E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
moderate to severe ulcerative colitis |
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E.1.1.1 | Medical condition in easily understood language |
moderate to severe form of ulcerative colitis, an inflammatory bowel disease that causes long-lasting inflammation and ulcers in the digestive tract |
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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 |
To evaluate the efficacy of PF-06826647 in induction of endoscopic response in participants with moderate to severe ulcerative colitis (UC). |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of PF-06826647 in induction of clinical remission in participants with moderate to severe UC.
• To evaluate the efficacy of PF-06826647 in induction of endoscopic remission in participants with moderate to severe UC.
• To evaluate the efficacy of PF-06826647 in induction of mucosal healing in participants with moderate to severe UC.
• To evaluate the efficacy of PF-06826647 in induction of clinical response with participants with moderate to severe UC.
• To evaluate the efficacy of PF-06826647 in induction of clinical outcomes based on total/partial Mayo scores in participants with moderate to severe UC.
• To evaluate the safety and tolerability of PF-06826647 in participants with moderate to severe UC. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Age and Sex:
1. Male or female participants between the ages of 18 (or the minimum country specific age of consent if >18) and 75 years, inclusive, at Visit 1 (Screen 1).
Type of Participant and Disease Characteristics:
2. Participants who are willing and able to comply with all scheduled visits, treatment plan, laboratory tests, lifestyle considerations, and other study procedures.
3. 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.
4. Participants with moderate to severe UC as defined by a total Mayo score (tMS) of ≥6, with a rectal bleeding subscore of ≥1 and an endoscopic subscore of ≥2 (any friability = 2).
5. Active disease beyond the rectum (>15 cm of active disease from the anal verge at the screening endoscopy).
6. Participants must have inadequate response to, loss of response to, or intolerance to at least one conventional therapy for UC:
• Oral, intravascular, or intramuscular corticosteroids;
• Immunosuppressants (azathioprine [AZA], 6 MP, or methotrexate [MTX]);
• Anti tumor necrosis factor (TNF) inhibitors (eg, infliximab, adalimumab, or golimumab);
• Anti integrin inhibitors (eg, vedolizumab);
• JAK inhibitor (eg, tofacitinib);
• Anti-IL-12/IL-23 inhibitors (eg, ustekinumab).
Local standards of care, as well as investigator assessment should be considered in any assessment.
7. Participants currently receiving permissible treatment for UC are eligible providing they have been on stable doses.
8. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
Weight:
9. Body weight must be >40 kg.
Informed Consent:
10. Capable of giving signed informed consent, which includes compliance with the requirements and restrictions listed in the informed consent document and in the protocol. |
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E.4 | Principal exclusion criteria |
1. 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.
2. Participants with known colonic stricture and participants with history of colonic or small bowel obstruction, resection, or stoma.
3. Participants with significant trauma or major surgery within 4 weeks of screening or planned a surgery during the study.
4. Participants with a history of bowel surgery within 6 months prior to baseline.
5. Participants displaying clinical signs of fulminant colitis or toxic megacolon.
6. Participants with primary sclerosing cholangitis.
7. Participants with evidence of colonic dysplasia, adenomas or neoplasia. However, participants with adenomatous polyps identified on screening endoscopy will be eligible if the polyps have been completely removed and pathologic report is negative.
8. Participants with any condition possibly affecting oral drug absorption (eg, gastrectomy, clinically significant diabetic gastroenteropathy, or certain types of bariatric surgery such as gastric bypass). Procedures such as gastric banding that simply divide the stomach into separate chambers are NOT exclusionary.
9. Have current or recent (within the past year) history of severe, progressive, or uncontrolled renal, hepatic, hematologic, gastrointestinal, metabolic, endocrine, pulmonary, cardiovascular, immunologic (eg, Felty’s syndrome) or neurologic disease, including but not limited to the following:
• History of acute coronary syndrome (eg, myocardial infarction, unstable angina pectoris) or any history of cerebrovascular disease within 24 weeks before screening;
• Chronic heart failure New York Heart Association Grade IV;
• History of liver cirrhosis;
• History of recurrent (≥2) venous thrombosis or any arterial thromboembolism or known blood clotting disorders.
