Clinical Review
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301
`
`Apriso (mesalamine)
`
`10.2 STUDY PROTOCOL MPUC3004
`
`10.2.1 Protocol Summary
`
`Title: A Multicenter, Randomized, Double-Blind, Placebo-Controlled Trial to Evaluate the Use
`of Mesalamine Pellet Formulation 1.5 g QD to Maintain Remission from Mild to Moderate
`Ulcerative Colitis.
`
`Study Centers
`
`A total of 257 patients from 37 centers participated in this study. There were 29 study sites in
`the US and eight in Russia. The US sites had an average of 3.6 patients per site for a total of
`103 randomized patients. The Russian sites had an average of 19.3 patients per sit for a total of
`154 randomized patients.
`
`See Appendix 10.4.2 for a chart of study centers and investigators participating in Study
`MPUC3 004.
`
`Study Period
`
`24 December 2004 to 08 August 2007
`
`Objectives
`
`The primary study objective was to assess the ability of encapsulated mesalmine granules (eMG)
`at 1.5 g once daily to maintain remission of mild to moderate ulcerative colitis (UC) as measured
`by rectal bleeding and endoscopic mucosal appearance as compared with placebo after six
`months of treatment.
`'
`
`The secondary objective was to compare the safety and tolerability of long-term dosing with
`eMG at 1.5 g once daily compared with placebo in the maintenance of remission from mild to
`moderate UC.
`
`Study Design
`
`This was a randomized, multi-center, double—blind, placebo-controlled Phase 3 study to compare
`the maintenance of remission in patients with demonstrated mild to moderate ulcerative colitis
`using eMG 1.5 g once daily as compared to placebo. Maintenance was measured by rectal
`bleeding and endoscopic mucosal appearance after six months of treatment. For patients who
`discontinued the study prior to Month 6, an end of study Visit was conducted including
`sigmoidoscopy and the rectal bleeding and mucosal appearance scores from that visit were used
`to determine treatment failure or success.
`
`92
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`

`

`Clinical Review
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-3 01
`
`Apriso (mesalamine)
`
`MO Comment: The study design appears adequate to achieve the study objective.
`
`10.2.2
`
`Inclusion Criteria
`
`. Age older than 18
`Males or non-pregnant, non-lactating females of non-child-bearing potential or agreeing
`to an acceptable form of birth control as outlined in the protocol.
`. Historically confirmed diagnosis of mild to moderate UC in remission at least one month,
`but not more than 12 months with a history of at least one flare within the past 12 months
`Confirmed cmrent remission defined as a rectal bleeding score on revised Sutherland
`DAI of 0 (none) and sigrnoidoscopy score of 0 to 1 for mucosal appearance (0=intact
`mucosa; 1=erythema, decreased vascular pattern, granularity, no mucosal hemorrhage).
`
`10.2.3
`
`Exclusion Criteria
`
`DJ
`
`. History of receiving immunosuppressive therapy (e.g., azathioprine, 6-mercaptopurine)
`or corticosteroids (oral, intravenous, or topical rectal) within 30 days prior to screening.
`History ofinfectious, ischemic, or immunologic disease involving the GI tract.
`. History ofa significant medical condition, including, but not limited to, psychiatric
`conditions, impaired immune fimction, HIV, in-bom errors of metabolism, hepatitis B or
`C, unstable cardiovascular disease, unstable renal disease, coagulopathy, or unstable
`pulmonary disease.
`History of current or malignancy or same within the last five years, except basal cell
`carcinoma of the skin, or if female, cervical carcinoma in situ that has been surgically
`excised.
`
`History of any prior bowel surgery, except appendectomy.
`Any of the following laboratory abnormalities: Serum Cr or BUN >1.5 ULN, CrCl <60
`mL/min, twice the ULN for ALT, AST, or total bilirubin.
`. Current excessive alcohol use or drug dependence.
`.
`History of allergy or intolerance to aspirin, mesalmine, or other salicylates.
`. Personal history of phenylketonuria or history of parent’s having the same.
`
`7 8
`
`9
`
`9‘.“
`
`M0 comment: Inclusion and exclusion criteria are appropriate for the study.
`
`10.2.4 Primary Efficacy Endpoint
`
`The primary efficacy endpoint was the proportion of patients 'who remained relapse~free after six
`months of treatment. The endpoint was calculated using the results of all randomized patients
`who received at least one dose of study drug. Relapse or treatment failure was defined as a rectal
`bleeding score of 1 or more and mucosal appearance score of 2 or more, both as described in the
`
`93
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`

