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Denosumab (DMAB) Discontinuation And Switching In Glucocorticoid-Induced Osteoporosis (GIOP): A Pilot Study

Primary Purpose

Osteoporosis

Status
Recruiting
Phase
Phase 4
Locations
United States
Study Type
Interventional
Intervention
DMAB Discontinuation and Switching
Sponsored by
University of Alabama at Birmingham
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Osteoporosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Women and men, age 18 years or older and able to provide informed consent (IC)
  • ≥ 3 months of glucocorticoid use at > 7.5 mg /day (prednisone equivalent dose) and anticipated to remain on glucocorticoids for at least six months
  • A baseline BMD T-score of ≤ -2.0 at the lumbar spine, total hip, or femoral neck; OR
  • A BMD T-score ≤ -1.0 at the lumbar spine, total hip, or femoral neck and a history of an osteoporotic fracture.

Exclusion Criteria:

  • • Patients with fewer than three lumbar vertebrae that could be evaluated on dual energy x-ray absorptiometry (DXA)

    • Treatment with bisphosphonates in the preceding 2 years
    • Greater than 24 months (>4 injections) of prior treatment with denosumab
    • Women of childbearing potential, who are not currently using birth control, are pregnant, planning to become pregnant, or are breastfeeding. For women of childbearing potential: refusal to use 2 highly effective forms of contraception and to continue this practice for 7 months after last injection of study medication*
    • Men planning to conceive in the next 12 months
    • Unstable systemic medical condition
    • Uncontrolled hyperthyroidism
    • Uncontrolled hypothyroidism
    • History of Addison disease
    • History of osteomalacia
    • History of osteonecrosis of the jaw (ONJ)
    • History of atypical femur fracture
    • History of tooth extraction, jaw surgery, dental implants, or other dental surgery within the prior 6 months
    • History of anorexia nervosa, bulimia (by history or physical) or obvious malnutrition.
    • Invasive dental work(implants/surgery) planned in the next 2 years
    • History of Paget's disease of bone
    • Other bone diseases which affect bone metabolism
    • Vitamin D deficiency [25(OH) vitamin D level < 20 ng/mL (<49.9 nmol/L)]
    • Hypercalcemia >10% above upper limit of normal (ULN)
    • Elevated transaminases or total bilirubin ≥ 2.0 x ULN
    • History of any solid organ or bone marrow transplant
    • Malignancy within the last 5 years (except cervical carcinoma in situ or basal cell carcinoma or localized squamous cell carcinoma of the skin)
    • Hypocalcemia <10% below lower limit of normal (LLN)
    • Estimated glomerular filtration rate < 30 mL/minute/1.73 m^2
    • Intolerance to calcium supplements, vitamin D supplements
    • Contraindication to, or poorly tolerant of denosumab therapy (including hypersensitivity to the drug)
    • Contraindication to, or poorly tolerant of zoledronic therapy (including hypersensitivity to the drug)
    • Contraindication to, or poorly tolerant of alendronate (including hypersensitivity to the drug and sever gastro-intestinal intolerance to oral bisphosphonates)
    • Recipient of an investigational drug within 4 weeks prior to study drug administration
    • Not a good candidate for study participation in opinion of investigator

Sites / Locations

  • University of Alabama at BirminghamRecruiting

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm Type

Active Comparator

Active Comparator

Active Comparator

Arm Label

Denosumab (DMAB) to Alendronate (ALN)

DMAB to "Early" Zoledronic Acid (ZA)

DMAB to "Late" ZA

Arm Description

Switch from Denosumab 60 mg administered subcutaneously (SC) to weekly oral alendronate (70 mg; started 6 months after last denosumab dose)

Switch from Denosumab 60 mg administered subcutaneously (SC) to one "early" zoledronic acid infusion (5 mg; 6 months after last denosumab dose)

Switch from Denosumab 60 mg administered subcutaneously (SC) to one "late" zoledronic acid infusion (5 mg; 9 months after last denosumab dose)

Outcomes

Primary Outcome Measures

CTX absolute difference V1 vs. V3
Log of the absolute difference in CTX values between randomization (V1) and 6 months after randomization

