| 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 | 20.1 |
| 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-06687234 in induction of clinical remission in subjects with UC and a partial response to anti-TNF-α;
• To evaluate the safety and tolerability of PF-06687234 in subjects with UC and a partial response to anti-TNF-α.
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| E.2.2 | Secondary objectives of the trial |
• To evaluate the efficacy of PF-06687234 in induction of endoscopic improvement in subjects with UC and partial response to anti-TNF-α;
• To evaluate histological improvement in subjects with UC and partial response to anti-TNF-α;
• To evaluate the efficacy of PF-06687234 in induction of clinical response in subjects with UC and a partial response to anti-TNF-α.
• To describe the PK of PF-06687234 in subjects with UC.
• To evaluate the immunogenicity of PF-06687234 in subjects with UC.
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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 |
| “Pharmacokinetic substudy” with primary objective to assess pK of administered IP |
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| E.3 | Principal inclusion criteria |
1. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
2. Willing and able to comply with scheduled visits, treatment plan, laboratory tests and other study procedures.
3. Male and/or female subjects ≥18 years to ≤75 years of age and weight > 40 kg at the time of informed consent. For subjects in South Korea: male and/ or female ≥19 years to ≤70 years of age and weight > 40 kg at the time of informed consent.
4. A diagnosis of active UC (histologic) for ≥4 months. A biopsy report supporting the diagnosis prior to the baseline visit must be available in the source documents. In addition, a report documenting disease duration and extent of disease (eg, proctosigmoiditis, left-sided colitis, or pancolitis) based upon prior endoscopy must also be available in the source documentation.
5. Subjects who have partial response to anti-TNF (infliximab) and active UC as defined by (via screening endoscopy) a total Mayo Score ≥5 but ≤9 and an endoscopic subscore ≥2. Endoscopy (flexible sigmoidoscopy or colonoscopy), should be performed within 14 days of baseline (Day 1). The endoscopic Mayo subscore assessed by the Central Reader must be available at the baseline visit. The assessment by the Central Reader will be used to derive the total Mayo score to determine study eligibility. Primary non-responder to anti-TNF therapy should be excluded.
6. UC extending at least 25 cm proximal to the anal verge at the time of the screening endoscopy. Only a portion, of the 25 cm of involved colon must be graded with Mayo endoscopic subscore of 2.
7. Must be on a stable dose 5- to 10 mg/kg of Remicade® or protocol specified infliximab biosimilars (see Protocol Appendix 5) for a minimum of 14 weeks (4 doses) and a maximum of two years prior to study entry with no anticipation of need for change in infliximab treatment regimen throughout the study (no switches from pre-study infliximab version to a different infliximab version will be permitted through Week 12). For a subject who has recently switched dose or dosing intervals of infliximab during maintenance therapy, the subject must be on the same dose and dosing interval for at least two treatment cycles (minimum 12 weeks) before study entry. Subject must maintain the same infliximab regimen of every 6 weeks or every 8 weeks throughout the study.
8. Subjects currently receiving the following treatment for UC are eligible provided they have been on stable doses as described below:
- Oral 5-aminosalicylic acid derivative (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 date of total Mayo Score assessment.
- 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 date of total Mayo Score assessment. Decreases in steroid use due to AEs are allowed.
- 6-MP, azathioprine (AZA) (≤ 2.5 mg/kg), or MTX stable dose for 8 weeks prior to baseline.
9. Male subjects able to father children and female subjects of childbearing potential and at risk for pregnancy must agree to use two methods of contraception throughout the study and until the Week 16 visit (or 28 days after the last dose of IP).
- Women of childbearing potential (WOCBP) will be eligible provided these women use two methods of contraception throughout the study and until the Week 16 visit (or 28 days after the last dose of IP), as outlined in Protocol Section 4.4.
- Female subjects of nonchildbearing potential must meet at least 1 of the following criteria:
10. 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;
- Have undergone a documented hysterectomy and/or bilateral oophorectomy;
- Have medically confirmed ovarian failure.
All other female subjects (including female subjects with tubal ligations) are considered to be of childbearing potential. |
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| E.4 | Principal exclusion criteria |
1. Pregnant female subjects; breastfeeding female subjects (S.); fertile male S. & female S. of childbearing potential who are unwilling or unable to use 2 methods of contraception as per protocol for the duration of the study (Wk16 visit) or for at least 28days (d.) after the last dose of IP
2. S. with a diagnosis or documented history of total colectomy &/or pouchitis, indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, radiation colitis, & diverticular disease associated with colitis, or clinical findings suggestive of Crohn's disease
3. S. considered in imminent need for surgery or with major elective surgery scheduled to occur during the study
4. S. with extensive colitis for at least 8yrs who have not had a colonoscopy with surveillance biopsies within 2yrs of the baseline visit
5. S. with history of or at screening endoscopy, biopsy documented colonic dysplasia or neoplasia. S. with prior history of adenomatous polyps will be eligible if the polyps have been completely removed & pathology is negative.
