Open-Label Induction and Maintenance Study of Oral Tofacitinib in Pediatric Patients with Moderately to Severely Active Ulcerative Colitis
- Trial ID
- 2023-509694-22-00
- Protocol
- A3921210
- Sponsor
- Pfizer Inc.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this study is to evaluate the **efficacy** of tofacitinib based on remission in pediatric participants with moderately to severely active **ulcerative colitis** (UC). This is clinically relevant as achieving remission is a critical goal in the management of UC, particularly in pediatric populations, where the disease can significantly impact growth and development.
Secondary objectives include:
- Evaluating the overall efficacy of tofacitinib during induction, maintenance, and extension phases.
- Assessing the effect of tofacitinib on biomarkers.
- Evaluating the pharmacokinetics (PK) of tofacitinib during induction and maintenance.
- Assessing the taste acceptability of tofacitinib oral solution and/or the acceptability of the tofacitinib film-coated tablet, if applicable, at Week 2 of the open-label induction phase.
Participants
The clinical trial involves a total of **77 participants** diagnosed with **Ulcerative Colitis (UC)**, specifically targeting a pediatric population. The study includes both male and female subjects aged between 2 to less than 18 years, with a minimum weight of 10 kg at baseline. Participants were selected based on a confirmed clinical diagnosis of UC for at least 12 weeks prior to baseline, with evidence of colonic inflammation consistent with UC. The trial population is characterized by individuals with moderately to severely active UC, as defined by a Mayo score of 6 or higher, a rectal bleeding score of at least 1, and an endoscopic subscore of 2 or more. The study includes participants who have had an inadequate response or intolerance to TNF inhibitors or other therapies, depending on their geographical location. Lifestyle considerations such as diet and physical activity are not specified, but participants must be willing and able to comply with scheduled visits and study procedures. The trial does not require contraception methods for male participants, while female participants must adhere to specific contraceptive guidelines if of childbearing potential. The study population is considered vulnerable, given the pediatric nature of the participants.
Plans and Procedures
The clinical trial is designed to evaluate the efficacy of **tofacitinib** in pediatric participants with moderately to severely active **ulcerative colitis**. This study is structured as an open-label, induction, and maintenance trial, with a primary objective of assessing remission based on the Mayo score after 44 weeks in the maintenance phase. The trial is expected to span from June 18, 2021, to March 12, 2029, with participant involvement lasting up to 39 weeks. The study employs a randomized, controlled methodology to ensure robust data collection and analysis.
Participants will undergo a series of study visits, beginning with an inclusion (screening) visit to confirm eligibility based on criteria such as age, weight, and previous treatment history. The inclusion criteria require participants to be between 2 to less than 18 years old, with a clinical diagnosis of **ulcerative colitis** for at least 12 weeks prior to baseline. The screening process will include endoscopic evaluation to confirm disease activity and extent. Following the screening, participants will enter the induction phase, with follow-up visits scheduled at weeks 8 and 16 to monitor response and adjust treatment as necessary.
The maintenance phase will continue with regular assessments, culminating in an end-of-study visit at week 44. During these visits, primary and secondary endpoints, such as changes in Mayo and PUCAI scores, endoscopic improvement, and remission rates, will be evaluated. Participants are expected to comply with scheduled visits, treatment plans, and laboratory tests throughout the study duration. Conditions that may lead to early termination from the study include non-compliance with the protocol, adverse events, or withdrawal of consent. The trial aims to provide comprehensive data on the safety and efficacy of **tofacitinib** in managing pediatric **ulcerative colitis**.
Treatment
The clinical trial involves the administration of **XELJANZ 1 mg/mL oral solution**, which contains the active substance **tofacitinib**. This pharmaceutical form is an oral solution, and the medication is administered orally. The maximum daily dose is 7 mg, with a total maximum dose of 7980 mg over a treatment period of 39 weeks. The product is manufactured by Pfizer Europe MA EEIG and is not a pediatric formulation. The trial aims to evaluate the efficacy of tofacitinib in pediatric participants with moderately to severely active ulcerative colitis.
Another formulation used in the trial is **Tofacitinib citrate**, available as a film-coated tablet. This formulation also contains the active substance tofacitinib citrate and is administered orally. The maximum daily dose for this formulation is 10 mg, with a total maximum dose of 11400 mg over the same treatment period of 39 weeks. This product is manufactured by Pfizer Inc. and is also not a pediatric formulation. The trial does not include any non-experimental treatments such as standard-of-care therapy, placebo, or comparator treatment.
Participant compliance with the dosing schedule is monitored throughout the trial to ensure adherence to the prescribed regimen. The trial does not involve any additional devices or specific compliance monitoring tools beyond standard clinical practice. The study is designed to assess the therapeutic potential of tofacitinib in achieving remission in the target population.
Efficacy
The efficacy of the clinical trial will be assessed through a series of primary and secondary endpoints. The primary endpoint is the achievement of **remission** by central read Mayo score following 44 weeks in the maintenance phase. Secondary endpoints include a variety of measures such as response by Mayo score at different time points (induction Week 8, induction Week 16, maintenance Week 44), remission by Mayo score with both local and central reads, and changes from baseline in Mayo scores over time. Additional secondary endpoints involve the Pediatric Ulcerative Colitis Activity Index (PUCAI) score, with assessments of response, remission, and changes from baseline over time.
