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

• ClinicalTrials.gov Identifier: NCT03040765
• Recruitment Status: Terminated
• First Posted: February 2, 2017
• Last Update Posted: December 12, 2019
• Sponsor: Hamad Medical Corporation
• Information provided by (Responsible Party): Hamad Medical Corporation

Tracking Information

• First Submitted Date: January 22, 2017
• First Posted Date: February 2, 2017
• Last Update Posted Date: December 12, 2019
• Actual Study Start Date: May 14, 2018
• Actual Primary Completion Date: April 8, 2019 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: April 11, 2017)

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

Original Primary Outcome Measures (submitted: January 31, 2017)

• 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 improvement in Dual-energy X-ray absorptiometry scan from the baseline [ Time Frame: 12 months ]
• Number of participants with treatment-related adverse events as assessed by CTCAE v4.0 [ Time Frame: 12 months ]

Current Secondary Outcome Measures (submitted: April 11, 2017)

• 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
• 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

• Original Secondary Outcome Measures: Not Provided
• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Denosumab Versus Zoledronic Acid in Thalassemia-Induced Osteoporosis
• Official Title: Denosumab Versus Zoledronic Acid for Patients With Beta-Thalassemia Major-Induced Osteoporosis

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

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
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Thalassemia Majors (Beta-Thalassemia Major)
• Osteoporosis

Intervention

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

Study Arms

• Active Comparator: Denosumab

  Denosumab 60 MG/ML Prefilled Syringe

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

  Intervention: Drug: Denosumab 60 MG/ML Prefilled Syringe
• Active Comparator: Zoledronic Acid

