| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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.
MAINTENANCE THERAPY
To demonstrate the efficacy of RPC1063 versus placebo maintenance therapy on clinical remission. |
|
| E.2.2 | Secondary objectives of the trial |
INDUCTION THERAPY
Demonstrate
-the efficacy of RPC1063 versus placebo on induction of clinical response
-the efficacy of RPC1063 versus placebo on achieving endoscopic improvement
-the efficacy of RPC1063 versus placebo on achieving histologic remission
-the safety and tolerability of RPC1063 induction therapy
MAINTENANCE THERAPY
Demonstrate
-the efficacy of RPC1063 versus placebo in maintaining clinical response
-the efficacy of RPC1063 versus placebo on achieving endoscopic improvement
-the efficacy of RPC1063 versus placebo on durability of clinical remission
-the efficacy of RPC1063 versus placebo on maintaining clinical remission among patients who achieved remission during induction therapy
-the efficacy of RPC1063 versus placebo, in achieving corticosteroid-free remission among patients receiving corticosteroids at entry into the Maintenance Period
-the safety and tolerability of RPC1063 maintenance therapy |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients aged 18 to 75 years (at screening), inclusive
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 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
7. 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
8. Female patients of childbearing potential:
Must agree to practice a highly effective method of contraception throughout the trial until completion of the 75-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 vasectomised partner sexual abstinence
Male patients:
Must agree to use a latex condom during sexual contact with women of childbearing potential while participating in the study until completion of the 75-day Safety Follow-up Visit.
All patients:
Periodic abstinence (calendar, symptothermal, post-ovulation methods),withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods of contraception.
Female Condom and male condom should not be used together.
9. Must provide written informed consent and have the ability to be compliant with the schedule of protocol assessments
10. 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 |
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| 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
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
• 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)
• 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. Known active bacterial, viral, fungal, mycobacterial infection, or other infection (including tuberculosis [TB] or atypical mycobacterial disease [but excluding fungal infection of nail beds, minor upper respiratory tract infections and minor skin infections]) or any major episode of infection that required hospitalization or treatment with intravenous antibiotics within 30 days of screening or oral antibiotics within 14 days of screening
10. History of cancer, including solid tumors and hematological malignancies (except basal cell and in situ squamous cell carcinomas of the skin or uterine cervix that have been excised and resolved) or colonic mucosal dysplasia
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 8 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 antimotility
medications (such as diphenoxylate/atropine) during Screening
15. Receipt of a live vaccine or live attenuated vaccine within 4 weeks prior to randomization
16. Planned concurrent treatment with immunosuppressive agents (eg,
azathioprine [AZA], 6-mercaptopurine [6-MP], or methotrexate) after
randomization. Patients receiving AZA, 6-MP, or methotrexate at
Screening must discontinue treatment with these agents prior to
randomization
17. Treatment with Class Ia or Class III anti-arrhythmic drugs or
treatment with two or more agents in combination known to prolong PR
interval
18. Patients who were primary non-responders to 2 or more biologic
agents approved for the treatment of UC (eg, anti-TNF agents or
vedolizumab)
Exclusions Related to Laboratory Results:
19. Serum creatinine > 1.4 mg/dL for females or > 1.6 mg/dL for males
20. Liver function impairment or persisting elevations of aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 2 times the upper limit of normal (ULN), or direct bilirubin > 1.5 times the ULN
21. Platelet count < 100,000/uL
22. Hemoglobin < 8.5 g/dL
23. Neutrophils < 1500 ¬/uL
24. Absolute white blood cell count < 3500/uL
25. Absolute lymphocyte count < 800/uL
26. ECG showing any clinically significant abnormality
27. Forced expiratory volume at 1 second (FEV1) or forced vital capacity (FVC) < 70% of predicted values at screening |
|
| 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
Primary Efficacy Endpoint:
- The proportion of patients in clinical remission at Week 10.
INDUCTION PHASE Cohort 2
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.
MAINTENANCE PHASE
Primary Efficacy Endpoint:
- The proportion of patients in clinical remission at 52 weeks
|
|
| 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
Key Secondary Efficacy Endpoints:
- The proportion of patients with a clinical response at Week 10
- The proportion of patients with endoscopic improvement at Week 10
- The proportion of patients with mucosal healing at Week 10
MAINTENANCE PHASE
Key Secondary Efficacy Endpoints:
- The proportion of patients with a clinical response at 52 weeks
- The proportion of patients with endoscopic improvement at 52 weeks
- The proportion of patients with durable clinical remission
- The proportion of patients in clinical remission at 52 weeks in the subset of patients who were
in remission at Week 10
- The proportion of patients with corticosteroid-free remission
- The proportion of patients with mucosal healing at 52 weeks
OTHER ENDPOINTS
Safety
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). |
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| 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) |
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| 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 | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 117 |
| 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 |
| Austria |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 10 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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