Therapy of the Skeletal Disease of Type 2 Diabetes With Denosumab

NCT03457818 | Terminated Phase 2 Results DMC FDA Drug

• 1 other identifier: AAAR7827
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 1

Brief Summary

The goal of the study is to characterize the effect of Prolia® (denosumab) on indices of bone strength in type 2 diabetes (T2D). The investigational plan involves administration of Prolia® or identical placebo for 12 months as a randomized double-blind placebo-controlled trial in 66 T2D postmenopausal women assigned to Prolia® or placebo. The study will include assessment of different measures of bone quality: skeletal microarchitecture, including measurement of skeletal cortical pores; bone mineral density; bone material quality, and accumulation of advanced glycation endproducts (AGEs) in collagen. This information will help to determine whether Prolia® treatment in type 2 diabetes has skeletal benefits.

Conditions

Diabetes Mellitus, Type 2; Osteoporosis

Keywords

Prolia; Denosumab; Diabetes

Outcome Measures

Primary Outcomes (1)

• Change in Cortical Porosity (Ct.Po) (%) by High Resolution Peripheral Quantitative Computed Tomography (HR-pQCT) Imaging From Baseline to 6 and 12 Months.

  The primary outcome is the 12 months change in Ct.Po and the primary intent-to-treat analysis is a one-way ANCOVA with the fixed effect of treatment (treated vs. placebo), and baseline Ct.Po as a continuous covariate.

  Baseline, 6 months and 12 months

Secondary Outcomes (2)

• Change in Serum Collagen Type I C-Telopeptide (s-CTX) (ng/ml) and Tartrate-resistant Acid Phosphatase 5b (TRAP 5b) (ng/ml) by Blood Test From Baseline to 3, 6 and 12 Months.

  Baseline, 3 months, 6 months and 12 months

• Change in Dual-energy X-ray Absorptiometry (DXA) (gm/cm2) at Lumbar Spine, Femoral Neck, Total Hip and Radius From Baseline to 6 and 12 Months.

  Screening visit, 6 months and 12 months

Other Outcomes (1)

• Change in Skin Autofluorescence (SAF) (Unitless) From Baseline to 6 and 12 Months.

  Baseline, 6 months and 12 months

Study Arms (2)

Treatment Group

EXPERIMENTAL

Denosumab 60 mg/ml \[Prolia\] SC at baseline and 6 months.

Drug: Denosumab 60 mg/ml [Prolia]

Control Group

PLACEBO COMPARATOR

Placebo SC at Baseline and 6 months.

Other: Placebo

Interventions

Denosumab 60 mg/ml [Prolia] DRUG

Denosumab 60 mg will be administered subcutaneously in the upper arm at the Baseline and 6 Month Visits

Also known as: Prolia®

Treatment Group

Placebo OTHER

Placebo will be administered subcutaneously in the upper arm at the Baseline and 6 Month Visits

Control Group

Eligibility Criteria

• Age: 50 Years - 90 Years
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• An understanding, ability and willingness to fully comply with study procedures and restrictions.
• Ability to voluntarily provide written, signed and dated informed consent as applicable to participate in the study.
• Postmenopausal women age ≥ 50 and ≤ 90 years at time of consent.
• Diagnosis of T2D for ≥ 2 years. Upon review of patient's medical history, patient will be confirmed to currently have reasonably controlled T2D as assessed by the investigator, with HbA1c ≤ 8.4%. If HbA1c is ≥ 8.5%, re-screening will be allowed after approximately 3 months following adjustment of diabetes therapy.
• DXA T-score ≤ -1.0 at one or more sites (lumbar spine, femoral neck, total hip or distal 1/3 radius).
• Normal albumin-adjusted serum calcium level.

You may not qualify if:

