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`CENTER FOR DRUG EVALUATION AND
`RESEARCH
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`APPLICATION NUMBER:
`202107Orig1s000
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`STATISTICAL REVIEW(S)
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`U.S. Department of Health and Human Services
`Food and Drug Administration
`Center for Drug Evaluation and Research
`Office of Translational Sciences
`Office of Biostatistics
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`S TAT I S T I C A L R E V I E W A N D E VA L U AT I O N
`CLINICAL STUDIES
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`NDA/BLA Serial Number: 202107
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`Drug Name: Corlux® (mifepristone)
`Indication(s): To reduce the effects of hypercortisolism in patients with endogenous
`Cushing’s syndrome
`Applicant: Corcept Therapeutics
`Date(s): 04/25/2011
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`Review Priority: Standard
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`Biometrics Division: 2
`Statistical Reviewer: Japobrata Choudhury, Ph.D.
`Concurring Reviewers: Todd Sahlroot, Ph.D.
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`Medical Division: Metabolic and Endocrine Products
`Clinical Team: Marina Zemskova, M.D., Dragos Roman, M.D., Mary Parks, M.D.
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`Project Manager: Jena Weber
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`Keywords:
`Link to DBII key Words: Clinical Studies, NDA Review
`http://intranetapps.fda.gov/scripts/ob_apps/ob/eWork/uploads/eWork/2009/Keywords-in-DFS.htm
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`Reference ID: 3073844
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`Table of Contents
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`1. EXECUTIVE SUMMARY ...............................................................................................................................3
`2.1
`OVERVIEW....................................................................................................................................................5
`2.2
`DATA SOURCES ............................................................................................................................................8
`3. STATISTICAL EVALUATION.......................................................................................................................8
`3.1
`DATA AND ANALYSIS QUALITY....................................................................................................................8
`3.2
`EVALUATION OF EFFICACY...........................................................................................................................8
`3.3 EVALUATION OF SAFETY ..................................................................................................................................33
`4.
` FINDINGS IN SPECIAL/SUBGROUP POPULATIONS ..........................................................................34
`4.1
`GENDER, RACE, AGE, AND GEOGRAPHIC REGION ......................................................................................34
`4.2
`OTHER SPECIAL/SUBGROUP POPULATIONS.................................................................................................36
`5. SUMMARY AND CONCLUSIONS ..............................................................................................................36
`5.1
`STATISTICAL ISSUES AND COLLECTIVE EVIDENCE .....................................................................................36
`5.2
`CONCLUSIONS AND RECOMMENDATIONS ...................................................................................................37
`APPENDICES (ADD WHEN NEEDED) ..............................................................................................................39
`CHECK LIST...........................................................................................................................................................43
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`Reference ID: 3073844
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`EXECUTIVE SUMMARY
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`1.
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`The objective of this study was to examine the safety and efficacy of mifepristone for treatment
`of the signs and symptoms of hypercortisolemia in subjects with endogenous Cushing's
`syndrome from ACTH-dependent or ACTH-independent disorders.
`
`This was a 24-week, open-label study of the administration of mifepristone to subjects with
`Cushing's syndrome. The sponsor states, “An open-label design was chosen for this study
`because of the lack of an approved comparator drug that was available commercially.”
`Following a screening period of up to 6 weeks, 50 subjects were assigned to receive 300 mg
`mifepristone once daily (QD). Because the optimal dose of mifepristone for each subject was
`not known, dose escalation was undertaken cautiously with careful observation of clinical
`status. Dose escalations beyond 300 mg were made under some conditions.
`
`Subjects belonged to one of two study cohorts. The C-DM cohort (n=29) consisted of subjects
`with Cushing's syndrome and diabetes or impaired glucose tolerance. The C-HT cohort (n=21)
`consisted of subjects with Cushing's syndrome and a diagnosis of hypertension only (without
`diabetes or impaired glucose tolerance). Each cohort had a separate primary efficacy endpoint.
