 (0.0%) 3 (1.2%)
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 (pharmaverseadam). Data cut-off: 2014-07-01.
open.csr display t-disposition (in_text variant); generated from the committed ARD.

t-disposition

5 Diagnosis and Main Criteria for Inclusion

Patients with mild to moderate Alzheimer's disease.

The full inclusion and exclusion criteria are a property of the protocol and are not derivable from the analysis datasets; in a real report this field is authored prose reviewed against the protocol, and open.csr classifies it as a boilerplate block for exactly that reason — it carries no bindings, so no gate can vouch for it, and it must be approved by a person.

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6 Test Product, Dose and Mode of Administration, Batch Number

Xanomeline, administered transdermally as a Transdermal Therapeutic System (TTS) patch, at a low dose and a high dose.

Dose strengths and batch numbers are properties of the protocol and the investigational product record and are not carried in the analysis datasets, so they are not reported here.

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7 Duration of Treatment

Mean duration of exposure to study drug was 147.8 days in the placebo group, 85.9 days in the xanomeline low dose group and 112.2 days in the xanomeline high dose group.

Exposure differed substantially between the groups, which matters for the reading of the safety results below: crude proportions of patients reporting an event are not exposure-adjusted. The extent of exposure is summarised in 13.3.

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13.3 Extent of Exposure to Study Drugin_text

t-exposure · in_text variant · study CDISCPILOT01 · data cut-off 2014-07-01

Extent of Exposure (Summary)
Study CDISCPILOT01 — Safety Analysis Set
Placebo (N=86) Xanomeline Low Dose (N=96) Xanomeline High Dose (N=72) Total (N=254)
Duration of exposure (days)
   n 86 96 72 254
   Mean (SD) 147.8 (62.13) 85.9 (70.66) 112.2 (65.52) 114.3 (71.17)
   Median 182.0 62.5 96.5 130.5
   Q1, Q3 130.0, 183.0 21.5, 180.5 53.5, 183.0 43.0, 183.0
   Min, Max 0, 210 0, 212 15, 200 0, 212
Total dose administered (mg)
   Mean (SD) 0.0 (0.0) 4638.9 (3815.6) 8341.5 (5182.9) 4117.8 (4893.8)
   Median 0.0 3375.0 7114.5 2025.0
   Min, Max 0, 0 0, 11448 810, 15417 0, 15417
Average daily dose (mg)
   Mean (SD) 0.00 (0.00) 54.00 (0.00) 72.89 (9.68) 41.18 (30.85)
   Median 0.00 54.00 75.90 54.00
Overall dose intensity (%)
   n 0 95 72 167
   Mean (SD) 100.0 (0.00) 135.0 (17.92) 115.1 (20.96)
   Median 100.0 140.6 100.0
Cumulative exposure, n (%)
   ≥ 1 day 85 (98.8%) 95 (99.0%) 72 (100.0%) 252 (99.2%)
   ≥ 30 days 78 (90.7%) 65 (67.7%) 67 (93.1%) 210 (82.7%)
   ≥ 90 days 67 (77.9%) 40 (41.7%) 38 (52.8%) 145 (57.1%)
   ≥ 180 days 55 (64.0%) 25 (26.0%) 26 (36.1%) 106 (41.7%)
Duration, total dose, average daily dose and dose intensity are the overall-study ADEX parameters TDURD, TDOSE, AVDDSE and TDOSINT respectively.
Exposure categories are cumulative: a subject exposed for 200 days is counted in every category up to 180 days.
Q1 and Q3 are type-2 (SAS-compatible) quantiles, as computed by {cards}; they differ from R’s default type-7 quantiles.
Percentages are based on the number of subjects in the safety analysis set for each treatment group.
Placebo subjects have no ADEX dose-intensity (TDOSINT) records because planned placebo dose is zero; the dose-intensity rows are therefore empty for that column.
Source: adex, adsl (pharmaverseadam). Data cut-off: 2014-07-01.
open.csr display t-exposure (in_text variant); generated from the committed ARD.

t-exposure

8 Reference Therapy, Dose and Mode of Administration, Batch Number

Matching placebo patch. Batch numbers are not carried in the analysis datasets.

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9 Criteria for Evaluation

Not populated in this demonstration.

9.1 Efficacy

Not populated in this demonstration.

9.2 Safety

Safety was evaluated from treatment-emergent adverse events, coded to system organ class and preferred term, and summarised by treatment group; from serious adverse events, deaths and adverse events leading to withdrawal; and from the extent of exposure to study drug.

Laboratory values, vital signs and concomitant medications are collected in the source study and are analysed in the reference clinical study report for this dataset, but no analysis results datasets for them exist in this framework yet, so they are not evaluated here.

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10 Statistical Methods

Descriptive statistics only. Continuous measures are summarised as number of patients, mean, standard deviation, median, quartiles, minimum and maximum; categorical measures as counts and percentages of the analysis population. No hypothesis test is performed and no confidence interval is presented, so nothing in this synopsis should be read as a statistical comparison between groups.

