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 |
Ulcerative colitis is a form of inflammatory bowel disease (IBD) that causes inflammation and ulcers in the colon resulting in abdominal pain and bloody diarrhea. |
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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 |
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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 |
1. To assess the safety and tolerability of PRA023 following 12-weeks of induction therapy 2. To compare the efficacy of PRA023 vs placebo for induction of clinical remission at Week 12
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E.2.2 | Secondary objectives of the trial |
Compare the efficacy of PRA023 vs placebo for induction of: - endoscopic improvement - clinical response - histologic remission - histologic-endoscopic mucosal improvement - mucosal healing
Compare the efficacy of PRA023 vs placebo for change in IBDQ
Compare the efficacy of PRA023 vs placebo in subjects who are companion diagnostic positive (CDx+) for induction of: - clinical remission - endoscopic improvement - clinical response - histologic remission - histologic-endoscopic mucosal improvement - mucosal healing
Compare the efficacy of PRA023 in CDx+ vs CDx- subjects for induction of clinical remission.
Compare the efficacy of PRA023 vs placebo for change in IBDQ Compare the efficacy of PRA023 vs placebo in CDx+ subjects for change in IBDQ |
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E.2.3 | Trial contains a sub-study | Yes |
E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
Title: Pharmacokinetic Sub-Study Date and Version: 11MAR2021, V01 Objective: To better understand the PK of PRA023 in subjects with UC and to evaluate the PK of PRA023 at steady state |
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E.3 | Principal inclusion criteria |
Subjects are required to meet the following criteria in order to be included in the study: 1. Male or female ≥18 years of age 2. Subjects must have had a documented diagnosis of UC (endoscopy + histology) to be eligible for study participation. For subjects with no documented confirmation of UC diagnosis or if previous diagnosis is not deemed conclusive, UC diagnosis must be confirmed at time of screening colonoscopy 3. Moderately to severely active UC as defined by 3-component Modified Mayo Score (3 components of rectal bleeding, stool frequency, and endoscopy) of 4 to 9, inclusive, with Modified Mayo endoscopic subscore ≥2 and rectal bleeding subscore ≥ 1. 4. Subjects must satisfy at least one of the following criteria: a) In the past, had an inadequate response to one or more of the following treatments: i. Oral prednisone ≥ 40 mg/day (or equivalent) or budesonide ≥ 9 mg/day for at least 2 weeks ii. Corticosteroid dependence as defined by failed to successfully taper to < 10 mg/day of prednisone equivalent (i.e., had a flare of disease) within 3 months of starting therapy, or if relapse occurs within 3 months of stopping corticosteroids iii. Immunosuppressants (azathioprine ≥ 2 mg/kg/day or 6-mercaptopurine ≥ 1.0 mg/kg/day [or documentation of a therapeutic concentration of 6-thioguanine nucleotide]) for at least 12 weeks iv. An approved anti-TNF agent at an approved labeled dose for at least 8 weeks v. Vedolizumab at the approved labelled dose for at least 8 weeks vi. An approved JAK inhibitor (e.g., tofacitinib) at an approved labelled dose for at least 8 weeks vii. An approved anti-IL-12/23 (e.g., ustekinumab) at an approved labelled dose for at least 8 weeks viii. An approved sphingosine 1-phosphate receptor (S1PR) modulator at an approved labelled dose for least 12 weeks OR b) Had been intolerant to one or more of the above-mentioned treatments (e.g., unable to achieve doses or treatment durations because of dose limiting side effects [e.g., leukopenia, psychosis, uncontrolled diabetes, elevated liver enzymes]). OR c) Currently receiving one or more of the following treatments: i. Oral Prednisone ≥ 10 mg/day (or equivalent) for at least 3months ii. Immunosuppressants [azathioprine ≥ 2 mg/kg/day or 6-mercaptopurine ≥ 1.0 mg/kg/day (or documentation of a therapeutic concentration of 6 thioguanine nucleotide)] for at least 8 weeks Notes on subjects who have had prior biologic/biologic-like therapy(ies) (anti-TNF, JAK inhibitor, anti-IL-23, and/or anti-integrin): i. The study will include a maximum of 70% subjects who have had prior biologic/biologic-like therapy(ies) experience. Upon reaching the maximum number of allowed biologic/biologic-like experienced subjects (70%), subjects who have had prior biologic/biologic-like experience will no longer be allowed to enter the study. ii. Subject cannot have failed (no response, insufficient response, loss of response, and/or intolerance) > 3 classes or > 4 individual biologic/biologic-like therapies (exclusion criterion #26). 5. For subjects who are women of childbearing potential (WOCBP) involved in any sexual intercourse that could lead to pregnancy, the subject has used two highly effective methods of contraception for at least 4 weeks prior to Day 1 and agrees to continue to use two highly effective methods of contraception until at least 12 weeks after the last dose of study drug. 6. Male subjects must use two highly effective methods of contraception from screening to 12 weeks after the last dose of study drug. 7. Subject must meet drug stabilization requirements, as applicable: a) Oral corticosteroid treatment must have been reduced to the equivalent of ≤ 20 mg prednisone or ≤ 9 mg budesonide daily at a stable dose for at least 2 weeks prior to randomization. b) Oral aminosalicylates should be at a stable dose for at least 2 weeks prior to randomization. c) Azathioprine and 6-mercaptopurine should be at a stable dose for at least 4 weeks prior to randomization. 8. Able to provide written informed consent and understand and comply with the requirements of the study. |
