Clinical trial NCT04624230: Evaluation of Oral Tofacitinib in Children Aged 2 to 17 Years Old Suffering From Moderate to Severe Ulcerative Colitis
Official title: OPEN-LABEL INDUCTION AND MAINTENANCE STUDY OF ORAL CP-690,550 (TOFACITINIB) IN CHILDREN WITH MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE3
Conditions: Ulcerative Colitis
Keywords: Ulcerative Colitis
Pediatric
Tofacitinib Oral
Mayo
PUCAI
Flare
Lead sponsor: Pfizer
Sponsor class: INDUSTRY
First posted: 2020-11-10
Enrollment: 120
Sex: ALL
Minimum age (years): 2
Maximum age (years): 17
Standard ages: CHILD
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SEQUENTIAL
Intervention model description: Single Group
Primary purpose: TREATMENT

Brief summary: 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.


Eligibility criteria: Inclusion Criteria:

* Evidence of a personally signed and dated informed consent document and assent document.
* Males and females 2 to less than18 years old and weighing at least 10 kg.
* Having a pathology report that confirms colonic inflammation consistent with UC with a clinical diagnosis of UC for at least 12 weeks prior to baseline, with biopsy report supporting the diagnosis of UC.
* Participants diagnosed with UC at age less than 6 years old, must have had testing and be negative for monogenic disorders associated with very early onset IBD.
* Moderately to severely active UC as defined (via screening colonoscopy) by a Mayo score of at least 6, with a rectal bleeding score of at least 1 and an endoscopic subscore of at least 2.
* Pediatric Ulcerative Colitis Activity Index (PUCAI) score greater or equal to 35 .
* No history of dysplasia or colon cancer.
* No evidence or history of untreated or inadequately treated active or latent infection with Mycobacterium Tuberculosis.
* For participants outside of the United States or the European Union: 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-mercaptopurine;
  * TNF inhibitors or anti integrin therapy.
* For participants in the United States and the European Union: have had an inadequate response or intolerance to TNF inhibitors.
* Stable doses of the following therapies for UC:

  * Oral 5 Aminosalicyclic acids (ASA) or sulfasalazine
  * Oral corticosteroids equivalent to prednisone at most 1 mg/kg up to a maximum of 20 mg/day or budesonide up to 9 mg/day.
* female participant is eligible if she is not pregnant or breastfeeding, If she is a woman of child bearing potential, she needs to be using a contraceptive method that is highly effective (with a failure rate of \<1% per year).

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, or history of colectomy, extensive small bowel resection ( greater than100 centimetres) or short bowel syndrome, or hospitalization for UC related reason(s) within 2 weeks of baseline visit.
* 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 who have previously received tofacitinib or another Janus Kinase inhibitor.
* Vaccination or exposure 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 having received azathioprine, 6-mercaptopurine, methotrexate, thioguanine, infliximab, adalimumab, golimumab, ustekinumab, interferon, cyclosporine, mycophenolate, tacrolimus, IV or rectally administered corticosteroids, natalizumab, vedolizumab, other antiadhesion molecules, or investigational drugs during the specified time periods prior to baseline whereby they may still have pharmacokinetic and/or pharmacodynamic effect in the body of the participant.
* Previous treatment by leukocyte apheresis including selective lymphocyte, monocyte, or granulocyte apheresis, or plasma exchange within 6 months prior to baseline.
* Treatment by specified prohibited concomitant medications, including moderate to potent CYP3A inducers or inhibitors 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.
* Chronic and frequent use of antimotility agents for control of diarrhea (ie, diphenoxylate hydrochloride with atropine sulfate or loperamide).
* History of bowel surgery, including cholecystectomy within 6 months prior to baseline, history of appendectomy within 3 months prior to baseline, or significant trauma or major surgery within 4 weeks of screening visit are excluded.
* 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.

Primary outcomes:
measure: Remission by central read Mayo score following 44 weeks in the maintenance phase.
timeFrame: Outcome measured at the end of the 44 weeks of the maintenance phase.
