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The Efficacy of Denosumab in Active Crohn's Disease

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02321280
Recruitment Status : Completed
First Posted : December 22, 2014
Last Update Posted : October 15, 2018
Sponsor:
Collaborators:
University of Toronto
McMaster University
Information provided by (Responsible Party):
Charles Bernstein, University of Manitoba

Brief Summary:

Denosumab, a fully human monoclonal antibody to RANKL was approved for the treatment of postmenopausal osteoporosis in June 2010. It is administered subcutaneously once every 6 months and is highly effective in reducing the risk of vertebral, non-vertebral, and hip fracture risk. There are 3 main concepts underpinning the rationale for using Denosumab to treat CD.

  1. CD is associated with an increased risk for osteoporosis and the biology of osteoporosis and T cell mediated inflammation, thought to be integral in CD, involve the RANKL paradigm
  2. Animal models of bone loss and colitis treated with RANKL inhibitors improve both bone mass and colitis. A dinitrofluorobenzene sulfonic acid (DNBS) model of colitis in our lab showed significant improvement with Denosumab treatment compared to vehicle (saline) treatment.
  3. CD is associated with an increase in mutations at the locus that encodes for RANKL The investigators are conducting an open label pilot study of single dose Denosumab 120 mg s.c. to patients with active Crohn's disease, with assessment of clinical response and remission at 12 weeks.

Condition or disease Intervention/treatment Phase
Crohn Disease Drug: Denosumab Phase 1 Phase 2

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 2 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Denosumab (A Monoclonal Antibody to Receptor Activator of Nuclear Factor-Kappa B Ligand (RANKL) in Crohn's Disease
Study Start Date : February 2015
Actual Primary Completion Date : April 20, 2018
Actual Study Completion Date : April 20, 2018

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Crohn's Disease
Drug Information available for: Denosumab

Arm Intervention/treatment
Experimental: Single arm single dose of denosumab
Open label = Single dose administration of single dose Denosumab 120 mg subcutaneously
Drug: Denosumab
Single dose subcutaneous administration
Other Names:
  • Xgeva
  • Prolia




Primary Outcome Measures :
  1. Disease Response [ Time Frame: week 12 ]
    A drop in CDAI of 100 points


Secondary Outcome Measures :
  1. Disease Remission [ Time Frame: week 12 ]
    Decrease in CDAI to ≤150 points at 12 weeks.

  2. fecal calprotectin decrease [ Time Frame: week 12 ]
    In those with elevated fecal calprotectin at baseline, reduction in fecal calprotectin to <250 ug/g at week 12.

  3. CRP decrease [ Time Frame: week 12 ]
    for those with increased CRP at baseline change in CRP to normal at week 12

  4. Endoscopy score decrease [ Time Frame: week 12 ]
    For those who underwent endoscopy within 1 month of study enrollment as part of standard of care and who underwent a repeat endoscopy within 1 month of study completion as part of standard of care, improvement in endoscopy by Crohn's Disease Endoscopy Inflammation Score (CDEIS) between baseline and second endoscopy.

  5. MRI improvement [ Time Frame: week 12 ]
    For those who underwent abdominal MRI within 1 month of study enrollment as part of standard of care and who underwent a repeat abdominal MRI within 1 month of study completion as part of standard of care then improvement in MRI findings by central reader (Dr H Greenberg) between baseline and second abdominal MRI.

  6. Safety will be assessed for any unforeseen adverse events at each study visit [ Time Frame: week 12 ]
    Serum calcium will be assessed at 3 days post drug administration and every 4 weeks. There is a rare incidence of hypocalcemia with use of this drug. Osteonecrosis of the jaw will be assessed at every study visit. This drug is rarely associated with this outcome especially in cancer patients. Liver enzymes every 4 weeks will be assessed.



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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Subject has provided informed consent.
  2. Male or female subjects, 18 to 80 years of age, inclusive.
  3. Prior diagnosis of CD confirmed by endoscopy or imaging for > 3 months prior to enrollment with active disease, defined as a Crohn's Disease Activity Index (CDAI) score >220 to <450 and at least one of either: fecal calprotectin >250 ug/g feces, or CRP >8 mg/L.
  4. Patients will have evidence of ileocolonic, colonic, or ileal disease that is visualized either endoscopically or on MRI within the prior 6 months.
  5. Patients must carry at least one G allele at rs2062305.
  6. Patients will be eligible for the study if they are receiving any of the following:

    • mesalamine for >8 weeks with the dose remaining stable for 4 weeks prior to screening;
    • a maximum of 20 mg of prednisone per day (or steroid equivalent), with the dose remaining stable for 2 weeks prior to screening. Steroids must be held stable for the first 4 weeks of the study and then must be tapered by 5 mg per week, to be discontinued entirely by week 8;
    • 6-mercaptopurine, methotrexate or azathioprine for ≥3 months, with the dose remaining stable for 8 weeks prior to screening;

Exclusion Criteria:

  1. Monoclonal antibody or experimental agent use within 12 weeks before screening.
  2. Use of non-approved drugs for CD.
  3. Anticipated need for surgery within 12 weeks
  4. Active sepsis, or use of antibiotics within two weeks prior to screening for the treatment of infection.
  5. Pregnant, lactating or planning to become pregnant during the study
  6. Inability to reliably use birth control for men and women during the course of therapy.
  7. Known allergy to Denosumab or ingredients in formulation
  8. Treatment of cancer within the last 5 years (except for non-melanoma skin cancers).
  9. Recent jaw infection, invasive dental procedures (tooth extraction, dental implants or surgery), anti-angiogenic medications, or hypocalcemia within 1 month prior to screening.
  10. Patients will also be excluded if they meet any of the following criteria: Proctocolectomy or total colectomy; stoma; a history of allergy to murine proteins; or treatment with parenteral corticosteroids or corticotropin within four weeks before screening. Serum Hg < 80 g/L, liver enzymes ≥ 2-fold elevated, or other serum biochemistry considered unsafe, or requiring treatment, in the opinion of the investigator.

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): NCT02321280


Locations
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Canada, Manitoba
University of Manitoba
Winnipeg, Manitoba, Canada, R3A 1R9
Sponsors and Collaborators
University of Manitoba
University of Toronto
McMaster University
Investigators
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Principal Investigator: Charles N Bernstein, MD University of Manitoba
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Responsible Party: Charles Bernstein, Distinguished Professor of Medicine, University of Manitoba
ClinicalTrials.gov Identifier: NCT02321280    
Other Study ID Numbers: DIC 2014
First Posted: December 22, 2014    Key Record Dates
Last Update Posted: October 15, 2018
Last Verified: October 2018
Additional relevant MeSH terms:
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Crohn Disease
Inflammatory Bowel Diseases
Gastroenteritis
Gastrointestinal Diseases
Digestive System Diseases
Intestinal Diseases
Denosumab
Bone Density Conservation Agents
Physiological Effects of Drugs