This study has been transitioned to CTIS with ID 2023-509694-22-00 check the CTIS register for the current data. Primary objective: • To evaluate the efficacy of tofacitinib based on remission in pediatric participants with moderately to severely…
ID
Source
Brief title
Condition
- Gastrointestinal inflammatory conditions
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
• 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.
Secondary outcome
Secondary Endpoints:
• 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 by PUCAI score over time.
• 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 reactive protein (hsCRP) levels
over time.
• 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).
Tertiary/Exploratory Endpoint(s):
• Collection of banked biospecimens unless prohibited by local regulations or
ethics committee decision. Additional information on collection and potential
use is provided in the Banked Biospecimens section 7.5 of the protocol.
• Change from baseline in IMPACT III scores over time.
• Change from baseline in TUMMY-UC scores over time
• Corticosteroid use over time.
• Change from baseline in UCEIS over time (induction, maintenance).
Safety Endpoins:
• Incidence and severity of adverse events and serious adverse events.
• Incidence and severity of clinical laboratory abnormalities, and change from
baseline in clinical laboratory values.
• Incidence of clinically significant changes in physical examination from
baseline.
• Incidence of vital sign abnormalities and changes from baseline in vital sign
measurements during treatment.
• Summary of adjudicated safety events (eg, cardiovascular, opportunistic
infection, hepatic, gastrointestinal perforations and malignancy).
• Tanner stage to assess pubertal maturation.
• Change from baseline in height z score over time.
• Change from baseline in weight z score over time.
Background summary
Tofacitinib is a potent, selective inhibitor of the Janus kinase (JAK) family
of kinases with a high degree of selectivity against other kinases. In kinase
assays, tofacitinib inhibits JAK1, JAK2, JAK3, and to a lesser extent tyrosine
kinase 2 (TyK2). In cellular settings where JAK kinases signal in pairs,
tofacitinib preferentially inhibits signaling by heterodimers containing JAK3
and/or JAK1 with functional selectivity over JAK2 homodimer signaling.
The tofacitinib Phase 3 adult ulcerative colitis (UC) program evaluated the
efficacy and safety of tofacitinib in adult patients with moderately to
severely active UC who had prior failure or intolerance to corticosteroids,
azathioprine/6 mercaptopurine (AZA/6 MP), and/or tumor necrosis factor
inhibitor (TNFi) agents. The program consists of 2 completed, identically
designed 8 week induction studies (A3921094 and A3921095) with tofacitinib 10
mg twice a day (BID) or placebo, 1 completed 52 week maintenance study
(A3921096) with tofacitinib 5 mg BID, tofacitinib 10 mg BID, or placebo, and 1
ongoing open label long term extension (LTE) study (A3921139) with tofacitinib
5 mg BID and tofacitinib 10 mg BID.
In both induction studies (A3921094 and A3921095), statistically significantly
higher proportions of participants in the tofacitinib 10 mg BID group achieved
the primary endpoint of remission as well as the key secondary endpoint of
mucosal healing at Week 8 compared with placebo. The tofacitinib 10 mg BID
group also had statistically significantly higher proportions of participants
with the secondary endpoints of clinical response and endoscopic remission at
Week 8 as compared with placebo. These results were supported by all other
secondary and exploratory efficacy endpoints and patient reported outcomes
(PROs). The observed treatment effects were consistent regardless of prior
TNFi treatment. Tofacitinib 5 mg BID for induction was not studied in the
Phase 3 adult studies.
In the maintenance study (A3921096), both tofacitinib 5 mg BID and 10 mg BID
demonstrated significantly greater treatment effects versus placebo for
remission at Week 52 (primary endpoint), mucosal healing at Week 52, and
sustained corticosteroid-free remission among participants in remission at
baseline (key secondary endpoints). Tofacitinib 5 mg BID and 10 mg BID also
demonstrated significantly greater proportions of participants with clinical
response compared with placebo. Time to treatment failure was significantly
different in the tofacitinib 5 mg BID and 10 mg BID treatment groups compared
with placebo, with earlier and more frequent events in the placebo group. The
efficacy of tofacitinib 5 mg BID and 10 mg BID was supported by all other
secondary and exploratory efficacy endpoints and patient reported outcomes
(PROs).
