Therapy of the Skeletal Disease of Type 2 Diabetes With Denosumab

• Sponsor: Mishaela Rubin (Other)
• Overall Status: Terminated
• CT.gov ID: NCT03457818
• Collaborator: (none)
• Enrollment: 8
• Location: 1
• Arms: 2
• Actual Duration (Months): 19.1
• Patients Per Site Per Month: 0.4

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Diabetes Mellitus, Type 2; Osteoporosis	Drug: Denosumab 60 mg/ml [Prolia]; Other: Placebo	Phase 2

Detailed Description

Type 2 Diabetes Mellitus (T2DM) has become one of the most important diseases of our time. Recent research shows that diabetes has negative effects on bones and that people with diabetes might be more likely to break a bone. We don't know the reasons for this, but we suspect that normal bone replacement is slowed down in diabetes and this could slow down the growth of new bone. It is possible that the normal bone material becomes weaker because sugar-related components ("Advanced Glycation Endproducts") are making the bone more brittle. The investigators have shown in past research that people who have type 2 diabetes are more likely to have both weaker bone with lower "bone material strength" and also higher levels of sugar-related components ("Advanced Glycation Endproducts"). This study will focus on attempting to lower the sugar-related components ("Advanced Glycation Endproducts") by treating a group of patients with type 2 diabetes with a medication Prolia® or denosumab for one year. The investigators will compare postmenopausal women both before and after denosumab use and study them in terms of different bone features based on blood tests, bone imaging, a bone indentation test and a measurement of sugar-related components in the skin. This study will help to clarify if using this medication helps improve bone strength in women with diabetes.

Study Design

• Study Type: Interventional
• Actual Enrollment: 8 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Intervention Model Description: 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.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.
• Masking: Double (Participant, Investigator)
• Masking Description: Clinical Research Coordinators
• Primary Purpose: Prevention
• Official Title: Therapy of the Skeletal Disease of Type 2 Diabetes With Denosumab
• Actual Study Start Date: Nov 7, 2018
• Actual Primary Completion Date: Jun 10, 2020
• Actual Study Completion Date: Jun 10, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Treatment Group Denosumab 60 mg/ml [Prolia] SC at baseline and 6 months.	Drug: Denosumab 60 mg/ml [Prolia]; Denosumab 60 mg will be administered subcutaneously in the upper arm at the Baseline and 6 Month Visits; Other Names: Prolia®
Placebo Comparator: Control Group Placebo SC at Baseline and 6 months.	Other: Placebo; Placebo will be administered subcutaneously in the upper arm at the Baseline and 6 Month Visits

Outcome Measures

Primary Outcome Measures

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

Secondary Outcome Measures

1. 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]

   Secondary outcomes will be analyzed using ANCOVA models with P-value adjustment for multiple endpoint comparisons.

2. 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]

   Secondary outcomes will be analyzed using ANCOVA models with P-value adjustment for multiple endpoint comparisons.

Other Outcome Measures

1. Change in Skin Autofluorescence (SAF) (Unitless) From Baseline to 6 and 12 Months. [Baseline, 6 months and 12 months]

   Exploratory outcomes will be analyzed using ANCOVA models with P-value adjustment for multiple endpoint comparisons.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 50 Years to 90 Years
• Sexes Eligible for Study: Female
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. An understanding, ability and willingness to fully comply with study procedures and restrictions.

2. Ability to voluntarily provide written, signed and dated informed consent as applicable to participate in the study.

3. Postmenopausal women age ≥ 50 and ≤ 90 years at time of consent.

4. 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.

5. DXA T-score ≤ -1.0 at one or more sites (lumbar spine, femoral neck, total hip or distal 1/3 radius).

6. Normal albumin-adjusted serum calcium level.

Exclusion Criteria:

1. Hormone replacement treatment use (to avoid the influence of estrogen).

2. Fractures (excluding skull, facial bones, metacarpals, fingers, toes, and fractures associated with severe trauma) within 12 months.

3. A history of pathological fractures (eg, due to Paget's disease, myeloma, metastatic malignancy).

4. Type 1 diabetes.

5. 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).

6. 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.

7. 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.

8. Clinically significant hypersensitivity to denosumab or any components of denosumab 60 mg.

9. Known sensitivity to any of the products to be administered during the study (e.g., calcium or vitamin D).

10. Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after the end of treatment.

11. 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.

12. 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

1. DXA T-score of ≤ -3.5 at any site.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Columbia University Irving Medical Center - Harkness Pavillion	New York	New York	United States	10032

Sponsors and Collaborators

• Mishaela Rubin

Investigators

• Principal Investigator: Mishaela Rubin, MD, Columbia University

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Apr 17, 2021

More Information

Publications

• 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. Epub 2006 Jun 27.
• 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.
• 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. Epub 2006 Oct 27. Review.
• Zebaze R, Libanati C, McClung MR, Zanchetta JR, Kendler DL, Høiseth 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.

