| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS |
|
| E.1.1.1 | Medical condition in easily understood language |
| MODERATE TO SEVERE ULCERATIVE COLITIS |
|
| 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 | 10017947 - Gastrointestinal disorders |
|
| 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):
• To evaluate the efficacy of tofacitinib based on remission in pediatric participants with moderately to severely active UC. |
|
| E.2.2 | Secondary objectives of the trial |
Secondary Objective(s):
• To evaluate the overall efficacy of tofacitinib during induction during induction, maintenance and extension.
• To evaluate the effect of tofacitinib on biomarkers.
• To evaluate tofacitinib PK during induction and maintenance.
• To evaluate taste acceptability of tofacitinib oral solution, and/or acceptability of tofacitinib film coated tablet, if applicable, at Week 2 of the open label induction phase.
|
|
| 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 and assent document (as appropriate) indicating that the subject or a legally acceptable representative/parent(s)/legal guardian has been informed of all pertinent aspects of the study.
2. Males and females 2 to <18 years old and weighing at least 10 kg at baseline.
3. Participants with a clinical diagnosis of UC for at least 12 weeks prior to baseline and with a pathology report that confirms colonic inflammation consistent with UC at any time prior to enrollment. A biopsy report supporting the diagnosis prior to the baseline visit must be available in the source documents (can be obtained from biopsies performed at screening if prior pathology report is not available). In addition, a report documenting disease duration and extent of disease (eg, proctosigmoiditis, left sided colitis, or pancolitis) based on prior endoscopy must also be available in the source documentation.
4. Participants diagnosed with UC at age less than 6 years old, must have had testing for very early onset (VEO) IBD and be negative for monogenic disorders associated with VEO IBD.
5. Participants with moderately to severely active UC as defined (via screening endoscopy) by a Mayo score of ≥6, with a rectal bleeding score of ≥1 and an endoscopic subscore (Mayo) of ≥2 (assessed by local read). Endoscopy must be performed within 14 days of baseline visit. If the participant had a colonoscopy with biopsies showing no dysplasia or colon cancer within 12 months prior to baseline with appropriate documentation in source, then the baseline endoscopy may be either colonoscopy (with or without random biopsies) or flexible sigmoidoscopy (with or without random biopsies). However targeted biopsies should be obtained if there are observed abnormalities or lesions of clinical concern during endoscopy. All pathology reports must be available in the source document prior to enrollment.
Note: The Mayo endoscopic subscore assessed locally will be used to derive the Mayo score to determine eligibility
6. Pediatric Ulcerative Colitis Activity Index (PUCAI) score >/= 35 at baseline.
7. No history of dysplasia or colon cancer.
8. No evidence or history of untreated or inadequately treated active or latent infection with Mycobacterium tuberculosis (TB).
9. For participants outside of the US or the EU: have had an inadequate response or been intolerant to at least one prior therapy as listed below or have a medical contraindication to such therapies:
• Oral or intravenous (IV) corticosteroids;
• Azathioprine or 6-MP;
• Anti TNF or anti-integrin therapy.
10. For participants in the US and the EU: have had an inadequate response or intolerance to TNF inhibitors.
11. Stable doses of the following therapies for UC for designated time and throughout study (Note: The following therapies for UC are not required, however allowed, and if taken, must remain stable for those subjects who are taking them at the time of enrollment):
• Oral 5 ASA or sulfasalazine for at least 4 weeks prior to baseline.
• Oral corticosteroids equivalent to prednisone </=1 mg/kg up to a maximum of 20 mg/day or budesonide up to 9 mg/day at least 2 weeks prior to baseline.
12. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
13. No contraception methods are required for male participants in this study, as the calculated safety margin is ≥100 fold between the estimated maternal exposure due to seminal transfer and the no observed adverse effect level (NOAEL) for serious manifestations of developmental toxicity in nonclinical studies.
A female participant is eligible to participate if she is not pregnant or breastfeeding, and at least 1 of the following conditions applies:
- Is not a woman of childbearing potential (WOCBP) (see definitions in Section 4.3.4.1) OR
Is a WOCBP and using a contraceptive method that is highly effective (with a failure rate of <1% per year), as described in Section 4.3.4.2, during the intervention period and for at least 12 weeks after the last dose of study intervention. If a highly effective method that is user dependent is chosen, a second effective method of contraception, as described in Section 4.3.4.2, must also be used. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
|
|
| E.4 | Principal exclusion criteria |
1. Diagnosis of indeterminate colitis, isolated proctitis, microscopic colitis, infectious colitis, Crohn's disease, or clinical findings suggestive of Crohn's disease.
2. History of symptomatic obstructive intestinal strictures or active ostomy.
3. History of colectomy, extensive small bowel resection (>100 cm) or short bowel syndrome. Participants hospitalized for UC related reason(s) within 2 weeks of baseline visit other than for standard of care monitoring/observation or performing baseline endoscopic procedure.
4. Any factors or clinical characteristics potentially related to the risk of venous thromboembolism (see Section 7.2.3, Risk Factor Check for VTE) that may increase the risk associated with study participation or study intervention 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.
5. Participants who have previously received tofacitinib or another Janus Kinase inhibitor.
6. Participants vaccinated or exposed to a live or attenuated vaccine:
• Within the 6 weeks prior to the first dose of study drug; OR
• Who are expected to be vaccinated or to have household exposure to these vaccines during treatment or during the 6 weeks following discontinuation of study drug.
