| 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 | 14.1 |
| 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 65 years, inclusive
2. Have had UC diagnosed at least 3 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 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. Men and women of childbearing potential must agree to use adequate birth control measures during the study. Acceptable methods of birth control in this study include: surgical sterilization, intrauterine device, oral contraceptive, contraceptive patch, long acting injectable contraceptive, partner’s vasectomy, double-barrier method (condom or diaphragm with spermicide) or abstinence during study participation and for 30 days after their last dose of treatment of study treatment
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 ≤ 20 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 sigmoidoscopy 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 study treatment or must have had a colonoscopy at screening to assess for polyps. The adenomatous polyps must be removed prior to their first dose of study drug.
10. Ability to provide written informed consent and to be compliant with the schedule of protocol assessments
11. Documentation of positive varicella zoster virus (VZV) IgG antibody status
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
|
|
| 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 gonadotrophin (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 ischemic heart disease, myocardial infarction, congestive heart failure, stroke, transient ischemic attack, sick sinus syndrome, recurrent syncope, second degree or higher atrioventricular (AV) block, prolonged QTcF interval (QT interval corrected for HR according to Fridericia's formula) (QTcF > 450 msec males, > 470 msec females), other clinically significant conduction abnormalities or any other significant cardiac condition that could jeopardize a patient’s health during the study in the opinion of the treating Investigator
8. Resting HR less than 55 beats per minute (bpm)
9. History of diabetes mellitus
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 or known presence of recurrent or chronic infection (e.g., hepatitis A, B, C or E, 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 any immune-modifying biologic agent including abatacept, infliximab, etanercept, adalimumab, anakinra, vedolizumab or golimumab within 4 months prior to randomization. Patients unresponsive to vedolizumab will be excluded.
17. History of treatment with a biologic agent within 5 half-lives of that agent
18. History of treatment with an investigational agent within 5 half-lives of that agent
19. History of treatment with topical rectal steroids within 2 weeks of screening
20. Receipt of a live vaccine within 4 weeks prior to screening
21. Previous treatment with lymphocyte-depleting therapies (e.g., Campath, anti-CD4, cladribine, rituximab, ocrelizumab, cyclophosphamide, mitoxantrone, total body irradiation, bone marrow transplantation, alemtuzumab, daclizumab)
22. Previous treatment with D-penicillamine, leflunomide or thalidomide
23. Previous treatment with lymphocyte trafficking blockers (e.g., natalizumab, fingolimod)
24. History of treatment with IVIg, plasmapheresis, within 3 months prior to randomization
25. Treatment with immunosuppressive agents (e.g., azathioprine, 6-MP, or methotrexate) within 4 weeks of the sigmoidoscopy used for baseline Mayo Score
26. Use of therapies that are not allowed based on CYP3A4 metabolism (i.e. strong to moderate inhibitors) within 4 weeks prior to randomization
27. Treatment with medications with a known impact on the cardiac conduction system (e.g., beta blockers, calcium channel blockers, Class Ia or Class III anti-arrhythmic drugs)
28. Serum creatinine > 1.4 mg/dL for women or > 1.6 mg/dL for men
29. Liver function impairment or persisting elevations of AST or ALT > 2 times the upper limit of normal (ULN), or direct bilirubin > 1.5 times the ULN
30. Platelet count < 100,000/μL
31. Hgb < 8.5 g/dL
32. Neutrophils < 1.5 /μL
33. Absolute WBC count < 3500/μL
34. Absolute lymphocyte count < 800/μL
35. ECG showing clinically significant abnormality (e.g. acute ischemia, any heart conduction abnormality)
36. 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) |
| 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 | 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) | 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 45 |
| 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 |
| Australia |
| Belgium |
| Canada |
| Czech Republic |
| Germany |
| Hungary |
| Israel |
| Korea, Republic of |
| New Zealand |
| Poland |
| Russian Federation |
| Slovakia |
| 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 | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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