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Double Blind, Placebo-controlled Trial to Establish Safety and Efficacy of Ritlecitinib in Celiac Disease Patients in Remission

Primary Purpose

Celiac Disease

Status
Recruiting
Phase
Phase 2
Locations
United States
Study Type
Interventional
Intervention
Ritlecitinib
Placebo
Gluten
Sponsored by
Massachusetts General Hospital
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Celiac Disease focused on measuring Celiac Disease, Gluten, Gluten Challenge, Ritlecitinib

Eligibility Criteria

18 Years - 75 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Male and/or female subjects (including Women of Childbearing Potential (WOCBP)) ≥18 years to ≤75 years of age at the time of informed consent Have a body mass index ≥17 to <40 (and a body weight >45 kg at the Screening Visit). Agree to make every effort to avoid pregnancy (see lifestyle outline below) from the time of signing the informed consent throughout the duration of the trial, if the subject is a woman of childbearing potential and sexually active with a non-sterilized male partner. Have well controlled biopsy-proven CeD, compliant with a GFD for ≥6 months preceding Screening, with resolution of CeD symptoms, normalization of CeD serology (defined as </= 2 times the upper limit of normal), and (as determined at time of screening endoscopy) negative histology (Marsh 0, 1 or 2). Be HLA-DQ2.5 and/or HLA-DQ8 positive, as assessed at screening. If subjects have already been genotyped, then results from previous testing may be used in lieu of genotyping at screening. Must obtain negative SARS-CoV-2 test result (molecular diagnostic such as RT-PCR or RT-qPCR at the discretion of the investigator) at the screening visit and both timepoints prior to endoscopy (day 1 &15). Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures Agree to avoid strenuous exercise during the study, especially within one week prior to the scheduled study visits and maintain adequate hydration (recommended) Avoid consumption of grapefruit juice exceeding 8 ounces (~240 ml) total in a day while in the study (recommended) Agree to the following contraception criteria: Subjects who are, in the opinion of the investigator, sexually active and at risk for pregnancy with their partner(s) must agree to use 2 methods of effective contraception (at least 1 highly effective method) throughout the study and for at least 28 days after the last dose of investigational product. The investigator or his or her designee, in consultation with the subject, will confirm that the subject has selected 2 appropriate methods of contraception for the individual subject and his/her partner(s) from the list of permitted contraception methods (see below) and will confirm that the subject has been instructed in their consistent and correct use. At time points indicated in the Schedule of Activities, the investigator or designee will inform the subject of the need to use 2 methods of effective contraception (at least 1 highly effective method) consistently and correctly and document the conversation, and the subject's affirmation, in the subject's chart. In addition, the investigator or designee will instruct the subject to call immediately if 1 or both selected contraception methods are discontinued or if pregnancy is known or suspected in the subject or partner. Highly effective methods of contraception are those that, alone or in combination, result in a failure rate of less than 1% per year when used consistently and correctly (i.e., perfect use) and include the following: Implantable progestogen-only hormone contraception associated with inhibition of ovulation. Intrauterine device (IUD). Intrauterine hormone-releasing system (IUS). Bilateral tubal occlusion or tubal ligation. Vasectomized partner: Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used. The spermatogenesis cycle is approximately 90 days Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral; intravaginal; transdermal Progestogen-only hormone contraception associated with inhibition of ovulation: oral; injectable. Sexual abstinence: Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. Male condom or female condom: All sexually active male subjects must agree to prevent potential transfer to and exposure of partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning with the first dose of investigational product and continuing for at least 28 days after the last dose of investigational product. Male subjects must refrain from donating sperm during the study and for 90 days after the last dose of investigational product. Exclusion Criteria: Have a history of gluten triggered acute symptoms (≤24 hours after gluten exposure), and/or severe symptoms (abdominal pain interfering with daily activities, diarrhea with >5 stools/day), and/or prolonged symptoms (duration >7 days). A history of any abdominal or pelvic surgery <3 months before trial enrollment; prior surgery abdominal or pelvic surgery (e.g., cholecystectomy, appendectomy, and hysterectomy) are permitted if performed >3 months before trial enrollment. Subjects considered in imminent need for surgery or with elective surgery scheduled to occur during the study Have a positive or borderline positive IgA anti-tissue transglutaminase serology at Screening (defined as >/= 2 times the upper limit of normal). Have Marsh 3a-c determined by pathology at Screening Endoscopy A diagnosis of any other inflammatory gastrointestinal disorder Ongoing immunosuppression or receive any treatment within 3 months the starting of the trial that might alter T cell repertoire or phenotype. Has a confirmed history of a SARS-CoV-2 infection within the previous 2 months of the screening visit. Any history of either untreated or inadequately treated latent or active TB infection by Interferon Gamma Release Assay during screening or within 12 weeks prior to randomization, current treatment for active or latent TB infection or evidence of currently active TB by chest x-ray, residing with or frequent close contact with individual(s) with active TB. Positive screening for HIV, Hepatitis B, Hepatitis C.

