Evaluation of Oral Tofacitinib in Children Aged 2 to 17 Years Old Suffering From Moderate to Severe Ulcerative Colitis

Sponsor

Pfizer (Industry)

Overall Status

Recruiting

CT.gov ID

NCT04624230

Collaborator

(none)

120

Enrollment

Locations

Arm

Anticipated Duration (Months)

1.5

Patients Per Site

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Ulcerative Colitis	Drug: tofacitinib	Phase 3

Study Design

Study Type:

Interventional

Anticipated Enrollment :

120 participants

Allocation:

N/A

Intervention Model:

Sequential Assignment

Intervention Model Description:

Single GroupSingle Group

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

OPEN-LABEL INDUCTION AND MAINTENANCE STUDY OF ORAL CP-690,550 (TOFACITINIB) IN CHILDREN WITH MODERATELY TO SEVERELY ACTIVE ULCERATIVE COLITIS

Actual Study Start Date :

Aug 12, 2021

Anticipated Primary Completion Date :

Dec 21, 2026

Anticipated Study Completion Date :

Mar 12, 2029

Arms and Interventions

Arm	Intervention/Treatment
Experimental: tofacitinib 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.	Drug: tofacitinib 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.

Arm

Intervention/Treatment

Experimental: tofacitinib

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.

Drug: tofacitinib

Outcome Measures

Primary Outcome Measures

Remission by central read Mayo score following 44 weeks in the maintenance phase. [Outcome measured at the end of the 44 weeks of the maintenance phase.]
Remission is defined by central endoscopy read Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and a rectal bleeding subscore of 0. The primary outcome Mayo score is the summation of 4 subscores as listed below : patient reported stool frequency (scored 0 to 3) patient reported rectal bleeding (scored 0 to 3) central read findings on endoscopy (scored 0 to 3) physician's global assessment (scored 0 to 3) The Mayo score has a scale from 0 to 12 points, with the lower score indicating lower ulcerative colitis (UC) disease activity.

Secondary Outcome Measures

Response by Mayo score [Outcome measured at induction Week 8, induction Week 16, and maintenance Week 44]
Response by Mayo score is defined by a decrease from baseline in Mayo score of at least 3 points and at least 30%, with an accompanying decrease in the subscore for rectal bleeding of at least 1 point or absolute subscore for rectal bleeding of 0 or 1.
Remission by Mayo score [Outcome measured at induction Week 8, induction Week 16, and maintenance Week 44]
Remission by Mayo score with local and central endoscopy read (induction Week 8, induction Week 16), and with local endoscopy read only (maintenance week 44).
Change from baseline in Mayo score. [Outcome measured at induction Week 8, induction Week 16, and maintenance Week 44]
Response measured by Partial Mayo Score [Outcome measured through study completion, an average of 3 and a half years]
Response is defined by a partial Mayo score decrease of 2 points or more from baseline. This score is based on the summation of the following subscores : stool frequency (scored 0 to 3) rectal bleeding (scored 0 to 3) physician global assessment (PGA) (scored 0 to 3) The partial Mayo score has a scale from 0 to 9, with the lower score indicating lower ulcerative colitis (UC) disease activity.
Change from baseline in Partial Mayo score [Outcome measured through study completion, an average of 3 and a half years]
Change in partial Mayo score. This score is the summation of 3 distinct dimensions as listed below : stool frequency (scored 0 to 3) rectal bleeding (scored 0 to 3) physician global assessment (PGA) (scored 0 to 3) The partial Mayo score has a scale from 0 to 9, with the lower score indicating lower ulcerative colitis (UC) disease activity.
Response by PUCAI score [Outcome measured through study completion, an average of 3 and a half years]
The Pediatric Ulcerative Colitis Activity Index (PUCAI) score is the summation of 6 dimensions that are all reported by the investigator. The PUCAI score varies from 0 to 85 points, with the lower score indicating lower ulcerative colitis (UC) disease activity. The 6 dimensions of the PUCAI score are as follows : abdominal pain rectal bleeding stool consistency of most stools number of stools per 24 hours nocturnal stools activity level Response is defined by a PUCAI score decrease of 20 points or more.
Change from baseline in PUCAI score [Outcome measured through study completion, an average of 3 and a half years]
The Pediatric Ulcerative Colitis Activity Index (PUCAI) score is the summation of 6 dimensions that are all reported by the investigator abdominal pain rectal bleeding stool consistency of most stools number of stools per 24 hours nocturnal stools activity level The PUCAI score varies from 0 to 85 points, with the lower score indicating lower ulcerative colitis (UC) disease activity.
Percentage of Participants Achieving Endoscopic Improvement at Week 8, 16, and 44 [Outcome measured at induction Week 8, induction Week 16, and maintenance Week 44]
Endoscopic improvement is defined by Mayo endoscopic sub-score of 0 or 1. The Mayo endoscopic sub-score is used to assess ulcerative colitis activity, and ranges from 0 to 3, and is based on the findings during endoscopy. A lower score is indicative of a lower ulcerative colitis (UC) disease activity.
Time to flare [Outcome measured from 2 to 4 months in the study, through study completion, an average of 3 and a half years]
Change from baseline in fecal calprotectin levels [Outcome measured through study completion, an average of 3 and a half years]
Change from baseline in serum high sensitivity C-Reactive Protein (hsCRP) levels [Outcome measured through study completion, an average of 3 and a half years]
Corticosteroid free remission by Partial Mayo Score [Outcome measured through study completion, an average of 3 and a half years]
Remission is defined by a partial Mayo score of 2 points or lower, with no individual subscore exceeding 1 point and rectal bleeding subscore of 0. The subscores of the partial Mayo score are: stool frequency (scored 0 to 3) rectal bleeding (scored 0 to 3) physician global assessment (PGA) (scored 0 to 3)
Average plasma concentration of tofacitinib (Cavg) [Outcome measured at 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 by choosing one of 5 choices [Outcome measured at induction week 2]
Taste acceptability will be assessed by asking the participant to select one of 5 choices which most adequately reflects the participant's response to taste. Age appropriate tools (using wording and/or graphic facial expressions) will be used to assess taste acceptability.
Peak (maximum) plasma concentration of tofacitinib (Cmax) [Outcome measured at baseline, induction Week 8, induction Week 16, maintenance Week 16, maintenance Week 44]
Percentage of Participants Achieving Endoscopic Remission at Week 8, 16, and 44 [Outcome measured at induction Week 8, induction Week 16, and maintenance Week 44]
Endoscopic remission is defined by a Mayo endoscopic subscore of 0, out of a maximum of 3 points. The Mayo endoscopic sub-score is used to assess ulcerative colitis activity, and ranges from 0 to 3, and is based on the findings during endoscopy. A lower score is indicative of a lower ulcerative colitis (UC) disease activity.
Remission by PUCAI score [Outcome measured through study completion, an average of 3 and a half years]
The Pediatric Ulcerative Colitis Activity Index (PUCAI) score is the summation of 6 dimensions that are all reported by the investigator. The PUCAI score varies from 0 to 85 points, with the lower score indicating lower ulcerative colitis (UC) disease activity. The 6 dimensions of the PUCAI score are as follows : abdominal pain rectal bleeding stool consistency of most stools number of stools per 24 hours nocturnal stools activity level Remission is defined by a PUCAI score of less than 10 points.