• Hormone replacement treatment use (to avoid the influence of estrogen).
• Fractures (excluding skull, facial bones, metacarpals, fingers, toes, and fractures associated with severe trauma) within 12 months.
• A history of pathological fractures (eg, due to Paget's disease, myeloma, metastatic malignancy).
• Type 1 diabetes.
• Disorders associated with altered skeletal structure or function (chronic renal disease stage 4 or worse, chronic liver disease, malignancy, hypoparathyroidism or hyperparathyroidism, acromegaly, Cushing's syndrome, hypopituitarism, chronic obstructive pulmonary disease, alcohol intake \> 3 units/day).
• Treatment with any of the following drugs in past year: anticonvulsant therapy, pharmacological doses of thyroid hormone (TSH\<normal is permitted if subject has normal T4, clinical euthyroidism and is in steady-state), adrenal or anabolic steroids, calcitonin, estrogen or selective estrogen receptor modulator, sodium fluoride (other than dental treatment), teriparatide, denosumab, abaloparatide, strontium or aromatase inhibitors; any history of bisphosphonate treatment. Corticosteroid use permitted if subject is in steady-state.
• Serum 25(OH)D levels \< 20 ng/ml. If 25(OH)D levels are \< 20 ng/ml, rescreening will be allowed following a vitamin D loading regimen of 50,000 IU/week for 4 weeks. If serum 25(OH)D levels are ≥ 20 ng/ml after supplementation, the subject will be allowed to enroll.
• Clinically significant hypersensitivity to denosumab or any components of denosumab 60 mg.
• Known sensitivity to any of the products to be administered during the study (e.g., calcium or vitamin D).
• Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after the end of treatment.
• Female subject of child bearing potential and is not willing to use, in combination with her partner, highly effective contraception during treatment and for 5 months after the end of treatment.
• Significant dental/oral disease, including prior history or current evidence of osteonecrosis/osteomyelitis of the jaw, or the following:
• Active dental or jaw condition which requires oral surgery
• Non-healed dental/oral surgery
• Planned invasive dental procedures for the course of the study

Sponsors & Collaborators

• Mishaela Rubin: lead

Study Sites (1)

Columbia University Irving Medical Center - Harkness Pavillion

New York, New York, 10032, United States

Location

Related Publications (4)

• Bonds DE, Larson JC, Schwartz AV, Strotmeyer ES, Robbins J, Rodriguez BL, Johnson KC, Margolis KL. Risk of fracture in women with type 2 diabetes: the Women's Health Initiative Observational Study. J Clin Endocrinol Metab. 2006 Sep;91(9):3404-10. doi: 10.1210/jc.2006-0614. Epub 2006 Jun 27.

  PMID: 16804043 BACKGROUND

• Vestergaard P. Discrepancies in bone mineral density and fracture risk in patients with type 1 and type 2 diabetes--a meta-analysis. Osteoporos Int. 2007 Apr;18(4):427-44. doi: 10.1007/s00198-006-0253-4. Epub 2006 Oct 27.

  PMID: 17068657 BACKGROUND

• Furst JR, Bandeira LC, Fan WW, Agarwal S, Nishiyama KK, McMahon DJ, Dworakowski E, Jiang H, Silverberg SJ, Rubin MR. Advanced Glycation Endproducts and Bone Material Strength in Type 2 Diabetes. J Clin Endocrinol Metab. 2016 Jun;101(6):2502-10. doi: 10.1210/jc.2016-1437. Epub 2016 Apr 26.

  PMID: 27115060 BACKGROUND

• Zebaze R, Libanati C, McClung MR, Zanchetta JR, Kendler DL, Hoiseth A, Wang A, Ghasem-Zadeh A, Seeman E. Denosumab Reduces Cortical Porosity of the Proximal Femoral Shaft in Postmenopausal Women With Osteoporosis. J Bone Miner Res. 2016 Oct;31(10):1827-1834. doi: 10.1002/jbmr.2855. Epub 2016 May 19.

  PMID: 27082709 BACKGROUND

MeSH Terms

Conditions

Diabetes Mellitus, Type 2; Osteoporosis; Diabetes Mellitus

Interventions

Denosumab

Condition Hierarchy (Ancestors)

Glucose Metabolism Disorders; Metabolic Diseases; Nutritional and Metabolic Diseases; Endocrine System Diseases; Bone Diseases, Metabolic; Bone Diseases; Musculoskeletal Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Limitations and Caveats

The study was terminated due to poor enrollment compounded by the COVID-19 pandemic. Data was not collected.

Results Point of Contact

• Title: Dr. Mishaela Rubin
• Organization: Columbia University

mrr6@cumc.columbia.edu

2019528237

Study Officials

• Mishaela Rubin, MD

  Columbia University

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: DOUBLE
• Who Masked: PARTICIPANT, INVESTIGATOR
• Masking Details: Clinical Research Coordinators
• Purpose: PREVENTION
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Associate Professor of Medicine

Model Details: The study is a 12 month randomized (2:1 assignment) double-blind placebo-controlled trial of T2D postmenopausal women assigned to either Denosumab 60 mg subcutaneously (SC) at baseline and 6 months (n=44) or placebo (n=22); total study n=66.

Study Record Dates

• First Submitted: January 18, 2018
• First Posted: March 8, 2018
• Study Start: November 7, 2018
• Primary Completion: June 10, 2020
• Study Completion: June 10, 2020
• Last Updated: July 3, 2024
• Results First Posted: May 11, 2021

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)