Each summary is produced once, as an analysis results dataset, and every rendering of it — the in-text table, the post-text table, and each number quoted in this prose — is read back from that one dataset. The generated provenance appendix records, for each display, which dataset the numbers came from.

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11 Summary — Conclusions

Not populated in this demonstration.

11.1 Efficacy Results

Not populated in this demonstration.

11.2 Safety Results

Treatment-emergent adverse events were reported by {{value:ae-any-n-total}} patients in the safety analysis set overall. In the xanomeline high dose group they were reported by {{value:ae-any-pct-high}}% of the {{value:safety-n-high}} patients treated.

The proportion reporting at least one event rose with dose: {{value:ae-any-n-placebo}} patients receiving placebo compared with {{value:ae-any-n-xanomeline}} across the two xanomeline arms combined — an excess of {{value:ae-excess-high-vs-placebo}} patients in the high dose arm relative to placebo. An overview of treatment-emergent adverse events is given in 13.4; events by system organ class and preferred term, and the listing of deaths, serious adverse events and adverse events leading to withdrawal, accompany this synopsis in Section 13.

The combined and difference figures above are derived values: the store declares them as structural arithmetic over other named values rather than storing an answer, so the assembler re-evaluates them at build time against the committed analysis results datasets. A derived value that no longer reproduces is a build failure, not a footnote.

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13.4 Overview of Treatment-Emergent Adverse Eventsin_text

t-ae-overview · in_text variant · study CDISCPILOT01 · data cut-off 2014-07-01

Overview of Treatment-Emergent Adverse Events (Summary)
Study CDISCPILOT01 — Safety Analysis Set
Placebo (N=86) Xanomeline Low Dose (N=96) Xanomeline High Dose (N=72) Total (N=254)
Adverse events
   Number of events 281 427 414 1122
   Subjects with ≥1 adverse event 65 (75.6%) 84 (87.5%) 68 (94.4%) 217 (85.4%)
   Subjects with a serious adverse event 0 (0.0%) 2 (2.1%) 1 (1.4%) 3 (1.2%)
   Subjects with a fatal adverse event 2 (2.3%) 1 (1.0%) 0 (0.0%) 3 (1.2%)
   Subjects with a related adverse event 43 (50.0%) 77 (80.2%) 64 (88.9%) 184 (72.4%)
Subjects by severity, n (%)
   Mild 58 (67.4%) 64 (66.7%) 64 (88.9%) 186 (73.2%)
   Moderate 25 (29.1%) 58 (60.4%) 46 (63.9%) 129 (50.8%)
   Severe 5 (5.8%) 16 (16.7%) 8 (11.1%) 29 (11.4%)
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 (pharmaverseadam). Data cut-off: 2014-07-01.
open.csr display t-ae-overview (in_text variant); generated from the committed ARD.

t-ae-overview

11.3 Conclusion

No clinical conclusion is drawn. This is a demonstration report built on a teaching dataset, and the only claim it makes is about its own construction: that the numbers in its prose, the numbers in its tables and the numbers in the full clinical study report assembled from the same library are the same numbers, and that this is enforced by the build rather than asserted by a reviewer.

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12 Date of the Report

This synopsis carries no fixed report date. It is regenerated from the library on every build, and the build stamp recorded in the provenance appendix is its date.

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13 Supporting Displays

13.1 Subject Dispositionpost_text

t-disposition · post_text variant · study CDISCPILOT01 · data cut-off 2014-07-01

Subject Disposition
Study CDISCPILOT01 — Intent-to-Treat Analysis Set
Placebo (N=86) Xanomeline Low Dose (N=96) Xanomeline High Dose (N=72) Total (N=254)
Disposition, n (%)
   Subjects randomised 86 (100.0%) 96 (100.0%) 72 (100.0%) 254 (100.0%)
   Subjects treated 86 (100.0%) 96 (100.0%) 72 (100.0%) 254 (100.0%)
   Completed the study 58 (67.4%) 25 (26.0%) 27 (37.5%) 110 (43.3%)
   Discontinued the study 28 (32.6%) 71 (74.0%) 45 (62.5%) 144 (56.7%)
Reason for discontinuation, n (%)
   Death 2 (2.3%) 1 (1.0%) 0 (0.0%) 3 (1.2%)
   Other / not specified 26 (30.2%) 70 (72.9%) 45 (62.5%) 141 (55.5%)
Deaths, n (%)
   Died on study 2 (2.3%) 1 (1.0%) 0 (0.0%) 3 (1.2%)
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 (pharmaverseadam). Data cut-off: 2014-07-01.
open.csr display t-disposition (post_text variant); generated from the committed ARD.

