| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Digestive System Diseases [C06] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10045365 |
| E.1.2 | Term | Ulcerative colitis |
| E.1.2 | System Organ Class | 100000004856 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
INDUCTION THERAPY
Demonstrate the efficacy of RPC1063 versus placebo on induction of clinical remission in adults.
MAINTENANCE THERAPY
To demonstrate the efficacy of RPC1063 versus placebo maintenance therapy on clinical remission in adults. |
|
| E.2.2 | Secondary objectives of the trial |
INDUCTION THERAPY
Demonstrate efficacy of RPC1063 vs placebo
- on induction of clinical response in adults
- on achieving endoscopic improvement in adults
- on achieving histologic remission in adults
Demonstrate safety and tolerability of RPC1063 induction therapy in all patients
MAINTENANCE THERAPY
Demonstrate efficacy of RPC1063 vs placebo
- in maintaining clinical response in adults
- on achieving endoscopic improvement in adults
- on durability of clinical remission in adults
- on maintaining clinical remission among patients who achieved remission during induction therapy in adults
- in achieving corticosteroid-free remission among patients receiving corticosteroids at entry into Maintenance Period in adults
Demonstrate safety and tolerability of RPC1063 maintenance therapy in all patients
Exploratory: Explore the efficacy of RPC1063 vs placebo on induction of clinical remission, clinical response, endoscopic improvement, and histologic remission in adolescents |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Must meet one of the following criteria: 1. Male or female adult patients aged 18 to 75 years (at Screening), inklusive for Cohort 1 or Cohort 2, or Male or female adolescent patients aged 12 to < 18 years (at Screening) with a body weight ≥ 45 kg for Cohort 3. Note: Countries or sites with local restrictions that prohibit enrollment of adolescents (aged 12 to <18 years) will only enroll patients who are aged 18 to 75 years, inclusive. Enrollment of adolescent patients will only begin after the applicable regulatory requirements for studying patients in that age group have been satisfied and the necessary health authority agreements have been granted.
2. Have had UC diagnosed at least 3 months prior to first investigational drug administration. The diagnosis should be confirmed by clinical and endoscopic evidence and corroborated by a histopathology report (note: endoscopy and histopathology may be performed at Screening if no prior
report is readily available)
3. Evidence of UC extending ≥ 15 cm from the anal verge as determined by Baseline endoscopy (flexible sigmoidoscopy or colonoscopy)
4. Have active UC defined as a complete Mayo score of 6 to 12 inclusive, with endoscopic subscore of ≥ 2, a rectal bleeding score of ≥ 1, and a stool
frequency score ≥ 1
5. Must be currently receiving treatment with at least 1 of the following therapies and must continue on these therapies during Induction:
- Oral aminosalicylates at a therapeutic dose for their disease (eg, mesalamine, sulfasalazine, olsalazine, balsalazide), with the dose stable
for at least 3 weeks, prior to Screening endoscopy
- Prednisone (doses ≤ 20 mg per day) or equivalent receiving a stable dose for at least 2 weeks prior to Screening endoscopy
- Budesonide MMX therapy receiving a stable dose for at least 2 weeks prior to Screening endoscopy
6. Have undergone colonoscopy (or are willing to undergo colonoscopy
during Screening):
- within the past 2 years, to screen for dysplasia (unless otherwise recommended by local and national guidelines) if the patient has had
left-sided colitis of > 12 years duration or total/extensive colitis of > 8 years duration
- within the past 5 years, to screen for polyps if the patient age is > 45 years
- if oral aminosalicylates or corticosteroids have been recently discontinued, they must have been stopped for at least 2 weeks prior to
the endoscopy used for Baseline Mayo Score
7. Females of childbearing potential (FCBP): Must agree to practice a highly effective method of contraception throughout the trial until completion of the 90-day safety follow-up visit. Highly effective methods of contraception are those that alone or in combination result in a failure rate of a Pearl index of less than 1% per year when used consistently and correctly. Acceptable methods of birth control in the trial are the following:
- combined hormonal (oestrogen and progestogen containing) contraception, which may be oral, intravaginal, or transdermal
- progestogen-only hormonal contraception associated with inhibition of ovulation, which may be oral, injectable, or implantable
- placement of an intrauterine device (IUD)
- placement of an intrauterine hormone-releasing system (IUS)
- bilateral tubal occlusion
- vasectomized partner
- complete sexual abstinence
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational
amenorrhoea method are not acceptable methods of contraception.
8. Must provide written informed consent/assent and have the ability to be compliant with the schedule of protocol assessments. The parent/legal guardian of the adolescent must sign an informed consent form. In addition, adolescent patients must also agree to participate in the study by signing an assent.
