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 (UC) which is a type of inflammatory bowel disease. |
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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 | 19.0 |
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 |
- To evaluate the safety and tolerability of PF-06480605 in subjects with moderate to severe UC. - To evaluate the efficacy of PF-06480605 in induction of endoscopic improvement (as assessed by Mayo endoscopic subscore) at Week 14 in subjects with moderate to severe UC. |
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E.2.2 | Secondary objectives of the trial |
- To evaluate the efficacy of PF-06480605 in induction of remission at Week 14 (defined as a total Mayo score ≤ 2 with no individual subscore > 1) in subjects with moderate to severe UC. - To evaluate the efficacy of PF-06480605 in induction of endoscopic remission at Week 14 (defined as a Mayo endoscopic subscore of 0) in subjects with moderate to severe UC. - To describe the PK of PF-06480605 in subjects with moderate to severe UC. - To evaluate the immunogenicity of PF-06480605 in subjects with moderate to severe UC. - To evaluate disease and pathway related biomarkers (ie, hsCRP and fecal calprotectin), and serum sTL1A. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Evidence of a personally signed and dated informed consent document indicating that the subject or a legally acceptable representative has been informed of all pertinent aspects of the study.
2. Subjects who are willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
3. Male and/or female subjects between ≥18 and ≤65 years of age at the time of informed consent.
4. Male subjects able to father children and female subjects of childbearing potential and at risk for pregnancy must agree to use two highly effective methods of contraception throughout the study and until the Week 26 visit (or 98 days after the last dose of IP). Women of childbearing potential (WOCBP) will be eligible for this study while pEFD toxicology studies are ongoing provided these women use two highly effective methods of contraception throughout the study and until the Week 26 visit (or 98 days after the last dose of IP), as outlined in Section 4.3. The investigators will be notified of the summary results of the pEFD toxicology studies upon their completion. Female subjects who are not of childbearing potential (ie, meet at least 1 of the following criteria): •Have undergone a documented hysterectomy and/or bilateral oophorectomy; •Have medically confirmed ovarian failure; or •Achieved postmenopausal status, defined as follows: cessation of regular menses for at least 12 consecutive months with no alternative pathological or physiological cause; and have a serum follicle-stimulating hormone (FSH) level confirming the post-menopausal state.
5. A diagnosis of UC for ≥4 months. A biopsy report must be available to confirm the histological diagnosis in the subject’s source documentation. In addition, a report documenting disease duration and extent of disease (eg, proctosigmoiditis, left-sided colitis, and pancolitis) based upon prior endoscopy must also be available in source documentation.
6. Subjects with moderate to severe active UC as defined (via screening colonoscopy) by a total Mayo score of ≥6, with a rectal bleeding subscore of ≥1 and an endoscopic subscore of ≥2 on the Mayo.
7. Active disease beyond the rectum (>15 cm of active disease at the screening colonoscopy).
8. Must have inadequate response to, loss of response to, or intolerance to at least one conventional therapy for UC: •Steroids; •Immunosuppressants (AZA [azathioprine], 6-MP, or MTX [methotrexate]); •Anti-TNF inhibitors (eg, infliximab, adalimumab, or golimumab); •Anti-integrin inhibitors (eg, vedolizumab).
9. Subjects currently receiving the following treatment for UC are eligible provided 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 total Mayo score screening procedures. •Oral corticosteroids (prednisone equivalent up to 20 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 total Mayo core screening procedures. Decreases in steroid use due to AEs are allowed. •6-MP or AZA (≤2.5 mg/kg) stable dose for 8 weeks prior to baseline. Decreases due to AEs are permitted. |
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E.4 | Principal exclusion criteria |
1. Subjects with a diagnosis of indeterminate colitis, ischemic colitis, radiation colitis, diverticular disease associated with colitis, microscopic colitis or CD. Subjects with clinical findings suggestive of CD (eg, fistulae, granulomas on biopsy) are also excluded.