t-disposition

13.2 Demographic and Baseline Characteristicspost_text

t-demographics · post_text variant · study CDISCPILOT01 · data cut-off 2014-07-01

Demographic and Baseline Characteristics
Study CDISCPILOT01 — Safety Analysis Set
Placebo (N=86) Xanomeline Low Dose (N=96) Xanomeline High Dose (N=72) Total (N=254)
Age (years)
   n 86 96 72 254
   Mean (SD) 75.2 (8.59) 76.0 (8.11) 73.8 (7.94) 75.1 (8.25)
   Median 76.0 78.0 75.5 77.0
   Min, Max 52, 89 51, 88 56, 88 51, 89
Age group, n (%)
   18-64 14 (16.3%) 8 (8.3%) 11 (15.3%) 33 (13.0%)
   >64 72 (83.7%) 88 (91.7%) 61 (84.7%) 221 (87.0%)
Sex, n (%)
   F 53 (61.6%) 55 (57.3%) 35 (48.6%) 143 (56.3%)
   M 33 (38.4%) 41 (42.7%) 37 (51.4%) 111 (43.7%)
Race, n (%)
   WHITE 78 (90.7%) 90 (93.8%) 62 (86.1%) 230 (90.6%)
   BLACK OR AFRICAN AMERICAN 8 (9.3%) 6 (6.3%) 9 (12.5%) 23 (9.1%)
   AMERICAN INDIAN OR ALASKA NATIVE 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
Ethnicity, n (%)
   HISPANIC OR LATINO 3 (3.5%) 6 (6.3%) 3 (4.2%) 12 (4.7%)
   NOT HISPANIC OR LATINO 83 (96.5%) 90 (93.8%) 69 (95.8%) 242 (95.3%)
Baseline weight (kg)
   n 86 96 72 254
   Mean (SD) 62.76 (12.77) 67.82 (14.49) 69.55 (14.35) 66.60 (14.12)
   Median 60.56 66.68 68.95 66.46
   Min, Max 34.02, 86.18 41.73, 106.14 44.45, 107.96 34.02, 107.96
Baseline height (cm)
   Mean (SD) 162.6 (11.52) 163.7 (10.30) 165.9 (10.28) 163.9 (10.76)
   Min, Max 137.2, 185.4 135.9, 195.6 146.1, 190.5 135.9, 195.6
Baseline BMI (kg/m2)
   Mean (SD) 23.63 (3.67) 25.22 (4.39) 25.17 (3.97) 24.67 (4.09)
   Min, Max 15.06, 33.25 15.31, 40.17 13.67, 34.57 13.67, 40.17
Percentages are based on the number of subjects in the safety analysis set for each treatment group.
Baseline weight, height and body mass index are the ADVS records flagged ABLFL = 'Y'.
Source: adsl (pharmaverseadam), baseline vital signs from advs. Data cut-off: 2014-07-01.
open.csr display t-demographics (post_text variant); generated from the committed ARD.

t-demographics

13.3 Extent of Exposure to Study Drugpost_text

t-exposure · post_text variant · study CDISCPILOT01 · data cut-off 2014-07-01

Extent of Exposure to Study Drug
Study CDISCPILOT01 — Safety Analysis Set
Placebo (N=86) Xanomeline Low Dose (N=96) Xanomeline High Dose (N=72) Total (N=254)
Duration of exposure (days)
   n 86 96 72 254
   Mean (SD) 147.8 (62.13) 85.9 (70.66) 112.2 (65.52) 114.3 (71.17)
   Median 182.0 62.5 96.5 130.5
   Q1, Q3 130.0, 183.0 21.5, 180.5 53.5, 183.0 43.0, 183.0
   Min, Max 0, 210 0, 212 15, 200 0, 212
Total dose administered (mg)
   Mean (SD) 0.0 (0.0) 4638.9 (3815.6) 8341.5 (5182.9) 4117.8 (4893.8)
   Median 0.0 3375.0 7114.5 2025.0
   Min, Max 0, 0 0, 11448 810, 15417 0, 15417
Average daily dose (mg)
   Mean (SD) 0.00 (0.00) 54.00 (0.00) 72.89 (9.68) 41.18 (30.85)
   Median 0.00 54.00 75.90 54.00
Overall dose intensity (%)
   n 0 95 72 167
   Mean (SD) 100.0 (0.00) 135.0 (17.92) 115.1 (20.96)
   Median 100.0 140.6 100.0
Cumulative exposure, n (%)
   ≥ 1 day 85 (98.8%) 95 (99.0%) 72 (100.0%) 252 (99.2%)
   ≥ 30 days 78 (90.7%) 65 (67.7%) 67 (93.1%) 210 (82.7%)
   ≥ 90 days 67 (77.9%) 40 (41.7%) 38 (52.8%) 145 (57.1%)
   ≥ 180 days 55 (64.0%) 25 (26.0%) 26 (36.1%) 106 (41.7%)
Duration, total dose, average daily dose and dose intensity are the overall-study ADEX parameters TDURD, TDOSE, AVDDSE and TDOSINT respectively.
Exposure categories are cumulative: a subject exposed for 200 days is counted in every category up to 180 days.
Q1 and Q3 are type-2 (SAS-compatible) quantiles, as computed by {cards}; they differ from R’s default type-7 quantiles.
Percentages are based on the number of subjects in the safety analysis set for each treatment group.
Placebo subjects have no ADEX dose-intensity (TDOSINT) records because planned placebo dose is zero; the dose-intensity rows are therefore empty for that column.
Source: adex, adsl (pharmaverseadam). Data cut-off: 2014-07-01.
open.csr display t-exposure (post_text variant); generated from the committed ARD.