9. Patients must have documentation of positive Varicella zoster virus IgG antibody status or complete Varicella zoster virus vaccination at
least 30 days prior to randomization |
|
| E.4 | Principal exclusion criteria |
Exclusions Related to General Health:
1. Have severe extensive colitis as evidenced by:
• Physician judgment that the patient is likely to require colectomy or ileostomy within 12 weeks of Baseline
• Current or recent (within 3 months) evidence of fulminant colitis, toxic megacolon, or bowel perforation
2. Diagnosis of Crohn’s disease or indeterminate colitis or the presence or history of a fistula consistent with Crohn’s disease or microscopic colitis or radiation colitis or ischemic colitis
3. Have positive stool examination for pathogens (ova and parasites, bacteria) or positive test for toxin producing Clostridium difficile (C. difficile) at Screening. PCR (polymerase chain reaction) examination of the stool for C. difficile may be used to exclude false positives. If positive, patients may be treated and retested. Documentation of a negative test result for pathogens (ova and parasites, bacteria) is required within 60 days of Day 1.
4. Pregnancy, lactation, or a positive serum β-human chorionic gonadotropin (β-hCG) measured during Screening
5. Clinically relevant hepatic, neurological, pulmonary, ophthalmological, endocrine, psychiatric, or other major systemic disease making implementation of the protocol or interpretation of the trial difficult or that would put the patient at risk by participating in the trial
6. Clinically relevant cardiovascular conditions, including history or presence of:
• Recent (within the last 6 months) occurrence of myocardial infarction, unstable angina, stroke, transient ischemic attack, decompensated heart failure requiring hospitalization, Class III/IV heart failure, sick sinus syndrome, or severe untreated sleep apnea
• For adult patients: Prolonged Fridericia’s corrected QT interval (QTcF; QTcF > 450 msec for males, > 470 msec for females), or at additional risk for QT interval prolongation (eg, hypokalemia, hypomagnesemia, congenital long-QT syndrome, concurrent therapy with QT prolonging drugs)
• For Adolescent patients: Prolonged Fridericia’s corrected QT interval (QTcF; QTcF > 450 msec for both males and females), or at additional risk for QT interval prolongation (eg, hypokalemia, hypomagnesemia, congenital long-QT syndrome)
• Resting HR < 55 bpm when taking vital signs as part of a physical exam at Screening
7. History of diabetes mellitus type 1 or uncontrolled diabetes mellitus type 2 with glycosylated Hb (HbA1c) >9 %, or diabetic patients with significant comorbid conditions such as retinopathy or nephropathy
8. History of uveitis (within the last year) or macular edema
9. Subject has a known active bacterial, viral or fungal infection [excluding fungal infection of nail beds, minor upper respiratory tract infections, and minor skin infections], a mycobacterial infection (including tuberculosis[TB] or atypical mycobacterial disease), or any major episode of infection that required hospitalization or treatment with intravenous (IV) antibiotics within 30 days of Screening or oral antibiotics within 14 days of Screening
10. Recurrent or chronic infection (eg, hepatitis A, B or C, human immunodeficiency virus (HIV); recurrent urinary tract infections are allowed
11. History of alcohol or drug abuse within 1 year prior to randomization
....
Exclusions Related to Medications:
12. History of treatment with a biologic agent within 10 weeks or 5 elimination half-lives (whichever is less) of that agent prior to randomization
13. History of treatment with an investigational agent within 5 elimination half-lives of that agent prior to randomization
14. History of treatment with topical rectal 5-aminosalicylic acid or topical rectal steroids within 2 weeks of Screening endoscopy or anti-motility medications (such as diphenoxylate/atropine) during Screening
15. Receipt of a live vaccine within 4 weeks prior to randomization
16. Planned concurrent treatment with immunosuppressive agents (eg, AZA, 6-MP or methotrexate) after randomization. Patients receiving AZA,6-MP or methotrexate at Screening must discontinue treatment with these agents prior to randomization
......
20. Platelet count <100,000/uL
21. Hemoglobin <8.5 g/dL
22. Neutrophils <1500 ¬/uL
23. Absolute white blood cell count <3500/uL
24. Absolute lymphocyte count <800/uL
...
28. Patients receiving treatment with breast cancer resistance protein (BCRP) inhibitors (eg, cyclosporine, eltrombopag)
29. Is receiving treatment with any of the following drugs or interventions within the corresponding timeframe:
At randomization - CYP2C8 inhibitors (eg, gemfibrozil or clopidogrel) and inducers (eg, rifampicin)
Two weeks prior to randomization - Monoamine oxidase inhibitors (eg, selegiline, phenelzine)
30. Adolescent patients with delayed growth or delayed pubertal development and who will not maintain a stable dose of corticosteroids through Week 10
... |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
The efficacy endpoints will be formally examined with statistical hypothesis tests conducted on the efficacy results obtained from patients randomized and dosed in Cohort 1. Cohort 2 is open-label and does not contain a control group
INDUCTION PHASE Cohort 1 in Adult Patients
Primary Efficacy Endpoint:
- The proportion of adult patients in clinical remission at Week 10.