Secondary Outcome Measures

Full Information

First Posted
November 22, 2019
Last Updated
January 20, 2023
Sponsor
University of Alabama at Birmingham
Collaborators
Maastricht University, Vrije Universiteit Brussel, Amgen
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1. Study Identification

Unique Protocol Identification Number
NCT04177940
Brief Title
Denosumab (DMAB) Discontinuation And Switching In Glucocorticoid-Induced Osteoporosis (GIOP): A Pilot Study
Official Title
Denosumab (DMAB) Discontinuation And Switching In Glucocorticoid-Induced Osteoporosis (GIOP): A Pilot Study
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Recruiting
Study Start Date
August 17, 2020 (Actual)
Primary Completion Date
January 31, 2024 (Anticipated)
Study Completion Date
August 31, 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Alabama at Birmingham
Collaborators
Maastricht University, Vrije Universiteit Brussel, Amgen

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Investigators will test the hypothesis that an increase in bone turnover markers (e.g. carboxy-terminal collagen crosslinks (CTX) and P1NP) in patients currently taking chronic glucocorticoids will be attenuated more in those who switch from denosumab to "late" zoledronic acid (9 months after last denosumab dose) compared to participants randomized to "early" zoledronic acid (6 months after last denosumab dose) or weekly alendronate (6 months after last denosumab dose).
Detailed Description
This is an open-label, randomized, parallel-group pilot clinical trial in which Denosumab users will be assigned in a 1:1:1 allocation to one the following groups: Switch from Denosumab 60 mg administered subcutaneously (SC) to weekly oral alendronate (70 mg; started 6 months after last denosumab dose) OR Switch from Denosumab 60 mg administered subcutaneously (SC) to one "early" zoledronic acid infusion (5 mg; 6 months after last denosumab dose) OR Switch from Denosumab 60 mg administered subcutaneously (SC) to one "late" zoledronic acid infusion (5 mg; 9 months after last denosumab dose) Participants will be advised to maintain adequate calcium and vitamin D intake per United States Department of Agriculture (USDA) and Department of Health and Human Services (DHHS) guidelines. All individuals will need ≥ 12 months of previous denosumab treatment (minimum of 2 doses) prior to switching to assigned randomization arm. The minimum number of doses (n = 2) is based on published data that the rebound in BMD might be less pronounced in patients receiving very limited denosumab. According to a systematic review of patients with multiple vertebral fractures following denosumab cessation, those with ≤2 years of denosumab treatment had fewer fractures compared with those with >2 years. Therefore, the maximum number of prior doses (n = 4) is based on higher incidence of rebound loss of bone mineral density (BMD), more rapid turnover, and potentially greater vertebral fractures after discontinuation of denosumab in patients who received more extensive treatment. Investigators will limit the trial to a more restricted use of denosumab duration (2-4 doses) to maintain greater homogeneity, given the somewhat smaller planned sample size. Users of denosumab will be sorted into two groups: Prevalent users: Defined as individuals with a minimum of one previous dose of denosumab, and up to 4 previous doses of denosumab (maximum). Prevalent users with one previous dose will receive a second dose of denosumab before proceeding to assigned randomization arm. Therefore, randomization will occur 2 weeks after screening visit if they had already 2-4 denosumab doses. New denosumab users: Defined as individuals who have not previously received denosumab. New users will receive two doses of denosumab before proceeding to assigned randomization arm.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Osteoporosis

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 4
Interventional Study Model
Crossover Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
45 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Denosumab (DMAB) to Alendronate (ALN)
Arm Type
Active Comparator
Arm Description
Switch from Denosumab 60 mg administered subcutaneously (SC) to weekly oral alendronate (70 mg; started 6 months after last denosumab dose)
Arm Title
DMAB to "Early" Zoledronic Acid (ZA)
Arm Type
Active Comparator
Arm Description
Switch from Denosumab 60 mg administered subcutaneously (SC) to one "early" zoledronic acid infusion (5 mg; 6 months after last denosumab dose)
Arm Title
DMAB to "Late" ZA
Arm Type
Active Comparator
Arm Description
Switch from Denosumab 60 mg administered subcutaneously (SC) to one "late" zoledronic acid infusion (5 mg; 9 months after last denosumab dose)
Intervention Type
Drug
Intervention Name(s)
DMAB Discontinuation and Switching
Intervention Description
Investigators will test the hypothesis that an increase in bone turnover markers (e.g. CTX and P1NP) in patients currently taking chronic glucocorticoids will be attenuated more in those who switch from denosumab to "late" zoledronic acid (9 months after last denosumab dose) compared to participants randomized to "early" zoledronic acid (6 months after last denosumab dose) or weekly alendronate (6 months after last denosumab dose
Primary Outcome Measure Information:
Title
CTX absolute difference V1 vs. V3
Description
Log of the absolute difference in CTX values between randomization (V1) and 6 months after randomization
Time Frame
6 months post randomization