t-exposure

13.4 Overview of Treatment-Emergent Adverse Eventspost_text

t-ae-overview · post_text variant · study CDISCPILOT01 · data cut-off 2014-07-01

Overview of Treatment-Emergent Adverse Events
Study CDISCPILOT01 — Safety Analysis Set
Placebo (N=86) Xanomeline Low Dose (N=96) Xanomeline High Dose (N=72) Total (N=254)
Adverse events
   Number of events 281 427 414 1122
   Subjects with ≥1 adverse event 65 (75.6%) 84 (87.5%) 68 (94.4%) 217 (85.4%)
   Subjects with a serious adverse event 0 (0.0%) 2 (2.1%) 1 (1.4%) 3 (1.2%)
   Subjects with a fatal adverse event 2 (2.3%) 1 (1.0%) 0 (0.0%) 3 (1.2%)
   Subjects with a related adverse event 43 (50.0%) 77 (80.2%) 64 (88.9%) 184 (72.4%)
Subjects by severity, n (%)
   Mild 58 (67.4%) 64 (66.7%) 64 (88.9%) 186 (73.2%)
   Moderate 25 (29.1%) 58 (60.4%) 46 (63.9%) 129 (50.8%)
   Severe 5 (5.8%) 16 (16.7%) 8 (11.1%) 29 (11.4%)
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 (pharmaverseadam). Data cut-off: 2014-07-01.
open.csr display t-ae-overview (post_text variant); generated from the committed ARD.

