| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Moderate To Severe Crohn's Disease (CD)
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| E.1.1.1 | Medical condition in easily understood language |
| Moderate To Severe Crohn's Disease |
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| 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 | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10011401 |
| E.1.2 | Term | Crohn's disease |
| E.1.2 | System Organ Class | 10017947 - Gastrointestinal disorders |
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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 |
Primary Objective(s) during the Induction Period
• To evaluate the efficacy of PF-06651600 and PF-06700841 compared to placebo at Week 12 in subjects with moderate to severe CD.
Primary Objective(s) during the Open Label Extension Period
• To assess the safety and tolerability of PF-06651600 and PF- 6700841 therapy during open label extension period for subjects with moderate to severe CD.
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| E.2.2 | Secondary objectives of the trial |
During the Induction Period
• To evaluate the safety and tolerability of PF-06651600 and PF-06700841 compared to placebo in subjects with moderate to severe CD over 12 weeks.
• To evaluate the efficacy of PF-06651600 and PF-06700841 compared to placebo during induction of additional endoscopic endpoints in subjects with moderate to severe CD.
During the Open Label Extension Period
• To evaluate the efficacy of PF-06651600 and PF-06700841 as maintenance therapy in subjects with moderate to severe CD. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male and/or female subjects (including Women of Child Bearing Potential (WOCBP)) ?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 ?5 years of age at the time of informed consent.
2. Documented diagnosis of ileal, ileocolonic, or colonic CD with a minimum disease duration of 3 months, as determined by endoscopic and histopathology assessment.
3. Endoscopic (central reading) confirmation of active disease with total SES-CD total score of at least 7 (?7)). For isolated ileal disease, SES-CD total score should be at least 4 (?4).
4. An average daily liquid/soft stool frequency (SF) ?2.5 or daily abdominal pain (AP) score ?2.0.
5. Must have inadequate response to, loss of response to, or intolerance to at least one conventional therapy for CD:
• Steroids;
• Immunosuppressants (azathioprine [AZA], 6-MP, or methotrexate [MTX]);
• Anti-TNF inhibitors (infliximab, adalimumab, or certolizumab);
• Anti-integrin inhibitors (eg, vedolizumab);
• Anti-IL-12/23 inhibitor (ustekinumab).
However, this inclusion should be met only after the usual clinical practice in each center has been fulfilled, which may involve administration of more than one line of previous treatment.
Note: Further guidance information related to this inclusion criteria can be found in the protocol
6. Subjects currently receiving the following treatment for CD are eligible providing they have been on stable doses as described below:
• Oral corticosteroids (prednisone or equivalent 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 AEs are allowed.
• Oral 5-ASA or sulfasalazine are allowed providing that the dose is stable for at least 4 weeks prior to baseline.
• Crohn's disease-related antibiotics are allowed providing that the dose is stable for at least 4 weeks prior to baseline. If antibiotics are stopped prior to baseline, they must be discontinued at least 4 days prior to baseline.
7. Female subjects of childbearing potential must test negative for pregnancy at screening visit and baseline visit.
8. 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.
9. Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study.
10. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
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| E.4 | Principal exclusion criteria |
1. Diagnosis of indeterminate colitis, microscopic colitis, ischemic colitis, infectious colitis, radiation colitis, diverticular disease, ulcerative colitis (UC), or clinical findings suggestive of UC.
2. Presence of active (draining) fistulae or intra-abdominal or perineal abscesses.
3. Strictures with obstructive symptoms.
4. Short bowel syndrome.
5. History of bowel perforation requiring surgical intervention within the past 12 months.
6. Previous bowel surgery resulting in an existing stoma. Subjects who have a j-pouch are excluded, as a j-pouch can result in a stoma.
7. History of bowel surgery within 6 months prior to baseline.
8. Subjects considered in imminent need for surgery or with elective surgery scheduled to occur during the study.
9. Subjects displaying clinical signs of fulminant colitis or toxic megacolon.
10. Subjects with primary sclerosing cholangitis.
11. Subjects with evidence of colonic adenomas, dysplasia or neoplasia. However, subjects with prior history of adenomatous polyps or any adenomatous polyps identified on screening will be eligible if the polyps have been completely removed and the subjects are free of polyps at baseline per the assessment of the investigator based on the screening colonoscopy.
