Denosumab for Type 1 Diabetes

Recruiting at 4 trial locations

Overseen By Arthur Riggs Diabetes & Metabolism Research Institute at City of Hope

Age: 18 - 65

Sex: Any

Travel: May Be Covered

Time Reimbursement: Varies

Trial Phase: Phase 1 & 2

Recruiting

Sponsor: City of Hope Medical Center

Must not be taking: Immunosuppressants, Anticonvulsants, Steroids, others

Disqualifiers: Vitamin D3 deficiency, Eating disorder, Obesity, others

Approved in 4 Jurisdictions

Trial Summary

What is the purpose of this trial?

Type 1 diabetes (T1D) arises from abnormal immune cell-mediated injury to beta cells that make insulin. The injured beta cells can then no longer make the needed amount of insulin to stay healthy. However, in the early stages of T1D, some beta cells are still alive and functioning. Treatment to protect the beta cells against injury at this time could slow the progress of disease. Denosumab is an approved treatment for osteoporosis (a disease that thins and weakens the bones), high blood calcium levels, bone cancer, and other bone problems in patients who have cancer. The research team has found that the bone pathway that denosumab works on to treat these bone conditions also has effects on the health of the beta cells. Lab studies suggest that denosumab may protect and/or increase the number of beta cells and improve how well they work. This study will test whether denosumab is safe and improves beta cell function and blood sugar control in people with early T1D.

Will I have to stop taking my current medications?

The trial requires that you stop taking any diabetes medications other than insulin within 3 months of enrollment. If you are on other specific medications like immunosuppressants or certain bone-related drugs, you may also need to stop those.

What data supports the effectiveness of the drug Denosumab for Type 1 Diabetes?

Research shows that Denosumab, by inhibiting the RANKL/RANK pathway, can protect and promote the growth of insulin-producing cells in the pancreas, which are often damaged in Type 1 Diabetes. This suggests that Denosumab might help preserve these cells and improve insulin production in people with this condition. ^{1 2 3 4 5}

Is denosumab generally safe for humans?

Denosumab has been linked to rare cases of liver problems, including immune-related liver injury and severe liver damage. While it is used for various conditions, these rare side effects should be considered when evaluating its safety. ^{5 6 7 8 9}

Research Team

Fouad Kandeel, MD, PhD

Principal Investigator

City of Hope Medical Center

Rupangi Vasavada, PhD

Principal Investigator

City of Hope Medical Center

Eligibility Criteria

This trial is for individuals with early-stage Type 1 Diabetes, where some insulin-producing beta cells are still functioning. The study aims to protect these cells and slow disease progression.

Inclusion Criteria

Serum calcium (corrected for albumin) within normal limits per site's local lab

My C-peptide levels are above 0.6 ng/ml, confirmed by a test.

Agreement by women of childbearing potential (WOCBP) and males of childbearing potential to use a highly effective method of birth control for the course of the study through at least 5 months from the last dose of protocol therapy

Exclusion Criteria

I have only used insulin for my diabetes in the last 3 months.

I haven't had any bone fractures in the last year.

History of delayed puberty unless there is radiologic evidence of skeletal maturity

Trial Timeline

Screening

Participants are screened for eligibility to participate in the trial

2-4 weeks

Treatment

Participants receive denosumab 60 mg or placebo subcutaneously every 3 months for a total of 4 injections

12 months

4 visits (in-person)

Follow-up

Participants are monitored for safety and effectiveness after treatment

4 weeks

Treatment Details

Interventions

• Denosumab (Monoclonal Antibodies)

Trial Overview The trial is testing Denosumab, a drug normally used for bone-related conditions, to see if it can safeguard the remaining beta cells in Type 1 Diabetes patients and improve their blood sugar control.

Participant Groups

Group I: Denosumab Experimental Treatment 1 Intervention

Denosumab 60 mg subcutaneous injection

Group II: Placebo Placebo Group 1 Intervention

Normal Saline 1.0 ml subcutaneous injection

Denosumab is already approved in Canada, Japan for the following indications:

Approved in Canada as Prolia for:

• Treatment of osteoporosis in postmenopausal women at high risk for fracture
• Treatment to increase bone mass in men with osteoporosis at high risk for fracture

Approved in Japan as Prolia for:

• Treatment of osteoporosis in postmenopausal women
• Treatment of bone loss associated with hormone ablation therapy for prostate cancer

Who Is Running the Clinical Trial?

City of Hope Medical Center

Lead Sponsor

Trials

614

Recruited

1,924,000+

Findings from Research

In a phase 2 trial involving 84 children and young adults with newly diagnosed type 1 diabetes, golimumab significantly improved endogenous insulin production compared to placebo, as shown by a higher 4-hour C-peptide AUC at week 52 (0.64 vs. 0.43 pmol/mL, P<0.001).

Golimumab also led to a lower requirement for exogenous insulin, with 43% of participants achieving partial remission compared to only 7% in the placebo group, indicating its potential efficacy in preserving beta-cell function.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Golimumab and Beta-Cell Function in Youth with New-Onset Type 1 Diabetes. Quattrin, T., Haller, MJ., Steck, AK., et al.[2022]

Type 1 diabetes remains a serious, life-threatening condition, but there are promising therapies that may help preserve insulin production and improve patient outcomes, particularly through combination treatments.

