| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Moderate to severe Ulcerative Colitis (UC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| Ulcerative colitis is a chronic inflammatory condition of the gastrointestinal tract characterized by continuous inflammation that is localized to the colon |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| 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 |
|
| 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 |
| To evaluate the efficacy of PF-06651600 and PF-06700841 at Week 8 in subjects with moderate to severe UC. |
|
| E.2.2 | Secondary objectives of the trial |
•To evaluate the safety and tolerability of PF-06651600 and PF-06700841 in subjects with moderate to severe UC.
•To evaluate the efficacy of PF-06651600 and PF-06700841 in induction of remission at Week 8 in subjects with moderate to severe UC.
•To evaluate the efficacy of PF-06651600 and PF-06700841 at Week 32 in subjects with moderate to severe UC.
•To evaluate the efficacy of PF-06651600 and PF-06700841 for achieving remission at Week 32.
•To evaluate the efficacy of PF-06651600 and PF-06700841 in improvement of endoscopic appearance at Week 8 and/or Week 32 in subjects with moderate to severe UC.
•To evaluate the effect of PF-06651600 and PF-06700841 in induction of other clinical outcomes in subjects with moderate to severe UC.
•To evaluate the effect of PF-06651600 and PF-06700841 in induction on patient reported outcomes (PRO) in subjects with moderate to severe UC.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and/or female subjects ≥18 years to ≤75 years of age at the time of informed consent. For subjects in Korea: Male and/or female subjects ≥19 years to ≤75 years of age at the time of informed consent.
2. Diagnosis (endoscopic and histological) of UC for ≥3 months prior to entry into the study. A report supporting disease duration and extent (eg, proctosigmoiditis, left-sided colitis, or pancolitis) based upon prior endoscopy including a biopsy report must be available in the source documentation.
3. Subjects with moderate to severe active UC as defined by a total Mayo score of ≥6, with a rectal bleeding subscore of ≥1 and an endoscopic subscore of ≥2. Endoscopy (colonoscopy or flexible sigmoidoscopy) must be performed within 10 days of baseline, preferably 5 to 7 days prior to baseline, to allow calculation of Total Mayo Score. The endoscopic subscore assessed by the Central Reader must be available at the baseline visit and will be used to derive the total Mayo score to determine study eligibility.
4. Active disease beyond the rectum (>15 cm of active disease from the anal verge at the screening endoscopy).
5. Must have inadequate response to, loss of response to, or intolerance to at least one conventional therapy for UC:
• Steroids;
• Immunosuppressants (azathioprine [AZA], 6-MP, or methotrexate [MTX]);
• Anti-TNF inhibitors (eg, infliximab, adalimumab, or golimumab);
• Anti-integrin inhibitors (eg, vedolizumab).
Please refer to the Protocol Appendix 1 for guidance only. Local standards of care, as well as investigator assessment should be considered in any assessment.
6. Subjects currently receiving the following treatment for UC are eligible providing they have been on stable doses as described below:
• Oral 5-ASA or sulfasalazine stable dose for at least 4 weeks prior to baseline. If oral 5-ASA treatment has been recently discontinued, it must have been stopped for at least 2 weeks prior to baseline.
• Oral corticosteroids (dose equivalent to prednisone up to 25 mg/day; budesonide up to 9 mg/day) stable dose for at least 2 weeks prior to baseline. If oral corticosteroids have been recently discontinued, they must have been stopped at least 2 weeks prior to baseline. Decreases in steroid use due to adverse events are allowed.
7. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
8. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
9. Female subjects of childbearing potential (Women of child-bearing potential: WOCBP) must test negative for pregnancy at screening visit and baseline visit.
10. Female subjects considered to be of non-childbearing potential must meet at least 1 of the following criteria:
a. Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; status may be confirmed with a serum follicle-stimulating hormone (FSH) level confirming the postmenopausal state;
b. Have undergone a documented hysterectomy and/or bilateral oophorectomy;
c. Have medically confirmed ovarian failure.
All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential. |
|
| E.4 | Principal exclusion criteria |
1. Female subjects who are pregnant or wish to become pregnant; breastfeeding female subjects; male subjects with partners currently pregnant; male subjects able to father children and female subjects of childbearing potential who are unwilling or unable to use 2 effective methods of contraception (at least 1 highly effective method) as outlined in the protocol for the duration of the study and for at least 28 days after the last dose of investigational product.
2. Presence of indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, radiation colitis, and diverticular disease associated with colitis, or clinical findings suggestive of Crohn’s disease (eg, fistulae, granulomas on biopsy).
3. Subjects with known colonic stricture and subjects with history of colonic or small bowel obstruction or resection.
4. Subjects with significant trauma or major surgery within 4 weeks of screening.
5. Subjects considered in imminent need for surgery or with elective surgery scheduled to occur during the study.
6. Subjects with a history of bowel surgery within 6 months prior to baseline.
7. Subjects displaying clinical signs of fulminant colitis or toxic megacolon.
8. Subjects with primary sclerosing cholangitis.
9. Subjects with history of colonic or small bowel stoma.
10. Subjects with evidence of colonic dysplasia, adenomas or neoplasia. However, subjects with adenomatous polyps identified on screening endoscopy will be eligible if the polyps have been completely removed and follow-up surveillance per local guidelines is negative.
