| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderately to severely active Ulcerative Colitis |
|
| 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 |
| Compare the efficacy of RPC1063 vs placebo for induction of clinical remission at Week 8 in patients with moderately to severely active UC. |
|
| E.2.2 | Secondary objectives of the trial |
- Compare the efficacy of RPC1063 vs placebo at weeks 8 and 32 as measured by clinical response, clinical remission, and mucosal healing
- Compare the overall safety and tolerability of RPC1063 vs placebo for the duration of the study |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Males or female patients aged 18 to 75 years, inclusive
2. Have had UC diagnosed at least 2 months prior to screening. The diagnosis of UC must be confirmed by endoscopic and histologic evidence
3. Have active UC confirmed on endoscopy with ≥ 15 cm involvement
4. Have active UC defined as Mayo score of 6-12 inclusive with endoscopic subscore of ≥ 2
5. Have undergone colonoscopy or sigmoidoscopy within the past 2 years for extent of disease, and if the UC has been present for > 10 years, have had a colonoscopy with biopsy to rule out dysplasia
6. Female patients of childbearing potential:
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
- Vasectomised partner
- Sexual abstinence
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), spermicides only, and lactational amenorrhoea method are not acceptable methods of contraception.
7. Must be currently receiving treatment with at least 1 of the following therapies:
a. Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, balsalazide) for at least 6 weeks with the dose stable for at least 3 weeks prior to screening endoscopy
b. Prednisone (doses ≤ 30 mg) or equivalent for at least 4 weeks and receiving a stable dose for at least 2 weeks
8. 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
9. All patients aged 45 years or over must have had a colonoscopy to screen for adenomatous polyps within 5 years of their first dose of investigational drug or must have had a colonoscopy at screening to assess for polyps. The adenomatous polyps must be removed prior to their first dose of investigational drug.
10. Ability to provide written informed consent and to be compliant with the schedule of protocol assessments
11. Patients must have documentation of positive Varicella Zoster virus (VZV) IgG antibody status or complete VZV vaccination at least 30 days prior to randomization.
12. Documentation of no evidence of chronic lung disease or tuberculosis (TB) on a chest X-ray completed within the 6 months prior to screening. If a chest X-ray was not done in the 6 months preceeding the Screening visit, it may be performed during the Screening visit.
|
|
| E.4 | Principal exclusion criteria |
1. Have severe extensive colitis evidenced by:
- Physician judgment that patient is likely to require colectomy or ileostomy within 12 weeks of baseline
- Current evidence of fulminant colitis, toxic megacolon or bowel perforation
- Previous total colectomy
- Have 4 or more of the following:
Temp > 38°C, Heart rate (HR) > 110 (bpm); Focal severe or rebound abdominal tenderness; Anemia (hemoglobin [Hgb] < 8.5 g/dL); Transverse colon diameter > 5cm on plain X-ray
2. Diagnosis of Crohn’s disease or indeterminate colitis or the presence or history of a fistula consistent with Crohn’s disease
3. Have positive stool culture for pathogens (O+P, bacteria) or positive test for C. difficile at screening. If C. difficile is positive, the patient may be treated and retested
4. Have had treatment with cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil (MMF) within 16 weeks of screening
5. Pregnancy, lactation, or a positive serum beta human chorionic gonadotropin (hCG) measured during screening
6. Clinically relevant hepatic, neurological, pulmonary, ophthalmological, endocrine, psychiatric or other major systemic disease making implementation or interpretation of the study difficult or that would put the patient at risk
7. Clinically relevant cardiovascular conditions, including history or presence of:
i. 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
ii. Prolonged QTcF interval (QTcF > 450 msec males, > 470 msec females), or at additional risk for QT prolongation (e.g., hypokalemia, hypomagnesemia, congenital long-QT syndrome, concurrent therapy with QT prolonging drugs)
iii. Patients with other pre-existing stable cardiac conditions who have not been cleared for the study by an appropriate cardiac evaluation by a cardiologist
8. Resting HR less than 55 beats per minute (bpm) when taking vitals as part of a physical exam at Screening
9. History of diabetes mellitus type 1, or uncontrolled diabetes mellitus type 2 with hemoglobin A1c > 7%, or diabetic patients with significant co-morbid conditions such as retinopathy or nephropathy
10. History of uveitis
11. Known active bacterial, viral, fungal, mycobacterial infection or other infection (including TB or atypical mycobacterial disease [excluding fungal infection of nail beds]) or any major episode of infection that required hospitalization/treatment with intravenous (IV) antibiotics within 30 days or oral antibiotics within 14 days prior to screening
12. History of recurrent or chronic infection (e.g., hepatitis B or C, human immunodeficiency virus, syphilis, TB); recurring urinary tract infections are allowed
13. History of cancer, including solid tumors and hematological malignancies (except basal cell and in situ squamous cell carcinomas of the skin that have been excised and resolved)
14. History of alcohol or drug abuse within 1 year prior to randomization
15. History of or currently active primary or secondary immunodeficiency
16. History of treatment with a biologic agent within 5 half-lives of that agent prior to randomization
17. History of treatment with an investigational agent within 5 half-lives of that agent prior to randomization
18. History of treatment with topical rectal steroids within 2 weeks of screening
19. Receipt of a live vaccine or attenuated live vaccine within 4 weeks prior to randomization
20. Previous treatment with lymphocyte-depleting therapies (e.g., Campath, anti-CD4, cladribine, rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, total body irradiation, bone marrow transplantation, alemtuzumab, daclizumab)
21. Previous treatment with D-penicillamine, leflunomide or thalidomide
22. Previous treatment with natalizumab or fingolimod)
23. History of treatment with IVIg, plasmapheresis, within 3 months prior to randomization
24. Planned concurrent treatment with immunosuppressive agents (e.g., azathioprine, 6-MP, or methotrexate) after randomization. Subjects receiving azathioprine, 6-MP or methotrexate at screening must discontinue treatment with these agents prior to dosing with investigational drug.
25. Treatment with Class Ia or Class III anti-arrhythmic drugs or treatment with two or more agents in combination known to prolong PR interval.
26. Treatment with any of the following drugs or interventions within the corresponding timeframe:
- At randomization: CYP2C8 inhibitors (eg, gemfibrozil or clopidogrel) or inducers (eg, rifampicin)
- Two weeks prior to randomization: Monoamine oxidase inhibitors (eg, selegiline, phenelzine)
(Please refer to the protocol for the remaining criteria) |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of patients in clinical remission, defined as a Mayo score of ≤ 2 points and with no individual subscore of > 1 point |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Efficacy Endpoints:
• Proportion of patients with a clinical response at Week 8, defined as a reduction from baseline in Mayo score of ≥ 3 points and ≥ 30%, and a decrease from baseline in the rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of ≤ 1 point
• Change from baseline in Mayo score at Week 8
• Proportion of patients with mucosal healing at Week 8, defined by an endoscopy subscore of ≤ 1 point
• Proportion of patients in clinical remission at Week 32 defined as Mayo score of ≤ 2 points with no individual subscore of > 1 point
• Proportion of patients with a clinical response at Week 32, defined as a reduction from baseline in Mayo score of ≥ 3 points and ≥ 30%, and a decrease from baseline in the rectal bleeding subscore of ≥ 1 point or an absolute rectal bleeding subscore of ≤ 1 point
• Proportion of patients with mucosal healing at Week 32, defined by an endoscopy subscore of ≤ 1 point
Safety Endpoints:
• The incidence and type of AEs, SAEs, AEs leading to discontinuation of study treatment, target AEs of special interest, laboratory abnormalities, vital signs, ECG, and physical exam abnormalities
PK and PD Endpoints:
• PK assessments will include PK sampling to determine plasma concentration of RPC1063 and active metabolites at scheduled assessments during the treatment period (see Table 1 [IP and MP] and Table 2 [OLP] Schedule of Events)
• Absolute lymphocyte count (ALC) derived from blinded hematology laboratory results
• Plasma protein biomarkers (cytokines, chemokines, other inflammatory proteins)
• Stool analysis for fecal biomarkers – fecal lactoferrin and calprotectin
• Total immunoglobulins (Igs) - IgA, IgG, IgM |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Optional open-label treatment period |
|
| 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 | 3 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 15 |
| 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 |
| Belgium |
| Bulgaria |
| Greece |
| Hungary |
| Israel |
| Korea, Republic of |
| Netherlands |
| Poland |
| Russian Federation |
| Slovakia |
| Ukraine |
| 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 | 7 |
| E.8.9.1 | In the Member State concerned months | 3 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 7 |
| E.8.9.2 | In all countries concerned by the trial months | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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