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Identification of Biomarkers of Tofacitinib Therapy in Patients With Ulcerative Colitis (PROPHETIC)

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ClinicalTrials.gov Identifier: NCT04576000
Recruitment Status : Recruiting
First Posted : October 5, 2020
Last Update Posted : October 5, 2020
Sponsor:
Information provided by (Responsible Party):
Alimentiv Inc.

Brief Summary:

This study aims to provide new mechanistic insights into the molecular determinants of response or nonresponse to tofacitinib therapy and the biological heterogeneity that exists in Ulcerative Colitis. This study will include patients who are initiating tofacitinib therapy according to standard of care. This study consists of:

The main study:

  • Part 1: 8-week induction therapy followed by an 8-week maintenance therapy
  • Part 2: Patients who continue tofacitinib therapy after part 1 will be followed further for a total of 2 years, or until discontinuation of tofacitinib therapy (whichever is first)

The pharmacokinetic and pharmacodynamic substudy:

  • Patients who consent to the substudy will be randomized (up to 30 subjects maximum) into 1 of 5 arms (different sampling time points), where pharmacokinetics and pharmacodynamics will be analyzed on day 1, week 4, and week 8 of induction of tofacitinib therapy

Condition or disease Intervention/treatment
Ulcerative Colitis Drug: Tofacitinib

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Study Type : Observational
Estimated Enrollment : 100 participants
Observational Model: Cohort
Time Perspective: Prospective
Official Title: PhaRmacOkinetics and PHarmacodynamic BiomarkErs of TofacItinib Therapy in Patients With Ulcerative Colitis (PROPHETIC)
Actual Study Start Date : August 25, 2020
Estimated Primary Completion Date : March 2023
Estimated Study Completion Date : March 2023

Resource links provided by the National Library of Medicine


Group/Cohort Intervention/treatment
Open-Label Group
Eligible patients will include those who will be prescribed tofacitinib as part of their routine medical care.
Drug: Tofacitinib
Tofacitinib induction therapy will be administered according to Standard Of Care (SOC)




Primary Outcome Measures :
  1. Identify predictive fecal biomarkers that are associated with a change from baseline in UC-100 score [ Time Frame: 8 weeks ]
    The UC-100 is a composite disease activity index consisting of clinical, endoscopic, and histological findings. The UC-100 is calculated by summing the weighted Mayo Clinic Score (MCS) stool frequency and endoscopy subscores, and the Robarts Histopathology Index (RHI) score as follows: UC-100 Score = 1 + (16 X stool frequency) + (6 X endoscopic subscore) + (RHI score). The total UC-100 score ranges from 1 to 100, with higher scores representing more severe disease activity.

  2. Identify predictive fecal biomarkers that are associated with a change from baseline in UC-100 score [ Time Frame: 16 weeks ]
    The UC-100 is a composite disease activity index consisting of clinical, endoscopic, and histological findings. The UC-100 is calculated by summing the weighted Mayo Clinic Score (MCS) stool frequency and endoscopy subscores, and the Robarts Histopathology Index (RHI) score as follows: UC-100 Score = 1 + (16 X stool frequency) + (6 X endoscopic subscore) + (RHI score). The total UC-100 score ranges from 1 to 100, with higher scores representing more severe disease activity.

  3. Identify predictive blood biomarkers that are associated with a change from baseline in UC-100 score [ Time Frame: 8 weeks ]
  4. Identify predictive blood biomarkers that are associated with a change from baseline in UC-100 score [ Time Frame: 16 weeks ]
  5. Identify predictive tissue biomarkers that are associated with a change from baseline in UC-100 score [ Time Frame: 8 weeks ]
  6. Identify predictive tissue biomarkers that are associated with a change from baseline in UC-100 score [ Time Frame: 16 weeks ]