`
`The primary endpoint for subjects in C-DM was evaluation of response based on the change in
`AUC for glucose (AUCglucose) from baseline to Week 24/ET for the 2-hour oGTT in the mITT
`population. A responder was a subject who had at least a 25% decrease in AUC from baseline.
`A response in AUCglucose was observed in 60% of the subjects (1-sided 95% CI lower bound,
`42%). The sponsor considered this result to be statistically significant because the lower bound
`of the 95% CI was greater than 20%, the pre-specified margin of clinical significance. I also
`computed a 2-sided 95% confidence interval for the response rate. The lower bound of the 2-
`sided 95% confidence interval was 40.4%. The mean change from baseline in AUC was -8722
`(2-sided 95% CI = (-13184, -4260), p=.0009) from a baseline mean of 30670.
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`HbA1c was not the primary endpoint in C-DM (it was a secondary endpoint) but nevertheless is
`an important clinical measure of diabetic control. The mean change from baseline in HbA1c
`was -1.11 (2-sided 95% CI = (-1.56, -0.65), p=.0001) from a baseline mean of 7.36. While it
`can be difficult to assess changes from baseline in AUCglucose and HbA1c in the absence of a
`control group, the observed changes were of sufficient magnitude so that they could be
`attributed to the action of the drug since hyperglycemia would be expected to persist without
`treatment and in the absence of significant fluctuations in cortisol and ACTH levels.
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`Reference ID: 3073844
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`Nevertheless, clinical judgment should be given priority in this open-label study with titration
`and meager data.
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`The primary efficacy variable for subjects in C-HT was evaluation of response based on the
`change in diastolic blood pressure from baseline to Week 24. A responder was a subject who
`had at least a 5 mmHg reduction in dBP from baseline. A response for diastolic blood pressure
`was observed in 38% of the subjects (1-sided 95% CI lower bound, 21%). The sponsor
`considered this result to be statistically significant because the lower bound of the 95% CI was
`greater than 20%, the pre-specified margin of clinical significance. I also computed a 2-sided
`95% confidence interval for the response rate. The lower bound of the 2-sided 95% confidence
`interval was 16.8% which fell below the margin.
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`The mean change from baseline in dBP (mmHg) was -0.1 (2-sided 95% CI = (-4.6, 4.6), p=.98)
`from a baseline mean of 82.9. Therefore, across the two dBP endpoints, there was no statistical
`evidence of diastolic blood pressure lowering in the C-HT cohort.
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`Labeling
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`Though no statistical significance was claimed for the secondary efficacy variables, there is one danger
`that non-statisticians may not be fully alert that these descriptive statistics do not mean much. They are
`just numerical results based on one sample; there is no assurance or confidence regarding the population
`or the reality.
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`The definition of a Responder in the key secondary efficacy variable: “A responder was defined
`as a subject whose median reviewer score was + 1 at any reviewed visit after baseline through
`Week 24/ET” with the phrase “at any reviewed visit,” gives multiple opportunities for a success
`and is not as dependable as a response at any one time-point. Therefore, the results of this key
`variable, if are allowed to be in the labeling at all, this point should be emphasized.
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`2.
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`INTRODUCTION
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`Reference ID: 3073844
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`2.1 Overview
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`
`Note: Tables and Figures presented in this document are referenced by “below” or “above”.
`Those referenced with an extended numbering system are in the NDA Study Report. Unless
`mentioned otherwise, the source of all information is the sponsor’s submission. The reviewer’s
`interpretations, comments, or conclusions are clearly identified under notes, comments, or
`separate sections.
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`Objectives: The primary objective of the study was to evaluate the safety and efficacy of
`mifepristone in the treatment of the signs and symptoms of endogenous Cushing's syndrome.