`

`Clinical Review
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22—301
`
`Apriso (mesalamine)
`
`revised Sutherland Disease Activity Index (DAI). Patients who experienced an UC flare or
`initiated medication used previously to treat UC were also considered a treatment failure. Early
`study termination was not considered to be a relapse unless the reason for early termination was
`lack of efficacy or discontinuation due to a UC—related AE.
`
`This primary endpoint represents a change from the definition of treatment failure presented in
`the original study protocol. Originally, the Applicant planned to count all premature
`withdrawals as having relapsed regardless of the reason for premature study discontinuation.
`The protocol amendment which changed this definition was made August 9, 2007, after
`completion of Study MPUC3004, but before unblinding of the data. Efficacy results using both
`this original definition and the revised definition are presented in the Efficacy Results section
`10. 2. 12.2 below.
`
`The Sutherland DAI is comprised of four indices of disease: stool frequency, rectal bleeding,
`mucosa] appearance, and a physician’s rating of disease severity. Each index is evaluated on a
`scale of 0 to 3, with a maximum total score of 12. To improve the clarity of the DA], the term
`friability was removed from the mucosa] appearance definitions resulting in the revised DAI
`used for studies MPUC3003 and MPUC3004. The change was requested by the Agency at the
`06 October 2004 End of Phase 2 Meeting. The term “mild friability” was removed from the
`mucosa] appearance score of l and replaced with “erythema, decreased vascular pattern,
`granularity, no mucosa] hemorrhage.” The term “moderate friability” was removed from the
`mucosa] appearance score of 2 and replaced with “mucosal hemorrhage without blood in the
`lumen or gross ulceration, marked erythema, absent vascular pattern, and small ulcers.” To
`calculate the DAI, sigmoidoscopy was performed at screening and at Month6/EOS.
`Unscheduled sigmoidoscopies were also performed if a patient experienced a' flare in disease
`activity. Efforts were made to have the same clinician perform all sigmoidoscopies for a given
`patient.- Study patients self-reported rectal bleeding and stool frequency symptoms for scoring.
`
`The number and proportion of relapse—free patients after 6 months of treatment/EDS was
`summarized by treatment group using the ITT population. For all endpoints, comparisons
`between treatment groups were based on a Cochrane-Mante] Haensze] test, stratifying by
`country. As a sensitivity analysis to assess the effect of protocol compliance on drug efficacy,
`the primary efficacy analysis was also done using the per protocol population, those patients
`without a major protocol violation. Only the primary result obtained from the ITT population
`was considered to be inferential.
`
`10.2.5 Secondary Efficacy Endpoints
`
`Secondary efficacy analyses were performed using all randomized patients who received at least
`one dose of study drug. Statistical tests on secondary endpoints were performed in a hierarchical
`fashion. Once a non—significant p—value (>0.05) was encountered, all subsequent significance
`tests were considered exploratory in nature. The hierarchy of the secondary endpoints was as
`follows:
`
`94
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`

`

`Clinical Review
`
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301
`Apriso (mesalamine)
`
`1. The number and proportion of patients in each level of change from baseline in rectal
`bleeding score at Months 1, 3, and 6/EOS.
`2. The number and proportion of patients in each level of change from baseline in mucosal ‘
`appearance score at Month 6/EOS.
`3. The number and proportion of patients in each level of change from baseline in
`physician’s rating of disease activity at Months 1, 3, and 6/EOS.
`4. The number and proportion of patients maintaining the revised Sutherland DAI _<_2 with
`no individual component >1 and rectal bleeding score of 0 at Month6/EOS.
`5. Mean change from baseline in the revised Sutherland DAI at Month 6/EOS.
`6. Relapse-free duration, defined as the number of days between the start of study drug and
`the date that relapse is first detected or early termination from the study, plus 1 day.
`7. The ntunber and proportion of patients in each level of change from baseline in stool
`frequency score at Months 1, 3, and 6/EOS.
`
`Clinical Reviewer ’s Comment: Currently, there is no validated disease activity index usedfor
`ulcerative colitis. Instead, a host of indices, many involving endoscopy, are used to measure
`disease activity. The Sutherland Disease Activity Index is a commonly used disease activity
`index.
`
`10.2.6 Treatment
`
`Upon enrollment in the study, patients were randomly assigned to a treatment group in a 2:1
`(activezplacebo) ratio. Patients received 0.375 g eMG capsules or matched placebo product at
`each study visit in an adequate amount to allow proper dosing until the next scheduled visit.
`Patients self-administered four capsules once daily, in the morning, for not more than 24 weeks.
`All study site personnel were blinded to the patient treatment assignment.
`
`10.2.7 Monitoring
`
`Once patients were enrolled in the study, they underwent screening within seven days prior to
`randomization and beginning of product administration (Dayl). Screening included informed
`consent, assessment of concomitant medications, medical history, physical examination,
`laboratory measurements, and sigmoidoscopy. The Laboratory measurements included serum
`chemistry and hematology panels, serum BHCG, serum HIV, Hepatitis A and B, and urinalysis
`for calculation of creatinine clearance. Each patient’s initial revised Sutherland DAI score was
`also calculated.
`,
`
`On study Dayl , eligible patients were seen in the office to have Study 'Visit 1. During this visit,
`patients underwent physical examination and repeat serum hematology, blood chemistry, and
`urinalysis testing. In addition, each patient’s DAI score was calculated using the sigmoidoscopy
`score obtained during screening. Patients received a one month supply of the appropriate study
`drug along with daily diary cards to monitor compliance, concomitant medications, and ABS.
`Adverse events and concomitant medications were also recorded at this Visit and during each
`subsequent telephone contact and in-office visit.
`
`95
`
`