Eligibility Criteria

Criteria

Ages Eligible for Study:

2 Years to 17 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Phoenix Children's Hospital	Phoenix	Arizona	United States	85016
2	Children's Hospital Los Angeles	Los Angeles	California	United States	90027
3	University of California, San Francisco (Admin Only)	San Francisco	California	United States	94158
4	University of California, San Francisco Benioff Children's Hospital	San Francisco	California	United States	94158
5	University of California, San Francisco Pediatric Clinical Research Center (PCRC)	San Francisco	California	United States	94158
6	Connecticut Children's Infusion Center	Farmington	Connecticut	United States	06032
7	Connecticut Children's Medical Center	Hartford	Connecticut	United States	06106
8	Nicklaus Children's Hospital	Miami	Florida	United States	33155
9	Outpatient Pediatric Research Center Children's Healthcare of Atlanta	Atlanta	Georgia	United States	30329
10	Boston Children's Hospital	Boston	Massachusetts	United States	02115
11	Atlantic Children's Health-Pediatric Gastroenterology & Nutrition	Morristown	New Jersey	United States	07960
12	Goryeb Children's Hospital (Endoscopy only)	Morristown	New Jersey	United States	07960
13	Atlantic Health System- Morristown Medical Center (Pharmacy)	Morristown	New Jersey	United States	07962
14	Northwell Health - Cohen Children's Medical Center	Lake Success	New York	United States	11042
15	Northwell Health - Cohen Children's Medical Center	New Hyde Park	New York	United States	11040
16	Weill Cornell Medicine - New York Presbyterian Hospital	New York	New York	United States	10021
17	Mount Sinai Hospital (Investigational Drug Pharmacy)	New York	New York	United States	10029
18	Mount Sinai Hospital Endoscopy Center (Endoscopy Only)	New York	New York	United States	10029
19	Susan and Leonard Feinstein Inflammatory Bowel Disease Clinical Center at Mount Sinai	New York	New York	United States	10029
20	Columbia University Irving Medical Center	New York	New York	United States	10032
21	CUIMC Research Pharmacy - Milstein Hospital (Pharmacy Only)	New York	New York	United States	10032
22	Morgan Stanley Children's Hospital, CUIMC	New York	New York	United States	10032
23	Duke University Health System	Durham	North Carolina	United States	27710
24	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio	United States	45229
25	Buerger Center for Advanced Pediatric Care	Philadelphia	Pennsylvania	United States	19104
26	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania	United States	19104
27	Roberts Center for Pediatric Research	Philadelphia	Pennsylvania	United States	19146
28	Texas Children's Hospital - Clinical Research Center	Houston	Texas	United States	77030
29	Texas Children's Hospital - Wallace Tower	Houston	Texas	United States	77030
30	Texas Children's Hospital - West Tower	Houston	Texas	United States	77030
31	Seattle Children's Hospital	Seattle	Washington	United States	98105
32	Children's Wisconsin	Milwaukee	Wisconsin	United States	53226
33	Women's and Children's Hospital, Women's and Children's Health Network Inc.	North Adelaide	South Australia	Australia	5006
34	The Royal Children's Hospital	Parkville	Victoria	Australia	3052
35	Hôpital Universitaire Des Enfants Reine Fabiola	Brussels		Belgium	1020