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`Methodology: This was a 24-week, open-label study of the administration of mifepristone to
`subjects with Cushing's syndrome. Following a screening period of up to 6 weeks, 50 subjects
`were assigned to receive 300 mg mifepristone once daily (QD). Because the optimal dose of
`mifepristone for each subject was not known, dose escalation was undertaken cautiously with
`careful observation of key signs and symptoms of Cushing's syndrome. Dose escalations
`beyond 300 mg were made under the following conditions:
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`If no clinical improvement had been seen,
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`If the drug had been well tolerated, and
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`Based on the subject's weight at the escalation visit.
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`After 14 days of dosing at 300 mg QD, the dose of mifepristone could have been increased as
`outlined below:
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`Reference ID: 3073844
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`All doses were given as a single daily dose.
`a Dose escalation stopped at Week 6 for subjects weighing <60 kg.
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`Dose escalation was not required if significant clinical improvement was noted at the current
`dosing level. In cases of severe hypercortisolism the dose of mifepristone could have been
`increased beyond 1200 mg QD (or 900 mg QD for subjects weighing -: 60 kg) with the
`approval of the medical monitor (note: there was no such occurrence in this study). However,
`the dose was not to be increased beyond a weight-adjusted dose of 20 mg/kg per day. Subjects
`who completed this study (CI073-400) were given the opportunity to continue receiving
`mifepristone by entering an extension study under a separate protocol (Study C1073-415).
`Number of Subjects (Planned and Analyzed): 50 subjects were planed; 50 subjects were
`analyzed for safety; 46 subjects were analyzed for efficacy in the modified intent-to-treat
`(mITT) population. There were 29 subjects in the cohort of subjects with diabetes mellitus
`and/or impaired glucose tolerance (C-DM) and 21 subjects in the cohort of subjects with
`hypertension (C-HT).
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`Diagnosis and Main Criteria for Inclusion: Male or female subjects who were >=18 years old
`with endogenous Cushing's syndrome and had Type 2 diabetes (or impaired glucose function)
`OR hypertension were eligible to participate in this study.
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`Test Product, Dose and Mode of Administration, Lot Number: 300 mg mifepristone tablets
`administered orally once daily; number of tablets adjusted depending upon escalation schedule
`described above.
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`Duration of Treatment: up to 24 weeks
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`Criteria for Evaluation: Efficacy:
`The primary efficacy endpoints (described in further detail below) were based on assessments of
`glucose and blood pressure.
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`The key secondary efficacy endpoint was based on Data Review Board (DRB) assessments of
`the signs and symptoms Cushing's syndrome as well as laboratory findings.
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`Statistical Methods:
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`Efficacy: Primary Efficacy Endpoints:
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`The primary endpoint for subjects with Cushing's syndrome and diabetes mellitus (or impaired
`glucose tolerance) (C-DM cohort) was the change in the area under the concentration-time cure
`for glucose (AUCglucose) in the 2-hour oral glucose tolerance test (oGTT) from baseline to
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`Week 24 in subjects with diabetes/impaired glucose tolerance with or without hypertension at
`screening. A responder analysis using the modified Intent-to- Treat (mI'l‘I') population was used
`to measure success on this primary eflicacy endpoint. A responder was defined as a subject who
`experienced at least a 25% decrease in AUCglucose from baseline to Week 24. This efficacy
`measurement was to be declared successful if the lower limit of the exact 95% binomial
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`confidence interval for the responder rate was >= 20%.
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`Changes in diastolic blood pressure were analyzed for subjects with Cushing's syndrome and a
`diagnosis of hypertension (C-HT) at screening (i.e., without impaired glucose tolerance or
`diabetes) as a primary endpoint. A responder analysis of the reduction in diastolic blood
`pressure from baseline to Week 24 was performed for the efficacy population. A responder was
`defined as a subject who experienced 3 >= 5 mmHg decline in diastolic blood pressure from
`baseline to Week 24. This eflicacy measurement was to be declared successful if the lower limit
`of the exact 95% binomial confidence interval for the responder rate was >=20%.
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`The study was considered to have had a positive outcome and to have achieved the primary
`endpoint if either of the two primary measures described above were positive.