The safety data from the overall UC clinical program showed that the safety
profile of tofacitinib treatment in the adult UC population was consistent with
that of the rheumatoid arthritis (RA) population. There was evidence of dose
effect for herpes zoster (HZ), consistent with other indications. The overall
safety profile of tofacitinib was also similar to that of TNFi agents except
for a higher rate of HZ. The majority of HZ events were cutaneous zoster
involving 1 or 2 adjacent dermatomes. The totality of data supports an overall
acceptable safety profile for both tofacitinib 5 mg BID and 10 mg BID
maintenance therapy in moderately to severely active adult UC patients.
Following completion of the pivotal trials for the adult UC program, data from
an ongoing study in rheumatoid arthritis study A3921133 in RA patients over 50
years of age with at least one cardiovascular risk factor showed a higher rate
of pulmonary embolism (PE) with tofacitinib 10 mg BID compared to tofacitinib 5
mg BID or TNF inhibitors. Venous thromboembolism (VTE) subsequently was
assessed as an important identified risk for tofacitinib. While the background
VTE events in pediatric UC population is low and some VTE risk factors are
uncommon in this population, a risk of VTE with tofacitinib treatment cannot be
excluded in the pediatric UC population. Therefore, tofacitinib 5 mg BID will
be investigated in this study, initially in induction with the option to dose
escalate to tofacitinib 10 mg BID if individual dose escalation criteria are
met, and subsequently in maintenance and extension also with the option for
dose escalation if flare criteria are met. For additional risk minimization
measures, please refer to Section 1.2.1.
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 enrolled1. Outside of the US and EU, TNFi naïve and TNFi
experienced patients will be enrolled.
Study objective
This study has been transitioned to CTIS with ID 2023-509694-22-00 check the CTIS register for the current data.
Primary objective:
• To evaluate the efficacy of tofacitinib based on remission in pediatric
participants with moderately to severely active UC.
Secondary objectives:
• To evaluate the overall efficacy of tofacitinib 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 induction phase.
Tertiary/Exploratory Objective(s):
• To collect banked biospecimens for exploratory research, unless prohibited by
local regulations or ethics committee decision (Induction).
• To evaluate the effect of tofacitinib as induction, maintenance, and long
term therapy on quality of life.
• To evaluate the endoscopic efficacy of tofacitinib during induction and
maintenance.
Safety objectives:
• To evaluate the safety and tolerability of tofacitinib as induction,
maintenance, and long term therapy.
Study design
This 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.
Enrollment will be staggered by 4 cohorts to allow initial evaluation of PK and
safety in older participants prior to enrollment of younger participants, as
described in Figure 2. Enrollment Schema, protocol Section 3.1 Study Design,
Induction Phase.
The study consists of a screening visit, a 28-day baseline period, and a
12-week (84-day) treatment period, including a final evaluation at week 12
(end-of-treatment [EOT] visit, approximately 4 weeks [28 days] after the final
dose of study drug).
Intervention
Induction Phase
All eligible participants enrolled in Cohorts 1 and 2 of the study will
initially receive open label tofacitinib at a dose expected to produce
equivalent systemic exposure to that observed in adults receiving 5 mg BID in
the Induction phase, with the option for individual dose increase to 10 mg BID
at Week 4 or week 8 if dose escalation criteria are met. For participants who
start induction on 5 mg BID, individual dose escalation criteria at Week 4 or
week 8 are:
1. Pediatric Ulcerative Colitis Activity Index (PUCAI) rectal bleeding score is
at least 20 points (ie, 20 or 30 points) OR;
2. Decrease from baseline in PUCAI <20 points OR;
3. Absolute PUCAI score is >=45 points.
There is also a potential for opening Cohort 3 and Cohort 4, in which
participants will receive induction treatment with 10 mg BID (adult equivalent
dose) (ie, *de novo 10 mg BID*), after the first 26 participants complete at
least 8 weeks in Cohort 1 are assessed for efficacy, PK and safety. Details
can be found in study Protocol, Section 1.4 Rationale for Dose Selection.