`

`Clinical Review
`
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301
`
`Apriso (mesalamine)
`
`Visit 2 (Month 13:7 days) occurred in —office and was identical to Visit 1 with two exceptions.
`First, a modified DAI was-calculated for each patient, which did not include a sub-score for
`mucosal appearance because no sigmoidoscopy was performed. Second, a two month supply of
`study treatment was dispensed at this visit.
`Visit 3 (Month 3d:l4 days) was also identical to the previous in—office visits except patients
`received a three month supply of study drug.
`Visit 4 (Month 6i21 days) served as the end of study (EOS) visit. During this visit, patients
`underwent all of the physical examination and laboratory testing that occurred during screening,
`including sigmoidoscopy. Patients who discontinued the study for any reason prior to study
`completion had all of the EOS visit assessments done at the time of study withdrawal.
`
`'On Week 2, Month 2, Month 4, and Month 5, patients were contacted by telephone to have
`concomitant medications and adverse events recorded.
`
`A follow—up visit occurred Week 2 Post E08 :1: 3 days. For this visit, patients returned to the
`office for physical examination Concomitant medications and adverse events were also recorded
`at this visit. This was each patient’s final study-related visit.
`
`Unscheduled visits were to occur during the study if a patient experienced symptoms of relapse.
`Assessments performed at this visit were symptom directed at the investigator’s discretion. If
`patient assessment was positive for rectal bleeding, a stool specimen was obtained for
`Clostridium dijficile and ova and parasites. If the results were negative, a sigmoidoscopy was
`scheduled to occur within 7 days to determine whether or not the patient had experienced
`relapse. Oral antibiotic treatment with metronidazole and ciprofloxacin for C. dz'fi‘icile and ova
`and parasite infections for a 7 to 10 day course was allowed during the course of the study.
`
`96
`
`

`

`Clinical Review
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301
`
`Apriso (mesalamine)
`
`Scheduled In-Person Stud Assessments and Evaluations
`
`
`
`Screening Visit
`Visit 3
`Visit 4/EOS
`
`
`
`
`
`Follow-up Visit
`
`
`Study Assessment
`Visit 2
`(within 7 days
`
`
`(Month 6&21
`(Month 3
`(2 weeks post-
`
`
`
`prior to
`(Month 1)
`
`$14 days)
`days)
`EOS :l: 3 days)
`
`
`
`
`randomization
`
`
`
`Serum sample for HIV,
`He natitis B,C
`Clinical laborato
`
`tests'
`
`Clearance
`
`'
`
`Dis ense Stud Dru_
`Assess and record AEs
`
`concomitant medication di
`medication dia
`
`no
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`determine com 1 liance
`
`
`:symptom—directedplwsical exam only to be pelformed ifnecessary
`bincludes hematology, blood chemishy. and urinalysis
`°Sigmoidascopy component ofSutherland DA] will be scored utilizing the screening sigmoidoscopy score
`dDA] score will only include 3 ofthe 4 individual components, i. e., stoolfiequency, rectal bleeding, andphysician ’5' rating of
`disease activity.
`
`10.2.8 Control Procedures
`
`Randomization
`Patients who met eligibility criteria were identified by a consecutively assigned, unique Patient
`ID number. Just prior to study drug dispensation, patients who continued to be eligible were
`assigned a unique Treatment ID number via a randomization schedule. Study treatments were
`randomly assigned to consecutive treatment numbers using an allocation ratio of 2:1
`(eMG:placebo).
`
`Placebo control
`
`Each placebo consisted of color-matched granules over—encapsulated in matching hard gelatin
`capsules. Both the active study drug and the placebo were manufactured by Cardinal Health in
`Winchester, Kentucky and packaged identically.
`
`Blinding
`In this double-blind study, all study site personnel were blinded to the patient treatment
`assignment. In the case that a blind needed to be broken, a concealed section of the study drug
`label could be removed revealing the patient’s treatment assignment. A concealed section of the
`study drug label, attached to a detachable portion of the label contained the product
`
`'
`
`97
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`

