The Efficacy of Denosumab in Active Crohn's Disease

• Status: Completed
• Trial end date: 2018-04-20
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: University of Manitoba
• Collaborators: McMaster University; University of Toronto
• Treatments: Denosumab

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.