Secondary outcomes:
measure: Response by Mayo score
timeFrame: Outcome measured at induction Week 8, induction Week 16, and maintenance Week 44
measure: Remission by Mayo score
timeFrame: Outcome measured at induction Week 8, induction Week 16, and maintenance Week 44
measure: Change from baseline in Mayo score.
timeFrame: Outcome measured at induction Week 8, induction Week 16, and maintenance Week 44
measure: Response measured by Partial Mayo Score
timeFrame: Outcome measured through study completion, an average of 3 and a half years
measure: Change from baseline in Partial Mayo score
timeFrame: Outcome measured through study completion, an average of 3 and a half years
measure: Response by PUCAI score
timeFrame: Outcome measured through study completion, an average of 3 and a half years
measure: Change from baseline in PUCAI score
timeFrame: Outcome measured through study completion, an average of 3 and a half years
measure: Percentage of Participants Achieving Endoscopic Improvement at Week 8, 16, and 44
timeFrame: Outcome measured at induction Week 8, induction Week 16, and maintenance Week 44
measure: Time to flare
timeFrame: Outcome measured from 2 to 4 months in the study, through study completion, an average of 3 and a half years
measure: Change from baseline in fecal calprotectin levels
timeFrame: Outcome measured through study completion, an average of 3 and a half years
measure: Change from baseline in serum high sensitivity C-Reactive Protein (hsCRP) levels
timeFrame: Outcome measured through study completion, an average of 3 and a half years
measure: Corticosteroid free remission by Partial Mayo Score
timeFrame: Outcome measured through study completion, an average of 3 and a half years
measure: Average plasma concentration of tofacitinib (Cavg)
timeFrame: Outcome measured at baseline, induction Week 8, induction Week 16, maintenance Week 16, maintenance Week 44
measure: Evaluation of taste acceptability of tofacitinib oral solution, and acceptability of film coated tablet by choosing one of 5 choices
timeFrame: Outcome measured at induction week 2
measure: Peak (maximum) plasma concentration of tofacitinib (Cmax)
timeFrame: Outcome measured at baseline, induction Week 8, induction Week 16, maintenance Week 16, maintenance Week 44
measure: Percentage of Participants Achieving Endoscopic Remission at Week 8, 16, and 44
timeFrame: Outcome measured at induction Week 8, induction Week 16, and maintenance Week 44
measure: Remission by PUCAI score
timeFrame: Outcome measured through study completion, an average of 3 and a half years
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: Children's Hospital Los Angeles
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco Benioff Children's Hospital
state: California
city: San Francisco
country: United States
facility: University of California, San Francisco Pediatric Clinical Research Center (PCRC)
state: California
city: Farmington
country: United States
facility: Connecticut Children's Ambulatory Surgical Center
state: Connecticut
city: Farmington
country: United States
facility: Connecticut Children's Infusion Center
state: Connecticut
city: Hartford
country: United States
facility: Connecticut Children's Medical Center
state: Connecticut
city: Miami
country: United States
facility: Nicklaus Children's Hospital
state: Florida
city: Atlanta
country: United States
facility: Center for Advanced Pediatrics
state: Georgia
city: Atlanta
country: United States
facility: Children's Healthcare of Atlanta - Arthur M. Blank Hospital
state: Georgia
city: Boston
country: United States
facility: Boston Children's Hospital
state: Massachusetts
city: Morristown
country: United States
facility: Atlantic Children's Health-Pediatric Gastroenterology & Nutrition
state: New Jersey
city: Morristown
country: United States
facility: Goryeb Children's Hospital (Endoscopy only)
state: New Jersey
city: Morristown
country: United States
facility: Atlantic Health System- Morristown Medical Center (Pharmacy)
state: New Jersey
city: Lake Success
country: United States
facility: Northwell Health - Cohen Children's Medical Center
state: New York
city: New Hyde Park
country: United States
facility: Northwell Health - Cohen Children's Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Irving Medical Center
state: New York
city: New York
country: United States