  Zoledronic Acid 5Mg/Bag 100Ml Inj

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

  Intervention: Drug: Zoledronic Acid 5Mg/Bag 100Ml Inj

Publications *

• Baldini M, Forti S, Marcon A, Ulivieri FM, Orsatti A, Tampieri B, Airaghi L, Zanaboni L, Cappellini MD. Endocrine and bone disease in appropriately treated adult patients with beta-thalassemia major. Ann Hematol. 2010 Dec;89(12):1207-13. doi: 10.1007/s00277-010-1007-0. Epub 2010 Jun 26.
• Scacchi M, Danesi L, Cattaneo A, Valassi E, Pecori Giraldi F, Argento C, D'Angelo E, Mirra N, Carnelli V, Zanaboni L, Tampieri B, Cappellini MD, Cavagnini F. Bone demineralization in adult thalassaemic patients: contribution of GH and IGF-I at different skeletal sites. Clin Endocrinol (Oxf). 2008 Aug;69(2):202-7. doi: 10.1111/j.1365-2265.2008.03191.x. Epub 2008 Jan 21.
• Kyriakou A, Savva SC, Savvides I, Pangalou E, Ioannou YS, Christou S, Skordis N. Gender differences in the prevalence and severity of bone disease in thalassaemia. Pediatr Endocrinol Rev. 2008 Oct;6 Suppl 1:116-22.
• Voskaridou E, Terpos E. Pathogenesis and management of osteoporosis in thalassemia. Pediatr Endocrinol Rev. 2008 Oct;6 Suppl 1:86-93.
• Pietrapertosa AC, Minenna G, Colella SM, Santeramo TM, Renni R, D'Amore M. Osteoprotegerin and RANKL in the pathogenesis of osteoporosis in patients with thalassaemia major. Panminerva Med. 2009 Mar;51(1):17-23.
• Mahachoklertwattana P, Pootrakul P, Chuansumrit A, Choubtum L, Sriphrapradang A, Sirisriro R, Rajatanavin R. Association between bone mineral density and erythropoiesis in Thai children and adolescents with thalassemia syndromes. J Bone Miner Metab. 2006;24(2):146-52. doi: 10.1007/s00774-005-0661-0.
• Aslan I, Canatan D, Balta N, Kacar G, Dorak C, Ozsancak A, Oguz N, Cosan R. Bone mineral density in thalassemia major patients from antalya, Turkey. Int J Endocrinol. 2012;2012:573298. doi: 10.1155/2012/573298. Epub 2012 Jun 20.
• Pincelli AI, Masera N, Tavecchia L, Perotti M, Perra S, Mariani R, Piperno A, Mancia G, Grassi G, Masera G. GH deficiency in adult B-thalassemia major patients and its relationship with IGF-1 production. Pediatr Endocrinol Rev. 2011 Mar;8 Suppl 2:284-9.
• Pirinccioglu AG, Akpolat V, Koksal O, Haspolat K, Soker M. Bone mineral density in children with beta-thalassemia major in Diyarbakir. Bone. 2011 Oct;49(4):819-23. doi: 10.1016/j.bone.2011.07.014. Epub 2011 Jul 23.
• Skordis N, Ioannou YS, Kyriakou A, Savva SC, Efstathiou E, Savvides I, Christou S. Effect of bisphosphonate treatment on bone mineral density in patients with thalassaemia major. Pediatr Endocrinol Rev. 2008 Oct;6 Suppl 1:144-8.
• Soliman AT, El Banna N, Abdel Fattah M, ElZalabani MM, Ansari BM. Bone mineral density in prepubertal children with beta-thalassemia: correlation with growth and hormonal data. Metabolism. 1998 May;47(5):541-8. doi: 10.1016/s0026-0495(98)90237-2.
• Mahachoklertwattana P, Chuansumrit A, Sirisriro R, Choubtum L, Sriphrapradang A, Rajatanavin R. Bone mineral density, biochemical and hormonal profiles in suboptimally treated children and adolescents with beta-thalassaemia disease. Clin Endocrinol (Oxf). 2003 Mar;58(3):273-9. doi: 10.1046/j.1365-2265.2003.01707.x.
• Boyce BF, Xing L. Functions of RANKL/RANK/OPG in bone modeling and remodeling. Arch Biochem Biophys. 2008 May 15;473(2):139-46. doi: 10.1016/j.abb.2008.03.018. Epub 2008 Mar 25.
• Kearns AE, Khosla S, Kostenuik PJ. Receptor activator of nuclear factor kappaB ligand and osteoprotegerin regulation of bone remodeling in health and disease. Endocr Rev. 2008 Apr;29(2):155-92. doi: 10.1210/er.2007-0014. Epub 2007 Dec 5.
• Pepene CE, Crisan N, Coman I. Elevated serum receptor activator of nuclear factor kappa B ligand and osteoprotegerin levels in late-onset male hypogonadism. Clin Invest Med. 2011 Aug 1;34(4):E232. doi: 10.25011/cim.v34i4.15365.
• Michael H, Harkonen PL, Vaananen HK, Hentunen TA. Estrogen and testosterone use different cellular pathways to inhibit osteoclastogenesis and bone resorption. J Bone Miner Res. 2005 Dec;20(12):2224-32. doi: 10.1359/JBMR.050803. Epub 2005 Aug 1.
• Hofbauer LC, Hicok KC, Chen D, Khosla S. Regulation of osteoprotegerin production by androgens and anti-androgens in human osteoblastic lineage cells. Eur J Endocrinol. 2002 Aug;147(2):269-73. doi: 10.1530/eje.0.1470269.
• Grundt A, Grafe IA, Liegibel U, Sommer U, Nawroth P, Kasperk C. Direct effects of osteoprotegerin on human bone cell metabolism. Biochem Biophys Res Commun. 2009 Nov 20;389(3):550-5. doi: 10.1016/j.bbrc.2009.09.026. Epub 2009 Sep 11.
• Huber DM, Bendixen AC, Pathrose P, Srivastava S, Dienger KM, Shevde NK, Pike JW. Androgens suppress osteoclast formation induced by RANKL and macrophage-colony stimulating factor. Endocrinology. 2001 Sep;142(9):3800-8. doi: 10.1210/endo.142.9.8402.
• Kawano H, Sato T, Yamada T, Matsumoto T, Sekine K, Watanabe T, Nakamura T, Fukuda T, Yoshimura K, Yoshizawa T, Aihara K, Yamamoto Y, Nakamichi Y, Metzger D, Chambon P, Nakamura K, Kawaguchi H, Kato S. Suppressive function of androgen receptor in bone resorption. Proc Natl Acad Sci U S A. 2003 Aug 5;100(16):9416-21. doi: 10.1073/pnas.1533500100. Epub 2003 Jul 18.
• Gorny G, Shaw A, Oursler MJ. IL-6, LIF, and TNF-alpha regulation of GM-CSF inhibition of osteoclastogenesis in vitro. Exp Cell Res. 2004 Mar 10;294(1):149-58. doi: 10.1016/j.yexcr.2003.11.009.

Recruitment Information

• Recruitment Status: Terminated
• Actual Enrollment (submitted: December 10, 2019): 17
• Original Estimated Enrollment (submitted: January 31, 2017): 20
• Actual Study Completion Date: April 8, 2019
• Actual Primary Completion Date: April 8, 2019 (Final data collection date for primary outcome measure)

Eligibility 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

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Qatar

Administrative Information

• NCT Number: NCT03040765
• Other Study ID Numbers: 16441/16
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• 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

IPD Sharing Statement

• Plan to Share IPD: Undecided

• Current Responsible Party: Hamad Medical Corporation
• Original Responsible Party: Same as current
• Current Study Sponsor: Hamad Medical Corporation
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Principal Investigator: Mohamed Yassin; Hamad Medical Corporation

• PRS Account: Hamad Medical Corporation
• Verification Date: May 2018