Secondary Outcome Measures :
  1. Identify pharmacodynamic fecal biomarkers that are associated with a change from baseline in UC-100 score [ Time Frame: 8 weeks, 16 weeks ]
  2. Identify pharmacodynamic blood biomarkers that are associated with a change from baseline in UC-100 score [ Time Frame: 8 weeks, 16 weeks ]
  3. Identify pharmacodynamic tissue biomarkers that are associated with a change from baseline in UC-100 score [ Time Frame: 8 weeks, 16 weeks ]
  4. Identify a fecal biomarker signature as a surrogate measure for change from baseline in UC-100 score [ Time Frame: 8 weeks, 16 weeks ]
  5. Identify a blood biomarker signature as a surrogate measure for change from baseline in UC-100 score [ Time Frame: 8 weeks, 16 weeks ]
  6. Identify a tissue biomarker signature as a surrogate measure for change from baseline in UC-100 score [ Time Frame: 8 weeks, 16 weeks ]
  7. Identify whether colonic tissue pSTAT3 at week 8 and/or 16 correlates with change from baseline in UC-100 score [ Time Frame: 8 weeks, 16 weeks ]
  8. Evaluate long-term hospitalization rates, surgery rates, and corticosteroid use up to 2 years after initiation of tofacitinib therapy and identify baseline or early biomarker signatures associated with these long-term healthcare resource use outcomes [ Time Frame: 2 years ]
  9. Measure adverse drug reactions, clinical, endoscopic, and histologic response and remission rates to tofacitinib in a "real-world" population [ Time Frame: 16 weeks ]

Other Outcome Measures:
  1. Determine pharmacokinetic parameters at steady state in stool, colonic tissue, and serum samples [ Time Frame: 8weeks ]
    Pharmacokinetic parameters analysed: C-max

  2. Determine pharmacokinetic parameters at steady state in stool, colonic tissue, and serum samples [ Time Frame: 8weeks ]
    Pharmacokinetic parameters analysed: T-max

  3. Determine pharmacokinetic parameters at steady state in stool, colonic tissue, and serum samples [ Time Frame: 8weeks ]
    Pharmacokinetic parameters analysed: T-1/2

  4. Determine pharmacokinetic parameters at steady state in stool, colonic tissue, and serum samples [ Time Frame: 8weeks ]
    Pharmacokinetic parameters analysed: AUC (0-12)

  5. Determine pharmacokinetic parameters at steady state in stool, colonic tissue, and serum samples [ Time Frame: 8weeks ]
    Pharmacokinetic parameters analysed: AUC-inf

  6. Determine pharmacokinetic parameters at steady state in stool, colonic tissue, and serum samples [ Time Frame: 8weeks ]
    Pharmacokinetic parameters analysed: AUC-last

  7. Determine pharmacokinetic parameters at steady state in stool, colonic tissue, and serum samples [ Time Frame: 8weeks ]
    Pharmacokinetic parameters analysed: C-trough

  8. Determine pharmacokinetic parameters at steady state in stool, colonic tissue, and serum samples [ Time Frame: 8weeks ]
    Pharmacokinetic parameters analysed: C-avg

  9. Determine colonic tissue pSTAT3 levels over time, as a pharmacodynamic biomarker [ Time Frame: 8 weeks ]
  10. Evaluate the correlation between pharmacokinetics and pharmacodynamics related to tofacitinib therapy [ Time Frame: 8 weeks ]
  11. Develop a population pharmacokinetic/pharmacodynamic model to characterize the relationships between local and systemic drug exposure and clinical, endoscopic, histologic, or biologic response to therapy [ Time Frame: 8 weeks ]

Biospecimen Retention:   Samples With DNA
blood, fecal, and colonic tissue sampling


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Sampling Method:   Non-Probability Sample
Study Population
This study will involve subjects with moderately to severely active Ulcerative Colitis with plans to administer tofacitinib for at least 8 weeks, followed by tofacitinib maintenance therapy for an additional 8 weeks.
Criteria

Inclusion Criteria:

1.18 years of age or older.

2.Male or nonpregnant, nonlactating females.

3.Diagnosis of Ulcerative Colitis for at least 3 months prior to screening.

4.Moderately to severely active Ulcerative Colitis (total Mayo Clinic Score ≥ 6), with objective evidence of inflammation defined by a Mayo endoscopic subscore (MES) ≥ 2 and disease extending > 15 cm from the anal verge.

5.Physician plans to administer tofacitinib for at least 8 weeks as part of Standard of Care (SOC).