12. Subjects receiving the following therapies within the time period described below or expected to receive any of these therapies during the study period:
a. >9 mg/day of oral budesonide or >25 mg/day of prednisone or equivalent oral systemic corticosteroid dose within 2 weeks prior to baseline.
b. IV, IM (parenteral), or topical (rectal) treatment of 5-ASA or corticosteroid enemas/suppositories within 2 weeks prior to baseline.
c. Azathioprine, 6-mercaptopurine, or methotrexate within 2 weeks prior to baseline.
d. Anti-TNF inhibitors (or biosimilars thereof) as described below:
• Infliximab within 8 weeks prior to baseline;
• Adalimumab within 8 weeks prior to baseline;
• Certolizumab within 8 weeks prior to baseline;
e. Anti-integrin inhibitors (eg, vedolizumab) within 8 weeks prior to baseline.
f. Ustekinumab within 8 weeks prior to baseline.
g. Interferon therapy within 8 weeks prior to baseline.
h. 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).
i. Subjects who have received rituximab or other selective B lymphocyte-depleting agents within 1 year prior to baseline.
j. Subjects previously receiving leukocyte apheresis, including selective lymphocyte, monocyte, or granulocyte apheresis, or plasma exchange within 6 months prior to baseline.
k. Other marketed immunosuppressants or biologics with immunomodulatory properties within 3 months prior to baseline.
l. Subjects who have received other JAK inhibitors within 3 months prior to baseline.
m. Subjects who have not responded to or have been intolerant of other JAK inhibitors.
n. 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.
13. Participation in other studies involving investigational drug(s) within 30 days, or 5 half-lives of investigational product (IP) (whichever is greater), prior to study entry and/or during study participation.
14. Presence of active enteric infections (positive stool culture and sensitivity). Clostridium difficile infection (reference C. diff section) or pseudomembranous colitis, or known active invasive fungal infections such as histoplasmosis or parasitic infections. Subject with Clostridium difficile infection may be treated and re-tested or re-screened at the discretion of the Investigator.
15. Abnormal findings on the chest x-ray film such as presence of tuberculosis (TB), general infections, heart failure, or malignancy. A chest X-ray or other appropriate diagnostic imaging modality (ie, CT with or without IV contrast or MRI) performed within 12 weeks prior to screening may substitute for the chest X-ray taken at Screening. Documentation of the official negative reading must be located and available in the source documentation prior to Baseline (Day 1) randomization.
Please refer to the protocol for further exclusion criteria
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary Endpoint(s) during the Induction Period
• Proportion of subjects achieving clinically meaningful endoscopic improvement (reduction of ?3 points from baseline in SES-CD score) at Week 12 as assessed by central reading.
Primary Endpoint(s) during the Open Label Extension (OLE) Period
• Incidence and severity of laboratory abnormalities, vital signs, 12-lead ECG, adverse events, serious adverse events and withdrawals due to adverse events. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
At Week 12 during the induction period.
Please refer to the schedule of activities (open label extension period) in the protocol for the timepoints during the OLE period |
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| E.5.2 | Secondary end point(s) |
Secondary Endpoint(s) during the Induction Period
• Incidence and severity of laboratory abnormalities, vital signs, 12-lead ECG, adverse events, serious adverse events and withdrawals due to adverse events.
• Incidence of serious infections
• Mean change from baseline in SES-CD score at Week 12.
• Proportion of subjects achieving SES-CD 25 and SES-CD 50 (?25% and ?50% reduction in SES-CD from baseline) at Week 12.
• Proportion of subjects achieving endoscopic remission (SES-CD ?2) at Week 12
• Proportion of subjects achieving mucosal healing (complete absence of ulcers) at Week 12.
Secondary Endpoint(s) during the Open Label Extension Period
• Proportion of subjects achieving clinically meaningful endoscopic improvement (CMEI response) at week 64 among subjects who achieved CMEI response at Week 12.
• Proportion of subjects achieving SES-CD 25 and SES-CD 50 at Week 64 among subjects who achieved SES-CD 25 and SES-CD 50 at week 12 respectively. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| At various timepoints as detailed in the Schedule of Activities |
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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 | 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 | 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 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 76 |
| 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 |
| Austria |
| Belgium |
| Bosnia and Herzegovina |
| Canada |
| Croatia |
| Czech Republic |
| Georgia |
| Germany |
| Hungary |
| Italy |
| Korea, Republic of |
| Lebanon |
| Poland |
| Russian Federation |
| Saudi Arabia |
| Serbia |
| Slovakia |
| South Africa |
| Spain |
| Switzerland |
| Tunisia |
| Turkey |
| Ukraine |
| United Arab Emirates |
| 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 a Member State of the 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 application (ie, 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. |
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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 | 3 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | 9 |
| 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 | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 15 |
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