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Women and men, age 18 years or older and able to provide informed consent (IC) ≥ 3 months of glucocorticoid use at > 7.5 mg /day (prednisone equivalent dose) and anticipated to remain on glucocorticoids for at least six months A baseline BMD T-score of ≤ -2.0 at the lumbar spine, total hip, or femoral neck; OR A BMD T-score ≤ -1.0 at the lumbar spine, total hip, or femoral neck and a history of an osteoporotic fracture. Exclusion Criteria: • Patients with fewer than three lumbar vertebrae that could be evaluated on dual energy x-ray absorptiometry (DXA) Treatment with bisphosphonates in the preceding 2 years Greater than 24 months (>4 injections) of prior treatment with denosumab Women of childbearing potential, who are not currently using birth control, are pregnant, planning to become pregnant, or are breastfeeding. For women of childbearing potential: refusal to use 2 highly effective forms of contraception and to continue this practice for 7 months after last injection of study medication* Men planning to conceive in the next 12 months Unstable systemic medical condition Uncontrolled hyperthyroidism Uncontrolled hypothyroidism History of Addison disease History of osteomalacia History of osteonecrosis of the jaw (ONJ) History of atypical femur fracture History of tooth extraction, jaw surgery, dental implants, or other dental surgery within the prior 6 months History of anorexia nervosa, bulimia (by history or physical) or obvious malnutrition. Invasive dental work(implants/surgery) planned in the next 2 years History of Paget's disease of bone Other bone diseases which affect bone metabolism Vitamin D deficiency [25(OH) vitamin D level < 20 ng/mL (<49.9 nmol/L)] Hypercalcemia >10% above upper limit of normal (ULN) Elevated transaminases or total bilirubin ≥ 2.0 x ULN History of any solid organ or bone marrow transplant Malignancy within the last 5 years (except cervical carcinoma in situ or basal cell carcinoma or localized squamous cell carcinoma of the skin) Hypocalcemia <10% below lower limit of normal (LLN) Estimated glomerular filtration rate < 30 mL/minute/1.73 m^2 Intolerance to calcium supplements, vitamin D supplements Contraindication to, or poorly tolerant of denosumab therapy (including hypersensitivity to the drug) Contraindication to, or poorly tolerant of zoledronic therapy (including hypersensitivity to the drug) Contraindication to, or poorly tolerant of alendronate (including hypersensitivity to the drug and sever gastro-intestinal intolerance to oral bisphosphonates) Recipient of an investigational drug within 4 weeks prior to study drug administration Not a good candidate for study participation in opinion of investigator
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Jeff Foster, MP
Phone
2059966086
Email
pjfoster@uabmc.edu
First Name & Middle Initial & Last Name or Official Title & Degree
Josh Melnick, MPH
Phone
(205) 975-0583
Email
jmelnick@uabmc.edu
Facility Information:
Facility Name
University of Alabama at Birmingham
City
Birmingham
State/Province
Alabama
ZIP/Postal Code
35294
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Jeff Foster, MPH
Phone
205-996-6086
Email
pjfoster@uabmc.edu
First Name & Middle Initial & Last Name & Degree
Kenneth G Saag, MD, MsC

12. IPD Sharing Statement

Plan to Share IPD
Undecided

Learn more about this trial

Denosumab (DMAB) Discontinuation And Switching In Glucocorticoid-Induced Osteoporosis (GIOP): A Pilot Study

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