E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Moderately to severely Active Crohn's Disease |
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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 | 20.0 |
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 |
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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 |
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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 |
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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 |
The primary objective is to evaluate the efficacy of PRV-6527 for 12 weeks in the treatment of moderately to severely active CD, as measured by the Crohn’s Disease Activity Index (CDAI). |
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E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate the effect of PRV-6527 for 12 weeks on: Clinical • Colonic and ileal mucosa, based upon the Simple Endoscopic Score for CD (SES-CD) • Clinical symptoms, based upon the frequency of diarrheal stools and abdominal pain • Clinical symptoms, based upon the PRO-2 portion of CDAI Safety • Safety and tolerability of PRV-6527 in subjects with active CD Pharmacokinetics (PK) • Trough plasma concentrations of PRV-6527 and its active metabolites, M2 and M7 and their sum, in subjects with active CD Pharmacodynamics (PD) • PD effects measured by fecal calprotectin (FC) and ultrasensitive C-reactive protein (CRP) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Each subject must sign an informed consent form (ICF) indicating that he or she understands the purpose of and procedures required for the study and are willing to participate in the study. All subjects must be capable of signing their own ICF and complete the eDiary. 2. Subject must be a man or woman between 18 years and 75 (inclusive) years of age. 3. Has moderate to severe CD with a CDAI score between 220 and 450 (inclusive) and a histologic diagnosis of CD for at least 3 months before screening. The histological diagnosis should be confirmed locally from the screening colonoscopy if not previously documented at the site. 4. Has screening laboratory test results within the following parameters: a. Hemoglobin ≥8 g/dL b. WBC ≥2000 cells/μL c. Neutrophils ≥1500 cells/μL d. Creatinine ≤1.7 mg/dL e. Serum AST or ALT ≤2 x upper limit of normal (ULN) f. Total bilirubin ≤2 x ULN g. CPK ≤3 x ULN h. LDH ≤3 x ULN 5.SES-CD score ≥6 or ≥4 for ileal-only disease 6. Subject may be either biologic naïve or biologic experienced. Subjects who have had prior experience with anti-TNF, anti-integrin, or anti-MAdCAM-1 treatment would be eligible if they were primary nonresponders, secondary nonresponders, intolerant or allergic to anti-TNF agents (e.g. infliximab), or stopped such treatment for other reasons. Subjects who have had prior experience with anti-IL-12/23 (e.g. ustekinumab) or anti-IL-23 agents would be eligible if they were responders, secondary nonresponders, or stopped the treatment due to intolerance or reasons unrelated to efficacy. Primary nonresponders to anti-IL-12/23 or anti-23 are excluded (see Exclusion #6). 7. Female subjects must meet the following inclusion criteria: a. Women not of childbearing potential: Postmenopausal is defined as being >45 years of age with amenorrhea for at least 18 months) or >45 years of age with amenorrhea for at least 12 months and a confirmatory serum follicle stimulating hormone (FSH) level >40 IU/L with luteinizing hormone (LH) level >40 IU/L in women not receiving Hormone replacement therapy; permanently sterilized (eg, hysterectomy, bilateral salpingectomy, bilateral oophorectomy); or otherwise be incapable of pregnancy. Note: tubal ligation is not considered permanent sterilization. b. Women of childbearing potential: 1) Must have a negative serum β-human chorionic gonadotropin (β-hCG) at screening and a negative urine pregnancy test at Week 0 prior to dosing 2) Must practice a highly effective method of birth control (<1% failure rate) consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies such as established use (>3 months) of oral, injected or implanted highly effective hormonal methods of contraception; placement of an intrauterine device or intrauterine system; male partner sterilization (the vasectomized partner should be the sole partner for that subject); true abstinence (when this is in line with the preferred and usual lifestyle of the subject). 3).Must agree to use highly effective methods of birth control throughout the study for 3 months after receiving the last dose of study drug (placebo or PRV-6527). 4) Must agree not to donate eggs (ova, oocytes) for the purposes of assisted reproduction during the study and for 3 months after receiving the last dose of study drug. 8. Male subjects must meet the following criterion: A man who is sexually active with a woman of childbearing potential and has not had a vasectomy or otherwise surgically sterile must agree to highly effective birth control for their female partner as outlined above and must use condoms with spermicide during sexual intercourse, and this must continue for 3 months after receiving the last dose of study drug. All men must also not donate sperm during the study and for 3 months after receiving the last dose of study drug. 9. Subject must be able to read, understand and complete study questionnaires. 10. Subject must be willing and able to adhere to the prohibitions and restrictions specified in this protocol. |
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E.4 | Principal exclusion criteria |