Sites / Locations

  • Massachusetts General HospitalRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Active Comparator

Placebo Comparator

Arm Label

Ritlecitinib

Placebo

Arm Description

10g gluten + 200mg of Ritlecitinib

10g gluten + placebo

Outcomes

Primary Outcome Measures

Change in Small Intestinal Histology based on Vh:Cd ratio
Characterize the gluten-challenge induced changes in small intestine histology using standard for Celiac Disease histological assessments related to villus height to crypt depth ratio [Vh:Cd]
Patient Reported Outcome Surveys (CeD PRO survey evaluation)
Patient Reported Outcomes (PROs) - CeD PRO evaluation of gluten challenge-triggered symptoms

Secondary Outcome Measures

Serology
Serology tTG IgA, EMA, DGP
Changes in Small Intestinal Histology of intraepithelial lymphocytes (IELs)
Characterize the gluten-challenge induced changes in small intestine histology using standard for Celiac Disease histological assessments related to intraepithelial lymphocyte counts

Full Information

First Posted
November 1, 2022
Last Updated
March 19, 2023
Sponsor
Massachusetts General Hospital
Collaborators
Pfizer
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1. Study Identification

Unique Protocol Identification Number
NCT05636293
Brief Title
Double Blind, Placebo-controlled Trial to Establish Safety and Efficacy of Ritlecitinib in Celiac Disease Patients in Remission
Official Title
Double Blind, Placebo-controlled Trial to Establish Safety and Efficacy of Ritlecitinib to Prevent Gluten-induced Celiac Enteropathy and Symptoms in Celiac Disease Patients in Remission
Study Type
Interventional

2. Study Status

Record Verification Date
November 2022
Overall Recruitment Status
Recruiting
Study Start Date
March 1, 2023 (Actual)
Primary Completion Date
January 1, 2024 (Anticipated)
Study Completion Date
January 1, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Massachusetts General Hospital
Collaborators
Pfizer

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief Summary
Subjects include: aged 18 to 75 years, inclusive, have biopsy-confirmed disease that is clinically inactive as determined by negative celiac disease (CeD) serology and histology (determined via endoscopy at time of screening), have followed a gluten-free diet (GFD) for ≥6 months as reported by the subject, and be human leukocyte antigen (HLA)-DQ2.5 and/or HLA-DQ8 positive. Study involves the following randomized intervention; 10g gluten + 200mg of Ritlecitinib or placebo
Detailed Description
The investigators are proposing a double blind, placebo-controlled trial to establish safety and efficacy of ritlecitinib to prevent gluten-induced celiac enteropathy and symptoms in celiac disease (CeD) patients in remission. The results of this study will impact the therapeutic options in the future for individuals with CeD. Participants will take placebo capsule or ritlecitinib 200 mg capsule once per day. Both will be taken orally. All participants will take 10g gluten once per day, for a total of 21 days. Gluten will be taken orally by mixing the gluten powder into either hot chocolate or apple sauce. If participant unable to tolerate 10g of gluten daily, they will have the option to decrease to 5g daily after Day 3 of study.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Celiac Disease
Keywords
Celiac Disease, Gluten, Gluten Challenge, Ritlecitinib