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E.4 | Principal exclusion criteria |
1. WOCBP and men with WOCBP partner unwilling/ unable to use two highly effective methods of contraception 2. Women who are pregnant or breastfeeding 3. Women with a positive pregnancy test 4. Diagnosis of Crohn's disease or indeterminate colitis 5. UC limited to the rectum (<15 cm from anal verge) 6. Current evidence of fulminant colitis, toxic megacolon, or bowel perforation 7. Current or impending need for colostomy or ileostomy 8. Previous total proctocolectomy or subtotal colectomy 9. Surgical bowel resection within 3 months before screening 10. Concomitant primary sclerosing cholangitis (PSC) 11. Past or current evidence of colonic dysplasia that has not been completely removed 12. Scheduled or anticipate the need for surgery, except dermatologic procedures 13. History of clinically significant drug or alcohol abuse 14. Concomitant illness that is likely to require systemic glucocorticosteroid therapy during study (e.g., moderate to severe asthma) 15. Current symptoms of severe, progressive, or uncontrolled renal, hepatic, hematological, pulmonary, cardiac, neurological, ophthalmologic or cerebral disease that might place the subject at unacceptable risk for participation 16. Have history of cancer within the last 5 years (other than non-melanoma skin cell cancers cured by local resection). Existing non-melanoma skin cell cancers must be removed prior to enrollment. Subjects with carcinoma in situ or localized cervical cancer, treated with definitive surgical intervention, are allowed 17. At risk of tuberculosis (TB), specifically subjects with: (1) history of active TB; (2) current active TB OR (3) latent TB which was not successfully treated 18. With any serious bacterial infection within the last 3 months, unless treated and resolved with antibiotics, or any chronic bacterial infection. 19. Females who have had a breast cancer screening that is suspicious for malignancy or cannot be reasonably excluded from clinical, laboratory or other diagnostic evaluations 20. Active bacterial or viral infections including HIV, Hepatitis B or Hepatitis C infection during screening. Hepatitis C with no recurrence for ≥ 1 year are allowed 21. With herpes zoster reactivation or CMV that resolved less than 2 months prior to signing ICF 22. Received any live vaccines within 3 months or who will need live vaccine during the study. 23. Positive stool culture for enteric pathogens 24. Stool positive for clostridium difficile toxin 25. Any of the following lab values: a) Hgb < 8.0 g/dL (80 g/L) b) WBC < 2,500/mm3 (2.5 x 10E9/L) c) Neutrophils <1,000/mm3 (1 x 10E9/L) d) Platelets < 100,000/mm3 (100 x 10E9/L) e) Serum creatinine > 2 times upper limit of normal (ULN) f) Serum alanine aminotransferase (ALT) or aspartate aminotransferase > 2 times ULN g) Any other laboratory test results that show subject at unacceptable risk for participation 26. Failed > 3 classes (anti-TNF, anti-integrin, anti-IL12/23, JAK inhibitor, S1PR modulator) or > 4 individual biologic/biologic-like therapies 27. Any marketed biologic or biologic-like used for UC, 2 weeks for tofacitinib, 8 weeks for anti-TNF agents, 10 weeks for S1PR, and 12 weeks, for vedolizumab and ustekinumab prior to randomization or if drug level per therapeutic dose monitoring is greater than lower limit of detection. 28. Any biologic immunomodulators not covered in #27, used for UC or other conditions within 8 weeks prior to randomization or if drug level per therapeutic dose monitoring is greater than lower limit of detection 29. Rituximab within 1 year prior to randomization 30. Parenteral corticosteroids within 4 weeks or rectal administration of corticosteroids within 2 weeks prior to randomization 31. Rectal administration of 5-ASA within 2 weeks prior to randomization 32. Tacrolimus, methotrexate, cyclosporine, mycophenolate mofetil (CellCept®), immunoadsorption columns (such as Prosorba columns), D Penicillamine, Leflunomide, Thalidomide, fish-oil preparations, probiotics, fecal transplantation, non-steroidal anti-inflammatory agents (NSAIDs), aspirin > 81 mg/day within 2 weeks prior to randomization 33. Other investigational chemical agent within 30 days or other investigational biologic agent within 8 weeks or 5 half-lives (whichever is longer) of randomization 34. Prior exposure to PRA023 35. Prisoners or subjects who are compulsorily detained for treatment of either a psychiatric or physical illness must not be enrolled into this study 36. Legal or mental incapacitation, or inability to understand and comply with the requirements of the study |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. The proportion of subjects reporting adverse events (AEs), serious adverse events (SAEs), AEs leading to discontinuation, and markedly abnormal laboratory values. 2. The proportion of subjects in the 3-component Modified Mayo Score clinical remission (as defined by endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and stool frequency subscore of 0 or 1 and not greater than Baseline) at Week 12. The 3-component Modified Mayo Score ranges from 0-9 and includes rectal bleeding, stool frequency and endoscopic assessment domains.