`

`Clinical Review
`
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301
`
`Apriso (mesalamine)
`
`identification. This detachable portion was affixed to the label page in the CRF. Any broken
`blind was to be recorded on the appropriate page of the CRF with an explanation. If a blind was
`broken for any reason, the investigator was to notify immediately the appropriate Salix
`representative.
`
`Patients were dispensed blinded study drug at each study visit in an adequate amount to allow
`proper dosing until the next scheduled study Visit.
`
`Prior and Concomitant Therapy
`
`The dose, duration, and indication of all concomitant medications were recorded in each
`. patient’s file and CRF. Existing, permitted, concomitant treatments were not to be changed
`during the course of the study. Patients who experienced relapse could have been offered, at
`investigator discretion the option ofrece1v1ng standard treatment or enrolling'm an open-label
`extension study (MPUC3005).
`
`Prohibited concomitant medications were as follows.
`
`0
`
`Immunosuppressants including azathioprine, 6--mercaptopurine, and glucocorticoids
`TNF blockers, methotrexate, cyclosporine
`Alternative or complimentary therapies for UC or any other experimental drugs.
`Oral, rectal, or IV corticosteroids, glucocorticoids.
`Chronic NSAIDS , >6weeks (exception acetylsalicylic acid $150 mg/day).
`Oral antibiotics, Rifampin (metronidazole and ciprofloxacin were allowed for a seven to
`ten day course, if necessary).
`Psyllium-containing intestinal regulators, anticholinergics, sucralfate.
`Loperamide, opioids, opiates, and Lactulose or similar preparations used for diarrhea.
`Warfarin.
`
`Probenecid/sulphinpyrazone.
`Spironolactone/fiirosemide.
`Sulphonylureas.
`5-ASA medications
`
`‘
`
`Compliance
`
`Treatment compliance was assessed at Months 1, 3, and 6 during scheduled in-offrce visits. Site
`coordinators determined compliance by counting the capsules remaining in the bottles and
`directly questioning patients. Patients were instructed to record compliance in a daily diary. The
`study monitor confirmed capsule counts during monitoring Visits. Upon study completion, all
`unused, partially used, and fully used (empty) bottles and cartons along with a packing slip were
`returned to Cardinal Health Clinical Services for final drug reconciliation.
`
`Patient compliance was calculated during each study interval and at the end of the study using
`the following formula: 100 * (number of capsules dispensed—number of capsules returned)/ (4 *>
`
`98
`
`

