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Denosumab Versus Zoledronic Acid in Thalassemia-Induced Osteoporosis (DOHA)

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ClinicalTrials.gov Identifier: NCT03040765
Recruitment Status : Recruiting
First Posted : February 2, 2017
Last Update Posted : May 31, 2018
Sponsor:
Information provided by (Responsible Party):
Hamad Medical Corporation

Brief Summary:

This study is to compare the two medications Denosumab and Zoledronic Acid For Patients With Beta Thalassemia Major Induced Osteoporosis. Patients with B-thalassemia major induce osteoporosis will undergo baseline assessment of the bone densitometry by Dual-energy X-ray absorptiometry scan as a standard of care by the radiology department, then a blood test for bone specific Alkaline phosphatase and type-1 Carboxy Telopeptide will be measured by the chemistry lab.

Patients with B-Thalassemia Major induced osteoporosis, who are 18 years of age or more and willing to participate in the study will be enrolled after consenting by the primary investigator in hematology outpatient clinic. Patients with osteoporosis will receive one of the two medications, at the end of the year Dual-energy X-ray absorptiometry scan will be done to compare the response of the two medications. The potential risks include the drug-related side effects


Condition or disease Intervention/treatment Phase
Thalassemia Majors (Beta-Thalassemia Major) Osteoporosis Drug: Denosumab 60 MG/ML Prefilled Syringe Drug: Zoledronic Acid 5Mg/Bag 100Ml Inj Phase 3

Detailed Description:

Despite the significant improvements in the therapeutic management of beta thalassemia major (BTM) over the past few decades, osteoporosis is still a common finding, even in optimally treated patients. The relationships between bone mineral densities (BMD) and several clinical characteristics or hematological markers have been described. Chronic anemia, bone marrow expansion due to ineffective erythropoiesis, iron toxicity, calcium and zinc deficiencies, low vitamin D levels and endocrine complications have been suggested to contribute to the etiology of bone diseases in BTM. Nevertheless, the complex etiological mechanisms of this heterogeneous osteopathy remain incompletely clarified. A complex mechanism controls bone remodeling in human. This mechanism includes the receptor activator of nuclear factor kappa B ligand (RANKL), its natural receptor (RANK) and osteoprotegerin (OPG). The RANK/RANKL pathway is an essential to promote osteoclast formation and activation and prolongs osteoclast survival.

OPG acts as a decoy receptor for RANKL and prevents its interaction with RANK thereby inhibiting osteoclast formation, function, and survival. Alteration of the RANK/RANKL/OPG system for increased osteoclastic activity and enhanced osteoblastic dysfunction is proposed as an important mechanism in the etiology of osteoporosis in BTM. Hypogonadism, a common finding in BTM, is associated with enhanced RANKL activity. The sex steroid hormones, androgen, and estrogens, via their respective nuclear receptors, regulate BMD in humans and mice. Testosterone is likely to have direct and indirect inhibitory effects on human osteoclast formation and bone resorption. Animal model and cell culture studies suggest a direct inhibitory effect of androgens on the OPG/RANKL cytokines system. In human osteoblastic cells, testosterone and 5‑dihydrotestosterone mediate an androgen receptor‑induced specific inhibition of OPG messenger ribonucleic acid (mRNA) expression. Androgens have also been shown to block RANKL‑induced osteoclastic formation while RANKL expression was found to be up‑regulated in osteoblastic cells from androgen receptor‑deficient mice. The effect of oestradiol (E2) on osteoclast precursors and osteoclasts seems to be mediated by osteoblastic cells. Inhibitory effect of E2 is associated with the stimulated secretion of OPG by osteoblasts. Previous studies have focused on the characteristics of thalassemic patients with osteoporosis and their response to therapy with bisphosphonate. Because RANK‑RANKL and OPG play a significant role in bone resorption and seem to be the principal implicated mechanism for the development of osteoporosis in BTM, we will conduct this prospective study to evaluate the anti‑RANKL denosumab versus zoledronic acid on TM‑induced osteoporosis.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 40 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Denosumab Versus Zoledronic Acid for Patients With Beta-Thalassemia Major-Induced Osteoporosis
Actual Study Start Date : May 14, 2018
Estimated Primary Completion Date : May 2019
Estimated Study Completion Date : July 2019


Arm Intervention/treatment
Active Comparator: Denosumab

Denosumab 60 MG/ML Prefilled Syringe

Denosumab Dose: 60 milligrams, subcutaneous injection, every 6 months (twice a year)

Drug: Denosumab 60 MG/ML Prefilled Syringe
Denosumab 60 MG/ML will be administered to 20 patients with b-thalassemia major
Other Name: Prolia

Active Comparator: Zoledronic Acid

Zoledronic Acid 5Mg/Bag 100Ml Inj

Zoledronic acid will be 5 milligrams, Intravenous injection, once a year

Drug: Zoledronic Acid 5Mg/Bag 100Ml Inj
Zoledronic Acid 5Mg/Bag 100Ml Inj will be administered to 20 patients with b-thalassemia major
Other Name: Aclasta




Primary Outcome Measures :
  1. Number of patients with a 50 percent or greater reduction in type-1 collagen carboxy telopeptide from the baseline [ Time Frame: 12 months ]
    Number of patients with a 50 percent or greater reduction in type-1 collagen carboxy telopeptide from the baseline


Secondary Outcome Measures :
  1. Number of patients with a 50 percent or greater improvement in Dual-energy X-ray absorptiometry scan from the baseline [ Time Frame: 12 months ]
    Number of patients with a 50 percent or greater improvement in Dual-energy X-ray absorptiometry scan from the baseline

  2. Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 12 months ]
    Number of participants with treatment-related adverse events as assessed by CTCAE v4.0



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Willing to participate in the study
  • Age 18 years old or older
  • Eastern Cooperative Oncology Group Performance Status less than or equal 2

Exclusion Criteria:

  • Age less than 18 years old
  • Not willing to participate in the study
  • Vulnerable subjects or Eastern Cooperative Oncology Group Performance Status 3 or 4

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): NCT03040765


Contacts
Contact: Mohamed A Yassin 0097455037393 yassin@hamad.qa
Contact: Abdulqadir J Nashwan 0097444398591 anashwan@hamad.qa

Locations
Qatar
National Center for Cancer Care & Research (NCCCR) Recruiting
Doha, Qatar
Contact: Abdulqadir Nashwan         
Sponsors and Collaborators
Hamad Medical Corporation
Investigators
Principal Investigator: Mohamed Yassin Hamad Medical Corporation

Publications:

Responsible Party: Hamad Medical Corporation
ClinicalTrials.gov Identifier: NCT03040765     History of Changes
Other Study ID Numbers: 16441/16
First Posted: February 2, 2017    Key Record Dates
Last Update Posted: May 31, 2018
Last Verified: May 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Keywords provided by Hamad Medical Corporation:
Osteoporosis
Beta-Thalassemia Major
Denosumab
Zoledronic Acid

Additional relevant MeSH terms:
Osteoporosis
Thalassemia
beta-Thalassemia
Bone Diseases, Metabolic
Bone Diseases
Musculoskeletal Diseases
Metabolic Diseases
Anemia, Hemolytic, Congenital
Anemia, Hemolytic
Anemia
Hematologic Diseases
Hemoglobinopathies
Genetic Diseases, Inborn
Zoledronic acid
Diphosphonates
Denosumab
Bone Density Conservation Agents
Physiological Effects of Drugs