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Dose-Ranging Phase 2b Study of ABX464 in Moderate to Severe Ulcerative Colitis

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ClinicalTrials.gov Identifier: NCT03760003
Recruitment Status : Completed
First Posted : November 30, 2018
Last Update Posted : August 2, 2021
Sponsor:
Information provided by (Responsible Party):
Abivax S.A.

Brief Summary:
Phase IIb study to evaluate the efficacy and the safety of 3 dose-levels of ABX464, administered daily in patients with moderate to severe Ulcerative Colitis.

Condition or disease Intervention/treatment Phase
Ulcerative Colitis Drug: ABX464 25mg Drug: ABX464 50mg Drug: ABX464 100mg Drug: Placebo Phase 2

Detailed Description:

This phase IIb study will evaluate the efficacy and the safety of 3 dose-levels of ABX464, administered daily in improving Modified Mayo Score (MMS) in patients with moderate to severe Ulcerative Colitis who have inadequate response, loss of response, or intolerance with at least one of the following agents: immunosuppressant treatment (i.e. azathioprine, 6-mercaptopurine, methotrexate), tumor necrosis factor alpha [TNF-α] inhibitors, vedolizumab, JAK inhibitors and/or corticosteroid treatment .

Eligible patients will be randomized into 4 parallel intervention/treatment groups: 25mg q.d of ABX464, 50mg q.d of ABX464, 100mg q.d of ABX464, or matching placebo and will be treated for 16 weeks.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 254 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Randomized, double blind, placebo controlled, parallel groups
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Randomized, Double Blind, Placebo Controlled, Parallel Group, Multiple Dose, Induction Study to Evaluate the Safety, Tolerability and Optimal Dose of ABX464 Compared With Placebo in Patients With Moderate to Severe Ulcerative Colitis Who Have Inadequate Response, Loss of Response, or Intolerance With at Least One of the Following Agents: Immunosuppressant Treatment (i.e. Azathioprine, 6-mercaptopurine, Methotrexate), Tumor Necrosis Factor Alpha [TNF-α] Inhibitors, Vedolizumab, JAK Inhibitors and/or Corticosteroid Treatment
Actual Study Start Date : September 23, 2019
Actual Primary Completion Date : April 1, 2021
Actual Study Completion Date : April 16, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: ABX464
ABX464 will be administrated orally (Capsules) and daily for 16 weeks
Drug: ABX464 25mg
ABX464 25mg (One capsule of ABX464 25 mg + One capsule of placebo) once daily for 16 weeks

Drug: ABX464 50mg
ABX464 50mg (One capsule of ABX464 50 mg + One capsule of placebo) once daily for 16 weeks

Drug: ABX464 100mg
ABX464 100mg (two capsules of ABX464 50 mg) once daily for 16 weeks

Placebo Comparator: Matching Placebo
Matching placebo will be adminstrated orally (Capsules) and daily for 16 weeks
Drug: Placebo
Two capsules of placebo once daily for 16 weeks




Primary Outcome Measures :
  1. Modified Mayo Score [ Time Frame: Week 8 ]
    Reduction from baseline in Modified Mayo Score


Secondary Outcome Measures :
  1. Clinical remission [ Time Frame: Week 8 and Week 16 ]
    Clinical remission, based on the Mayo Scoring system, is defined as stool frequency subscore = 0 or 1 and rectal bleeding subscore = 0 and endoscopy subscore = 0 or 1 (modified to exclude friability).

  2. Clinical response [ Time Frame: Week 8 and Week 16 ]
    Clinical Response is defined as a reduction in Mayo Score of at least 2 points and greater than or equal to 30 percent from baseline with an accompanying decrease in rectal bleeding sub-score of greater than or equal to 1 point or absolute rectal bleeding sub-score of less than or equal to 1 point.

  3. Endoscopic Improvement [ Time Frame: Week 8 and Week 16 ]
    Endoscopic improvement is defined as a Mayo endoscopic sub score of ≤1 (excluding friability)

  4. Mucosal healing [ Time Frame: Week 8 and Week 16 ]
    Mucosal healing is defined as both endoscopic remission and histological remission (Geboes score < 2.0).