1. Ileostomy, colostomy, or short gut syndrome or is anticipated to require surgery in the next 6 months, or has tight stricture that prevents the passage of any colonoscope 2. Untreated active external or perianal fistula or abscess 3. Other gastrointestinal inflammatory diseases 4. Any malignancy or lymphoproliferative disorder other than nonmelanoma cutaneous malignancies or cervical carcinoma 5. Colon cancer or severe dysplasia 6. Primary nonresponder to anti-IL-12/23 or anti-IL-23 biologic treatment 7. Previously treated with natalizumab 8. Treated with tofacitinib, cyclosporine, or other immunosuppressives including biologics, other than thiopurines or methotrexate (MTX) within at least 5 half-lives before baseline (randomization). 9. Has been on a variety of doses of thiopurines or MTX within 8 weeks of screening 10. Treated with unstable doses of mesalamine (5-ASA) or chronic antibiotics within 30 days before screening 11. Treated with rectal steroids or systemic corticosteroids 12. Treated with proton pump inhibitors (PPIs) or cimetidine within 7 days before baseline (randomization). NOTE: Subjects may take non-cimetidine H2 receptor agonists, including high doses for refractory gastroesophageal reflux disease 13. Subject is receiving and/or is anticipated to require strong inhibitors or inducers of CYP3A4, CYP2C8, and CYP2C19 isoenzymes during the study Subject is receiving and/or is anticipated to require substrates of p-glycoprotein during the study 15. History of, or ongoing, chronic or recurrent infectious disease, including but not limited to endemic fungal infections, chronic renal infection, chronic chest infection, recurrent urinary tract infection, or a history of serious infection 16. Current signs or symptoms of an acute infection or infected skin wounds or ulcers, with the exception of nonserious infections in the opinion of the Investigator 17. Has or ever has had a non-TB mycobacterial infection or serious opportunistic infection (eg, cytomegalovirus colitis, Pneumocystis carinii, aspergillosis) 18. Female subject is pregnant, lactating, planning to become pregnant, or sexually active of childbearing potential and refuses to use highly effective birth control. Male subject is planning on fathering a child during and within 3 months after study Treatment 19. Received an investigational drug or used an invasive investigational medical device within 12 weeks before the planned first administration of study drug 20. Positive antibody to p24 antigen (Ab-p24Ag) for human immunodeficiency virus (HIV) 1 or 2 confirmed by HIV 1/2 Western blot, hepatitis C virus (HCV) at screening [(anti-HCV+ with HCV RNA+]; hepatitis B virus (HBV) [HBsAg+ or Total anti-HBc+ with HBV DNA+] at screening 21. Stool culture or microscopic examination positive for enteric pathogens, ova, and parasites. Positive Clostridium difficile toxin or glutamate dehydrogenase (GDH) (C. DIFF QUIK CHEK) with confirmatory positive polymerase chain reaction (PCR) at screening 22. Subject meets any of the following TB screening criteria: a. History of untreated latent or untreated active TB prior to screening b. Signs or symptoms suggestive of active TB upon medical history and/or physical examination c. Recent close contact with a person with active TB and has not been evaluated by a physician specializing in TB d. Positive QuantiFERON®-TB Gold Plus test result during screening. Subjects who have a newly identified positive QuantiFERON®-TB Gold Plus test result but have been ruled out for active TB (ie, asymptomatic and negative chest x-ray) and have completed appropriate treatment for latent TB may be enrolled e. Chest radiograph (posterior-anterior and lateral views), taken within 3 months before baseline and read by a qualified radiologist, with evidence of current active TB or old inactive TB that has not been fully treated 23. Severe, progressive, or uncontrolled renal, hepatic impairment including Hy's Law (ALT and/or AST ≥ 3x ULN AND total Bilirubin ≥ 2x ULN) and Primary sclerosing cholangitis, hematological, endocrine, pulmonary, cardiac, neurologic, cerebral, or psychiatric disease, or signs and symptoms thereof 24. Transplanted organ; a corneal transplant >12 weeks before screening is allowed 25. Unable or unwilling to undergo multiple venipunctures because of poor tolerability or lack of easy access to veins 26. Currently or intending to participate in any other study using an investigational agent or procedure during participation in this study. 27. Any condition for which, in the opinion of the Investigator, participation would not be in the best interest of the subject 28. Employees of the Investigator or study site, with direct involvement in the proposed study 29. Subject with a history of substance abuse or refuses to refrain from the use of marijuana and illicit drugs during the study. Occasional alcohol use is permitted |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
Clinical • Change from baseline to Week 12 in SES-CD score • Change from baseline to Week 12 in abdominal pain based on a Numerical Rating Scale (NRS) (0-10 scale) • Change from baseline to Week 12 in the number of daily loose or watery stools (type 6 or 7 stools) per week, as defined by the Bristol Stool Form Scale (BSFS) • Change from baseline to Week 12 in PRO-2 score Safety • Treatment Emergent Adverse Events (TEAEs), adverse events (AEs) leading to withdrawal and Serious Adverse Events (SAEs) • Clinically significant changes in vital signs, electrocardiogram (ECG), and laboratory tests PK • Cmin of PRV-6527 and its active metabolites, M2 and M7 and their sum PD • Change from baseline to Week 12 in ultrasensitive CRP • Change from baseline to Week 12 in FC |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
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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 | 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 | No |
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 | 2 |
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 | 29 |
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 |
Austria |
Germany |
Hungary |
Poland |
Russian Federation |
Spain |
Ukraine |
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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
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A subject will be considered to have completed the study if he or she has completed assessments at Week 16. |
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 1 |
E.8.9.1 | In the Member State concerned months | 6 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial years | 1 |
E.8.9.2 | In all countries concerned by the trial months | 6 |