At the end of the 8- or 16-week induction phase, only participants who achieve
composite response by PUCAI, defined by a PUCAI score decrease from baseline
of >=20 points and an absolute PUCAI score <35, will be eligible for the 44-week
maintenance phase of the study. Participants who do not achieve composite
response at the Week 8 induction visit, will receive an additional 8 weeks of
induction for a total of 16 weeks induction. For those participants who
receive the additional 8 weeks of induction, those who complete 16 weeks of
induction and achieve composite response as assessed by PUCAI score decrease of
>=20 points and PUCAI score of <35 points are eligible to continue in the
maintenance phase of the study.
In the maintenance phase, participants >=30 kg will be assigned to receive
tofacitinib 5 mg BID for up to 44 weeks with the possibility for dose
escalation to 10 mg BID if flare criteria are met. Participants <30 kg will
receive tofacitinib 5 mg BID adult equivalent dose for up to 44 weeks, with no
possibility for dose escalation.
Participants who complete the maintenance phase will be eligible for a 24-month
extension phase. In the extension phase, all participants will receive 5 mg BID
tofacitinib with the possibility for dose escalation to 10 mg BID for
participants >=30 kg, if flare criteria are met.
Study burden and risks
Potential safety risks for patients treated with tofacitinib are based on the
totality of the data including nonclinical and clinical observations, as well
as safety risks reported for other available therapies that may share common
pathways.
Safety findings and potential risks that may be associated with the use of
tofacitinib include serious and other important infections such as
tuberculosis, OIs and HZ, potential for malignancies including lymphoma and
lung cancer, and potential for gastrointestinal (GI) perforations. Patients
receiving tofacitinib may be at increased risk of NMSC, breast cancer,
melanoma, prostate cancer and pancreatic cancer
Based on nonclinical data, there is the potential for tofacitinib to have
effects on pregnancy and the fetus. Subjects taking a combination birth control
product (estrogen and progesterone) and who meet study criteria for a dose
increase because their ulcerative colitis got worse, will not be able to
increase their dose to 10 mg twice a day due to increased risk of venous
thromboembolism (blood clot).
Cardiovascular disease, major adverse cardiovascular events (including heart
attacks), GI perforation and ILD are serious comorbidities for some populations
in which tofacitinib has been studied and have been reported as potential risks
associated with other DMARD therapies.
The risk of developing a blood clot in the lungs (pulmonary embolism) or a
blood clot in the veins of the arms or the legs (deep vein thrombosis) may be
increased with tofacitinib.
Fractures (broken bones) have also happened in patients taking tofacitinib.
Laboratory changes observed with the oral use of tofacitinib in humans include
decreases in neutrophil counts, lymphocyte counts, and hemoglobin levels,
increases in serum creatinine, total cholesterol, HDL cholesterol, LDL
cholesterol, transaminases and creatine kinase. Recovery of laboratory changes
upon discontinuation of tofacitinib treatment is characteristically observed.
Taking into consideration the disease burden and unmet medical need of UC, the
expected efficacy of tofacitinib in this indication, and the safety profile of
this compound from the available data in inflammatory bowel disease and the
more extensive data from the other tofacitinib development programs, the
Sponsor believes that the overall risk benefit assessment for this study is
favourable.
Office F32120, Pfizer Inc. 500 Arcola Road
Collegeville PA 19426
US
Office F32120, Pfizer Inc. 500 Arcola Road
Collegeville PA 19426
US
Listed location countries
Age
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 moderate to severe active UC as defined (via screening
endoscopy ) by a total 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 enrolment.
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. Participants with documented evidence from a health professional of having
received 2 vaccinations for varicella zoster virus (VZV) or participants with
evidence of prior exposure to VZV based on positive serological testing at
screening (ie, VZV IgG Ab).
13. Willing and able to comply with scheduled visits, treatment plan,
laboratory tests, and other study procedures.
14. 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
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) 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 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.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2023-509694-22-00 |
| EudraCT | EUCTR2018-002378-30-NL |
| ClinicalTrials.gov | NCT04624230 |
| CCMO | NL75411.078.21 |