facility: CUIMC Research Pharmacy - Milstein Hospital (Pharmacy Only)
state: New York
city: New York
country: United States
facility: Morgan Stanley Children's Hospital, CUIMC
state: New York
city: Cincinnati
country: United States
facility: Cincinnati Children's Hospital Medical Center
state: Ohio
city: Philadelphia
country: United States
facility: Buerger Center for Advanced Pediatric Care
state: Pennsylvania
city: Philadelphia
country: United States
facility: Children's Hospital of Philadelphia
state: Pennsylvania
city: Philadelphia
country: United States
facility: Roberts Center for Pediatric Research
state: Pennsylvania
city: Houston
country: United States
facility: Texas Children's Hospital - RRO Regulatory (Administrative Offices - Regulatory Location)
state: Texas
city: Houston
country: United States
facility: Texas Children's Hospital
state: Texas
city: Seattle
country: United States
facility: Seattle Children's Hospital
state: Washington
city: Parkville
country: Australia
facility: The Royal Children's Hospital
state: Victoria
city: Leuven
country: Belgium
facility: Universitaire Ziekenhuizen Leuven
state: Vlaams Brabant
city: Brussels
country: Belgium
facility: Hôpital Universitaire Des Enfants Reine Fabiola
city: Brussels
country: Belgium
facility: Cliniques Universitaires Saint-Luc
city: Brussel
country: Belgium
facility: Universitair Ziekenhuis Brussel
city: Edmonton
country: Canada
facility: Stollery Children's Hospital University of Alberta
state: Alberta
city: Vancouver
country: Canada
facility: British Columbia Children's Hospital
state: British Columbia
city: Halifax
country: Canada
facility: IWK Health Centre
state: Nova Scotia
city: London
country: Canada
facility: London Health Sciences Centre - Children's Hospital
state: Ontario
city: Toronto
country: Canada
facility: The Hospital for Sick Children - Division of Gastroenterology, Hepatology and Nutrition
state: Ontario
city: Montreal
country: Canada
facility: CHU Sainte-Justine
state: Quebec
city: Tampere
country: Finland
facility: Tampereen yliopistollinen sairaala
city: BRON Cedex
country: France
facility: CHU de Lyon - Hôpital Femme Mère Enfant
city: Paris
country: France
facility: Hôpital Necker Enfants Malades
city: Munich
country: Germany
facility: Dr. von Haunersches Kinderspital, LMU
state: Bavaria
city: Debrecen
country: Hungary
facility: Debreceni Egyetem Klinikai Kozpont
state: Hajdú-bihar
city: Miskolc
country: Hungary
facility: Borsod- Abauj- Zemplen Megyei Kozponti Korhaz es Egyetemi Oktatokorhaz
city: Szeged
country: Hungary
facility: Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont
city: Be'er Ya'akov
country: Israel
facility: Shamir Medical Center (Assaf Harofeh)
city: Haifa
country: Israel
facility: Lady Davis Carmel Medical Center
city: Jerusalem
country: Israel
facility: Shaare Zedek Medical Center
city: Petah Tikva
country: Israel
facility: Schneider Children's Medical Center of Israel
city: Tel Aviv
country: Israel
facility: Tel-Aviv Sourasky Medical Center
city: Bergamo
country: Italy
facility: ASST Papa Giovanni XXIII Epatologia e Gastroenterologia Pediatrica e dei Trapianti
state: BG
city: Napoli
country: Italy
facility: A.O.U. Federico II
state: Naples
city: Roma
country: Italy
facility: Azienda Ospedaliero - Universitaria Policlinico Umberto I di Roma
state: RM
city: Bologna
country: Italy
facility: Azienda USL di Bologna - IRCCS ISNB - Programma Gastroenterologia Pediatrica
city: Obu-shi
country: Japan
facility: Aichi Children's Health and Medical Center
state: Aichi
city: Kurume-shi
country: Japan
facility: Kurume University Hospital
state: Fukuoka
city: Maebashi
country: Japan
facility: Gunma University Hospital
state: Gunma
city: Sendai-shi
country: Japan
facility: Miyagi Children's Hospital
state: Miyagi
city: Izumi
country: Japan
facility: Osaka Women's and Children's Hospital
state: Osaka
city: Takatsuki-shi
country: Japan
facility: Osaka Medical and Pharmaceutical University Hospital
state: Osaka
city: Saitama-shi
country: Japan
facility: Saitama Prefectural Children's Medical Center
state: Saitama
city: Shimotsuke
country: Japan
facility: Jichi Medical University Hospital
state: Tochigi
city: Bunkyo-ku
country: Japan
facility: Juntendo University Hospital
state: Tokyo
city: Setagaya-ku
country: Japan
facility: National Center for Child Health and Development
state: Tokyo
city: Amsterdam
country: Netherlands
