Oral Tofacitinib for Ulcerative Colitis in Children

Recruiting in Palo Alto (17 mi)

+112 other locations

Age: < 18

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 3

Recruiting

Sponsor: Pfizer

Must not be taking: CYP3A inducers, inhibitors

Disqualifiers: Crohn's disease, HIV, Hepatitis B, others

No Placebo Group

Pivotal Trial (Near Approval)

Prior Safety Data

Approved in 2 Jurisdictions

Trial Summary

What is the purpose of this trial?

This study, A3921210 is designed to evaluate the efficacy, safety and pharmacokinetics (PK) of tofacitinib in pediatric participants with moderately to severely active UC. In the US and EU, patients with prior TNFi failure or intolerance will be enrolled. Outside of the US or EU, patients having had inadequate response or intolerance to oral or IV corticosteroids or azathioprine or 6-mercaptopurine or TNFi will be enrolled. All eligible participants will initially receive open label tofacitinib at a dose expected to produce equivalent systemic exposure to that observed in adults receiving 5 mg BID with the option for individual dose increase to 10 mg BID adult dose equivalent if dose escalation criteria are met. The primary objective of this study is to evaluate the efficacy of tofacitinib based on remission in pediatric participants with moderately to severely active UC. The primary endpoint is remission by central read Mayo score following 44 weeks in the maintenance phase. Remission is defined by a Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and a rectal bleeding subscore of 0. The study Design is an open-label Phase 3 study that includes a screening period of up to 4-weeks duration, an 8-week or 16-week induction phase, a 44-week maintenance phase, and a 24-month extension phase for pediatric participants with moderately to severely active UC. Participants will have a follow-up visit 4 weeks after the last dose of study intervention and a telephone contact 8 weeks later to assess for any adverse events (AEs)/serious adverse events (SAEs). The total maximum duration of this study will be up to 180 weeks.

Will I have to stop taking my current medications?

The trial allows participants to stay on stable doses of certain medications for ulcerative colitis, like oral 5-aminosalicylic acids or sulfasalazine, and oral corticosteroids up to specified limits. However, some medications must be stopped before joining the trial, such as azathioprine, 6-mercaptopurine, and certain other drugs, as they may still affect the body.

What data supports the effectiveness of the drug tofacitinib for treating ulcerative colitis in children?

A case report showed that tofacitinib successfully treated a 13-year-old girl with severe ulcerative colitis, leading to complete remission without the need for steroids. Additionally, tofacitinib has been effective in adults with inflammatory bowel disease, and its safety and efficacy have been demonstrated in clinical trials and real-world settings for moderate to severe ulcerative colitis. ^{1 2 3 4 5}

Is Tofacitinib safe for children with ulcerative colitis?

Tofacitinib has been used safely in children with severe ulcerative colitis, as shown in a case report where a 13-year-old girl achieved remission without surgery. In adults, studies show that serious side effects are similar to other treatments, with no increase in blood clots or major heart issues. ^{2 3 4 5 6}

How is the drug tofacitinib unique for treating ulcerative colitis in children?

Tofacitinib is unique because it is an oral medication that targets the JAK/STAT pathway, which helps reduce inflammation in ulcerative colitis. Unlike some other treatments, it is a small molecule drug that can be taken by mouth, offering an alternative for children who have not responded to other therapies like steroids or biologics. ^{2 4 7 8 9}

Research Team

Pfizer CT.gov Call Center

Principal Investigator

Pfizer

Eligibility Criteria

Children aged 2-17 with moderate to severe ulcerative colitis (UC) can join this trial. They must weigh at least 10 kg and have a confirmed UC diagnosis for over 12 weeks, with specific test results showing active disease. Those who've had certain treatments or surgeries recently, live vaccines, or have other health issues like infections or low blood counts cannot participate.

Inclusion Criteria

I have never had colon cancer or precancerous colon conditions.

I do not have an untreated or poorly treated TB infection.

My ulcerative colitis is moderate to severe, confirmed by a colonoscopy.

Exclusion Criteria

I have had major bowel surgery or recent hospital visits for UC.