Immunosuppressive therapies, such as anti-CD3 and anti-CD20 monoclonal antibodies, combined with agents that protect and regenerate β-cells, like GLP-1, could potentially lead to milder disease and even a cure for some patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Therapies to Preserve β-Cell Function in Type 1 Diabetes. Ludvigsson, J.[2023]

Inhibition of the RANKL/RANK pathway using osteoprotegerin and denosumab has been shown to protect both rodent and human β cells from cytokine-induced death, suggesting a potential mechanism for preserving insulin-producing cells in type 1 diabetes.

In vivo studies demonstrated that osteoprotegerin can reverse recent-onset type 1 diabetes in mice, leading to improved glucose control and increased β cell proliferation, indicating its therapeutic potential for managing this condition.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

RANKL/RANK is required for cytokine-induced beta cell death; osteoprotegerin, a RANKL inhibitor, reverses rodent type 1 diabetes. Kondegowda, NG., Filipowska, J., Do, JS., et al.[2023]

In a study involving 52 patients with new-onset type 1 diabetes, two courses of teplizumab significantly reduced the decline in insulin production (C-peptide levels) over 2 years, showing a 75% improvement compared to the control group.

Common side effects of teplizumab included rash and upper respiratory infections, but the treatment was effective in preserving insulin production and reducing the need for external insulin in some patients, with specific metabolic and immunologic characteristics helping to identify those who would respond best.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders. Herold, KC., Gitelman, SE., Ehlers, MR., et al.[2021]

Denosumab, a monoclonal antibody that inhibits RANKL, shows consistent pharmacokinetics across a large population of 1,076 subjects, including both healthy individuals and cancer patients, indicating its effectiveness in preventing osteoclast activation and survival.

The study found that after administering denosumab, over 95% of patients achieved more than 97% RANKL occupancy, suggesting that dosage adjustments based on body weight, age, race, or tumor type are unnecessary for patients with bone metastases.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic analysis of denosumab in patients with bone metastases from solid tumours. Gibiansky, L., Sutjandra, L., Doshi, S., et al.[2021]

Denosumab is effective for treating RANKL-mediated disorders in children and adolescents, but it is not always curative and may need to be combined with other treatments or surgery.

Due to potential safety concerns and limited high-level evidence, careful planning and expert oversight are essential to manage risks and define treatment goals when using denosumab in pediatric patients.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Management of RANKL-mediated disorders with denosumab in children and adolescents: a global expert guidance document. Vanderniet, JA., Szymczuk, V., Högler, W., et al.[2023]

Denosumab, a medication used to prevent osteoporosis in patients with low bone mineral density, has been associated with rare cases of hepatotoxicity, including a newly reported case of immune-mediated liver injury in a 43-year-old woman after three years of treatment.

The patient's liver function tests showed significantly elevated levels of liver enzymes, indicating potential drug-induced liver injury, which was confirmed by a liver biopsy revealing chronic inflammation and interface hepatitis.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Denosumab-Induced Immune Hepatitis. Ostrovsky, V., Malnick, S., Ish-Shalom, S., et al.[2021]

In a 2-year study involving 1239 patients with rheumatoid arthritis, denosumab 60 mg showed a low incidence of adverse drug reactions (ADRs) at 3.0%, with hypocalcemia and osteonecrosis of the jaw being the most common issues.

Denosumab was effective in preventing the progression of bone erosion in 91.3% of patients, indicating its potential as a safe treatment option for managing rheumatoid arthritis without new safety concerns.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of denosumab in Japanese patients with rheumatoid arthritis: a 2-year post-marketing surveillance study. Tanaka, Y., Mizutani, H., Fujii, K., et al.[2023]

A 72-year-old woman developed severe liver damage (submassive hepatic necrosis) after receiving denosumab, indicating a potential adverse drug reaction linked to immune response and cytokine induction.

The case highlights that RANKL inhibition by denosumab can lead to significant liver injury, as evidenced by elevated liver enzymes and proinflammatory cytokines, suggesting careful monitoring is needed for patients receiving this treatment.

NCBI (Pubmed)

pubmed.ncbi.nlm.nih.gov

Severe hepatocytotoxicity linked to denosumab. Malnick, S., Maor, Y., Melzer, E., et al.[2018]

References

1. United States pubmed.ncbi.nlm.nih.gov

Golimumab and Beta-Cell Function in Youth with New-Onset Type 1 Diabetes. [2022]

2. New Zealand pubmed.ncbi.nlm.nih.gov

Therapies to Preserve β-Cell Function in Type 1 Diabetes. [2023]

3. United States pubmed.ncbi.nlm.nih.gov

RANKL/RANK is required for cytokine-induced beta cell death; osteoprotegerin, a RANKL inhibitor, reverses rodent type 1 diabetes. [2023]

4. United States pubmed.ncbi.nlm.nih.gov

Teplizumab (anti-CD3 mAb) treatment preserves C-peptide responses in patients with new-onset type 1 diabetes in a randomized controlled trial: metabolic and immunologic features at baseline identify a subgroup of responders. [2021]

5. Switzerland pubmed.ncbi.nlm.nih.gov

Population pharmacokinetic analysis of denosumab in patients with bone metastases from solid tumours. [2021]

6. United States pubmed.ncbi.nlm.nih.gov

Management of RANKL-mediated disorders with denosumab in children and adolescents: a global expert guidance document. [2023]

7. Switzerland pubmed.ncbi.nlm.nih.gov

Denosumab-Induced Immune Hepatitis. [2021]

8. England pubmed.ncbi.nlm.nih.gov

Safety and effectiveness of denosumab in Japanese patients with rheumatoid arthritis: a 2-year post-marketing surveillance study. [2023]

9. Italy pubmed.ncbi.nlm.nih.gov

Severe hepatocytotoxicity linked to denosumab. [2018]