`

`Clinical Review
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301
`
`Apriso (mesalamine)
`
`number of days of exposure). A patient was considered compliant if he or she took at least 70%
`of the study drug.
`
`10.2.9 Safety evaluation
`
`The primary measure of safety was the incidence of treatment-emergent adverse events
`(TEAEs). The safety and tolerability of the study medication was also assessed by monitoring
`laboratory test results (hematology, chemistry, calculated creatinine clearance, and urinalysis),
`physical examination, reported concomitant medications, and vital signs.
`
`An adverse event was defined as any untoward medical occurrence in a patient which did not
`necessarily have to have a causal relationship with this treatment.
`
`10.2.10
`
`Protocol Amendments
`
`Protocol Amendment 1 was finalized April 19, 2005.. This date is after the study began, but
`before study completion. The Amendment was introduced for the following main reasons:
`1. To increase the geographic scope of the study to include international sites.
`2. To introduce less restrictive inclusion criteria such that patients could be in remission 512
`months, instead of S6 months.
`3. To outline procedures for patients who are believed to be experiencing a flare in disease
`activity
`4. To reduce the minimum washout period for immunosuppressants from 90 days to 30 days
`5. To allow the concomitant use of PPIs
`
`Protocol Amendment 2 was finalized 09 August 2007. This date is after study completion. The
`Amendment was introduced for the following main reasons:
`
`9°
`
`1. To change the number of randomized patient for the study from 300 to 250.
`2. To change the definition of relapse to no longer include patients terminating early for
`reasons other than lack of efficacy or a UC-related AE.
`To enumerate secondary endpoints allowing hierarchical testing.
`4. To change the ITT population definition from all randomized patients to all randomized
`patients who received at least one dose of study drug.
`To add a sensitivity analysis to the primary efficacy analysis using the PP population
`To specify the major protocol deviations excluded from the PP population
`To add a modified last observation carried forward (LOCF) procedure for imputing
`missing values of primary and secondary efficacy endpoint for patients who terminated
`the study early.
`-
`i 8. To designate the 6 month/EDS time point as the single time point for secondary analyses
`to reduce the likelihood of a type 1 error resulting form multiple secondary efficacy
`variable collected at numerous time points.
`
`>199
`
`99
`
`

`

`Clinical Review
`
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301
`
`Apriso (mesalamine)
`
`10.2.1 1
`
`Statistical Methods
`
`Data Set Analyzed
`
`The intent-to—treat (ITT) population was defined as all randomized patients who received at least
`one dose of study drug. The per protocol (PP) population included all patients in the ITT
`population without a major protocol deviation. Major protocol deviations were defined prior to
`un-blinding of the data and included deviations from specific inclusion criteria, use of prohibited
`mediations that would interfere with study results; and wrongfill dispensation of study drug. The
`safety population included all randomized patients who received at least one dose of study drug
`and provided at least one post-baseline safety assessment.
`
`10.2.12
`
`Study Results
`
`10.2. [2.]
`
`Demographics and Baseline Disease Characteristics
`
`In a late stage protocol. amendment, the Applicant changed the number of planned patients from
`300 to 250. Therefore, Study MPUC3004 is smaller than study MPUC3003 by about 50
`patients.
`
`Overall, the eMG and placebo groups did not vary significantly with regard to demographic
`characteristics. There were slightly more females in the eMG grouP (56.0%). In the placebo
`group, there were slightly more males (52% ). In both treatment groups, the majority of patients
`were younger than 65 years of age (91% eMG, 88% placebo) and White (95% eMG, 97%
`placebo). Likewise, the number of patients from Russia and the US were similar and nearly
`evenly distributed across treatment groups.
`
`100
`
`

`

`Clinical Review
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22—301
`
`Apriso (mesalamine)
`
`
`
`
`
`Female
`ears n,%
`
`A_e
`
`Mean SD
`
`‘
`; Race
`
`Median (min,max)
`n,%
`
`.
`
`Asian
`Black/AA
`White
`
`‘
`3 Ethnici
`
`MlSSin_
`n,%
`
`
`
`
`
`
`1%:
`
`5v
`
`ow.
`
`5 9.1
`5.7 14.0
`
`608, 82)
`
`56 95.1
`
`(0.6
`
`5.6 14.1
`6(18, 76
`
`.
`
`22 (47.5
`35 52.5
`
`231 89.9
`26 10.1
`45.6 14.0
`46 (18,82)
`
`(2.
`46 95.7
`
`(2.4
`(5.4
`i—_ 60 97.6
`s 94.6
`|-!_ —
`.-1_ 02 62.2
`2 55.9
`207.8
`mm
`
`35
`
`—
`
`
`
`Ab—v—\oqexex0‘-'AA4:.w:—
`..mox—max~Ox—t-—.p.-—-—-UIN
`
`
`
`\ouwox-b—n...._."-
`
`mu.\oNA-h-004:4:\o4:-oooN\oN00a.o‘N9°..00N2
`*A..0“.04:a4:.
`
`
`
`
`
`
`
`
`_ 3
`__ 6.5 4.0
`.
`_- 6.4 510,757 -_—_s
`_—
`
`;_
`i—l_ 5.5 4.0 -l—-_
`—_ 6.4 510,717 -_—-—i
`i-_II— __.
`
` 25.2 (175,384) _
`
`
`
`_I— 26.0 4.6 -_-l_:
`— 25.1 (169,413)
`Source: Summary Table 14.1.4, Table 10. MPUC3004 Study Report
`APatients were allowed to check more than one race and so percentages may be greater than 100%
`' American Indian/Alaskan Native
`” Afiiean—American
`
`In general, the patients in each. treatment group did not differ greatly in baseline disease
`characteristics. In both treatment groups, patients had a mean duration of disease of about 290
`weeks.
`
`101
`
`