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`Key Secondary Endpoint:
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`Clinical improvement as determined by the DRB: a responder analysis was used to determine
`clinical improvement in all subjects. The DRB performed a review of eight categories of
`clinical parameters to evaluate whether a subject's signs and symptoms of Cushing's syndrome
`had changed. For this secondary efficacy endpoint, a responder was defined as a subject whose
`median reviewer score was +1 (of possible ratings of -l , 0, or + l) at any reviewed visit after
`baseline though Week 24/ET. This eflicacy measurement was to be declared successful if the
`lower limit of the exact 95% binomial confidence interval for the responder rate was >= 30%.
`
`—INDICATIONS AND USAGE— (mifeplismne) is a cortisol memblocket indicated to treat the
`dinimlandmetabolicefi'ectofhypelmtisolisminpafiamwiflr
`muCuslring'ssyndrm,inchrdingz
`O PafimtswflhCushing'sdisusewhohawnMadeqntdyrmdedbmmkpsedafiasngay
`
`O Pafimlswnhi'sdisuscwhoarenotmdidawsfori
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`Mifepristone (C-IO73, referred to previously as CORLUX) is a glucocorticoid-receptor type II
`antagonist (GR-II) that also acts as an antagonist of the progesterone receptor.
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`Mifepristone, in a 200 mg tablet formulation, is currently approved and marketed in the
`United States
`S as Mife rexo b Danco Laboratories, LLC for the medical termination of
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`irefici.b
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`Reference ID: 3073844
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`2.2 Data Sources
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`STATISTICAL EVALUATION
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`\\fdswa150\NONECTD\N202107\S 001\2011-04-15\Folder 6\n202107\m5\datasets\c1073-400
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`3.
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`3.1 Data and Analysis Quality
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`No apparent concern.
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`3.2 Evaluation of Efficacy
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`Study Design and Endpoints
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`This was a 24-week, open-label study of the administration of mifepristone to subjects with
`Cushing's syndrome. Following a screening period of up to 6 weeks, 50 subjects were assigned
`to receive 300 mg mifepristone once daily (QD). Because the optimal dose of mifepristone for
`each subject was not known, dose escalation was undertaken cautiously with careful
`observation of clinical status. Dose escalations beyond 300 mg were made under the following
`conditions:
`
`If no clinical improvement had been seen, If the drug had been well tolerated, and Based on the
`subject's weight at the escalation visit.
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`After 14 days of dosing at 300 mg QD, the dose of mifepristone could have been increased as
`outlined in Table below:
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`All doses were given as a single daily dose.
`a Dose escalation stopped at Week 6 for subjects weighing <60 kg.
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`Dose escalation was not required if significant clinical improvement was noted at the current
`dosing level. In cases of severe hypercortisolism, the dose of mifepristone could have been
`increased beyond 1200 mg QD (or 900 mg QD for subjects weighing 0: 60 kg) with the
`approval of the medical monitor; however, the dose was not to be increased beyond a weight-
`adjusted dose of 20 mg/kg per day. Dosing was to be interrupted and the subjects treated with
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`Reference ID: 3073844
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`exogenous corticosteroids if signs of adrenal insufficiency were noted.
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`The primary efficacy assessments were based on measurements of glucose (based on 2-hour, 75
`gram oral glucose tolerance tests (oGTT) and blood pressure.
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`Other secondary and exploratory efficacy assessments included:
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`use of concomitant medications for diabetes and hypertension
`body weight
`hemoglobin HbA1c (glycosylated hemoglobin)
`systolic blood pressure
`skin and physical appearance (including photographs)
`waist circumference
`body composition
`bone density of the spine and hip (based on dual-energy x-ray absorptiometr (DXA)
`scan)
`bone metabolism markers (osteocalcin, urinary N-telopeptide of type I collagen (NTxJ,
`and bone specific alkaline phosphatase)
`cognitive and psychiatric assessments (Beck Depression Inventory n and Trail Making
`Test); and the Short Form (SF)-36 Health Survey.