7.Participants receiving the following treatments:
• AZA, 6 MP, methotrexate (MTX), or thioguanine within 2 weeks prior to baseline.
• Infliximab therapy within 2 weeks prior to baseline unless an undetectable serum level has been documented following the last dose of infliximab therapy prior to baseline.
• Adalimumab therapy within 4 weeks prior to baseline unless an undetectable serum level has been documented following the last dose of adalimumab therapy prior to baseline.
• Golimumab therapy within 4 weeks prior to baseline unless an undetectable serum level has been documented following the last dose of golimumab therapy prior to baseline.
• Ustekinumab therapy within 6 weeks prior to baseline unless an undetectable serum level has been documented following the last dose of ustekinumab therapy prior to baseline.
• Interferon therapy within 8 weeks prior to baseline.
• Cyclosporine, mycophenolate, or tacrolimus within 4 weeks prior to baseline.
• Intravenous (IV) corticosteroids within 2 weeks prior to baseline.
• Rectally administered formulations of corticosteroids or 5 ASA within 1 week of screening endoscopy.
• Natalizumab within 1 year prior to baseline.
• Vedolizumab therapy within 6 weeks prior to baseline unless an undetectable serum level has been documented following the last dose of vedolizumab therapy prior to baseline.
8. Investigational drugs within 3 months of baseline. Other antiadhesion molecules within 5 half-lives prior to baseline unless an undetectable serum level has been documented following the last dose of other antiadhesion molecule therapy prior to baseline
9. Participants previously receiving leukocyte apheresis including selective lymphocyte, monocyte, or granulocyte apheresis, or plasma exchange within 6 months prior to baseline.
10. Participants receiving prohibited concomitant medications, including moderate to potent CYP3A inducers or inhibitors (see Appendix 3) in the specified time periods prior to the first dose of study drug or are expected to receive any of these medications during the study period.
11. Participants who require chronic and frequent use of antimotility agents for control of diarrhea (ie, diphenoxylate hydrochloride with atropine sulfate or loperamide).
12. Participants with a history of bowel surgery, including cholecystectomy within 6 months prior to baseline. Participants with appendectomy within 3 months prior to baseline are excluded.
13. Participants with significant trauma or major surgery within 4 weeks of screening visit.
14. Participants with the following laboratory values at screening:
• Hemoglobin level <9.0 g/dL
• An absolute white blood cell (WBC) count of <3.0 x 10^9/L (<3000/mm³) or absolute neutrophil count of <1.2 x 10^9/L (<1200/mm³) or absolute lymphocyte count of <0.75 x 10^9/L (<750/mm³).
• Thrombocytopenia, as defined by a platelet count <100 x 10^9/L (<100,000/mm³).
• Estimated Glomerular filtration rate (GFR) </=40 mL/min/1.73 m² . GFR will be calculated by the Central lab using the bedside Schwartz formula (see Appendix 4).
• Total bilirubin, aspartate aminostransferase (AST) or alanine aminotransferase (ALT) more than 1.5 times the upper limit of normal.
Note: Participants with a history of Gilbert's syndrome may have a direct bilirubin measured and are eligible for the study provided the direct bilirubin is </= upper limit of normal (ULN).
15. Participants who have positive stool examinations for enteric pathogens, pathogenic ova or parasites, or C. difficile toxin at screening.
Please refer to the section 4.2 Exclusion criteria in the Protocol Amendment 3 dated 08April2022.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary endpoint(s):
• Remission by central read Mayo score following 44 weeks in the maintenance phase. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 44 in the maintenance phase |
|
| E.5.2 | Secondary end point(s) |
• response by Mayo score (Induction Week 8, Induction Week 16, Maintenance Week 44).
• Remission by Mayo score with local and central read (induction Week 8, induction Week 16), and with local read (maintenance week 44).
• Change from baseline in Mayo score (induction Week 8, induction Week 16, maintenance Week 44).
• Partial Mayo Score response over time.
• Change from baseline in Partial Mayo scores over time.
• Response/remission by PUCAI score over time.
• Change from baseline in PUCAI score over time.
• Endoscopic improvement (previously known as mucosal healing) (induction Week 8, induction Week 16, maintenance Week 44).
• Endoscopic remission (induction Week 8, induction Week 16, maintenance Week 44).
• Remission at maintenance week 44 (Mayo and PUCAI) and extension (PUCAI only) amongst participants who achieved remission at the end of
Induction. Rectal bleeding subscore of 0 over time.
• Time to flare (maintenance, extension)
• Change from baseline in fecal calprotectin levels over time.
• Change from baseline in high sensitivity C-reactiveprotein (hsCRP) levels over time.
• Corticosteroid free remission Corticosteroid free remission by Partial Mayo Score over time.
• Change from baseline in lymphocyte subset counts (induction Week 8, induction Week 16, maintenance Week 44; extension Month 24).
• PK: plasma concentrations (baseline, induction Week 8, induction Week 16, maintenance Week 16, maintenance Week 44).
• Evaluation of taste acceptability of tofacitinib oral solution, and acceptability of film-coated tablet, if applicable, (Week 2). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| various timepoint for each secondary endpoint are defined within the endpoint |
|
| 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 | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 34 |
| 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 |
| Canada |
| Israel |
| Japan |
| United Kingdom |
| United States |
| Belgium |
| Finland |
| France |
| Germany |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Slovakia |
| Spain |
| Sweden |
|
| 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
|
|
| 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 | 5 |
| E.8.9.1 | In the Member State concerned days | 0 |
| 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 | 0 |
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