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Masking Description
Double-blind
Allocation
Randomized
Enrollment
30 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Ritlecitinib
Arm Type
Active Comparator
Arm Description
10g gluten + 200mg of Ritlecitinib
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
10g gluten + placebo
Intervention Type
Drug
Intervention Name(s)
Ritlecitinib
Intervention Description
200mg Ritlecitinib
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
Placebo
Intervention Type
Other
Intervention Name(s)
Gluten
Intervention Description
10g of gluten
Primary Outcome Measure Information:
Title
Change in Small Intestinal Histology based on Vh:Cd ratio
Description
Characterize the gluten-challenge induced changes in small intestine histology using standard for Celiac Disease histological assessments related to villus height to crypt depth ratio [Vh:Cd]
Time Frame
Through study completion, average of 1 year.
Title
Patient Reported Outcome Surveys (CeD PRO survey evaluation)
Description
Patient Reported Outcomes (PROs) - CeD PRO evaluation of gluten challenge-triggered symptoms
Time Frame
Through study completion, average of 1 year.
Secondary Outcome Measure Information:
Title
Serology
Description
Serology tTG IgA, EMA, DGP
Time Frame
Through study completion, average of 1 year.
Title
Changes in Small Intestinal Histology of intraepithelial lymphocytes (IELs)
Description
Characterize the gluten-challenge induced changes in small intestine histology using standard for Celiac Disease histological assessments related to intraepithelial lymphocyte counts
Time Frame
Through study completion, average of 1 year.
Other Pre-specified Outcome Measures:
Title
Characterize the stool microbiome pre- and -post gluten challenge.
Description
Characterize the stool, intestinal and blood microbiome pre- and post-gluten challenge. We expect that the intestinal permeability will be increased resulting in microbiome changes following gluten challenge.
Time Frame
Through study completion, average of 1 year.
Title
Characterize the blood microbiome pre- and -post gluten challenge.
Description
Characterizing the blood microbiome. Sent off for analysis to characterize the specific microbiome (whole blood).
Time Frame
Through study completion, average of 1 year.
Title
Characterize the intestinal microbiome pre- and -post gluten challenge.
Description
Characterizing the intestinal microbiome through the use of intestinal biopsies. Sent off for analysis to characterize the specific microbiome.
Time Frame
Through study completion, average of 1 year.
Title
Detection of gluten peptides in urine and stool samples
Description
Analyze stool and urine for presence of gluten peptides during challenge to ensure compliance in gluten exposure for 3 weeks
Time Frame
Through study completion, average of 1 year.
Title
Creation of intestinal organoids from biopsy samples
Description
Create and profile ex vivo intestinal organoids pre- and post-gluten challenge using biopsy samples collected from the small intestine.
Time Frame
Through study completion, average of 1 year.
Title
Cytokines profiling
Description
Pro-inflammatory cytokines profiling
Time Frame
Through study completion, average of 1 year.
Title
Characterize the transcriptome from duodenal biopsy samples and blood
Description
Characterize the transcriptome (bulk RNA sequencing and single-cell RNA sequencing) of duodenal biopsy samples and blood pre- and post-challenge. We expect that intestinal gluten challenge will induce effector cells that acquire pathogenic phenotypes.
Time Frame
Through study completion, average of 1 year.
Title
Changes in gluten-specific T cells in small intestinal biopsies
Description
To characterize changes in gluten-specific T cells and pathology in the small intestine with specific focus on biomarkers likely to change with therapeutic CeD treatment.
Time Frame
Through study completion, average of 1 year.
Title
Changes in gluten-specific pathology in small intestinal biopsies
Description
To characterize changes in gluten-specific T cells and pathology in the small intestine with specific focus on biomarkers likely to change with therapeutic CeD treatment.
Time Frame
Through study completion, average of 1 year.
Title
Characterize the t-cell receptors (TCR) repertoire duodenal biopsy samples pre- and post-challenge
Description
Characterize the TCR repertoire (single-cell and bulk TCR sequencing) in duodenal biopsy samples pre- and post-challenge. We expect that intestinal gluten challenge will induce in lamina propria clonal expansion of HLA-DQ-restricted, gluten-specific T-cells.
Time Frame
Through study completion, average of 1 year.
Title
Compare for each patient t-cell receptors (TCR) repertoire of duodenal biopsy samples (single-cell and bulk TCR sequencing) with the peripheral blood TCR repertoire
Description
Compare for each patient the t-cell receptors (TCR) repertoire of duodenal biopsy samples (single-cell and bulk TCR sequencing) with the peripheral blood TCR repertoire (bulk TCR sequencing) of the same patient. We expect that the gluten-challenge induced pathogenic clones will be identified in peripheral blood.
Time Frame
Through study completion, average of 1 year.
Title
Ex vivo identification and validation of DQ-restricted gliadin specific t-cell receptors (TCR)
Description
Ex vivo identification and validation of DQ-restricted gliadin specific t-cell receptors (TCR)
Time Frame
Through study completion, average of 1 year.
Title
Assess correlation between gluten-specific blood T cells and standard CeD histological assessments.
Description
To assess correlation between gluten-specific blood T cells and standard CeD histological assessments.
Time Frame
Through study completion, average of 1 year.
Title
Assess changes from Baseline in gluten-specific T cells in blood.
Description
To assess changes from Baseline in gluten-specific T cells in blood.
Time Frame
Through study completion, average of 1 year.