t-ae-overview

13.5 Treatment-Emergent Adverse Events by System Organ Class and Preferred Termpost_text

t-ae-common · post_text variant · study CDISCPILOT01 · data cut-off 2014-07-01

Treatment-Emergent Adverse Events by System Organ Class and Preferred Term
Study CDISCPILOT01 — Safety Analysis Set
Placebo (N=86) Xanomeline Low Dose (N=96) Xanomeline High Dose (N=72) Total (N=254)
GENERAL DISORDERS AND ADMINISTRATION SITE CONDITIONS 21 (24.4%) 51 (53.1%) 36 (50.0%) 108 (42.5%)
   APPLICATION SITE PRURITUS 6 (7.0%) 23 (24.0%) 21 (29.2%) 50 (19.7%)
   APPLICATION SITE ERYTHEMA 3 (3.5%) 13 (13.5%) 14 (19.4%) 30 (11.8%)
   APPLICATION SITE DERMATITIS 5 (5.8%) 9 (9.4%) 7 (9.7%) 21 (8.3%)
   APPLICATION SITE IRRITATION 3 (3.5%) 9 (9.4%) 9 (12.5%) 21 (8.3%)
   APPLICATION SITE VESICLES 1 (1.2%) 5 (5.2%) 5 (6.9%) 11 (4.3%)
   FATIGUE 1 (1.2%) 5 (5.2%) 5 (6.9%) 11 (4.3%)
   OEDEMA PERIPHERAL 2 (2.3%) 1 (1.0%) 2 (2.8%) 5 (2.0%)
   APPLICATION SITE SWELLING 0 (0.0%) 1 (1.0%) 2 (2.8%) 3 (1.2%)
   APPLICATION SITE URTICARIA 0 (0.0%) 2 (2.1%) 1 (1.4%) 3 (1.2%)
   CHILLS 1 (1.2%) 1 (1.0%) 1 (1.4%) 3 (1.2%)
   MALAISE 0 (0.0%) 1 (1.0%) 2 (2.8%) 3 (1.2%)
   PYREXIA 2 (2.3%) 1 (1.0%) 0 (0.0%) 3 (1.2%)
   APPLICATION SITE PAIN 0 (0.0%) 0 (0.0%) 2 (2.8%) 2 (0.8%)
   APPLICATION SITE PERSPIRATION 0 (0.0%) 0 (0.0%) 2 (2.8%) 2 (0.8%)
   APPLICATION SITE REACTION 1 (1.2%) 0 (0.0%) 1 (1.4%) 2 (0.8%)
   ASTHENIA 1 (1.2%) 1 (1.0%) 0 (0.0%) 2 (0.8%)
   CHEST DISCOMFORT 0 (0.0%) 1 (1.0%) 1 (1.4%) 2 (0.8%)
   CHEST PAIN 0 (0.0%) 0 (0.0%) 2 (2.8%) 2 (0.8%)
   OEDEMA 0 (0.0%) 2 (2.1%) 0 (0.0%) 2 (0.8%)
   PAIN 0 (0.0%) 1 (1.0%) 1 (1.4%) 2 (0.8%)
   APPLICATION SITE BLEEDING 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   APPLICATION SITE DESQUAMATION 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   APPLICATION SITE DISCHARGE 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   APPLICATION SITE DISCOLOURATION 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   APPLICATION SITE INDURATION 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   APPLICATION SITE WARMTH 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   FEELING ABNORMAL 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   FEELING COLD 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   INFLAMMATION 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   SECRETION DISCHARGE 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   SUDDEN DEATH 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   SWELLING 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   ULCER 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 20 (23.3%) 39 (40.6%) 39 (54.2%) 98 (38.6%)
   PRURITUS 8 (9.3%) 21 (21.9%) 25 (34.7%) 54 (21.3%)
   ERYTHEMA 8 (9.3%) 14 (14.6%) 14 (19.4%) 36 (14.2%)
   RASH 5 (5.8%) 13 (13.5%) 8 (11.1%) 26 (10.2%)
   HYPERHIDROSIS 2 (2.3%) 4 (4.2%) 8 (11.1%) 14 (5.5%)
   SKIN IRRITATION 3 (3.5%) 6 (6.3%) 5 (6.9%) 14 (5.5%)
   BLISTER 0 (0.0%) 5 (5.2%) 1 (1.4%) 6 (2.4%)
   RASH PRURITIC 0 (0.0%) 1 (1.0%) 2 (2.8%) 3 (1.2%)
   PRURITUS GENERALISED 0 (0.0%) 1 (1.0%) 1 (1.4%) 2 (0.8%)
   URTICARIA 0 (0.0%) 1 (1.0%) 1 (1.4%) 2 (0.8%)
   ACTINIC KERATOSIS 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   ALOPECIA 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   COLD SWEAT 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   DERMATITIS CONTACT 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   DRUG ERUPTION 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   RASH ERYTHEMATOUS 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   RASH MACULO-PAPULAR 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   SKIN EXFOLIATION 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   SKIN ODOUR ABNORMAL 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   SKIN ULCER 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
NERVOUS SYSTEM DISORDERS 8 (9.3%) 22 (22.9%) 23 (31.9%) 53 (20.9%)
   DIZZINESS 2 (2.3%) 9 (9.4%) 10 (13.9%) 21 (8.3%)
   HEADACHE 3 (3.5%) 3 (3.1%) 5 (6.9%) 11 (4.3%)
   SYNCOPE 0 (0.0%) 5 (5.2%) 2 (2.8%) 7 (2.8%)
   SOMNOLENCE 2 (2.3%) 3 (3.1%) 1 (1.4%) 6 (2.4%)
   TRANSIENT ISCHAEMIC ATTACK 0 (0.0%) 2 (2.1%) 1 (1.4%) 3 (1.2%)
   BURNING SENSATION 0 (0.0%) 0 (0.0%) 2 (2.8%) 2 (0.8%)
   LETHARGY 0 (0.0%) 1 (1.0%) 1 (1.4%) 2 (0.8%)