`muscle strength (sit-to-stand test and hand grip test)
`insulin levels
`laboratory measurements of thrombin-antithrombin (TAT), e-selectin, and adiponectin.
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`Patient Disposition, Demographic and Baseline Characteristics
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`Disposition of Subjects
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`The disposition of the study subjects is presented in Table below. A total of 50 subjects were
`enrolled in the study, and 34 completed the study. Of the 16 subjects who withdrew from the
`study, seven withdrew because of AEs (including one who died subsequently due to underlying
`illness) and two subjects died due to underlying illness while still participating in the study;
`these subjects are described in further detail in Section 12.3.1.3 of the NDA Report. Five
`subjects withdrew consent, one subject was too ill to travel (and subsequently died due to
`underlying illness) and one subject was withdrawn due to non-compliance with study
`procedures.
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`Overall, 34 (68%) of the 50 subjects completed the 24-week treatment period (20 of 29 subjects
`in the C-DM cohort and 14 of 21 subjects in the HT cohort). In total, 40 subjects (80%) attended
`the 6-week follow-up visit (22 in the C-DM cohort and 18 in the C-HT cohort), including the 34
`subjects who completed the 24-week treatment period as well as six subjects who terminated
`early.
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`Subject Disposition (ITT/Safety Population)
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`Reference ID: 3073844
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`Demographics and Other Baseline Characteristics
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`Demographics and body measurements of the study population at baseline are summarized in
`Table below. The majority of subjects were female (35/50, 70%) and white (42/50, 84%); the
`mean age of the study population was 45.4 years. Overall, the mean of weight, BMI, and waist
`circumference measurements at baseline were 99.5 kg, 35.7 kg/m2, and 119 cm, respectively.
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`Demographics and Body Measurements at Baseline (ITT/Safety Population)
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`.
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`C-DM
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`C-HT
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`Overall
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`Characteristic
`(N=29)
`(N=21}
`(N=50)
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`Sex, 11 (%)
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`Male
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`Female
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`Race, 11 (“A0
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`Black or Afi'ican American
`White
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`Ethnicity, n (%)
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`Hispanic or Latino
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`Not Hispanic or Latino
`I Age, years |
`Mean (SD)
`Median
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`Min, Max
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`Height, cm
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`Mean (SD)
`Median
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`Min, Max
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`Weight, kg
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`Mean (SD) '
`Median
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`Min, Max
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`BMI, kg/m2
`Mean (SD)
`Median
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`Min, Max
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`Waist circumference, cm
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`Mean (SD)
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`7 (24.1)
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`22 (75.9)
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`6 (20.7)
`23 (79.3)
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`2 (6.9)
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`27 (93.1)
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`8 (38.1)
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`13 (61.9)
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`2 (9.5)
`19 (90.5)
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`2 (9.5)
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`19 (90.5)
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`15 (30.0)
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`35 (70.0)
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`8 (16.0)
`42 (84.0)
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`4 (8.0)
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`46 (92.0)
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`44.4 (13.71)
`41.0
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`26, 71
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`46.7 (8.83)
`46.0
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`26, 67
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`45.4 (11.85)
`45 .0
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`26, 71
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`168 (12.11)
`168
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`”
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`166 (8.84)
`163
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`167 (10.31)
`166
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`143.5, 190.5
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`154.0, 185.4
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`143.5, 190.5
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`-
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`105 (33.54)
`102
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`61.3, 198.7
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`91.4 (21.10)
`88.2
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`99.5 (29.55)
`92.4
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`62.7, 150.5
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`61.3, 198.7
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`37.4 (11.18)
`35.1
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`33.4 (7.44)
`31.8
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`35.7 (9.90)
`33.5
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`24.1, 66.4
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`24.5, 53.6
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`24.1, 66.4.