11. Subjects who meet either of the 2 criteria below are considered at risk for colorectal cancer and must have a colonoscopy prior to randomization. The colonoscopy and pathology reports (if biopsies obtained) must be available in the source documentation:
•If the subject is ≥50 years of age, a colonoscopy within 10 years of screening is required to exclude adenomatous polyps. Subjects with adenomatous polyps identified on screening endoscopy will be eligible after complete polypectomy and follow-up surveillance per local guidelines is negative.
•If the subject has had extensive (ie, greater than left sided) colitis for ≥8 years or disease limited to left side of colon (ie, distal to splenic flexure) for ≥10 years, regardless of age, a colonoscopy within 1 year of screening visit is required to survey for dysplasia. Subjects with dysplasia or cancer identified on biopsies will be excluded.
12. Subjects receiving the following therapies within the time period described below or expected to receive any of these therapies during the study period:
•>9 mg/day of oral budesonide or >25 mg/day of prednisone or equivalent oral systemic corticosteroid dose within 2 weeks prior to baseline.
•IV, IM (parenteral), or topical (rectal) treatment of 5-ASA or corticosteroid enemas/suppositories within 2 weeks prior to baseline.
•Azathioprine, 6-mercaptopurine, or methotrexate within 2 weeks prior to baseline
•Anti-TNF inhibitors (or biosimilars thereof) as described below:
- Infliximab within 8 weeks prior to baseline;
- Adalimumab within 8 weeks prior to baseline;
- Golimumab within 8 weeks prior to baseline.
- Anti-integrin inhibitors (eg, vedolizumab) within 8 weeks prior to baseline.
•Interferon therapy within 8 weeks prior to baseline.
•Subjects with prior treatment with lymphocyte-depleting agents/therapies within 1 year prior to baseline (eg, CamPath® [alemtuzumab], alkylating agents [eg, cyclophosphamide or chlorambucil], total lymphoid irradiation, etc).
•Subjects who have received rituximab or other selective B lymphocyte-depleting agents within 1 year prior to baseline.
•Subjects previously receiving leukocyte apheresis, including selective lymphocyte, monocyte, or granulocyte apheresis, or plasma exchange within 6 months prior to baseline.
•Other marketed immunosuppressants or biologics with immunomodulatory properties within 3 months prior to baseline.
•Other investigational procedures(s) or product(s), such as immunosuppressants used in transplantation (eg, mycophenolate mofetil, cyclosporine, rapamycin, or tacrolimus) or live (attenuated) vaccine within 30 days prior to baseline.
•Other JAK inhibitors within 3 months prior to baseline. Subjects who have not responded to or have been intolerant of other JAK inhibitors.
•Participation in other studies involving investigational drug(s) (IPs) within 30 days, or 5-half-lives of IP (whichever is greater), prior to study entry and/or during study participation.
Please refer to the protocol for additional exclusion criteria |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Total Mayo score at Week 8 |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
- Incidence and severity of adverse events, serious adverse events and withdrawals due to adverse events.
- Incidence of serious infections (see Section 7.2.8 for definition).
- Proportion of subjects achieving remission* based on total Mayo score of ≤2 with no individual subscore >1 at Week 8.
- Total Mayo score at Week 32.
- Proportion of subjects in remission* based on total Mayo score of ≤2 with no individual subscore >1 at Week 32.
- Proportion of subjects achieving improvement in endoscopic appearance (defined as a Mayo endoscopic subscore of ≤1) at Week 8 and/or at Week 32
- Proportion of subjects achieving clinical response at Week 8.
- Proportion of subjects in endoscopic remission at Week 8.
- Proportion of subjects in symptomatic remission at Week 8.
- Proportion of subjects achieving deep remission at Week 8.
- Partial Mayo scores and change from baseline over time at Weeks 2, 4 and 8.
- Change from baseline at Week 8 in total Mayo score.
- The scores and change from baseline in Inflammatory Bowel Disease Questionnaire (IBDQ) Total score and domains (Bowel Symptoms, Systemic Symptoms, Emotional Function and Social Function) at Weeks 4 and 8.
- The proportion of subjects with IBDQ total score ≥170 at Weeks 4 and 8.
- The proportion of subjects with ≥16 point increase in IBDQ total score from baseline at Weeks 4 and 8.
- Proportion of subjects with improvement in IBDQ bowel symptom domain at Weeks 4 and 8. The improvement is defined as an increase of at least 1.2 points from baseline in average score among IBDQ bowel symptom domain (items 1, 5, 9, 13, 17, 20, 22, 24, 26, 29).
- The scores and change from baseline in Short Form 36 version 2, acute (SF-36v2) (physical and mental component summary scores: PCS & MCS, and 8 domain scores) at Weeks 4 and 8.
- The scores and change from baseline in EuroQoL 5 Dimensions (EQ-5D-3L & EQ-5D VAS) at Weeks 4 and 8. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Timepoints are as specified above |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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 | 8 |
| 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 | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 103 |
| 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 |
| Bulgaria |
| Canada |
| Czech Republic |
| Denmark |
| Georgia |
| Germany |
| Hungary |
| Israel |
| Italy |
| Korea, Republic of |
| Lithuania |
| Netherlands |
| Poland |
| Romania |
| Russian Federation |
| Serbia |
| Slovakia |
| Spain |
| Turkey |
| 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
|
| End of trial in a Member State of the European Union is defined as the time at which it is deemed that a sufficient number of subjects have been recruited and completed the study as stated in the clinical trial application (CTA) and ethics application in the Member State. Poor recruitment (recruiting less than the anticipated number in the CTA) by a Member State is not a reason for premature termination but is considered a normal conclusion to the study in that Member State. |
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 4 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 2 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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