36	Cliniques Universitaires Saint-Luc	Brussels		Belgium	1200
37	Universitair Ziekenhuis Brussel	Brussel		Belgium	1090
38	Universitaire Ziekenhuizen Leuven	Leuven		Belgium	3000
39	University of Alberta Hospital	Edmonton	Alberta	Canada	T6G 1C9
40	British Columbia Children's Hospital	Vancouver	British Columbia	Canada	V6H 3V4
41	IWK Health Centre	Halifax	Nova Scotia	Canada	B3K 6R8
42	London Health Sciences Centre - Children's Hospital	London	Ontario	Canada	N6A 5W9
43	CHU Sainte-Justine	Montreal	Quebec	Canada	H3T 1C5
44	Tampereen yliopistollinen sairaala	Tampere		Finland	33520
45	CHU de Lyon - Hôpital Femme Mère Enfant	BRON Cedex		France	69677
46	Hôpital Necker Enfants Malades	Paris		France	75015
47	Dr. von Haunersches Kinderspital, LMU	Munich	Bavaria	Germany	80337
48	Debreceni Egyetem Klinikai Kozpont	Debrecen		Hungary	4032
49	Borsod- Abauj- Zemplen Megyei Kozponti Korhaz es Egyetemi Oktatokorhaz	Miskolc		Hungary	3526
50	Szegedi Tudomanyegyetem Szent-Gyorgyi Albert Klinikai Kozpont	Szeged		Hungary	6720
51	Shamir Medical Center (Assaf Harofeh)	Be'er Ya'akov		Israel	7033001
52	Lady Davis Carmel Medical Center	Haifa		Israel	3436212
53	The Edith Wolfson Medical Center	Holon		Israel	5822012
54	Shaare Zedek Medical Center	Jerusalem		Israel	9103102
55	Schneider Children's Medical Center of Israel	Petah Tikva		Israel	4920235
56	Tel-Aviv Sourasky Medical Center	Tel Aviv		Israel	6423906
57	ASST Papa Giovanni XXIII	Bergamo	BG	Italy	24127
58	A.O.U. Federico II	Napoli	Naples	Italy	80131
59	A.O.U. Policlinico Umberto I	Roma	RM	Italy	00161
60	Aichi Children's Health and Medical Center	Obu-shi	Aichi	Japan	474-8710
61	Kurume University Hospital	Kurume-shi	Fukuoka	Japan	830-0011
62	Gunma University Hospital	Maebashi	Gunma	Japan	371-8511
63	Miyagi Children's Hospital	Sendai-shi	Miyagi	Japan	989-3126
64	Osaka Women's and Children's Hospital	Izumi	Osaka	Japan	594-1101
65	Osaka Medical and Pharmaceutical University Hospital	Takatsuki-shi	Osaka	Japan	569-8686
66	Saitama Children's Medical Center	Saitama-shi	Saitama	Japan	330-8777
67	Juntendo University Hospital	Bunkyo-ku	Tokyo	Japan	113-8431
68	National Center for Child Health and Development	Setagaya-ku	Tokyo	Japan	157-8535
69	Szpital Uniwersytecki nr 1 im. dr. A. Jurasza w Bydgoszczy	Bydgoszcz		Poland	85-094
70	Instytut "Centrum Zdrowia Matki Polki"	Lodz		Poland	93-338
71	Korczowski Bartosz, Gabinet Lekarski	Rzeszow		Poland	35-302
72	WIP Warsaw IBD Point Profesor Kierkus	Warszawa		Poland	00-728
73	Instytut "Pomnik - Centrum Zdrowia Dziecka"	Warszawa		Poland	04-730
74	Uniwersytecki Szpital Kliniczny im. Jana Mikulicza-Radeckiego we Wroclawiu	Wroclaw		Poland	50-369
75	Narodny ustav detskych chorob	Bratislava		Slovakia	833 40
76	Hospital Sant Joan de Déu	Esplugues de Llobregat	Barcelona	Spain	08950
77	Hospital Materno-Infantil de Málaga (Hospital Regional Universitario de Málaga)	Malaga	Málaga	Spain	29011
78	Hospital Infantil Universitario Niño Jesus	Madrid		Spain	28009
79	Karolinska Universitetssjukhuset Barngastroenterologi, hepatologi och nutrition	Stockholm		Sweden	171 76
80	Royal London Children's Hospital	Edinburgh	London	United Kingdom	E1 1FR
81	NHS Lothian	Edinburgh		United Kingdom	EH16 4TJ
82	Royal Hospital for Children	Glasgow		United Kingdom	G51 4TF