Data Analysis Plan for SFDR2002:
Safety and Efficacy of Inerdiel versus Actiniel and Placebo

Title: A Randomized, Double-Blind, Active and Placebo-Controlled, Parallel-Groups 12-Week Trial Evaluating the Safety and Efficacy of Inerdiel 50mcg BID versus Actiniel 100mcg  and Placebo in Adult Subjects with moderate mentarthric impairment.


1.                               Preface AND BACKGROUND

This document describes in detail the statistical methods that will be used to summarize and analyze the background, efficacy, and safety data from SFDR2002.  All decisions regarding analysis, defined in this document, have been made prior to any review of the study data. 


Mentarthric impairment is a condition that affects a small percentage of people.  It occurs when rheumatoid arthritis, coupled with shizophrenia-like tendencies, combine to produce the illusion of bloating and abdominal discomfort.   Actiniel, a psychoactive substance, is the only treatment so far that has been approved for mentarthria; it works by relieving perceived abdominal discomfort.  The sponsors wish to seek approval for Inerdiel, another psychoactive substance, which relieves symptoms through relief of both arthritis and schizophrenia, thereby relieving the perceived abdominal discomfort as a by-product.

2.                               Study Objective(S) and Endpoint(S)

The objective of this trial is to demonstrate superior efficacy and comparable safety of Inerdiel compared Actiniel in subjects with moderate mentarthic impairment. 


The primary endpoints chosen to show the efficacy of the products are

·        Patient-reported symptoms at each weekly visit, ending with week 12.  A single measure on a 1,2,3,4,5 Likert scale response will be obtained at each visit.

·        Acting physician-reported evaluation of signs and symptoms at each weekly visit, ending with week 12, assessed blindly from the patient reports.


Secondary endpoints are

·        Change from baseline in each of the 36 measurements used in the SF-36 quality of life questionnaire.

·        Survival in study (measuring patient drop-out rate)


Safety measures will include adverse events, clinical laboratory results, 12-lead ECGs, and vital signs.


3.                               Study Design

This is a randomized, double-blind, placebo and active-controlled parallel-group trial.  The study will be conducted on an outpatient basis.


Qualified subjects will be randomly assigned to one of three treatment groups for 12 weeks of treatment.  The three possible treatment groups are:

i.         Inerdiel 50mcg BID

ii.       Actiniel 100mcg  BID

iii.      Vehicle Placebo

Double-blind treatment (Visit 2, Treatment Day 1) will be started 14 ± 2 days after Visit 1 and continue for 12 weeks.  Subjects will return to the clinic at 1-week intervals for 4 weeks followed by visits at 2-week intervals, for a total of 10 visits (for a total of 84 (±2) days of study treatment).


4.                               Sequence of Planned Analyses

All analyses outlined in this document will be carried out once the study database has been authorized by Data Management staff, Clinical Statistics personnel have had an opportunity to inspect and approve the authorized database, and the treatment details have been attached to the subject data.  Protocol deviations will be identified before the treatment details are attached to the subject data.


As the study database is being authorized, Clinical Statistics personnel will create a SAS dataset of treatment details (subject number, treatment number and treatment description).  This database, once validated, will become part of the reporting database for this study.  Treatment numbers (variable TMT) will serve as the link between a subject’s treatment details and study data.


5.                               Sample size considerations

Sample size calculations assume a significance level of 0.05 and are based on two-sided t-tests.  The primary treatment comparison is the Inerdiel versus Placebo comparison.

Analysis of data from previous studies indicates that 100 patients per treatment group should provide more than 90% power to detect an average difference of .5 on the Likert scale, so 300 subjects will be randomized to the three groups, 100 subjects per group.


The power calculation described above does not consider multiple comparisons.


6.                               Analysis population

The population analyzed will be the intent-to-treat population consist of all randomized patients.  Analyses based on the Intent-to-Treat population will include all available data for these patients.  This population will form the basis for all safety, background, and demographic summarizes, as well as for the analysis of all efficacy measures and of health outcomes data.


7.                               Interim analyses

No interim analyses are planned for this study.


8.                               General considerations for data analyses

Two-sided statistical tests will be used throughout the analyses; p-values of a=0.05 or less will be considered to be statistically significant unless specified otherwise.  Symbols will be used to indicate significant model effects.  In general, actual values will be analyzed at baseline, and change from baseline will be analyzed at all on-treatment time points.

·        Data review

Prior to the authorization of the study database by Clinical Data Management personnel the data will be reviewed and any discrepancies or unclear data will be queried with the investigational sites using Data Clarification Forms (DCFs).

·        Covariates

All statistical tests of efficacy measures, demographic/background characteristics, and cardiovascular safety measures (QTc intervals, heart rate, and Holter monitoring results) will be adjusted for investigator cluster.  Investigator clusters will involve the combining of investigators from geographically similar regions.  This combining will be necessary when the number of patients recruited by individual investigators is small.


Parametric analyses will be based on models that include terms for treatment and cluster; nonparametric analyses will be stratified by investigator cluster.  In addition, analysis of covariance (ANCOVA) models assessing weekly results will include baseline value as a covariate and terms for treatment and investigator cluster.

·        Examination of subgroups

Subgroup analysis will be included in this study using age, ethnic, genotype and gender subgroups will be included for all endpoints. 

·        Premature discontinuation and missing data

For any subject who withdraws from the study prematurely, all available data up to the time of discontinuation will be included in the Intent-to-Treat analysis.

·        Multicenter study

Because of the large number of investigators participating in this study, and the possibility of small numbers of patients randomized at some investigational sites, groups or clusters of investigators will be used for statistical analyses instead of individual investigators.  Treatment-by-cluster interaction terms will be assessed for statistical significance. 

Potential treatment interactions with cluster will be assessed individually in separate models.

·        Multiple comparisons

The three treatment comparisons of primary interest are the Inerdiel 50mcg BID versus Actiniel 100mcg BID, the Inerdiel 50mcg BID vs placebo, and the Actiniel 100mcg BID versus placebo.   No adjustments for multiple comparisons will be considered. 


·        Assessment windows

As described in the protocol, a window of +2 days exists for each scheduled Visit.  Any data collected outside of a defined assessment window, or multiple measurements collected within the same assessment window will be defined as protocol violations.  For data collected outside the assessment window, the data will be used in the ITT analysis.  For multiple assessments, the last valid value will be used.


9.                               Study Population

9.1.                         Subject Accountability

The number of patients randomized, both overall and by investigator, will be summarized by treatment group.  The number of patients who complete the 12-week treatment period, as well as the number who withdraw early from the study and the specific reasons for withdrawal, will be summarized by treatment group.  Reasons for withdrawal due to worsening mentarthria will also be summarized by treatment group.


Summaries by treatment group will also be produced for screening failures (demography, reason for failure) and for run-in drop-outs (demography, AEs, reasons for withdrawal before randomization).


A summary table and a listing for individual patients will describe the protocol deviations for the clinical report.  Deviations will also be categorized as related to inclusion criteria, exclusion criteria, continuation criteria, or other sources.

9.2.                         Treatment Compliance

Compliance will be calculated as the total estimated number of doses used over the known time interval (based on treatment start and stop dates and clinic visit and diary dates) divided by the total expected use during that time period, multiplied by 100.



9.3.                         Other Descriptions of Study Population

The number of patients will be summarized by investigator and treatment group.  Patient demographic characteristics will be summarized by treatment group using summary statistics appropriate to the nature of the data.  Means, standard deviations, minima, medians, and maxima will be used to summarize age, height, and weight; frequency distributions will be used for gender, ethnic origin, age group, and child-bearing potential.


Inferential analyses of demographic characteristics (e.g., analysis of variance F-tests for age, height, and weight, and Cochran-Mantel-Haenszel tests for gender, age category, ethnic origin, tobacco use, child-bearing potential, and methods of contraception) will be used to assess the comparability of the treatment groups.  These tests will correct for investigator cluster.


10.                         Efficacy Analyses

In all analyses described below, the null hypothesis being tested is that of no treatment difference.  Alternative hypotheses assert the superiority over placebo in the cases of placebo comparisons, or superiority of Inerdiel over Actiniel in the case of the active comparison.   All statistical tests use a two-sided significance level of a=0.05 unless indicated otherwise.


·        Treatment comparisons

Statistical analyses data at each endpoint will be based on a change in response scores from baseline.  Treatment groups will be compared using an ANCOVA model with baseline response as the covariate and terms for treatment and investigator cluster.

·        Clinically meaningful differences between treatment groups

A difference of 0.5 or more between treatment groups at endpoint in the mean change from baseline will be considered to be a clinically meaningful difference.

·        Within-treatment group changes

In addition, changes from baseline at endpoint (either Treatment Week 12 or  Discontinuation Visit) will be assessed within each treatment group for each domain using t-tests.  Within-treatment changes from baseline will be examined for descriptive purposes in order to gauge the magnitude of absolute change for each treatment group.  For this study, a within-treatment change from baseline will be considered to be clinically meaningful if it is both statistically significant and is 0.5 or greater.

11.                         Safety analyses


11.1.                    Extent of Exposure

The extent of exposure, calculated as the number of days between start of treatment and end of treatment (i.e., treatment stop date minus treatment start date + 1), will be summarized by treatment group.


11.2.                    Adverse Events

Adverse events (AEs) will be summarized and grouped by body system and by AE within body system.  Results will be displayed in order of decreasing frequency, both across body systems and within each body system.  Drug-related AEs, serious AEs, most commonly occurring (defined as an incidence of >3% in any treatment group) AEs, and those AEs leading to withdrawal, will be summarized in a similar manner.  The incidences of the most commonly occurring AEs will be compared across treatment groups using two-sided Fisher’s exact tests. A by-patient listing of all AEs will also be provided.

11.3.                    Deaths, Serious Adverse Events and Other Significant Adverse Events

These will be investigated thoroughly and presented by patient and in summary form.  One-sided Fisher's exact tests will be used to compare incidences.


11.4.                    Other Safety Measures

For example, drug‑drug interactions.

Vital signs, ECG results, heart rate and cardiac abnormalities, and physical examination findings at the end of the study will be summarized by treatment group and by visit where appropriate.


ECG results will include summaries of heart rate, QT intervals, and an assessment by an independent cardiologist of clinically significant abnormalities.  The change from baseline in QTcs and heart rate and the actual values at screening and at baseline will be compared across treatment groups using ANOVA F-tests based on models which include terms for treatment and investigator cluster. 


12.                         Planned Analyses of Genotyping Data

If genotyping is included in this study, include a description of the planned analyses.

Genotyping data using 20 pre-defined single nucleotype polymorphisms (SNPs) will be obtained for each patient.  Subgroup analyses to detect significant treatment effects and significant interactions will be performed for various genotype subgroups, using ANOVA methods.