  5. Stool and rectal bleeding frequency [ Time Frame: Every visit ]
    Assessment of Reduction relative to baseline in stool and rectal bleeding frequency

  6. Partial Modified Mayo Score [ Time Frame: Every visit ]
    Change from baseline

  7. Modified Mayo Score [ Time Frame: Week 16 ]
    Change from baseline

  8. Fecal calprotectin [ Time Frame: Week 8 and Week 16 ]
    Reduction from baseline in fecal calproctectin

  9. C Reactive Protein [ Time Frame: Week 8 and Week 16 ]
    Reduction from baseline in CRP

  10. miR-124 expression [ Time Frame: Week 8 and Week 16 ]
    Increase in miR-124 expression in Total Blood and rectal tissue

  11. IBDQ [ Time Frame: Week 8 and Week 16 ]
    Scores and changes from baseline i

  12. Inflammatory Infiltrate [ Time Frame: Week 8 and Week 16 ]
    Inflammatory Infiltrate assessment in rectal/colon biopsies

  13. IL-6, TNFα, IL-1b, IL-10 plasma concentrations [ Time Frame: Every visit ]
    Change relative to baseline

  14. ABX464 and ABX464-N-Glu [ Time Frame: Every visit (Except D57) ]
    Serum concentration

  15. Endoscopy Remission [ Time Frame: Week 8 and Week 16 ]
    Mayo endoscopic sub score of 0

  16. Number and rate of all adverse events, causally-related adverse events, SAE and causally-related SAEs classified by severity [ Time Frame: Every visit ]
  17. Incidence of treatment-emergent serious adverse event [ Time Frame: Every visit ]
  18. Incidence of adverse events leading to investigational medicinal product discontinuation [ Time Frame: Every visit ]
  19. Number of clinically-significant laboratory abnormalities [ Time Frame: Every visit ]


Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Men or women age 18 - 75 years;
  • Diagnosis of moderate to severe active UC (including ulcerative proctitis if proximal extension of disease occurs beyond 10 cm) confirmed by endoscopy and histology at least 12 Weeks prior to screening visit. Moderate to severe active UC defined by Modified Mayo Score (MMS) of 5 to 9 inclusive (on a scale of 0-9). Moderate to severe active UC should be confirmed at screening visit with a centrally read endoscopy sub-score of at least 2 (on a scale of 0-3);
  • Patients having either a documented inadequate response, no response, a loss of response, or an intolerance (defined as the occurrence of at least one Adverse Reaction leading to treatment discontinuation) to either immunosuppressant treatment (i.e., azathioprine, 6-mercaptopurine, methotrexate), tumor necrosis factor [TNF] inhibitors, vedolizumab, JAK inhibitors and/or corticosteroid treatment. Inadequate response, no response, loss of response is defined as:

    i. Active disease or relapse in spite of thiopurines or methotrexate given at an appropriate dose for at least 3 months (i.e. azathioprine 2-2.5 mg/kg/day or mercaptopurine 1-1.5 mg/kg/day in the absence of leukopenia), and/or ii. Active disease despite corticosteroids treatment (prednisolone up to 0.75 mg/kg/day) over a period of 4 Weeks, and/or iii. Active disease or relapse in spite of adequate treatment (as defined in the SmPC) with tumor necrosis factor [TNF] inhibitors or vedolizumab, and/or iv. Active disease or relapse in spite of adequate treatment with JAK inhibitors over a period of at least 6 Weeks.

  • Patients receiving oral corticosteroids must have been on a stable dose of prednisone or prednisone equivalent (≤20 mg/day) or on beclomethasone diproprionate (≤5mg/day) or on budesonide MMX (≤9 mg/day) for at least 2 Weeks prior to the screening visit;
  • Topical corticosteroids and topical 5-aminosalicylic acid preparations must have been withdrawn at least 2 Weeks prior to the screening visit;
  • Patients who are on oral 5-aminosalicylic acid must have been on a stable dose for at least 4 Weeks prior to the screening visit;
  • Patients who are receiving immunosuppressants in the form of azathioprine, 6-mercaptopurine, or methotrexate needed to be on a stable dose for at least 4 Weeks prior to screening visit. Patients taking methotrexate also are advised to take folic acid 1 mg/day (or equivalent) supplementation if there is no contraindication;
  • Patients on probiotics (e.g., Culturelle® [Lactobacillus GG, i-Health, Inc.], Saccharomyces boulardii) must be on stable doses for at least 2 Weeks prior to the screening visit;
  • Patients on antidiarrheals (e.g., loperamide, diphenoxylate with atropine) must be on stable doses for at least 2 Weeks prior to the screening visit;
  • Patients who have received tumor necrosis factor [TNF] inhibitors, vedolizumab or other biologics must have discontinued therapy at least 8 Weeks prior to the screening visit due to lack or insufficient efficacy or intolerance;
  • Patients previously treated with cyclosporine, tacrolimus or JAK inhibitors must have discontinued therapy at least 4 Weeks prior to the screening visit due to lack or insufficient efficacy or intolerance;
  • Patients previously treated with tube feeding, defined formula diets, or parenteral alimentation/nutrition must have discontinued treatment 3 Weeks before the screening visit and must be able to take, orally, appropriate amount of food (calories) and liquids to maintain body weight;
  • Patients with surveillance colonoscopy defined as per ECCO guidelines;
  • Patients with the following hematological and biochemical laboratory parameters obtained at screening:

    i. Hemoglobin > 9.0 g dL-1; ii. Absolute neutrophil count ≥ 750 mm-3; iii. Platelets ≥ 100,000 mm-3; iv. Total serum creatinine ≤ 1.3 x ULN (upper limit of normal); v. Creatinine clearance > 90 mL min-1 by the Cockcroft-Gault equation within 60 days prior to baseline; vi. Total serum bilirubin < 1.5 x ULN; vii. Alkaline phosphatase, AST (SGOT) and ALT (SGPT) < 2 x ULN;

  • Patients are able and willing to comply with study visits and procedures as per protocol;
  • Patients should understand, sign and date the written voluntary informed consent form at the screening visit prior to any protocol-specific procedures are performed;
  • Patients should be affiliated to a social security regimen (for French sites only);
  • Females and males receiving the study treatment (potentially in combination with immunosuppressant) and their partners must agree to use a highly effective contraceptive method during the study and for 6 months after end of study or early termination. Contraception should be in place at least 2 Weeks prior to study participation. Women must be surgically sterile or if of childbearing potential must use a highly effective contraceptive method. Women of childbearing potential (WOCBP) will enter the study after confirmed menstrual period and a negative pregnancy test. Highly effective methods of contraception include true abstinence, intrauterine device (IUD) or hormonal contraception aiming at inhibition of ovulation, intrauterine hormone releasing system, bilateral tubal ligation, vasectomized partner. True abstinence is defined when this is in line with the preferred and usual lifestyle of the patient. In each case of delayed menstrual period (over one month between menstruations) confirmation of absence of pregnancy is required. This recommendation also applies to WOCBP with an infrequent or irregular menstrual cycle. Female and male patients must not be planning pregnancy during the trial and for 6 months post completion of their participation in the trial. In addition, male participants should use condoms and not donate sperm as long as contraception is required.

Exclusion Criteria:

  • Patients with Crohn's Disease (CD) or presence or history of fistula, indeterminate colitis (IC), infectious/ischemic colitis or microscopic colitis (lymphocytic and collagenous colitis);
  • History of toxic megacolon, abdominal abscess, symptomatic colonic stricture or stoma; history or imminent colectomy, colonic malignancy;
  • History or current evidence of colonic dysplasia or adenomatous colonic polyps. Patient with severe gastrointestinal complications; e.g., short bowel syndromes, recent or planned bowel surgery, Ileostomy and/or colostomy, recent bowel perforation;
  • History of more than one episode of herpes zoster or a history (single episode) of disseminated zoster;
  • Patients with active infections at screening such as infected abdominal abscess, Clostridium difficile (stool antigen and toxin required), CMV (positive IgM), TB and recent infectious hospitalization;
  • Patients previously treated with ABX464;
  • Acute, chronic or history of clinically relevant pulmonary, cardiovascular, hepatic, pancreatic or renal functional abnormality, encephalopathy, neuropathy or unstable CNS pathology such as seizure disorder, angina or cardiac arrhythmias, active malignancy or any other clinically significant medical problems as determined by physical examination and/or laboratory screening tests and/or medical history;
  • Acute, chronic or history of immunodeficiency or autoimmune disease;
  • History of malignancy excluding patients considered cured (5 years disease free survivors);
  • Serious illness requiring systemic treatment and/or hospitalization within 3 Weeks prior to baseline;
  • Pregnant or breast-feeding women;
  • Illicit drug or alcohol abuse or dependence;
  • Patients who received live vaccine 30 days or fewer before first dose of study treatment and/or who's planning to receive such a vaccine during the study duration;
  • Use of any investigational or non-registered product within 3 months or within 5 half-lives preceding baseline, whichever is longer and during the study;
  • Any condition, which in the opinion of the investigator, could compromise the patient's safety or adherence to the study protocol.

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): NCT03760003


Locations
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Sponsors and Collaborators
Abivax S.A.
Investigators
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Principal Investigator: Séverine VERMEIRE, MD Universitaire Ziekenhuizen Leuven
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Responsible Party: Abivax S.A.
ClinicalTrials.gov Identifier: NCT03760003    
Other Study ID Numbers: ABX464-103
First Posted: November 30, 2018    Key Record Dates
Last Update Posted: August 2, 2021
Last Verified: July 2021
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Abivax S.A.:
ABX464
Refractory patients
Phase 2b
Dose Ranging
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