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
75 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male and/or female subjects (including Women of Childbearing Potential (WOCBP)) ≥18 years to ≤75 years of age at the time of informed consent Have a body mass index ≥17 to <40 (and a body weight >45 kg at the Screening Visit). Agree to make every effort to avoid pregnancy (see lifestyle outline below) from the time of signing the informed consent throughout the duration of the trial, if the subject is a woman of childbearing potential and sexually active with a non-sterilized male partner. Have well controlled biopsy-proven CeD, compliant with a GFD for ≥6 months preceding Screening, with resolution of CeD symptoms, normalization of CeD serology (defined as </= 2 times the upper limit of normal), and (as determined at time of screening endoscopy) negative histology (Marsh 0, 1 or 2). Be HLA-DQ2.5 and/or HLA-DQ8 positive, as assessed at screening. If subjects have already been genotyped, then results from previous testing may be used in lieu of genotyping at screening. Must obtain negative SARS-CoV-2 test result (molecular diagnostic such as RT-PCR or RT-qPCR at the discretion of the investigator) at the screening visit and both timepoints prior to endoscopy (day 1 &15). Evidence of a personally signed and dated informed consent document indicating that the subject has been informed of all pertinent aspects of the study. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures Agree to avoid strenuous exercise during the study, especially within one week prior to the scheduled study visits and maintain adequate hydration (recommended) Avoid consumption of grapefruit juice exceeding 8 ounces (~240 ml) total in a day while in the study (recommended) Agree to the following contraception criteria: Subjects who are, in the opinion of the investigator, sexually active and at risk for pregnancy with their partner(s) must agree to use 2 methods of effective contraception (at least 1 highly effective method) throughout the study and for at least 28 days after the last dose of investigational product. The investigator or his or her designee, in consultation with the subject, will confirm that the subject has selected 2 appropriate methods of contraception for the individual subject and his/her partner(s) from the list of permitted contraception methods (see below) and will confirm that the subject has been instructed in their consistent and correct use. At time points indicated in the Schedule of Activities, the investigator or designee will inform the subject of the need to use 2 methods of effective contraception (at least 1 highly effective method) consistently and correctly and document the conversation, and the subject's affirmation, in the subject's chart. In addition, the investigator or designee will instruct the subject to call immediately if 1 or both selected contraception methods are discontinued or if pregnancy is known or suspected in the subject or partner. Highly effective methods of contraception are those that, alone or in combination, result in a failure rate of less than 1% per year when used consistently and correctly (i.e., perfect use) and include the following: Implantable progestogen-only hormone contraception associated with inhibition of ovulation. Intrauterine device (IUD). Intrauterine hormone-releasing system (IUS). Bilateral tubal occlusion or tubal ligation. Vasectomized partner: Vasectomized partner is a highly effective contraceptive method provided that the partner is the sole sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an additional highly effective method of contraception should be used. The spermatogenesis cycle is approximately 90 days Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of ovulation: oral; intravaginal; transdermal Progestogen-only hormone contraception associated with inhibition of ovulation: oral; injectable. Sexual abstinence: Sexual abstinence is considered a highly effective method only if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study intervention. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and the preferred and usual lifestyle of the participant. Male condom or female condom: All sexually active male subjects must agree to prevent potential transfer to and exposure of partner(s) to drug through ejaculate by using a condom consistently and correctly, beginning with the first dose of investigational product and continuing for at least 28 days after the last dose of investigational product. Male subjects must refrain from donating sperm during the study and for 90 days after the last dose of investigational product. Exclusion Criteria: Have a history of gluten triggered acute symptoms (≤24 hours after gluten exposure), and/or severe symptoms (abdominal pain interfering with daily activities, diarrhea with >5 stools/day), and/or prolonged symptoms (duration >7 days). A history of any abdominal or pelvic surgery <3 months before trial enrollment; prior surgery abdominal or pelvic surgery (e.g., cholecystectomy, appendectomy, and hysterectomy) are permitted if performed >3 months before trial enrollment. Subjects considered in imminent need for surgery or with elective surgery scheduled to occur during the study Have a positive or borderline positive IgA anti-tissue transglutaminase serology at Screening (defined as >/= 2 times the upper limit of normal). Have Marsh 3a-c determined by pathology at Screening Endoscopy A diagnosis of any other inflammatory gastrointestinal disorder Ongoing immunosuppression or receive any treatment within 3 months the starting of the trial that might alter T cell repertoire or phenotype. Has a confirmed history of a SARS-CoV-2 infection within the previous 2 months of the screening visit. Any history of either untreated or inadequately treated latent or active TB infection by Interferon Gamma Release Assay during screening or within 12 weeks prior to randomization, current treatment for active or latent TB infection or evidence of currently active TB by chest x-ray, residing with or frequent close contact with individual(s) with active TB. Positive screening for HIV, Hepatitis B, Hepatitis C.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Victoria Kenyon, MHA
Phone
617-643-4366
Email
vakenyon@partners.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Alessio Fasano, MD
Organizational Affiliation
Massachusetts General Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
Massachusetts General Hospital
City
Boston
State/Province
Massachusetts
ZIP/Postal Code
02114
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Victoria Kenyon, MHA
Phone
617-643-4366
Email
vakenyon@partners.org
First Name & Middle Initial & Last Name & Degree
Alessio Fasano, MD
First Name & Middle Initial & Last Name & Degree
Maureen Leonard, MD
First Name & Middle Initial & Last Name & Degree
Katherine Olshan, MD

12. IPD Sharing Statement

Plan to Share IPD
Undecided

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Double Blind, Placebo-controlled Trial to Establish Safety and Efficacy of Ritlecitinib in Celiac Disease Patients in Remission

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