| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderately to Severely Active Crohn's Disease |
|
| 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 | 10058815 |
| E.1.2 | Term | Crohn's disease acute episode |
| E.1.2 | System Organ Class | 100000004856 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10011402 |
| E.1.2 | Term | Crohn's disease (colon) |
| E.1.2 | System Organ Class | 100000004856 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10011403 |
| E.1.2 | Term | Crohn's disease aggravated |
| 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 Period: To assess endoscopic improvement following treatment with RPC1063;
Extension Period: To characterize the longer term safety of continued dosing of RPC1063 |
|
| E.2.2 | Secondary objectives of the trial |
Induction Period:
- to characterize clinical improvement, response, and remission following treatment with RPC1063;
- to assess changes in intestinal and blood biomarkers following treatment with RPC1063 by characterizing the following:
• Intestinal mucosa histopathologic disease activity
• Select cellular, protein, and molecular biomarkers in the intestinal mucosa and blood
• To assess the pharmacokinetics (PK) and pharmacodynamics (PD) of RPC1063
• To assess the safety of RPC1063
Extension Period:
- to characterize endoscopic improvement at Week 52; t
- to characterize the histopathological changes of the intestinal mucosa at Week 52; to characterize the effect of RPC1063 in maintaining clinical improvement over time |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients aged 18 to 75 years, inclusive;
2. Diagnosis of Crohn’s disease for at least 2 months (prior to Screening) by clinical endoscopic evidence and corroborated by a histology report (Note: histopathology may be performed during Screening if no prior report is readily available);
3. Crohn's disease Activity Index score of 220 to 450 inclusive with an SES-CD score of ≥ 6. (If disease isolated to ileum, the requirement will be a SES-CD score ≥ 4);
4. Average daily stool score ≥ 4 points and/or an average daily abdominal pain score of ≥ 2 points;
5. Patients must meet one of the following criteria:
• Have an inadequate response or loss of response to at least one of the following Crohn’s disease treatments:
- Aminosalicylates, oral aminosalicylates ≥2.4 g/day or ≥ 3 g/day sulfasalazine for at least 4 weeks
- Corticosteroids, oral prednisone ≥ 30 mg or budesonide ≥ 9 mg for at least 2 weeks or an equivalent (to oral prednisone) of intravenous corticosteroid for 1 week
- Immunomodulators, oral azathioprine ≥ 1.5 mg/kg or 6-mercaptopurine 0.75 mg/kg (documentation of therapeutic level of 6-thioguanine is also acceptable) or methotrexate ≥ 12.5 mg/week for at least 8 weeks
- Biologic therapy (TNFα antagonist or vedolizumab only) at an approved labeled dose used for induction therapy for at least 4 weeks or recurrence of disease activity despite scheduled maintenance therapy. (Biologic therapy exposed patients will be capped at 50% of total enrolled patients).
• And/or have been intolerant to any of the above mentioned therapies (e.g., unable to achieve doses, dose levels, or treatment durations because of treatment related side effects and/or laboratory abnormalities);
6. The following background therapies for Crohn’s disease will be permitted on a stable dose:
- Oral aminosalicylates (e.g., mesalamine, sulfasalazine, olsalazine, balsalazide) at a stable dose for at least 3 weeks prior to Screening endoscopy
- Prednisone (doses ≤ 20 mg per day) or equivalent at a stable dose for at least 2 weeks prior to Screening endoscopy
- Budesonide therapy at a stable dose (dose ≤ 9 mg per day) for at least 2 weeks prior to Screening endoscopy
- Antibiotics used for the treatment of Crohn’s disease (i.e., ciprofloxacin, metronidazole) at a stable dose for at least 2 weeks prior to Screening endoscopy.
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 endoscopy 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 (LAM) are not acceptable methods of contraception. Female condom and male condom should not be used together.