Any factors or clinical characteristics potentially related to the risk of venous thromboembolism 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 with the following laboratory values at screening: Hemoglobin level lower than 9.0 g/Dl, Absolute white blood cell (WBC) count lower than 3000/mm3, Absolute neutrophil count lower than 1200/mm3, Absolute lymphocyte count lower than 750/mm3, Thrombocytopenia as defined by a platelet count lower than 100,000/mm3, Estimated bedside Schwartz Glomerular filtration rate (GFR) lower or equal to 40 mL/min/1.73 m2, Total bilirubin, aspartate aminostransferase (AST) or alanine aminotransferase (ALT) more than 1.5 times the upper limit of normal, Positive stool examinations for enteric pathogens, pathogenic ova or parasites, or C. difficile toxin at screening, Participants infected with human immunodeficiency virus (HIV) or hepatitis B or C viruses, History of more than one episode of HZ, a history of disseminated HZ or disseminated herpes simplex, History or current symptoms of any lymphoproliferative disorder (eg, Epstein Barr Virus (EBV) related lymphoproliferative disorder, lymphoma, leukemia, myeloproliferative disorders, multiple myeloma, or signs and symptoms suggestive of currently lymphatic disease), Clinically significant infections currently or within 3 months prior to baseline (eg, those requiring hospitalization or parenteral antimicrobial therapy or opportunistic infections), a history of any infection requiring antimicrobial therapy within 2 weeks of baseline, or a history of any infection otherwise judged by the investigator to have the potential for exacerbation by participation in the study, Any malignancies or with a history of malignancies, with the exception of adequately treated or excised nonmetastatic basal cell or squamous cell cancer of the skin, Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or participants who are employees of the Sponsor, including their family members, directly involved in the conduct of the study, Participation in other studies involving investigational drug(s) within 2 months prior to study entry and/or during study participation, Other acute or chronic medical or psychiatric condition including recent (within the past year) or active suicidal ideation or behavior or laboratory abnormality 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, Pregnant female participants; breastfeeding female participants; fertile female participants of childbearing potential who are unwilling or unable to use a highly effective method of contraception as outlined in this protocol for the duration of the study and through the telephone follow up visit, History of allergies, intolerance or hypersensitivity to lactose or tofacitinib, or any other excipients of the investigational medicinal products, including placebos.

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

up to 4 weeks

Induction

Participants receive open-label tofacitinib to induce remission

8-16 weeks

Regular visits for monitoring and dose adjustments

Maintenance

Participants continue to receive tofacitinib to maintain remission

44 weeks

Regular visits for monitoring and assessment

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

1 in-person visit, 1 telephone contact

Extension

Participants may continue treatment in a long-term extension phase

24 months

Treatment Details

Interventions

• Tofacitinib (Janus Kinase (JAK) Inhibitor)

Trial Overview The trial is testing the drug Tofacitinib in children with UC. It starts with an open-label phase where all participants get Tofacitinib; doses may increase if needed. The main goal is to see if the drug helps achieve remission after 44 weeks of treatment by checking Mayo scores.

Participant Groups

Group I: tofacitinib Experimental Treatment 1 Intervention

Open label tofacitinib 5 mg BID weight based adult equivalent with the option for individual dose increase to 10 mg BID weight based adult equivalent for a limited time if dose escalation criteria are met, prior to returning to 5 mg BID.

Who Is Running the Clinical Trial?

Pfizer

Lead Sponsor

Trials

4,712

Recruited

50,980,000+

Known For

Vaccine Innovations

Top Products

Viagra, Zoloft, Lipitor, Prevnar 13

Albert Bourla

Pfizer

Chief Executive Officer since 2019

PhD in Biotechnology of Reproduction, Aristotle University of Thessaloniki

Patrizia Cavazzoni

Pfizer

Chief Medical Officer

MD from McGill University

Findings from Research

In a study of 15 children with pediatric ulcerative colitis treated with tofacitinib, 8 patients achieved clinical remission by week 8, indicating that tofacitinib can be effective for inducing remission in this population.

Failure to achieve remission by week 16 was strongly linked to the need for colectomy, highlighting the importance of early response to tofacitinib therapy in managing severe cases of ulcerative colitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Outcomes of Tofacitinib Use in an Irish Pediatric Cohort. Ryan, N., Cooper, S., Dominik, A., et al.[2023]

Tofacitinib, a small molecule JAK inhibitor, was successfully used to treat a 13-year-old girl with severe ulcerative colitis (UC) who had not responded to other biologic therapies, leading to complete clinical and endoscopic remission.

This case suggests that tofacitinib may be a safe and effective treatment option for pediatric patients with refractory UC, potentially reducing the need for surgical interventions like proctocolectomy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tofacitinib for a Child with Refractory Steroid-Dependent Ulcerative Colitis: A Case Report and Review of the Literature. Alajmi, R., Alabdulhadi, M., Alali, AA., et al.[2021]

In a study of 21 pediatric patients with medically refractory inflammatory bowel disease (IBD), tofacitinib demonstrated a clinical response in 42.9% of subjects after 12 weeks and maintained a similar response in 41.2% at 52 weeks, indicating its potential effectiveness for young patients.

Tofacitinib was generally well-tolerated, with no significant adverse events like thrombi or zoster reactivation reported, although some patients did discontinue treatment due to refractory disease or complications, suggesting the need for further research on its long-term safety and efficacy.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tofacitinib Therapy in Children and Young Adults With Pediatric-onset Medically Refractory Inflammatory Bowel Disease. Moore, H., Dubes, L., Fusillo, S., et al.[2022]

Tofacitinib is an oral medication that effectively blocks the JAK/STAT pathway, which is involved in inflammation, and has been approved for treating moderate to severe ulcerative colitis.