   AMNESIA 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   BALANCE DISORDER 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   COGNITIVE DISORDER 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   COMPLEX PARTIAL SEIZURES 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   COORDINATION ABNORMAL 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   HEMIANOPIA HOMONYMOUS 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   HYPERSOMNIA 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   PARAESTHESIA 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   PARAESTHESIA ORAL 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   PARKINSON'S DISEASE 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   PAROSMIA 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   PARTIAL SEIZURES WITH SECONDARY GENERALISATION 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   PSYCHOMOTOR HYPERACTIVITY 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   STUPOR 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   SYNCOPE VASOVAGAL 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
GASTROINTESTINAL DISORDERS 17 (19.8%) 15 (15.6%) 19 (26.4%) 51 (20.1%)
   DIARRHOEA 9 (10.5%) 5 (5.2%) 3 (4.2%) 17 (6.7%)
   VOMITING 3 (3.5%) 4 (4.2%) 6 (8.3%) 13 (5.1%)
   NAUSEA 3 (3.5%) 3 (3.1%) 6 (8.3%) 12 (4.7%)
   ABDOMINAL PAIN 1 (1.2%) 3 (3.1%) 1 (1.4%) 5 (2.0%)
   SALIVARY HYPERSECRETION 0 (0.0%) 0 (0.0%) 4 (5.6%) 4 (1.6%)
   DYSPEPSIA 1 (1.2%) 1 (1.0%) 0 (0.0%) 2 (0.8%)
   ABDOMINAL DISCOMFORT 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   CONSTIPATION 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   DYSPHAGIA 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   FLATULENCE 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   GASTROINTESTINAL HAEMORRHAGE 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   GASTROOESOPHAGEAL REFLUX DISEASE 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   GLOSSITIS 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   HIATUS HERNIA 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   RECTAL HAEMORRHAGE 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   STOMACH DISCOMFORT 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
CARDIAC DISORDERS 12 (14.0%) 14 (14.6%) 14 (19.4%) 40 (15.7%)
   SINUS BRADYCARDIA 2 (2.3%) 7 (7.3%) 8 (11.1%) 17 (6.7%)
   MYOCARDIAL INFARCTION 4 (4.7%) 2 (2.1%) 4 (5.6%) 10 (3.9%)
   ATRIAL FIBRILLATION 1 (1.2%) 2 (2.1%) 2 (2.8%) 5 (2.0%)
   SUPRAVENTRICULAR EXTRASYSTOLES 1 (1.2%) 1 (1.0%) 1 (1.4%) 3 (1.2%)
   VENTRICULAR EXTRASYSTOLES 0 (0.0%) 2 (2.1%) 1 (1.4%) 3 (1.2%)
   ATRIAL FLUTTER 0 (0.0%) 1 (1.0%) 1 (1.4%) 2 (0.8%)
   ATRIOVENTRICULAR BLOCK FIRST DEGREE 1 (1.2%) 1 (1.0%) 0 (0.0%) 2 (0.8%)
   BUNDLE BRANCH BLOCK RIGHT 1 (1.2%) 1 (1.0%) 0 (0.0%) 2 (0.8%)
   PALPITATIONS 0 (0.0%) 2 (2.1%) 0 (0.0%) 2 (0.8%)
   ATRIAL HYPERTROPHY 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   ATRIOVENTRICULAR BLOCK SECOND DEGREE 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   BRADYCARDIA 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   BUNDLE BRANCH BLOCK LEFT 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   CARDIAC DISORDER 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   CARDIAC FAILURE CONGESTIVE 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   SINUS ARRHYTHMIA 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   SUPRAVENTRICULAR TACHYCARDIA 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   TACHYCARDIA 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   VENTRICULAR HYPERTROPHY 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   WOLFF-PARKINSON-WHITE SYNDROME 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
INFECTIONS AND INFESTATIONS 16 (18.6%) 9 (9.4%) 13 (18.1%) 38 (15.0%)
   NASOPHARYNGITIS 2 (2.3%) 4 (4.2%) 6 (8.3%) 12 (4.7%)
   UPPER RESPIRATORY TRACT INFECTION 6 (7.0%) 1 (1.0%) 3 (4.2%) 10 (3.9%)
   INFLUENZA 1 (1.2%) 1 (1.0%) 1 (1.4%) 3 (1.2%)
   URINARY TRACT INFECTION 2 (2.3%) 0 (0.0%) 1 (1.4%) 3 (1.2%)
   CYSTITIS 1 (1.2%) 0 (0.0%) 1 (1.4%) 2 (0.8%)
   EAR INFECTION 2 (2.3%) 0 (0.0%) 0 (0.0%) 2 (0.8%)
   BRONCHITIS 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   CELLULITIS 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   CERVICITIS 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   GASTROENTERITIS VIRAL 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   HORDEOLUM 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   LOCALISED INFECTION 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   LOWER RESPIRATORY TRACT INFECTION 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   PNEUMONIA 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   RHINITIS 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   VAGINAL MYCOSIS 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   VIRAL INFECTION 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
