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Therapy of the Skeletal Disease of Type 2 Diabetes With Denosumab

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ClinicalTrials.gov Identifier: NCT03457818
Recruitment Status : Not yet recruiting
First Posted : March 8, 2018
Last Update Posted : July 30, 2018
Sponsor:
Information provided by (Responsible Party):
Mishaela Rubin, Columbia University

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 Type : Interventional  (Clinical Trial)
Estimated Enrollment : 66 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.
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
Estimated Study Start Date : August 2018
Estimated Primary Completion Date : June 2021
Estimated Study Completion Date : August 2021

Resource links provided by the National Library of Medicine

Drug Information available for: Denosumab

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 Name: 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




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

  3. Change in Bone Material Strength Index (BMSi) (unitless) by impact microindentation (IMI) from baseline to 12 months. [ Time Frame: Baseline 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. [ Time Frame: Baseline, 6 months and 12 months ]
    Exploratory outcomes will be analyzed using ANCOVA models with P-value adjustment for multiple endpoint comparisons.



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Ages Eligible for Study:   55 Years to 75 Years   (Adult, Older Adult)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

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 ≥ 55 and ≤ 75 years at time of consent.
  4. Diagnosis of T2D for ≥ 10 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. Dual energy x-ray absorptiometry (DXA) T-score ≤ -1.5 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 for blood clots or coagulopathy.
  7. Treatment with any of the following drugs in past year: corticosteroids ≥ 5 mg/day (>3 mos. at any time or >10 days), anticonvulsant therapy, pharmacological doses of thyroid hormone (TSH<normal), adrenal or anabolic steroids, aromatase inhibitors, calcitonin, bisphosphonates, estrogen or selective estrogen receptor modulator, sodium fluoride, denosumab, teriparatide, abaloparatide, strontium, fluoride, thiazolidinediones (TZDs), SGLT2 inhibitors.
  8. 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.
  9. Clinically significant hypersensitivity to denosumab or any components of denosumab 60 mg.
  10. Known sensitivity to any of the products to be administered during the study (e.g., calcium or vitamin D).
  11. Subject is pregnant or breast feeding, or planning to become pregnant within 5 months after the end of treatment.
  12. 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.
  13. 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

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): NCT03457818


Contacts
Contact: Maximo Gomez, M.D 212-304-5536 meg2230@columbia.edu
Contact: Rukshana Majeed, B.A 212-305-9489 rm3324@columbia.edu

Locations
United States, New York
Columbia University Medical Center - Harkness Pavillion Not yet recruiting
New York, New York, United States, 10032
Contact: Rukshana Majeed Clinical Research Coordinator    212-305-9489    rm3324@columbia.edu   
Contact: Beatriz Omeragic Clinical Research Coordinator    212-305-7364    bo2248@columbia.edu   
Principal Investigator: Mishaela Rubin, M.D.         
Sub-Investigator: Jessica Starr, M.D.         
Sponsors and Collaborators
Mishaela Rubin
Investigators
Principal Investigator: Mishaela Rubin, M.D Columbia University

Publications of Results:
Other Publications:
Responsible Party: Mishaela Rubin, Associate Professor of Medicine, Columbia University
ClinicalTrials.gov Identifier: NCT03457818     History of Changes
Other Study ID Numbers: AAAR7827
First Posted: March 8, 2018    Key Record Dates
Last Update Posted: July 30, 2018
Last Verified: July 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Mishaela Rubin, Columbia University:
Prolia
Denosumab
Diabetes

Additional relevant MeSH terms:
Diabetes Mellitus
Osteoporosis
Diabetes Mellitus, Type 2
Glucose Metabolism Disorders
Metabolic Diseases
Endocrine System Diseases
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Denosumab
Bone Density Conservation Agents
Physiological Effects of Drugs