• Responsible Party: Mishaela Rubin, Associate Professor of Medicine, Columbia University
• ClinicalTrials.gov Identifier: NCT03457818
• Other Study ID Numbers: AAAR7827
• First Posted: Mar 8, 2018
• Last Update Posted: Aug 3, 2022
• Last Verified: Aug 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Mishaela Rubin, Associate Professor of Medicine, Columbia University: Prolia; Denosumab; Diabetes
• Additional relevant MeSH terms: Osteoporosis; Diabetes Mellitus; Diabetes Mellitus, Type 2; Denosumab

Study Results

Participant Flow

Arm/Group Title	Treatment Group	Control Group
Arm/Group Description	Denosumab 60 mg/ml [Prolia] SC at baseline and 6 months. Denosumab 60 mg/ml [Prolia]: Denosumab 60 mg will be administered subcutaneously in the upper arm at the Baseline and 6 Month Visits	Placebo SC at Baseline and 6 months. Placebo: Placebo will be administered subcutaneously in the upper arm at the Baseline and 6 Month Visits
Period Title: Overall Study
STARTED	4	4
COMPLETED	0	0
NOT COMPLETED	4	4

Baseline Characteristics

Arm/Group Title	Treatment Group	Control Group	Total
Arm/Group Description	Denosumab 60 mg/ml [Prolia] SC at baseline and 6 months. Denosumab 60 mg/ml [Prolia]: Denosumab 60 mg will be administered subcutaneously in the upper arm at the Baseline and 6 Month Visits	Placebo SC at Baseline and 6 months. Placebo: Placebo will be administered subcutaneously in the upper arm at the Baseline and 6 Month Visits	Total of all reporting groups
Overall Participants	4	4	8
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	0 0%	0 0%	0 0%
>=65 years	4 100%	4 100%	8 100%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	69 (14)	69.5 (7)	69 (10)
Sex: Female, Male (Count of Participants)
Female	4 100%	4 100%	8 100%
Male	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	2 50%	0 0%	2 25%
White	2 50%	4 100%	6 75%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	4 100%	4 100%	8 100%

Outcome Measures

1. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

Study terminated

Arm/Group Title	Treatment Group	Control Group
Arm/Group Description	Denosumab 60 mg/ml [Prolia] SC at baseline and 6 months. Denosumab 60 mg/ml [Prolia]: Denosumab 60 mg will be administered subcutaneously in the upper arm at the Baseline and 6 Month Visits	Placebo SC at Baseline and 6 months. Placebo: Placebo will be administered subcutaneously in the upper arm at the Baseline and 6 Month Visits
Measure Participants	0	0

2. Secondary Outcome

Title	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.
Description	Secondary outcomes will be analyzed using ANCOVA models with P-value adjustment for multiple endpoint comparisons.
Time Frame	Baseline, 3 months, 6 months and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

3. Secondary Outcome

Title	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.
Description	Secondary outcomes will be analyzed using ANCOVA models with P-value adjustment for multiple endpoint comparisons.
Time Frame	Screening visit, 6 months and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

4. Other Pre-specified Outcome

Title	Change in Skin Autofluorescence (SAF) (Unitless) From Baseline to 6 and 12 Months.
Description	Exploratory outcomes will be analyzed using ANCOVA models with P-value adjustment for multiple endpoint comparisons.
Time Frame	Baseline, 6 months and 12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title

Arm/Group Description

Adverse Events

Time Frame	1 year
Arm/Group Title	Treatment Group		Control Group
Arm/Group Description	Denosumab 60 mg/ml [Prolia] SC at baseline and 6 months. Denosumab 60 mg/ml [Prolia]: Denosumab 60 mg will be administered subcutaneously in the upper arm at the Baseline and 6 Month Visits		Placebo SC at Baseline and 6 months. Placebo: Placebo will be administered subcutaneously in the upper arm at the Baseline and 6 Month Visits
All Cause Mortality
	Treatment Group		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		0/4 (0%)
Serious Adverse Events
	Treatment Group		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/4 (0%)		1/4 (25%)
Renal and urinary disorders
urinary tract infection	0/4 (0%)	0	1/4 (25%)	1
Other (Not Including Serious) Adverse Events
	Treatment Group		Control Group
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/4 (25%)		1/4 (25%)
Musculoskeletal and connective tissue disorders
back pain	0/4 (0%)	0	1/4 (25%)	1
Reproductive system and breast disorders
vaginal yeast infection	0/4 (0%)	0	1/4 (25%)	1
Skin and subcutaneous tissue disorders
rash	1/4 (25%)	1	0/4 (0%)	0

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.