`

`Clinical Review
`
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301
`
`Apriso (mesalamine)
`
`
`
`
`
`0.;
`
`
`
`
`.3
`
`
`
`
`-
`
`
`
`
`_-____
`
`—-_———
`
`
`
`
`
`
`
`
`
`
`
`
`
`
`N W' K .
`‘»§
`
`
`
`Duration of disease weeks __—
`
`
`
`
`
`——__—
`.-—_-_-—-
`
`_'——_—
`mm-
`mm-
`_———
`__-mn-—-
`
`man-m ~
`
`Ph sician’s ratin; of disease seven
`Baseline Renal Function (n,%)
`Cockcroft—Gault formula
`
`0 3 0 5
`
`0.3 O 5
`
`0.3 0 5
`
`65 69-9
`169 65-8
`mm
`
`
`
`
`
`
`
`Moderate 30-<60 mL/mm
`
`0 (0.0 mm-
`Severe (<30 mL/min)
`Saurce: Summary Table 14.1.6, Sponsor Table I l, MPUC3004 Clinical Stuaj) Report
`
`102
`
`

`

`Clinical Review
`
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22—301
`Apriso (mesalamine)
`
`A larger percentage of eMG patients completed the study (72.6%) as compared with placebo
`(61.3%). Reasons for study discontinuation are presented in the Patient Disposition Table below.
`
`V
`
`I
`
`n in,
`
`
`
`
`
`Patient Dis n osition, Stud MPUC3004
`
`
`
`_ ”my“
`I
`n m” - w.“ 2
`.
`a"
`I
`
`
`...~..,.u
`,1...
`y»... ,.-.. .
`uni—m-
`
`
`
`
`
`—‘_-lm--I-
`
`-'_—_.-
`
`_-_-[GE-—--I-
`
`——_—
`Source: Summary Table 14.1.1, 14.1.2, Data Listing I6. 2. I, Appendix 16.2, MPUC3004 Clinical Study Report
`
`
`
`
`
`Compliance
`
`Treatment compliance was comparable between treatment groups. The mean calculated study
`compliance was 97.2% in the eMG group and 97.5% in the placebo group.
`
`_ I 0.2.12.2
`
`Efficacy Analyses
`
`All randomized patients who’received at least one dose of study drug were included in the
`efficacy analyses. The last-observation—can'ied forward (LOCF) method was used for imputing'
`missing values of primary and secondary efficacy endpoints for patients who terminated early.
`Patients who terminated the study early due to lack of efficacy or UC-related AEs (abdominal
`pain, abdominal tenderness, ulcerative colitis, diarrhea, frequent bowel movements,
`hematochezia, loose stools, proctitis, rectal hemorrhage, rectal tenesmus, stomach discomfort,
`and watery stools) were classified as treatment failures. Patients who terminated the study early
`for other reasons were not considered treatment failures; In addition, patients who experienced a
`UC flare or initiated medication that had previously been used to treat UC were also considered
`treatment failures. For patients who withdrew prematurely for other reasons, the last observation
`carried for ward (LOCF) method was used to impute their EOS remission status.
`
`This primary endpoint represents a change from the definition of treatment failure presented in
`the original study protocol. Originally, the Applicant planned to count all premature
`withdrawals as having relapsed regardless of the reason for premature study discontinuation.
`The protocol amendment which changed this definition Was made August 9, 2007 after study
`completion, but before un-blinding of the data.
`
`103
`
`