PSYCHIATRIC DISORDERS 10 (11.6%) 11 (11.5%) 7 (9.7%) 28 (11.0%)
   CONFUSIONAL STATE 2 (2.3%) 3 (3.1%) 1 (1.4%) 6 (2.4%)
   AGITATION 2 (2.3%) 3 (3.1%) 0 (0.0%) 5 (2.0%)
   INSOMNIA 2 (2.3%) 0 (0.0%) 2 (2.8%) 4 (1.6%)
   ANXIETY 0 (0.0%) 3 (3.1%) 0 (0.0%) 3 (1.2%)
   DELUSION 1 (1.2%) 0 (0.0%) 1 (1.4%) 2 (0.8%)
   IRRITABILITY 1 (1.2%) 1 (1.0%) 0 (0.0%) 2 (0.8%)
   COMPLETED SUICIDE 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   DELIRIUM 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   DEPRESSED MOOD 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   DISORIENTATION 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   HALLUCINATION 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   HALLUCINATION, VISUAL 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   LIBIDO DECREASED 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   LISTLESS 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   NIGHTMARE 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   RESTLESSNESS 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
RESPIRATORY, THORACIC AND MEDIASTINAL DISORDERS 8 (9.3%) 9 (9.4%) 10 (13.9%) 27 (10.6%)
   COUGH 1 (1.2%) 5 (5.2%) 5 (6.9%) 11 (4.3%)
   NASAL CONGESTION 3 (3.5%) 1 (1.0%) 3 (4.2%) 7 (2.8%)
   DYSPNOEA 1 (1.2%) 1 (1.0%) 1 (1.4%) 3 (1.2%)
   EPISTAXIS 0 (0.0%) 1 (1.0%) 2 (2.8%) 3 (1.2%)
   PHARYNGOLARYNGEAL PAIN 0 (0.0%) 1 (1.0%) 1 (1.4%) 2 (0.8%)
   RHINORRHOEA 0 (0.0%) 1 (1.0%) 1 (1.4%) 2 (0.8%)
   ALLERGIC GRANULOMATOUS ANGIITIS 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   DYSPHONIA 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   EMPHYSEMA 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   HAEMOPTYSIS 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   PHARYNGEAL ERYTHEMA 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   POSTNASAL DRIP 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   PRODUCTIVE COUGH 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   RALES 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   RESPIRATORY TRACT CONGESTION 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
INVESTIGATIONS 10 (11.6%) 7 (7.3%) 5 (6.9%) 22 (8.7%)
   ELECTROCARDIOGRAM ST SEGMENT DEPRESSION 4 (4.7%) 1 (1.0%) 0 (0.0%) 5 (2.0%)
   ELECTROCARDIOGRAM T WAVE INVERSION 2 (2.3%) 1 (1.0%) 1 (1.4%) 4 (1.6%)
   BLOOD GLUCOSE INCREASED 0 (0.0%) 1 (1.0%) 1 (1.4%) 2 (0.8%)
   ELECTROCARDIOGRAM T WAVE AMPLITUDE DECREASED 1 (1.2%) 1 (1.0%) 0 (0.0%) 2 (0.8%)
   BIOPSY 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   BIOPSY PROSTATE 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   BLOOD ALKALINE PHOSPHATASE INCREASED 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   BLOOD CHOLESTEROL INCREASED 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   BLOOD CREATINE PHOSPHOKINASE INCREASED 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   BLOOD URINE PRESENT 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   BODY TEMPERATURE INCREASED 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   CYSTOSCOPY 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   HEART RATE INCREASED 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   HEART RATE IRREGULAR 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   NASAL MUCOSA BIOPSY 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   WEIGHT DECREASED 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
MUSCULOSKELETAL AND CONNECTIVE TISSUE DISORDERS 4 (4.7%) 7 (7.3%) 7 (9.7%) 18 (7.1%)
   BACK PAIN 1 (1.2%) 1 (1.0%) 3 (4.2%) 5 (2.0%)
   ARTHRALGIA 1 (1.2%) 2 (2.1%) 1 (1.4%) 4 (1.6%)
   SHOULDER PAIN 1 (1.2%) 2 (2.1%) 0 (0.0%) 3 (1.2%)
   MUSCLE SPASMS 0 (0.0%) 1 (1.0%) 1 (1.4%) 2 (0.8%)
   ARTHRITIS 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   FLANK PAIN 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   MUSCULAR WEAKNESS 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   MYALGIA 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   PAIN IN EXTREMITY 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
INJURY, POISONING AND PROCEDURAL COMPLICATIONS 4 (4.7%) 5 (5.2%) 5 (6.9%) 14 (5.5%)
   CONTUSION 1 (1.2%) 1 (1.0%) 2 (2.8%) 4 (1.6%)
   EXCORIATION 2 (2.3%) 1 (1.0%) 1 (1.4%) 4 (1.6%)
   FALL 1 (1.2%) 2 (2.1%) 1 (1.4%) 4 (1.6%)
   HIP FRACTURE 1 (1.2%) 0 (0.0%) 2 (2.8%) 3 (1.2%)
   SKIN LACERATION 1 (1.2%) 2 (2.1%) 0 (0.0%) 3 (1.2%)
   FACIAL BONES FRACTURE 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   JOINT DISLOCATION 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   WOUND 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