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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) |
1. The proportion of subjects with endoscopic improvement, as defined by endoscopy subscore ≤1 with no friability) at Week 12. 2. The proportion of subjects in 3-component Modified Mayo Score clinical response at Week 12. The 3-component Modified Mayo Score clinical response is defined by reduction from Baseline ≥2 points and ≥30% in modified Mayo Score, accompanied by a reduction ≥ 1 in rectal bleeding subscore or absolute rectal bleeding subscore ≤1. 3. The proportion of subjects in the 3-component Modified Mayo Score clinical remission (as defined by endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and stool frequency subscore of 0 or 1 and not greater than Baseline), in CDx+ subjects (Cohort 1 + Cohort 2) treated with PRA023 compared to CDx+ placebo-treated subjects at Week 12. The 3-component Modified Mayo Score ranges from 0-9 and includes rectal bleeding, stool frequency and endoscopic assessment domains. 4. The proportion of subjects with histologic remission (defined Geboes score ≤3.1) at Week 12. 5. The proportion of subjects with histologic-endoscopic mucosal improvement (defined as Geboes score ≤3.1 and endoscopy subscore ≤1 with no friability) at Week 12. 6. The proportion of subjects with endoscopic improvement, as defined by endoscopy subscore ≤1 with no friability, in CDx+ subjects (Cohort 1 + Cohort 2) treated with PRA023 compared to CDx+ placebo-treated subjects at Week 12. 7. The proportion of subjects in 3-component Modified Mayo Score clinical response in CDx+ subjects treated with PRA023 compared to CDx+ placebo-treated subjects at Week 12. The 3-component Modified Mayo Score clinical response is defined by reduction from Baseline ≥ 2 points and ≥ 30% in modified Mayo Score, accompanied by a reduction ≥ 1 in rectal bleeding subscore or absolute rectal bleeding subscore ≤ 1. 8. The proportion of subjects with histologic remission, defined as Geboes score ≤3.1, in CDx+ subjects (Cohort 1 + Cohort 2) treated with PRA023 compared to CDx+ placebo-treated subjects at Week 12. 9. The proportion of subjects with histologic-endoscopic mucosal improvement (defined as Geboes score ≤3.1 and endoscopy subscore ≤1 with no friability), in CDx+ subjects (Cohort 1 + Cohort 2) treated with PRA023 compared to CDx+ placebo-treated subjects at Week 12. 10. The proportion of subjects with clinical remission (defined as endoscopic subscore of 0 or 1, rectal bleeding subscore of 0, and stool frequency subscore of 0 or 1 and not greater than Baseline) in CDx+ subjects (Cohort 1 + Cohort 2) treated with PRA023 compared to in CDx- subjects treated with PRA023 at Week 12. 11. The proportion of subjects with mucosal healing (defined as Geboes score ≤2B.1 and endoscopy subscore of ≤ 1) at Week 12. 12. The proportion of subjects with mucosal healing (defined as Geboes score ≤2B.1 and endoscopy subscore of ≤ 1), in CDx+ subjects (Cohort 1 + Cohort 2) treated with PRA023 compared to CDx+ placebo-treated subjects at Week 12. 13. The proportion of subjects with IBDQ response, as defined by ≥ 16-point increase from Baseline at Week 12. 14. The proportion of subjects with IBDQ response, as defined by ≥ 16-point increase from Baseline, in CDx+ subjects (Cohort 1 + Cohort 2) treated with PRA023 compared to CDx+ placebo-treated subjects at Week 12. |
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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 | Yes |
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 | 3 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 23 |
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 |
Belarus |
Canada |
Georgia |
Israel |
Russian Federation |
Serbia |
Ukraine |
United States |
Belgium |
Bulgaria |
France |
Hungary |
Poland |
United Kingdom |
Czechia |
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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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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 | 4 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |