| 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 |
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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 | 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 |
| The primary objective of this study is to assess the efficacy of twice daily doses of tofacitinib in altering histological inflammation after 8 weeks of treatment in patients with moderate to severely active ulcerative colitis. |
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| E.2.2 | Secondary objectives of the trial |
- to assess immune cell infiltration in colonic mucosa by immunohistochemistry and assessment of mRNA expression.
- In addition, cytokine profiles in the peripheral blood will be assessed and microbiome analysis in feces and colonic mucosa will be performed to detect associations with response. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Subject must be at least 18 years of age.
2. Males and females with a documented diagnosis of UC ≥ 4 months prior to entry into the study. A biopsy report supporting the diagnosis must be available in the source documents.
3. Subjects with moderately to severely active UC as defined by a total Mayo score of ≥6, with a rectal bleeding score of ≥ 1 and an endoscopic (sigmoidoscopy) subscore of ≥ 2 on the Mayo score determined within 7 days of starting the study treatment (tofacitinib).
4. Subjects must have failed or be intolerant (discontinued the medication due to an adverse event as determined by the investigator) of at least one of the following treatments for UC:
- Oral corticosteroids
- Azathioprine or 6-mercaptopurine (6-MP).
- Anti-TNF therapy: infliximab, adalimumab or golimumab
5. No evidence of active or latent or inadequately treated infection with Mycobacterium tuberculosis (TB) as defined by negative QuantiFERON-TB Gold (QFT-G) In-Tube test and a chest radiograph, taken at or within the 3 months prior to a given screening visit, without changes suggestive of active TB infection as determined by a qualified radiologist.
6. If a subject has previously received an adequate course of therapy for either latent (9 months of isoniazid in a locale where rates of primary multi-drug TB resistance are <5% or an acceptable alternative regimen) or active (acceptable multi-drug regimen) TB infection, neither a QFT-G test nor a PPD test is needed, but a chest radiograph must still be obtained if not performed within 3 months prior to a given Screening visit. Documentation of adequate treatment for TB will be obtained prior to first dose of study drug.
- A subject who is currently being treated for active TB infection is to be excluded.
- A subject who is currently being treated for latent TB infection can only be enrolled with confirmation of current incidence rates of multi-drug resistant TB infection in the locale, documentation of an adequate treatment regimen, and with prior approval by the sponsor.
7. Female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 4 weeks after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active.
8. Women of childbearing potential must have a negative pregnancy test prior to study enrollment.
9. Subjects receiving non-prohibited concomitant medications for any reason, must be on a stable regimen, which is defined as not starting a new drug or changing dosage within 7 days or 5 half-lives (whichever is longer) prior to first study dose.
10. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, daily diary call, and other study procedures.
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| E.4 | Principal exclusion criteria |
1. Presence of indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, or clinical findings suggestive of Crohn’s disease.
2. Subjects without previous treatment for UC (ie, treatment-naïve).
3. Subjects displaying clinical signs of fulminant colitis or toxic megacolon.
4.Subjects with evidence of colonic adenomas or dysplasia. However, subjects with prior history of adenomatous polyps will be eligible if the polyps have been completely removed and the subjects are free of polyps at baseline.
5. Subjects at risk for colorectal cancer must have a Colonoscopy. Colonoscopy report and pathology report (if biopsies are obtained) must be available in the source document:
6. Subjects who have had surgery for UC or in the opinion of the Investigator, are likely to require surgery for UC during the study period.
7. Subjects who have positive stool examinations for enteric pathogens, pathogenic ova or parasites, or Clostridium difficile toxin at screening.
8. Subjects with clinically significant infections currently or within 6 months of baseline , a history of any infection requiring antimicrobial therapy within 2 weeks of baseline, or a history of any infection otherwise judged by the investigator to have the potential for exacerbation by participation in the study.
9. Subjects with a history of more than one episode of herpes zoster, a history of disseminated herpes zoster or disseminated herpes simplex.
10. Subjects infected with human immunodeficiency virus (HIV) or hepatitis B or C viruses
11. Subjects who have been vaccinated with live or attenuated vaccine within 6 weeks of baseline or scheduled to receive these vaccines during study period or within 6 weeks after last dose of study medication.
12. Subjects with history of any lymphoproliferative disorder
13. Subjects with malignancies or a history of malignancies, with the exception of adequately treated or excised non-metastatic basal cell or squamous cell cancer of the skin.
14. Subjects with a history of bowel surgery within 6 months prior to baseline.
15. Subjects with significant trauma or major surgery within 4 weeks of screening visit.
16. Subjects likely to require any type of surgery during the study period.
17. Subjects with the following laboratory values at screening:
• Hemoglobin levels <9.0 g/dL or hematocrit <30%.
• An absolute white blood cell (WBC) count of <3.0 x 109/L (<3000/mm3) or absolute neutrophil count of <1.2 x 109/L (<1200/mm3).
• Thrombocytopenia, as defined by a platelet count <100 x 109/L (<100,000/mm3).
• Subjects with estimated GFR 50 ml/min based on Cockcroft-Gault calculation.
• Subjects with total bilirubin, AST or ALT more than 1.5 times the upper limit of normal.
18. Subjects with evidence of or suspected liver disease ie, liver injury due to methotrexate or primary sclerosing cholangitis.
19. Subjects with current or recent history of severe, progressive, or uncontrolled renal, hepatic, hematological, gastrointestinal, metabolic , endocrine, pulmonary, cardiac, neurological disease.
20. Subjects with any condition possibly affecting oral drug absorption . Procedures such as gastric banding that simply divide the stomach into separate chambers are NOT exclusionary.
21. Women who are pregnant or lactating, or planning to become pregnant during the study period.
22. History of alcohol or drug abuse with less than 6 months of abstinence prior to baseline.
24. Donation of blood in excess of 500 mL within 8 weeks prior to baseline.
25. Subjects with a first-degree relative with a hereditary immunodeficiency.
26. Subjects who have previously participated in any study of CP-690,550.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
To investigate the efficacy of twice daily doses of tofacitinib (10 mg bid) to decrease histological inflammation after 8 weeks of treatment in patients with moderate to severely active ulcerative colitis measured by:
Median change in inflammatory infiltrates at week 8 in 2 colon biopsies as assessed by the Robarts Histopathology Index [Mosli, Gut, 2015] and the Geboes index [Geboes, Gut, 2000], by an independent GI pathologist.
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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) |
-Median change in symptoms as measured by the Simple Clinical Colitis Activity Index (SCCAI) at weeks 0, 2, 4 and 8.
-Median change in high sensitivity CRP and fecal calprotectin after treatment with tofacitinib for 8 weeks.
-Median improvement of endoscopic disease severity measured by the Mayo endoscopy score. All endoscopies (weeks 0 and 8) will be videotaped and assessed by 2 independent readers using the Mayo endoscopy score [Schroeder, NEJM, 19xx].Proportion of patients reaching mucosal healing (Mayo 0/1) after 8 weeks of tofacitinib. Proportion of subjects in endoscopic remission at Week 8. Endoscopic remission is defined by Mayo endoscopic subscore of 0.
-Incidence and severity of adverse events up to 84 days after initiating treatment.
-Proportion of subjects achieving clinical response at Week 8. Clinical response is defined by a decrease from baseline in Mayo score of at least 3 points and at least 30 percent, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or absolute subscore for rectal bleeding of 0 or 1.
-The proportion of subjects in clinical remission at Week 8. Clinical remission is defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point.
-The proportion of subjects in symptomatic remission at Week 8. Symptomatic remission is defined by a total Mayo score of 2 points or lower, with no individual subsocre exceeding 1 point, and both rectal bleeding and stool frequency subcore of 0.
-The proportion of subjects achieving deep remission at Week 8. Deep remission is defined by a total Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and a zero on both endoscopic and rectal bleeding subscores.
-Partial Mayo scores and change from baseline over time.
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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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | No |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| assess changes in colonic inflammation |
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| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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 | No |
| 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.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| 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 | 2 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
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