9. Ability to provide written informed consent and to be compliant with the schedule of protocol assessments;
10. Must have documentation of positive Varicella zoster virus (VZV), immunoglobulin G (IgG) antibody status or complete VZV vaccination at least 30 days prior to first dose of investigational drug;
11. For patients at high risk (i.e., family history, disease duration) for colonic malignancy, documented evidence of having had a surveillance colonoscopy within the last 2 years or according to local medical guidelines to evaluate for polyps, dysplasia, or malignancy. If no recent history of surveillance colonoscopy, this can be done as part of colonoscopy performed during Screening. |
|
| E.4 | Principal exclusion criteria |
1. Diagnosis of ulcerative colitis or indeterminate colitis
2. Crohn’s disease isolated to the stomach, duodenum, jejunum, or peri-anal region, without colonic or ileal involvement
3. Known strictures or stenosis leading to symptoms of obstruction
4. Current stoma or need for ileostomy or colostomy
5. Extensive small bowel resection or known diagnosis of short bowel syndrome;
6. Suspected or diagnosed intra-abdominal or perianal abscess that has not been appropriately treated;
7. Currently require or are anticipated to require surgical intervention for CD during the Induction Period
8. Currently receiving total parenteral nutrition;
9. Positive stool culture for pathogens or positive test for Clostridium difficile at Screening
10. Pregnancy, lactation, or a positive serum beta human chorionic gonadotropin (hCG) measured during Screening
11. 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
12. Clinically relevant cardiovascular conditions, including history or presence of:
- Recent 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 QTcF interval, or at additional risk for QT prolongation (e.g., hypokalemia, hypomagnesemia, congenital long-QT syndrome)
- Resting HR < 55 beats per minute (bpm) when taking vitals as part of a physical examination at Screening
- Mobitz type 2nd degree or 3rd degree AV block;
13. History of diabetes mellitus type 1, or uncontrolled diabetes mellitus type 2 with hemoglobin A1c > 9%, or diabetic patients with significant co-morbid conditions such as retinopathy or nephropathy
14. History of uveitis or known macular edema
15. 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.
16. History or known presence of recurrent or chronic infection; recurrent urinary tract infections are permitted.
17. History of cancer, including solid tumors and hematological malignancies;
18. Past or current evidence of colonic dysplasia
19. History of alcohol or drug abuse within 1 year prior to first dose of investigational drug'
20. History of or currently active primary or secondary immunodeficiency'
Exclusions Related to Medications:
21. History of treatment with a biologic agent within 5 elimination half-lives of that agent prior to first dose of investigational drug
22. History of treatment with an investigational agent within 5 elimination half-lives of that agent prior to first dose of investigational drug
23. History of treatment with topical rectal 5-ASA or steroids within 2 weeks of Screening
24. History of primary non-response to two approved biologic therapies used for the treatment of Crohn’s disease
25. Receipt of a live vaccine or live attenuated vaccine within 4 weeks prior to Screening
26. Previous treatment with lymphocyte-depleting therapies;
27. Treatment with cyclosporine, tacrolimus, sirolimus, or mycophenolate mofetil within 16 weeks of Screening;
28. Previous treatment with D-penicillamine, leflunomide, or thalidomide;
29. Previous treatment with natalizumab or fingolimod;
30. History of treatment with intravenous immune globulin (IVIg), plasmapheresis, within 3 months prior to first dose of investigational drug