`

`Clinical Review
`
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301
`Apriso (mesalamine)
`
`Clinical Reviewer ’s comment: The Applicant changed the definition ofrelapse after study
`completion, but before un—blt'nding. It is important to re-calculate the primary efficacy endpoint
`results usingthe original definition ofrelapse. See the Primary Endpoint Efiicacy Results Table
`below. These results show that the magnitude ofthe difference in efficacy between the eMG and
`placebo group is smaller; however, remains statistically significant.
`
`Primary Endpoint
`
`Statistical analysis for the primary endpoint, proportion of patients using eMG 1.5g/day who
`remained in remission at Month 6 versus placebo, utilized a CMH test controlling for country.
`At Month6/EOS, 79.9% of patients in the eMG group and 67.7% of patients in the placebo group
`remained relapse-flee (p<0.001) when using the revised definition of relapse which did not count
`all early terminations as treatment failures. When the data are analyzed using the original
`definition of the primary endpoint which counted all early withdrawals as relapses, the results
`become only marginally statistically significant, p=0.046.
`
`I oint
`Prima Efficac_ End
`
`
`
`
`0.046
`12% (0%, 24.5%)
`55/93=59.l%
`117/ 164: 71.3%
`Original
`MPUC3004
`0.029
`12 % (1.1%, 24%)
`63/93=67.7%
`13 l/l64=79.9%
`Revised
`ITT
`
`129/ l6l=80.l ,
`58/8667.4%
`g
`Revised
`PP
`Source ofDta: Statistical Reviewer Calculations
`
`Clinical Reviewer ’s comment: The Applicant changed the definition ofrelapse after study
`completion, but before un-blinding. The Applicant also decreased the planned study size from
`300 to 250 in a late stage protocol amendment. Overall, using both definitions ofrelapse,_ Study
`MP UC3003 showed a greater diflerence in efficacy between eMG andplacebo groups than did
`Study MPUC3004. Studies MPUC3003 and MP UC3004 used identical study designs and the
`only substantial dijference is the number ofpatients randomized suggesting that Study
`MP UC3004 may not have been adequately powered.
`
`Secondary Endpoints
`
`The statistical analyses of the secondary endpoints were performed in a hierarchical fashion.
`According to the Applicant’s statistical analysis plan, if statistical significance was not achieved
`for any secondary end point, all subsequent endpoints would be considered exploratory (and not
`inferential) in nature. In study MPUC3004, the difference between eMG and placebo did not
`reach the level of statistical significance for any of the secondary end points. Therefore, all
`secondary end points are to be considered exploratory in nature.
`
`Secondary endpoint six, Month 6 Cumulative relapse-free probability has the smallest nominal
`p-value. This endpoint is basically a re-statement of the primary endpoint. It is important that
`
`104
`
`

`

`Clinical Review
`
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22-301
`Apriso (mesalamine)
`
`this endpoint is highly statistically significant and further corroborates the primary endpoint’s
`statistical significance. However, it was also expected that the first two secondary endpoints,
`difference in rectal bleeding and mucosal appearance scores, would have reached the level of
`statistical significance given that they are directly related to the definition of relapse used in the
`study’s primary endpoint.
`
`Clinical Reviewer ’s Comment: The fact that the first two secondary endpoints did not reach
`statistical significance does not corroborate the study ’s primary endpoint andfurther suggests
`that the study may have been underpowered given the highly statistically significant results of
`Study MPUC3003, an identically designed study with 50 more randomizedpatients.
`
`. oints
`Stud MPUC3004 Seconda Efficac End
`
`Mesalamine
`Placebo
`Study 3004
`
`
`N= 164
`N= 93
`
`
`
`Change from Baseline in Rectal Bleeding
`
`
`
`
`-1
`1 (0.6)
`1 (1.1)
`138 (84.1)
`69 (74.2)
`
`
`
`12 (7.3)
`13 (14-0)
`
`
`
`12 (7.3)
`
`
`
`
`26 (15.9)
`
`13 (14.0)
`
`104 (63.4)
`56 (60.2)
`
`
`
`l8 (1 l.0)
`14 (15.1)
`
`
`
`16 (9.8)
`10 (10.8)
`
`
`
` Change from Baseline in Physician’s Rating of Disease
`
`Severity
`
`
`
`
`
`16 (9.8)
`10 (10.8)
`122 (74.4)
`60 (64.5)
`
`
`
`16 (9.8)
`16 (17.2)
`
`
`
`- 7(7.5)
`0 00
`Patients maintaining the Sutherland DA] 32 with no
`
`individual component of the Sutherland DAl >1 and
`
`
`rectal bleeding =0 at Month 6
`
`
`
`Successes: n (%)
`Failures: n
`
`.
`
`Mean change from baseline in the Sutherland DAl at
`
`Month 6/EOS
`'
`
`
`Mean SD
`
`
`Relapse-free duration
`
`
`Month 6 Cumulative relapse-free probability
`
`
`Stool Frequency at Month 6/EOS
`
`
`Patients in each IeVeI of change from baseline
`
`
`
`V Change from Baseline in Mucosal Appearance
`
`
`-1
`
`
`12 (7.3)
`
`
`27(1'720)
`0
`124 (75.6)
`
`
`
`
`
`8 (8 6)'
`11 (6.7)
`1
`
`
`
`14 (8.5)
`0 (9'7)
`2
`
`
`
`
`3 91.8)3 5 (5:4)
`
`
`
`Source: Summary Table 14.2.]. Appendix 16.2. 6, MPUC3004 Clinical Study Report
`
`P-Value
`
`0.496
`
`0.254
`
`0.039
`
`0.167
`
`0.024
`
`0.142
`
`
`
`
`
`
`
`
`
`SE
`
`54 (58.1)
`39 41.9
`
`0.8 (0.0)
`
`1.2. (2.7)
`
`105
`
`