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`124 (21.73)
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`111 (15.77)
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`119 (20.31)
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`1 15
`104
`120
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`Median
`Min, Max
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`97.9, 178.4 '
`88.5, 153.5
`88.5, 178.4
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`BMI = body mass index; C-DM = subjects with Chishing‘s syndrome and diabetes mellitus (or impaired
`glucose tolerance); C-HT -= subjects with Cushing’s syndrome and hypertension; ITT‘ - intent-to-treat;
`Max = maximum; Min = minimum; oG'IT - oral glucose tolerance test; SD - standard deviation.
`The GDM group included subjects with diabetes mellitus type 2 andfor impaired glucose tolerance at
`screening and Day 1 as detennined by 2 orrnore abnormal oGTTs. The C—HT group included subjects with a
`diagnosis of hypertension at screening but without diabetes mellitus type 2 andlor impaired glucose tolerance.
`Three subjects in the hypertension group (Subjects 07-006, 07—007, and 24-002) entered with a diagnosis-of
`diabetes not confinned by two abnormal oGTTs.
`The ITTISafety population is defined as all enrolled subjects who received at least 1 dose ofstudy medication.
`Source: Table 14.1.2.1.
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`Cushing's Syndrome History
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`Table below presents Cushing's syndrome etiology and history as well as the signs and
`symptoms of Cushing's syndrome noted at the screening visit.
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` A
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` total of 43 subjects had Cushing's disease as the etiology for their Cushing's syndrome. Four
`subjects had Cushing's syndrome with an etiology of ectopic ACTH secretion, and three
`subjects had Cushing's syndrome with an etiology of adrenal carcinoma. All subjects with
`Cushing's disease except one (Subject 24-005) had previously undergone pituitary surgery
`(Listing 16.2.4.2.2).
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`Cushing's Syndrome History and Signs/Symptoms at Screening (ITT/Safety
`Population)
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`Reference ID: 3073844
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`Statistical Methodologies
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`The following is copied from the Statistical Analysis Plan, dated Nov 5, 2010:
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`
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`“Primary Endpoint
`
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`Two separate primary efficacy endpoints will be assessed in study subjects with
`Cushing's syndrome based upon their co-morbid diagnosis of either Diabetes
`Mellitus Type 2 and/or impaired glucose tolerance or co-morbid hypertension
`(without co-existing Diabetes Mellitus Type 2 and/or impaired glucose tolerance
`as follows:
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`C-DM: Change in glucose tolerance as measured by AUCglucose on 5 point, 2
`hour, 75 gram oral glucose tolerance tests.
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`C-HT: Reduction in diastolic blood pressure.
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`Key Secondary Endpoint
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`For both C-DM and C-HT subjects, the key secondary endpoint will be an
`overall assessment of change in clinical status in Cushing's sign and symptoms,
`and laboratory findings. These efficacy assessments at each of the key tie points
`will be conducted for each subject by the Data Review Board (DRB), an
`independent panel of expert reviewers with expertise in Cushing's Syndrome.
`The reviewers will be blinded to the dates and sequence of all visits except the
`baseline and the 6-week safety follow-up visit. (Refer to Section 9.2.1 for
`description of analysis.)
`
`
`…
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`5.5.2 Treatment Duration
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`Total duration of treatment is calculated as the difference between the dates of
`last and first dose of study medication plus one day. These dosing dates will be
`obtained from the Drug Diary data. The first trial dose date (day 1) and the last
`trial dose date are defied as the dates on which the first dose and last doses are
`taken, respectively, as shown in the Drug Diary log. All subjects who have
`completed a total of 30 days of dosing, whether or not those 30 days were
`contiguous, will be regarded as part of the efficacy population. As par of the
`validation procedure, programmers will create a validation program that will
`independently verify that all days on drug for each subject have been included in
`the tabulation.
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`5.6 Linear Trapezoidal Rule
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`Reference ID: 3073844
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`The following parameters will be calculated based on the glucose and insulin
`concentration values from the 2-hour (5-point) oral glucose tolerance test
`(oGTT):
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`
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`AUCglucose(0-120) = area under the glucose concentration curve from
`time 0 to 120 minutes
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`AUCinsulin(0-120) = area under the insulin concentration curve from
`time 0 to 120 minutes
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`All AUC calculations will be performed using SAS version 9.2. These
`calculations will be validated using hand calculation. (see section 11.1.1 for
`expanded formula for hand calculations). Concentrations will not be corrected
`for baseline (time 0).