31. Planned concurrent treatment with immunosuppressive agents after enrollment.
32. Chronic non-steroidal anti-inflammatory drug (NSAID) use
33. Treatment with Class Ia or Class III anti-arrhythmic drugs or treatment with two or more agents in combination known to prolong PR interval
34. Treatment with any of the following drugs or interventions within the timeframe:
- At Day 1: CYP2C8 inhibitors or inducers
- 2 weeks prior to Day 1: monoamine oxidase inhibitors
Exclusions Related to Laboratory Results:
35. Serum creatinine >1.4 mg/dL for women or >1.6 mg/dL for men
36. 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
37. Platelet count <100,000/μL
38. Hgb <8.5 g/dL
39. Neutrophils < 1500/μL
40. Absolute WBC count < 3500/μL
41. Absolute lymphocyte count < 800/μL
42. ECG showing any clinically significant abnormality
43. 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) |
| Change in SES-CD from baseline at Week 12 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Induction Period
• Change in CDAI score from baseline at Week 12
• Proportion of patients with clinical remission based on CDAI at Week 12
• Proportion of patients with clinical response based on CDAI at Week 12
• Proportion of patients with clinical remission based on PRO2 definitions at Week 12
• Proportion of patients with clinical response based on PRO2 definitions at Week 12
• Proportion of patients with endoscopic remission based on SES-CD definitions at Week 12
• Proportion of patients with endoscopic response based on SES-CD definitions at Week 12
• Change in intestinal mucosa histopathologic features and disease activity
• Changes in biomarkers:
- Intestinal mucosa: immunohistochemistry and/or in situ hybridization (IHC/ISH) for example: CD20, CD4, CD8, Foxp3, α4 β7, CCR7, IFNα, IL17
- Intestinal mucosa: transcript profiling (mRNA) for example IFN
signature, T cell exhaustion signature, outcome signature, S1PR pathway
- Blood biomarkers for example C-reactive protein, d-dimer, IFNα, fibrin, collagen, elastin, and glycan fragments, fibrolysis and fibrogenesis markers
- Stool biomarkers for example fecal calprotectin and fibrolysis and fibrogenesis markers
• Improvement in perianal and enterocutaneous fistulas at Week 12 in those patients with fistulas at baseline
Extension Period
Efficacy Endpoints:
• Proportion of patients in endoscopic remission based on SES-CD definitions at Week 52
• Proportion of patients in endoscopic response based on SES-CD definitions at Week 52
• Proportion of patients in clinical remission based on CDAI at Week 52
• Proportion of patients in clinical response based on CDAI at Week 52
• Proportion of patients in clinical remission based on PRO2 definitions at Week 52
• Proportion of patients in clinical response based on PRO2 definitions at Week 52
• Proportion of patients in clinical remission at Week 52 based on CDAI and PRO2 definitions who are off corticosteroids of those on corticosteroids at baseline
• Proportion of patients in clinical remission based on CDAI over time
• Proportion of patients in clinical response based on CDAI over time
• Proportion of patients in clinical remission based on PRO2 definitions over time
• Proportion of patients in clinical response based on PRO2 definitions over time
• Change in intestinal mucosa histopathologic features, histologic disease activity, and biomarkers over time
• Change in fecal calprotectin and serum C-reactive protein (CRP) levels over time
• Improvement in perianal and enterocutaneous fistulas in those patients with fistulas at baseline over time
Pharmacokinetic and Pharmacodynamic Endpoints
• Plasma concentration of RPC1063 and active metabolites at scheduled assessments during the treatment period
• Absolute lymphocyte count (ALC) derived from hematology laboratory results
• Peripheral immune cell phenotype determined by Flow cytometry
Safety:
The incidence, severity, relationship and type of treatment-emergent adverse events (TEAEs), serious AEs (SAEs), AEs leading to discontinuation of investigational drug, and AEs of special interest, and clinically meaningful changes from baseline on clinical laboratory measures, vital signs, ECG, and physical examinations will be assessed.
The safety of patients will be monitored by collection of treatment-emergent AEs, serious adverse events (SAEs), physical examinations, vital sign measurements, ECG results, optical coherence tomography (OCT), pulmonary function tests (PFTs), and clinical laboratory tests. Patients who discontinue from treatment due to lack of response, AEs, or other reasons, even if alternative treatment is given, will be followed for 30 days for collection of safety data, including lymphocyte recovery, and for the assessment of their disease status. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Induction: at week 12
Extension: at week 52, W160 and FU visit
For details please check the study protocol |
|
| 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 | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| 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 |
| The trial comprises 2 periods: Induction (12 weeks) and Extension (148 weeks) |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 16 |
| 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 |
| Canada |
| Hungary |
| Poland |
| 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 | 3 |
| E.8.9.1 | In the Member State concerned months | 1 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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