2. Subjects with an imminent need for surgery or with elective surgery scheduled to occur during the study.
3. Subjects with colonic dysplasia or neoplasia.
4. Subjects with toxic megacolon.
5. Subjects with primary sclerosing cholangitis.
6. Subjects with known colonic stricture.
7. Subjects with history of colonic or small bowel stoma.
8. Subjects with a history of colonic or small bowel obstruction or resection.
9. Abnormal findings on the chest x-ray film performed routinely before initiating a new biologic therapy, such as presence of tuberculosis (TB), general infections, heart failure, or malignancy. Chest x-ray examination may be performed up to 12 weeks prior to screening.
10. Any current evidence of untreated latent or active TB infection, evidence of prior or currently active TB by chest x-ray, residing with or frequent close contact with individual(s) with active TB. Subjects who have a positive Mantoux (PPD) tuberculin skin test or a positive Interferon Gamma Release Assay (IGRA to be tested at the site’s local lab) during screening or within 12 weeks prior to randomization.
11. Presence of active enteric infections (positive stool culture and sensitivity). The presence of Clostridium difficile or pseudomembranous colitis. Known active invasive fungal infections such as histoplasmosis or parasitic infections. Subjects with clinically significant underlying disease that could predispose the subjects to infections. A history of serious infection (requiring parenteral antibiotic and/or hospitalization) within 4 weeks before Day 1. Pyoderma gangrenosum is allowed.
12. Known history of human immunodeficiency virus (HIV) based on documented history with positive serological test, or positive HIV serologic test at screening, tested at the site’s local lab.
13. Presence of transplanted organ. Skin grafts to treat pyoderma gangrenosum are allowed.
14. Significant concurrent medical condition as judged by the investigator at the time of screening or baseline visit.
15. Prior evidence of liver injury or toxicity due to methotrexate.
16. Abnormality in hematology and/or chemistry profiles during screening as defined in the protocol.
17. Subjects receiving the following therapies within the designated time period or are expected to receive any of these therapies during the study period: •>9 mg/day of oral budesonide or >20 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. •Biologics including anti-TNF inhibitors 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 12 weeks prior to baseline. •Other investigational procedure(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.
18. Current or history within 2 years of serious psychiatric disease or alcohol or drug abuse.
19. Subjects who are investigational site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or subjects who are Pfizer employees directly involved in the conduct of the study.
20. Participation in other studies involving investigational drug(s) within 30 days, or 5 half-lives of IP (whichever is greater), prior to baseline and/or during study participation.
21. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or IP administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the subject inappropriate for entry into this study.
22. Pregnant female subjects; 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 two highly effective methods of contraception as outlined in this protocol for the duration of the study and until the Week 26 visit (or 98 days after the last dose of IP) or longer based on the compound’s half-life characteristics.
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E.5 End points |
E.5.1 | Primary end point(s) |
- Safety and tolerability of PF-06480605: Treatment-Emergent Adverse Event (TEAEs), withdrawal due to AEs, and SAEs will be reported. - Endoscopic improvement at Week 14 (defined as a Mayo endoscopic subscore of 0 or 1, and without friability). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- The safety laboratory tests will be performed at times defined in the Schedule of Activities, page 20 of the protocol. - Endoscopic improvement will be assessed at Week 14 |
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E.5.2 | Secondary end point(s) |
- Remission at Week 14 (defined as a total Mayo score ≤ 2 with no individual subscore >1). - Endoscopic remission at Week 14 (defined as a Mayo endoscopic subscore of 0). - PF-06480605 plasma concentrations. - Incidence of development of anti-drug antibodies (ADAs) and neutralizing antibodies (NAbs). - Change from baseline in fecal calprotectin. - Change from baseline in hsCRP. - Change from baseline in serum total sTL1A. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Endoscopic remission will be assessed at Week 14 - The laboratory tests will be performed at times defined in the Schedule of Activities, page 20 of the 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 | No |
E.6.10 | Pharmacogenetic | No |
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 |
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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 | 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 | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
Belgium |
France |
Italy |
Korea, Republic of |
Netherlands |
Poland |
United States |
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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
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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 regulatory application 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. |
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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 | 0 |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 8 |
E.8.9.2 | In all countries concerned by the trial days | 0 |