INDUCTION PHASE Cohort 2 in Adult Patients
- Cohort 2 is open label; therefore, no formal analysis of efficacy endpoints will be conducted. All efficacy endpoints will be summarized and described without hypothesis testing and reported using descriptive statistics.
INDUCTION PHASE Cohort 3 in Adolescents
- For statistical analysis purposes, clinical remission and clinical response will be calculated using the Threecomponent
Mayo definition.
MAINTENANCE PHASE, Adult Patients
Primary Efficacy Endpoint:
- The proportion of adult patients in clinical remission at 52 weeks
MAINTENANCE PHASE, Adolescents
- For statistical analysis purposes, clinical remission and clinical response will be calculated using the Threecomponent
Mayo definition. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
At 10 weeks (Induction Visit I4/Week 10)
At 52 weeks (Maintenance Visit M5/Week 42)
|
|
| E.5.2 | Secondary end point(s) |
INDUCTION PHASE in Adult Patients
Key Secondary Efficacy Endpoints:
- The proportion of adult patients with a clinical response at Week 10
- The proportion of adult patients with endoscopic improvement at Week 10
- The proportion of adult patients with mucosal healing at Week 10
INDUCTION PHASE in Adolescents
Exploratory Endpoints:
- The proportion of adolescent patients in clinical remission at Week 10
- The proportion of adolescent patients with a clinical response at Week 10
- The proportion of adolescent patients with endoscopic improvement at Week 10
- The proportion of adolescent patients with mucosal healing at Week 10
- Change in complete Mayo score, partial Mayo score, 9-point Mayo score from Baseline to Week 10
- Proportion of adolescent patients with histologic remission at Week 10
- Proportion of adolescent patients with clinical response, remission, or endoscopic improvement at Week 10 in adolescent patients who were naive to or previously received anti-TNF therapy
- The proportion of adolescent patients with clinical remission based on Pediatric Ulcerative Colitis Activity Index [PUCAI] score (< 10) at Week 10
MAINTENANCE PHASE in Adult Patients
Key Secondary Efficacy Endpoints:
- The proportion of adult patients with a clinical response at 52 weeks
- The proportion of adult patients with endoscopic improvement at 52 weeks
- The proportion of adult patients with durable clinical remission
- The proportion of adult patients in clinical remission at 52 weeks in the subset of patients who were in remission at Week 10
- The proportion of adult patients with corticosteroid-free remission
- The proportion of adult patients with mucosal healing at 52 weeks
MAINTENANCE PHASE, Adolescent Patients (Cohort 3):
- The proportion of adolescent patients in clinical remission at 52 weeks
- The proportion of adolescent patients with a clinical response at 52 weeks
- The proportion of adolescent patients with endoscopic improvement at 52 weeks
- The proportion of adolescent patients with durable clinical remission
- The proportion of adolescent patients in clinical remission at 52 weeks in the subset of adolescent patients who were in remission at Week 10
- The proportion of adolescent patients with corticosteroid-free remission
- The proportion of adolescent patients with mucosal healing at 52 weeks
- Change in complete Mayo score, partial Mayo score, and 9-point Mayo score from Baseline to 52 weeks
- The proportion of adolescent patients with histologic remission at 52 weeks
- The proportion of adolescent patients with clinical response, remission, or endoscopic improvement at 52 weeks in adolescent patients who previously received anti-TNF therapy
- The proportion of adolescent patients in remission at 52 weeks while off corticosteroids for any length of time
- Change in the PUCAI score from Baseline to 52 weeks
- Proportion of adolescent patients with clinical remission based on the PUCAI score (< 10) at 52 weeks
OTHER ENDPOINTS
Safety for All Patients
Pharmacokinetic and pharmacodynamic |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
At 10 weeks (Induction Visit I4/Week 10)
At 52 weeks (Maintenance Visit M5/Week 42)
From the list of Other efficacy endpoints during maintenance phase (not primary or secondary) some endpoints are evaluated at 28 weeks (Maintenance Visit M3/Week 18), 40 weeks (Maintenance Visit M3/Week 30) and 52 weeks (Maintenance Visit M3/Week 42). |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| 2 phases. Induction (Cohort1: Random PlaceboContr; Cohort2: OpenLabel); Maintenance (PlaceboContr) |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 4 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 100 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Australia |
| Belarus |
| Belgium |
| Bulgaria |
| Canada |
| Czech Republic |
| Germany |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| New Zealand |
| Poland |
| Russian Federation |
| Slovakia |
| South Africa |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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