The efficacy and safety of tofacitinib have been validated through three phase III clinical trials and supportive real-life data, highlighting its important role in treatment strategies for ulcerative colitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tofacitinib in the treatment of ulcerative colitis: efficacy and safety from clinical trials to real-world experience. D'Amico, F., Parigi, TL., Fiorino, G., et al.[2020]

In a real-world study of 96 patients with ulcerative colitis, tofacitinib showed significant and rapid improvement in disease activity starting as early as day 3, with a notable decline in the simple clinical colitis activity index (SCCAI).

The safety profile of tofacitinib was consistent with previous findings, with low rates of discontinuation due to adverse events, and 25% of patients achieving steroid-free remission by day 14.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tofacitinib Response in Ulcerative Colitis (TOUR): Early Response After Initiation of Tofacitinib Therapy in a Real-world Setting. Long, MD., Afzali, A., Fischer, M., et al.[2023]

In a study of 1,026 patients with ulcerative colitis, tofacitinib showed a serious adverse event (SAE) incidence of 4.06 per 100 person-years, which is comparable to the 6.30 per 100 person-years in patients treated with anti-TNF inhibitors (TNFi).

No thromboembolic events were reported in the tofacitinib group, and the rates of herpes zoster and tuberculosis were similar between tofacitinib and TNFi groups, suggesting a favorable safety profile for tofacitinib in this patient population.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

The Comparative Risk of Serious Adverse Events With Tofacitinib and TNF Inhibitors in Patients With Ulcerative Colitis: The Korean Experience as Revealed by a National Database. Seo, GH., Jung, SH.[2022]

Tofacitinib, a selective Janus kinase inhibitor, successfully induced and maintained remission in a 9-year-old boy with moderately active ulcerative colitis (UC) after other biologic treatments failed.

This case suggests that tofacitinib is a safe and effective treatment option for pediatric patients with UC, even those who are steroid-dependent and refractory to other biologics.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Japanese pediatric patient with refractory steroid-resistant ulcerative colitis successfully treated with Tofacitinib: A case report. Kakiuchi, T., Yoshiura, M.[2023]

In a phase 2 trial involving 194 adults with moderately to severely active ulcerative colitis, tofacitinib showed a significant dose-dependent improvement in clinical response and remission rates compared to placebo, with the highest dose (15 mg) achieving a clinical response in 78% of patients (P<0.001).

Tofacitinib treatment was associated with an increase in cholesterol levels and a few cases of low neutrophil counts, indicating the need for monitoring but suggesting a favorable safety profile overall.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. Sandborn, WJ., Ghosh, S., Panes, J., et al.[2022]

In a long-term study of 142 patients with moderate to severe ulcerative colitis, tofacitinib maintained high efficacy, with 68.3% of patients in remission after 12 months and 50.4% still in remission after 36 months.

The safety profile of tofacitinib remained consistent over 36 months, with no new safety risks identified, indicating it is a safe long-term treatment option for ulcerative colitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Maintenance of Remission With Tofacitinib Therapy in Patients With Ulcerative Colitis. Colombel, JF., Osterman, MT., Thorpe, AJ., et al.[2022]

References

1. United States pubmed.ncbi.nlm.nih.gov

Outcomes of Tofacitinib Use in an Irish Pediatric Cohort. [2023]

2. United States pubmed.ncbi.nlm.nih.gov

Tofacitinib for a Child with Refractory Steroid-Dependent Ulcerative Colitis: A Case Report and Review of the Literature. [2021]

3. United States pubmed.ncbi.nlm.nih.gov

Tofacitinib Therapy in Children and Young Adults With Pediatric-onset Medically Refractory Inflammatory Bowel Disease. [2022]

4. England pubmed.ncbi.nlm.nih.gov

Tofacitinib in the treatment of ulcerative colitis: efficacy and safety from clinical trials to real-world experience. [2020]

5. England pubmed.ncbi.nlm.nih.gov

Tofacitinib Response in Ulcerative Colitis (TOUR): Early Response After Initiation of Tofacitinib Therapy in a Real-world Setting. [2023]

6. Korea (South) pubmed.ncbi.nlm.nih.gov

The Comparative Risk of Serious Adverse Events With Tofacitinib and TNF Inhibitors in Patients With Ulcerative Colitis: The Korean Experience as Revealed by a National Database. [2022]

7. United States pubmed.ncbi.nlm.nih.gov

Japanese pediatric patient with refractory steroid-resistant ulcerative colitis successfully treated with Tofacitinib: A case report. [2023]

8. United States pubmed.ncbi.nlm.nih.gov

Tofacitinib, an oral Janus kinase inhibitor, in active ulcerative colitis. [2022]

9. United States pubmed.ncbi.nlm.nih.gov

Maintenance of Remission With Tofacitinib Therapy in Patients With Ulcerative Colitis. [2022]