RENAL AND URINARY DISORDERS 4 (4.7%) 3 (3.1%) 3 (4.2%) 10 (3.9%)
   MICTURITION URGENCY 1 (1.2%) 1 (1.0%) 1 (1.4%) 3 (1.2%)
   DYSURIA 1 (1.2%) 1 (1.0%) 0 (0.0%) 2 (0.8%)
   NEPHROLITHIASIS 1 (1.2%) 0 (0.0%) 1 (1.4%) 2 (0.8%)
   CALCULUS URETHRAL 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   INCONTINENCE 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   POLLAKIURIA 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
METABOLISM AND NUTRITION DISORDERS 6 (7.0%) 1 (1.0%) 2 (2.8%) 9 (3.5%)
   DECREASED APPETITE 1 (1.2%) 0 (0.0%) 1 (1.4%) 2 (0.8%)
   FOOD CRAVING 1 (1.2%) 1 (1.0%) 0 (0.0%) 2 (0.8%)
   INCREASED APPETITE 1 (1.2%) 0 (0.0%) 1 (1.4%) 2 (0.8%)
   DEHYDRATION 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   DIABETES MELLITUS 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   HYPONATRAEMIA 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
VASCULAR DISORDERS 3 (3.5%) 3 (3.1%) 1 (1.4%) 7 (2.8%)
   HYPOTENSION 2 (2.3%) 1 (1.0%) 0 (0.0%) 3 (1.2%)
   HYPERTENSION 1 (1.2%) 1 (1.0%) 0 (0.0%) 2 (0.8%)
   HOT FLUSH 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   ORTHOSTATIC HYPOTENSION 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   WOUND HAEMORRHAGE 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
EYE DISORDERS 2 (2.3%) 2 (2.1%) 1 (1.4%) 5 (2.0%)
   VISION BLURRED 0 (0.0%) 1 (1.0%) 1 (1.4%) 2 (0.8%)
   CONJUNCTIVAL HAEMORRHAGE 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   CONJUNCTIVITIS 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   EYE ALLERGY 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   EYE PRURITUS 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   EYE SWELLING 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
SURGICAL AND MEDICAL PROCEDURES 2 (2.3%) 1 (1.0%) 2 (2.8%) 5 (2.0%)
   CATARACT OPERATION 1 (1.2%) 1 (1.0%) 0 (0.0%) 2 (0.8%)
   ACROCHORDON EXCISION 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   EYE LASER SURGERY 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   SKIN LESION EXCISION 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
EAR AND LABYRINTH DISORDERS 1 (1.2%) 2 (2.1%) 1 (1.4%) 4 (1.6%)
   VERTIGO 0 (0.0%) 1 (1.0%) 1 (1.4%) 2 (0.8%)
   CERUMEN IMPACTION 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   EAR PAIN 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
CONGENITAL, FAMILIAL AND GENETIC DISORDERS 0 (0.0%) 1 (1.0%) 2 (2.8%) 3 (1.2%)
   VENTRICULAR SEPTAL DEFECT 0 (0.0%) 1 (1.0%) 2 (2.8%) 3 (1.2%)
NEOPLASMS BENIGN, MALIGNANT AND UNSPECIFIED (INCL CYSTS AND POLYPS) 0 (0.0%) 2 (2.1%) 1 (1.4%) 3 (1.2%)
   COLON CANCER 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   MALIGNANT FIBROUS HISTIOCYTOMA 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   PROSTATE CANCER 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
REPRODUCTIVE SYSTEM AND BREAST DISORDERS 2 (2.3%) 0 (0.0%) 1 (1.4%) 3 (1.2%)
   BENIGN PROSTATIC HYPERPLASIA 1 (1.2%) 0 (0.0%) 1 (1.4%) 2 (0.8%)
   PELVIC PAIN 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
HEPATOBILIARY DISORDERS 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
   HYPERBILIRUBINAEMIA 1 (1.2%) 0 (0.0%) 0 (0.0%) 1 (0.4%)
IMMUNE SYSTEM DISORDERS 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
   HYPERSENSITIVITY 0 (0.0%) 1 (1.0%) 0 (0.0%) 1 (0.4%)
SOCIAL CIRCUMSTANCES 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
   ALCOHOL USE 0 (0.0%) 0 (0.0%) 1 (1.4%) 1 (0.4%)
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 (pharmaverseadam). Data cut-off: 2014-07-01.
open.csr display t-ae-common (post_text variant); generated from the committed ARD.

t-ae-common

13.6 Listing of Serious Adverse Eventspost_text

l-ae-serious · post_text variant · study CDISCPILOT01 · data cut-off 2014-07-01

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 01-709-1424 Xanomeline Low Dose 77 M NERVOUS SYSTEM DISORDERS SYNCOPE MODERATE POSSIBLE 5 5 RECOVERED/RESOLVED
2 01-718-1170 Xanomeline Low Dose 80 F NERVOUS SYSTEM DISORDERS SYNCOPE SEVERE PROBABLE 27 28 RECOVERED/RESOLVED
3 01-718-1371 Xanomeline High Dose 69 F NERVOUS SYSTEM DISORDERS PARTIAL SEIZURES WITH SECONDARY GENERALISATION SEVERE NONE 38 41 RECOVERED/RESOLVED
One row per serious adverse event record (AESER = 'Y').
Study day is relative to the first dose of study drug.
Source: adae (pharmaverseadam). Data cut-off: 2014-07-01.
open.csr display l-ae-serious (post_text variant); generated from the committed ARD.

l-ae-serious

14 Provenance of the Assembled Synopsis

ItemValue
displays[0].slugt-disposition
displays[0].number13.1
displays[0].titleSubject Disposition
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