facility: Amsterdam UMC, location VUmc Boelelaan
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Center - Sophia Children's Hospital
city: Lodz
country: Poland
facility: Instytut "Centrum Zdrowia Matki Polki"
city: Rzeszow
country: Poland
facility: Korczowski Bartosz, Gabinet Lekarski
city: Warsaw
country: Poland
facility: WIP Warsaw IBD Point Profesor Kierkus
city: Warszawa
country: Poland
facility: Instytut "Pomnik - Centrum Zdrowia Dziecka"
city: Wroclaw
country: Poland
facility: Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu
city: Bratislava
country: Slovakia
facility: Narodny ustav detskych chorob
city: Esplugues de Llobregat
country: Spain
facility: Hospital Sant Joan de Déu
state: Barcelona
city: Malaga
country: Spain
facility: Hospital Materno-Infantil de Málaga (Hospital Regional Universitario de Málaga)
state: Málaga
city: Madrid
country: Spain
facility: Hospital Infantil Universitario Niño Jesus
city: Göteborg
country: Sweden
facility: Sahlgrenska Universitetssjukhuset
city: Stockholm
country: Sweden
facility: Sachsska Children's and Youth Hospital/South General Hospital
city: Stockholm
country: Sweden
facility: Karolinska Universitetssjukhuset Barngastroenterologi, hepatologi och nutrition
city: London
country: United Kingdom
facility: King's College Hospital NHS Foundation Trust
state: Greater London
city: Birmingham
country: United Kingdom
facility: Birmingham Women's and Children's NHS Foundation Trust
state: WEST Midlands
city: Edinburgh
country: United Kingdom
facility: NHS Lothian
city: London
country: United Kingdom
facility: Bart's Health NHS Trust
Study officials:
affiliation: Pfizer
name: Pfizer CT.gov Call Center
role: STUDY_DIRECTOR
References:
citation: Benchimol EI, Bernstein CN, Bitton A, Carroll MW, Singh H, Otley AR, Vutcovici M, El-Matary W, Nguyen GC, Griffiths AM, Mack DR, Jacobson K, Mojaverian N, Tanyingoh D, Cui Y, Nugent ZJ, Coulombe J, Targownik LE, Jones JL, Leddin D, Murthy SK, Kaplan GG. Trends in Epidemiology of Pediatric Inflammatory Bowel Disease in Canada: Distributed Network Analysis of Multiple Population-Based Provincial Health Administrative Databases. Am J Gastroenterol. 2017 Jul;112(7):1120-1134. doi: 10.1038/ajg.2017.97. Epub 2017 Apr 18.
citation: Konstantinides SV, Meyer G, Becattini C, Bueno H, Geersing GJ, Harjola VP, Huisman MV, Humbert M, Jennings CS, Jimenez D, Kucher N, Lang IM, Lankeit M, Lorusso R, Mazzolai L, Meneveau N, Ni Ainle F, Prandoni P, Pruszczyk P, Righini M, Torbicki A, Van Belle E, Zamorano JL; ESC Scientific Document Group. 2019 ESC Guidelines for the diagnosis and management of acute pulmonary embolism developed in collaboration with the European Respiratory Society (ERS). Eur Heart J. 2020 Jan 21;41(4):543-603. doi: 10.1093/eurheartj/ehz405. No abstract available.
citation: Kelsen JR, Sullivan KE, Rabizadeh S, Singh N, Snapper S, Elkadri A, Grossman AB. North American Society for Pediatric Gastroenterology, Hepatology, and Nutrition Position Paper on the Evaluation and Management for Patients With Very Early-onset Inflammatory Bowel Disease. J Pediatr Gastroenterol Nutr. 2020 Mar;70(3):389-403. doi: 10.1097/MPG.0000000000002567.
citation: Turner D, Otley AR, Mack D, Hyams J, de Bruijne J, Uusoue K, Walters TD, Zachos M, Mamula P, Beaton DE, Steinhart AH, Griffiths AM. Development, validation, and evaluation of a pediatric ulcerative colitis activity index: a prospective multicenter study. Gastroenterology. 2007 Aug;133(2):423-32. doi: 10.1053/j.gastro.2007.05.029. Epub 2007 May 21.
citation: Otley A, Smith C, Nicholas D, Munk M, Avolio J, Sherman PM, Griffiths AM. The IMPACT questionnaire: a valid measure of health-related quality of life in pediatric inflammatory bowel disease. J Pediatr Gastroenterol Nutr. 2002 Oct;35(4):557-63. doi: 10.1097/00005176-200210000-00018.
citation: Marcovitch L, Nissan A, Mack D, Otley A, Hussey S, Mclean B, Lewis M, Croft N, Barakat FM, Griffiths AM, Turner D. Item Generation and Reduction Toward Developing a Patient-reported Outcome for Pediatric Ulcerative Colitis (TUMMY-UC). J Pediatr Gastroenterol Nutr. 2017 Mar;64(3):373-377. doi: 10.1097/MPG.0000000000001259.
citation: Taylor SJ, Whincup PH, Hindmarsh PC, Lampe F, Odoki K, Cook DG. Performance of a new pubertal self-assessment questionnaire: a preliminary study. Paediatr Perinat Epidemiol. 2001 Jan;15(1):88-94. doi: 10.1046/j.1365-3016.2001.00317.x.