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`Missing data for AUCglucose will be handled as described in Section 7.4.
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`6.1 Modified-Intent-to- Treat Population
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`The efficacy population is defined as all subjects who received a total of at least
`30 days of mifepristone during the 24-week treatment period. The primary and
`secondary endpoints will be evaluated using this modified Intent-to-treat
`population (mITT). The 30 days of treatment do not need to be consecutive.
`Subjects who receive >=30 days of mifepristone but terminate prior to week 24
`are included in the mITT population. The primary endpoint and secondary
`efficacy analyses will exclude the following subjects:
`
`C-DM:
`Did not undergo at least one oGTT at baseline (day 1) or did not have any oGTT
`with a valid AUCglucose measurement after day 1 (see Section 5.6 for the
`definition of valid AUCglucose measurement).
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`C-HT:
`Did not have blood pressure measured (or measured incorrectly) at baseline (day
`1) or did not have any valid measurement after day 1.
`
`ALL SUBJECTS:
`Entered the study with non-endogenous Cushing's syndrome.
`
`6.2 Completer Population
`The study completer population will consist of all subjects (C-DM and C-HT)
`who complete though the Week 24 visit, are on study drug at the tie of the week
`24 visit, and have been compliant with study medication. Compliance for each
`subject will be defined as having taken at least 80% of the study medication
`doses as described in the protocol.
`
`…
`
`
`7.2 Site
`
`There will be up to 30 clinical centers recruiting subjects. It is expected that
`many sites may enter less than two subjects. Site will not be included in the
`analysis of the primary endpoint due to the small sample size.
`
`
`
`
`Reference ID: 3073844
`
`14
`
`

`

`Potential site effects will be explored by summarizing primary analyses at
`relatively small versus relatively large sites, using the median number of
`subjects per site to define small and large.
`
`7.3 Sample Size
`
`The sample size of 50 subjects was chosen by clinical judgment. Published case
`reports suggest that mifepristone can reverse many of the signs and symptoms of
`hypercortisolemia. However, there have been no prospective clinical trials from
`which to estimate a treatment effect or standard deviation of treatment effect in
`subjects with Cushing's Syndrome.
`
`Prior to Amendment 5, the protocol stated that sample size would be re-
`estimated by the Data Review Board by estimating conditional power after 15
`C-DM and 10 C-HT subjects had completed the study. However, the pattern of
`subject enrollments into the study is such that the study will be fully enrolled (50
`subjects) prior to reaching the predefined point of sample size re-estimation.
`Therefore, the Data Review Board will not re-estimate the sample size.
`
`7.4 Data Handling/Imputation Methods
`
`7.4.1 Missing Data on Primary Endpoint Measures
`
`AUCglucose
`
`AUCglucose measures will be obtained for all subjects (C-DM and C-HT) at
`Baseline and Weeks 6, 10, 16, 24 (or early termination visit).
`
`When calculating the AUC at a given time point, the following rules for
`handling missing data will be applied:
`
` .
`
` If data for fasting plasma glucose (time point 0) or the plasma glucose 30
`minute post oral glucose administration time point are missing, no AUC
`calculation will be performed for that particular visit and the AUC for that visit
`will be counted as missing.
`
` .
`
` If glucose concentration data are not available for more than one oGTT (post
`oral glucose administration) time point (i.e., 30, 60, 90 and 120 minutes) for a
`particular visit, then the AUCglucose will not be calculated for that visit.
`
` .
`
` If data for only one plasma glucose (post oral glucose administration) time
`point other than the 30 minute time point (i.e., either 60 or 90 minutes) is
`missing, then AUC will be calculated using available data. For example, if 90
`minute value is missing, then a larger trapezoid will be constructed to connect
`the 60 min time point to the 120 min time point.