Endoscopic improvement and remission are also evaluated at specified intervals, alongside other parameters such as rectal bleeding subscore, time to flare, and changes in biomarkers like fecal calprotectin and high sensitivity C-reactive protein (hs-CRP) levels. The trial will also monitor corticosteroid-free remission by partial Mayo Score and changes in lymphocyte subset counts. Pharmacokinetic assessments will be conducted to measure plasma concentrations at various stages, and the acceptability of the tofacitinib oral solution and film-coated tablet will be evaluated at Week 2. These efficacy parameters will be collected and analyzed at designated time points throughout the trial to determine the overall effectiveness of the treatment in pediatric participants with moderately to severely active ulcerative colitis.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Evidence of a personally signed and dated informed consent document and assent document indicating that the participant or a legally acceptable representative/parent(s)/legal guardian has been informed of all pertinent aspects of the study.
- Males and females 2 to <18-years-old and weighing at least 10 kg at baseline.
- 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.
- Participants diagnosed with UC at age less than 6 years old, must have had testing for very early onset (VEO) inflammatory bowel disease (IBD) and be negative for monogenic disorders associated with VEO IBD.
- 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.
- Pediatric Ulcerative Colitis Activity Index (PUCAI) score ≥35 at baseline.
- No history of dysplasia or colon cancer.
- No evidence or history of untreated or inadequately treated active or latent infection with Mycobacterium tuberculosis (TB).
- 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; • TNF inhibitors or anti-integrin therapy.
- For participants in the US and the EU: have had an inadequate response or intolerance to TNF inhibitors.
- 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 participants who are taking them at the time of enrollment): • Oral 5-Aminosalicyclic acids (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.
- Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures.
- 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.
Exclusion Criteria
- Diagnosis of indeterminate colitis, isolated proctitis, microscopic colitis, infectious colitis, Crohn’s disease, or clinical findings suggestive of Crohn’s disease.
- History of symptomatic obstructive intestinal strictures or active ostomy.
- 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.
- Any factors or clinical characteristics potentially related to the risk of venous thromboembolism (see Section 7.2.4, 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.
- Participants who have previously received tofacitinib or another Janus Kinase inhibitor.
- 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.
- Participants receiving the following treatments: • AZA, 6MP, 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.
- 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.
- Participants previously receiving leukocyte apheresis including selective lymphocyte, monocyte, or granulocyte apheresis, or plasma exchange within 6 months prior to baseline.
- 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. • For moderate to potent CYP3A inducers, within 28 days or 5 half-lives, whichever is longer, prior to first dose of study drug. For moderate to potent CYP3A inhibitors, within 7 days or 5 half-lives, whichever is longer, prior to first dose of study drug.
- Participants who require chronic and frequent use of antimotility agents for control of diarrhea (ie, diphenoxylate hydrochloride with atropine sulfate or loperamide).
- 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.
- Participants with significant trauma or major surgery within 4 weeks of screening visit.
- 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 109/L (<3000/mm3) or absolute neutrophil count of <1.2 x 109/L (<1200/mm3) or absolute lymphocyte count of <0.75 x 109/L (<750/mm3). • Thrombocytopenia, as defined by a platelet count <100 x 109/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).
- Participants who have positive stool examinations for enteric pathogens, pathogenic ova or parasites, or C. difficile toxin at screening.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Belgium | Not Recruiting | 18 Jun 2021 | 4 |
 Finland | Not Recruiting | 18 Jun 2021 | 1 |
 France | Not Recruiting | 18 Jun 2021 | 3 |
 Germany | Not Recruiting | 18 Jun 2021 | 3 |
 Hungary | Not Recruiting | 18 Jun 2021 | 2 |
 Italy | Not Recruiting | 18 Jun 2021 | 5 |
 The Netherlands | Not Recruiting | 18 Jun 2021 | — |
 Poland | Not Recruiting | 18 Jun 2021 | 14 |
 Spain | Not Recruiting | 18 Jun 2021 | 1 |
 Sweden | Not Recruiting | 18 Jun 2021 | 2 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
XELJANZ 1 mg/mL oral solution | Test | ORAL SOLUTION | ORAL | 7 | 39 | PRD9172022 |
XELJANZ 1 mg/mL oral solution | Test | ORAL SOLUTION | ORAL | 7 | 39 | PRD9172029 |
XELJANZ 1 mg/mL oral solution | Test | ORAL SOLUTION | ORAL | 7 | 39 | PRD9172027 |
Tofacitinib citrate | Test | FILM-COATED TABLET | ORAL | 10 | 39 | PRD11085851 |
Tofacitinib citrate | Test | ORAL SOLUTION | ORAL | 7 | 39 | PRD11085894 |
XELJANZ 1 mg/mL oral solution | Test | ORAL SOLUTION | ORAL | 7 | 39 | PRD9172031 |