10. Cancer or history of cancer or history of any lymphoproliferative disorder (such as Epstein-Barr virus [EBV]-related lymphoproliferative disorder, history of lymphoma, leukemia, or signs and symptoms suggestive of current lymphatic disease), except for participants with adequately treated or excised non-metastatic basal cell or squamous cell carcinoma of the skin or cervical carcinoma in situ.
11. Infected with Mycobacterium tuberculosis (TB): History of multidrug resistant TB infection, any evidence of untreated, inadequately treated latent or active TB infection.
• A participant who is currently being treated for active TB infection is to be excluded.
• A participant who is currently being treated for latent TB infection with an adequate TB treatment regimen in the locale (in the opinion of the appropriately qualified personnel- which may include a pulmonary or infection disease specialist, or locally acceptable expert as defined by local guidelines) for at least 1 month can only be enrolled with documentation of treatment regimen, commitment of continuing treatment during the study and with prior approval by the sponsor.
12. History (single episode) of disseminated herpes zoster or disseminated herpes simplex, or a recurrent (more than one episode of) localized, dermatomal herpes zoster.
13. Clinically significant infections within 3 months of baseline (eg, those requiring hospitalization or parenteral antimicrobial therapy, or opportunistic infections), or a history of any infection otherwise judged by the investigator to have the potential for exacerbation by participation in the study.
14. Presence of transplanted organ; skin grafts are allowed.
15. Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the participant inappropriate for entry into this study.
16. Have been vaccinated with live or attenuated live vaccine within the 6 weeks prior to the first dose of study drug or expects to be vaccinated with these vaccines during treatment, or within the 8 weeks following the last dose of study drug.
17. Participants have received, are receiving or require treatment with prohibited prior/concomitant medications(s) including moderate to potent CYP1A2 and CYP3A4 inhibitors/inducers or CYP2D6 inhibitors or MATE substrates within certain time periods.
18. Previous administration with an investigational drug within 30 days (or as determined by the local requirement) or 5 half lives preceding the first dose of investigational product used in this study (whichever is longer).
19. Participants who have been intolerant of selective TYK2 inhibitors will be excluded from the study.
Further exclusion criteria are detailed in the protocol. |
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of participants achieving endoscopic response at Week 8. |
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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) |
• Proportion of participants with clinical remission based on 12-point or 9-point total Mayo score at Week 8.
• Proportion of participants with endoscopic remission at Week 8.
• Proportion of participants with mucosal healing at Week 8.
• Proportion of participants with a clinical response 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.
• Incidence and severity of adverse events, serious adverse events and withdrawals due to adverse events at time points specified in the Schedule of Activities (SoA).
• Incidence of serious infections at time points specified in the SoA.
• Change from baseline in clinical laboratory values (chemistry, hematology & lipids) at time points specified in the SoA.
• Incidence of clinically significant changes in Electrocardiogram (ECG) (heart rate, QT, QTc, PR and QRS intervals) at time points specified in the SoA.
• Change from baseline in vital signs (blood pressure, pulse rate and temperature measurements) at time points specified in the SoA. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
Individual timepoints are included in each bullet point above with reference to the SoA, contained within section 1.3 of the clinical trial protocol. |
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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 | Yes |
E.6.13.1 | Other scope of the trial description |
Patient Reported Outcomes |
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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) | 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 |
Open label extension treatment period |
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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 | 4 |
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 | 46 |
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 |
Armenia |
Australia |
Belgium |
Bosnia and Herzegovina |
Brazil |
China |
Croatia |
Czech Republic |
France |
Georgia |
Germany |
Hong Kong |
India |
Ireland |
Italy |
Lebanon |
Macedonia, the former Yugoslav Republic of |
Malaysia |
Mexico |
Morocco |
Norway |
Oman |
Poland |
Puerto Rico |
Qatar |
Romania |
Russian Federation |
Saudi Arabia |
Slovakia |
Spain |
Tunisia |
Turkey |
Ukraine |
United Arab Emirates |
United Kingdom |
United States |
Jordan |
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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
|
The end of the study is defined as the date of the last visit of the last participant in the study or last scheduled procedure shown in the Schedule of Activities of the protocol for the last participant in the study globally. |
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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 | 8 |
E.8.9.1 | In the Member State concerned days | 22 |
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 | 5 |
E.8.9.2 | In all countries concerned by the trial days | 26 |