`
` .
`
` If only the 120 minute plasma glucose is missing, the available time points will
`be used to calculate AUCglucose. In such a case, the 120 minute plasma glucose
`for the baseline oGTT will be disregarded. AUCglucose will be calculated using
`time points 0, 30, 60, 90 minutes; AUCglucose 0-90 will be used for both baseline
`and final observation.
`
`When evaluating the primary endpoint among C-DM subjects, an endpoint
`analysis will be calculated using the change from baseline AUCglucose to the last
`value for AUCglucose obtained (week 24 or early termination visit), provided that
`
`
`
`Reference ID: 3073844
`
`15
`
`

`

`that last observation occurred no more than 14 days after the patient stopped
`taking the medication. The 14 day period of time has been chosen because,
`based on the half-life of mifepristone, 14 days exceeds the expected duration of
`clearance of the drug from the circulation in the vast majority of people who
`take the drug. Thus the 14 day limit has been chosen to best reflect the effect of
`the drug on AUCglucose in situations where the interval between discontinuation
`of study drug and the last oGTT is prolonged. In the case where the last
`observation occurred more than 14 days after the patient stopped taking the
`medication, the most recent prior value of AUCglucose will be used.
`
`7.4.2 Blood Pressure
`Blood pressure evaluations will be taken for all subjects (C-DM and C-HT) at screening,
`baseline, days 7, 14, and 28, and weeks 6,8,10,12,16, 20, and 24 (or early termination).
`
`For the primary endpoint evaluation ofC-HT subjects, an endpoint analysis will be
`calculated using the change from baseline diastolic blood pressure to the last valid
`value of diastolic blood pressure obtained (week 24 or early termination visit),
`provided the last observation occurred no more than 14 days after the patient stopped
`taking the medication. In the case where the last observation occurred more than 14
`days after the patient stopped taking the medication, the most
`recent prior value of diastolic blood pressure will be used.
`
`
`…
`
`7.6 Examination of Subgroups
`
`Because of the sample size, no formal statistical analyses will be conducted for
`subgroups (e.g., treatment effect comparison by age, sex, or race). However,
`summary tables for primary and key secondary endpoints by sex and age will be
`provided in the CSR.
`
`…
`
`
`
`9.1 Analysis of Primary Endpoints
`
`9.1. Subjects with Cushing's Syndrome co-morbid with Diabetes Mellitus Type
`2 or impaired glucose tolerance (C-DM)
`
`The primary endpoint for this subject population will be the change in area
`under the cure for glucose (AUCglucose) from 2-hour oral glucose tolerance tests
`(oGTT) from baseline to Week 24 in subjects with diabetes/impaired glucose
`tolerance with or without hypertension at screening. A responder analysis using
`the efficacy population (mITT) will be used to measure success on this primary
`efficacy endpoint. A responder will be defined as a subject who experiences at
`least a 25% decrease in AUCglucose from baseline to week 24. The null and
`alternative hypotheses are as follows:
`
`Ho: π 25% reduction in the glucose AUC at 24 weeks ≤ 0.2
`
`Ha: π 25% reduction in the glucose AUC at 24 weeks >0.2
`
`This null hypothesis will be rejected in favor of the alternative if the lower limit
`of the exact one-sided 95% binomial confidence interval for the responder rate is
`greater than 20%.
`
`
`
`
`Reference ID: 3073844
`
`16
`
`

`

`Although there are anecdotal reports of spontaneous remissions in Cushing's
`syndrome, the cases are extremely rare. Twenty percent (20%) is an appropriate
`threshold to test against in this population, given that the spontaneous remission
`rate in individuals who are eligible for this study is close to 0%. These rare cases
`often occur in the setting of de novo Cushing's disease and have been largely
`due to apoplexy (pituitary hemorrhage). Subjects who are enrolled with prior
`pituitary radiotherapy could theoretically lead to a higher remission rate.
`Although the criteria used for establishing remission are no