`

`Clinical Review
`
`'-
`
`Aisha E. Peterson, MD, MPH, MBA .
`NDA 22-301
`Apriso (mesalamine)
`
`1 0. 2. 12. 3
`
`Safety Analyses
`
`The safety population was defined as all randomized patients who received at least one dose of
`study drug and had at least one post-baseline safety assessment. The safety population for Study
`MPUC3004 included 252 patients (161 eMG, 91 placebo).
`
`Extent of exposure
`
`As expected, study attrition occurred in bothtreatment groups. Approximately half (53% eMG,
`52% placebo) of study participants remained in the study for greater than 25 weeks.
`
`MPUC3004 Extent of Exposure
`
`PercentofPatients
`
`
`
`RemaininginSTudy
`
`Study Period (weeks)
`
` + eMG
`
`—-s——— placebo
`
`4
`
`8
`
`12
`
`16
`
`Concomitant Medications
`
`Overall, 54.0% of eMG patients, and 50.5% of placebo patients used concomitant medications
`during Study MPUC3004. The alimentary tract and metabolism medication groups were
`combined. A review of the medications in this group reveals thatthe reason for grouping these
`medications together was likely that the intended use of the medications could have been for G1
`or metabolic issues. For example, calcium carbonate is both a calcium supplement and an
`antacid. There were many concomitant medications used by study participants, but other than
`those listed in the Table below, most medications were used by only 1 or 2 patients.
`
`106
`
`

`

`,. Concomitant Med1cat1onsReorted b >2% of Patients
`
`
`
`
`.
`
`Clinical Review
`
`Aisha E. Peterson, MD, MPH, MBA
`NDA 22—301
`
`Apriso (mesalamine)
`
`
`
`z
`:
`l Alimentary Tract & Metabolism
`59 (36.6)
`33 (36.3)
`
`23 (14.3)
`9 (9.9)
`Fortrans
`.
`
`
`17 (10.6)
`9 (9.9)
`Macrogo] 4000
`
`
`Bismuth subsalicylate
`1 (0.6)
`4 (4.4)
`
`
`Balsalazide sodium
`0
`3 (3.3)
`Magnesium citrate
`l (0.6)
`2 (2.2)
`
`
`
`
`Omeprazole
`1 (0.6)
`2 92.2)
`.
`Magnesium hydroxide
`0
`2 (2.2)
`
`
`f Anti-infectives for Systemic Use
`34 (16.5)
`10 (10.6) '
`
`
`Azithromycin
`4 (2.5)
`4 (4.4)
`
`
`Amoxicillin
`4 (2.5)
`2 (2.2)
`Ciprofloxacin
`5 (3.1)
`1 (1.1)
`
`
`Cefalexin
`1 (0.6)
`2 (2.2)
`Blood and Blood Forming Organs
`2 (1.0)
`4 (4.3)
`
`
`
`
`‘
`Heparin
`0
`2 (2.2)
`Cardiovascular System
`12 (7.5)
`2 (2.2)
`
`
`'
`Preparation H
`0
`2 (2.2)
`
`
`Musculoskeletal System
`12 (7.5)
`2 (2.2)
`
`
`I
`Ibuprofen
`6 (3.7)
`l (1.1)
`
`
`3 Nervous System
`27 (16.8)
`s (8.8)
`
`
`5 (5.5)
`Paracetamol
`10 (6.2)
`.
`1 (1.1)
`Vicodin
`4 (2.5)
`
`
`5 Respiratory Medications
`11 (6.8)
`
`
`
`
`
`Loratadine
`l 0.6 __ ..
`_
`..
`Source. Summary Table l4. 3. 6 3, MPUC3004 Clinical Study Report
`
`1
`
`'
`
`The medications with the highest rate of use by eMG and placebo patients were Fortrans and
`Macro