6.Documentation of a negative test result for latent tuberculosis within the last 12 months, or according to routine clinical practice.

7.Able to participate fully in all aspects of this clinical trial, including collection of tissue biopsies.

8.Written informed consent must be obtained and documented.

Exclusion Criteria:

  1. Diagnosis of Crohn's disease or indeterminate colitis.
  2. An active, serious infection, including localized infections.
  3. Concomitant administration of biological therapies for Ulcerative Colitis or potent immunosuppressants, such as azathioprine and cyclosporine. Subjects with previous exposure to these treatments should undergo an appropriate washout period according to local practice prior to starting tofacitinib, in keeping with routine clinical practice.
  4. Hematology laboratory results that meet the following:

    1. absolute lymphocyte count < 500 cells/mm3
    2. absolute neutrophil count < 1000 cells/mm3
    3. hemoglobin < 9 g/dL
  5. Interval between live vaccinations and initiation of tofacitinib therapy should be in accordance with current vaccination guidelines regarding immunosuppressive agents.
  6. Serious underlying disease other than Ulcerative Colitis that in the opinion of the investigator may interfere with the subject's ability to participate fully in the study.
  7. Prior enrollment in the current study and having received tofacitinib.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04576000


Contacts
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Contact: Tanja van Viegen +31 20 5630 310 tanja.vanviegen@robartsinc.com

Locations
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United States, California
UCSD Recruiting
La Jolla, California, United States, 92037
Contact: William Sandborn, MD    858-657-5284    wsandborn@ucsd.edu   
Principal Investigator: William Sandborn, MD         
Cedars-Sinai Medical Center Recruiting
Los Angeles, California, United States, 90048
Contact: Dermot McGovern, MD, PhD    310-423-4100    mcgovernd@cshs.org   
Principal Investigator: Dermot McGovern, MD, PhD         
United States, Minnesota
Mayo Clinic Recruiting
Rochester, Minnesota, United States, 55905
Contact: William Faubion, MD    507-284-5035    faubion.william@mayo.edu   
Principal Investigator: William Faubion, MD         
Belgium
KU Leuven, Campus Gasthuisberg-IBD Studies Recruiting
Leuven, Flemish Brabant, Belgium, 3000
Contact: Severine Vermeire, MD, PhD    +32 16 344 255    severine.vermeire@uzleuven.be   
Principal Investigator: Severine Vermeire, MD, PhD         
Canada, Ontario
Mount Sinai Hospital Recruiting
Toronto, Ontario, Canada, M5G 1X5
Contact: Mark Silverberg, MD, PhD    +1 416-586-4800 ext 8336    mark.silverberg@sinaihealthsystem.ca   
Principal Investigator: Mark Silverberg, MD, PhD         
Italy
Humanitas University, Hamanitas Research Hospital Recruiting
Rozzano, Milan, Italy, 20089
Contact: Silvio Danese, MD, PhD    +39 28 224 5555    silvio.danese@hunimed.eu   
Principal Investigator: Silvio Danese, MD, PhD         
Netherlands
Amsterdam Medical Center, IBD Center Recruiting
Amsterdam, North Halland, Netherlands, 1105 AZ
Contact: Geert D'Haens, MD, PhD    +31 20 566 1125    g.dhaens@amsterdamumc.nl   
Principal Investigator: Geert D'Haens, MD, PhD         
Spain
IDIBAPS Recruiting
Barcelona, Spain, 08036
Contact: Julian Panes, MD    +34 932 275 418    jpanes@clinic.cat   
Principal Investigator: Julian Panes, MD         
Sponsors and Collaborators
Alimentiv Inc.
Investigators
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Principal Investigator: Vipul Jairath, MD, PhD Alimentiv Inc.
Publications:
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Responsible Party: Alimentiv Inc.
ClinicalTrials.gov Identifier: NCT04576000    
Other Study ID Numbers: RP1907
First Posted: October 5, 2020    Key Record Dates
Last Update Posted: October 5, 2020
Last Verified: September 2020

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Colitis
Colitis, Ulcerative
Ulcer
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Colonic Diseases
Intestinal Diseases
Pathologic Processes
Inflammatory Bowel Diseases
Tofacitinib
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action