6. S. who require infliximab dosing interval other than every 8wks during this study
7. S. displaying clinical signs of fulminant colitis or toxic megacolon
8. S. with primary sclerosing cholangitis
9. S. with known colonic stricture, or history of colonic or small bowel obstruction or resection
10. S. with history of or current colonic or small bowel stoma
11. History of known cyclic neutropenia, thrombocytopenia, lymphopenia, leukopenia or any history of chronic anemia (HGB<10g/dL) which is judged by the investigator (inv.) to have an unclear specific etiology or is non self-limiting
12. 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 12wks prior to screening. Documentation of the official reading must be located and available in the source documentation
13. Current evidence of active TB or latent TB infection or inadequately treated TB infection demonstrated by chest x-ray, a positive Mantoux (PPD) tuberculin skin test or a positive Interferon Gamma Release Assay during screening or within 12wks prior to randomization. The following are acceptable assays: QFT-G, QFT-GIT and T-SPOT® - TB test during screening or within 12wks prior to screening
14. Presence of active enteric infections (positive stool culture & sensitivity). The presence of Clostridium difficile infection or pseudomembranous colitis or history of recurrent Clostridium difficile infection. Known active invasive fungal infections such as histoplasmosis or parasitic infections
15. Known history of HIV based on documented history with positive serological test, or positive HIV serologic test at screening, tested at the site's local lab & as per local regulations
16. Presence of transplanted organ; skin grafts are allowed
17. Previous severe hypersensitivity reaction to infliximab or known hypersensitivity to inactive components of infliximab or to any murine protein
18. Exposure to a live (attenuated) vaccine within 30d. prior to screening or anticipated need for any live (attenuated) vaccine during the study
19. Significant concurrent medical condition at the time of baseline visit
20. S. receiving the therapies described in Protocol Sec. 4.2 within the designated time period or are expected to receive any of these therapies during the study period
21. S. with significant trauma or major surgery within 4wks of screening
22. Prior evidence of liver injury or toxicity due to methotrexate
23. History of sensitivity to heparin or heparin-induced thrombocytopenia
24. Abnormality in hematology &/or chemistry profiles during screening
25. Donation of blood in excess of 500mL within 8wks prior to baseline
26. History of alcohol or drug abuse with less than 6months of abstinence prior to baseline
27. Inv. site staff members directly involved in the conduct of the study & their family members, site staff members otherwise supervised by the inv., or subjects who are Pfizer employees, including their family members, directly involved in the conduct of the Study
28. Participation in other studies involving IP(s) within 30d., or 5 half-lives of IP, prior to study entry &/or during study participation
29. Other acute or chronic medical or psychiatric condition including recent or active suicidal ideation or behavior or laboratory abnormality that may increase the risk associated with study participation or IP administration or may interfere with the interpretation of study results &, in the judgment of the inv., would make the subject inappropriate for entry into this study
30. Known history of hypersensitivity, intolerance, or allergic reaction to PF-06687234 or any constituent of the IP
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| E.5 End points |
| E.5.1 | Primary end point(s) |
• Proportion of subjects in clinical remission at Week 12 (as defined by a modified total Mayo Score with traditional endoscopic subscore ≤1, stool frequency subscore ≤1 and rectal bleeding subscore = 0).
• Incidence and severity of adverse events, serious adverse events and withdrawals due to adverse events, ECGs, vital signs and safety laboratory tests. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The primary endpoint will be analyzed at Week 12 using exact Chan and Zhang method. The difference between treatment groups in the proportion of subjects in remission at Week 12 will be presented along with its 95% confidence interval. Subjects with missing remission data at Week 12 will be treated as treatment failure. As sensitivity analyses, the primary endpoint will also be analyzed using other methods for handling missing data which will be described in the SAP.
All clinical AEs, SAEs, TEAEs, withdrawal due to AEs, ECGs (on weeks 6,12,16), vital signs and safety laboratory data (on weeks 1,2,4,6,8,10,12,16) will be reviewed and summarized on an ongoing basis in a blinded manner during the study to evaluate the safety of subjects. |
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| E.5.2 | Secondary end point(s) |
• Proportion of subjects with endoscopic improvement at Week 12 (defined as decrease of ≥1 point in modified endoscopic subscore or an absolute endoscopy score of ≤1).
• Mean change from baseline at Week 12 in Geboes histology score.
• Proportion of subjects with a clinical response at Week 12 defined with a decrease from baseline of at least 3 points in total Mayo score with at least 30% change, accompanied by at least one point decrease or absolute score of 0 or 1 in rectal bleeding subscore.
• Proportion of subjects with change from baseline in partial Mayo Score of ≤2 with no individual subscore >1 at Weeks 2, 4, 6, 8, 12.
• Serum concentrations of PF-06687234.
• Incidence of the development of HAFAs and Nabs against PF-06687234. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
The proportion of subjects achieving endoscopic improvements or clinical response will be analyzed using same approach as for primary endpoint.
Change from baseline at Week 12 in Geboes histology score will be analyzed using analysis of covariance model with treatment group and baseline scores. Proportions of subjects with partial Mayo Score will be analyzed using generalized linear mixed effect model with treatment group, visit, treatment group by visit interaction and subjects as random effect.
PK concentration population: as all enrolled subjects who received at least one IP dose and in whom at least one concentration value is reported.
Immunogenicity assessment population: as all enrolled subjects who received at least one IP dose with at least one post-treatment HAFA determination. |
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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 | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| tolerability, histological improvement, immunogenicity |
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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 | 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
| 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 | 16 |
| 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 |
| Belgium |
| Germany |
| Israel |
| Italy |
| Korea, Republic of |
| Saudi Arabia |
| Serbia |
| Spain |
| United States |
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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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End of trial in EU 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 and ethics applications 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.
End of trial in all other participating countries is defined as LSLV. |
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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 | 1 |
| E.8.9.1 | In the Member State concerned months | 11 |
| E.8.9.1 | In the Member State concerned days | |
| 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 |
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