The Effects of Vitamin D and Calcium Supplementation to Parathyroid Hormone in CHB Patients Treated With TDF

NCT05313477 | Completed Phase 4 DMC

• 1 other identifier: Si 1045/2020
• Study Type: interventional
• Target: 64
• Locations: 1 country
• Sites: 1

Brief Summary

Nucleot(s)ide is an antiviral drug that can reduce the number of viruses, reduce the risk of HCC, regress hepatic fibrosis and reduce death from Hepatitis B viral infection. Tenofovir disoproxil fumarate (TDF) is one of nucleotide analogue that is recommended to treated patients with Hepatitis B viral infection. However, long-term TDF therapy may have side effects especially nephrotoxicity and bone toxicity. Previous studies in human immunodeficiency virus (HIV) infected patients who treated with TDF containing regimen antiretroviral therapy, in vitamin D supplement group had a statistic significance of low parathyroid hormone level and better in bone mineral density regardless of initial vitamin D level. Therefore, the main objective of this study is to evaluate the vitamin D and calcium supplement to patients with hepatitis B who have taken TDF, in parathyroid hormone level, bone mineral density, renal function and renal phosphate loss compared to patients who have no vitamin D and calcium supplement.

Conditions

Parathyroid Hormone; Tenofovir Disoproxil Fumarate; Chronic Hepatitis B Virus; Vitamin D

Keywords

Tenofovir disoproxil fumarate; Tenofovir; Chronic hepatitis B; Parathyroid hormone; Bone mineral density; Renal phosphate loss; Vitamin D; Calcium; TDF; PTH; CHB; HBV

Outcome Measures

Primary Outcomes (1)

• Change in serum parathyroid hormone

  Change from the baseline in serum parathyroid hormone as assessed by Electrochemiluminescent immunoassay (ECLIA)

  48weeks

Secondary Outcomes (3)

• Change in bone mineral density

  48weeks

• Renal function changes

  48weeks

• Change in renal phosphate loss

  48weeks

Study Arms (2)

Supplement group

ACTIVE COMPARATOR

Vitamin D2 supplement based on initial vitamin D level * ≥ 20ng/mL -\> vitamin D2 20,000unit/week * 10-19.9ng/mL -\> vitamin D2 40,000unit/week * \<10ng/mL -\> vitamin D2 60,000unit/week Calcium carbonate 1000mg/day

Drug: Ergocalciferol Capsules; Drug: Calcium carbonate

No supplement group

NO INTERVENTION

no medication supplement

Interventions

Ergocalciferol Capsules DRUG

Depend on initial 25(OH) vitamin D level If \<10ng/mL, 60000U of Ergocalciferol capsules per week If 10-19.9ng/mL, 40000U of Ergocalciferol capsules per week If \>20 ng/mL, 20000U of Ergocalciferol capsule per week

Supplement group

Calcium carbonate DRUG

1000mg of Calcium carbonate daily

Supplement group

Eligibility Criteria

• Age: 18 Years - 70 Years
• Sex: all
• Healthy Volunteers: Yes
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Age between 18 - 75 years old
• Chronic hepatitis B infected patients treated with TDF monotherapy
• eGFR ≥ 60 mL/ min/ 1.73 m2
• HBV viral load \<10 IU/ mL

You may not qualify if:

• HIV infection or hepatitis C co-infection
• Decompensated cirrhosis, including variceal bleeding, ascites, hepatic encephalopathy
• History of Hepatocellular carcinoma
• Active malignancy of cancer in other organs
• Pregnancy or lactation
• Primary hyperparathyroidism
• History of thyroid or parathyroid surgery
• History of radiation at neck area
• Any osteoporosis treatment or history of osteoporosis diagnosis
• Chronic kidney disease
• Current use of Vitamin D
• Adverse event or allergy to TDF
• Chronic hepatitis B patients with TDF resistance

Sponsors & Collaborators

• Mahidol University: lead

Study Sites (1)

Faculty of Medicine, Siriraj Hospital

Bangkok, 10700, Thailand

Location

Related Publications (32)

• Trepo C, Chan HL, Lok A. Hepatitis B virus infection. Lancet. 2014 Dec 6;384(9959):2053-63. doi: 10.1016/S0140-6736(14)60220-8. Epub 2014 Jun 18.

  PMID: 24954675 RESULT

• Lai CL, Yuen MF. Chronic hepatitis B--new goals, new treatment. N Engl J Med. 2008 Dec 4;359(23):2488-91. doi: 10.1056/NEJMe0808185. No abstract available.

  PMID: 19052131 RESULT

• European Association for the Study of the Liver. EASL 2017 Clinical Practice Guidelines on the management of hepatitis B virus infection. J Hepatol. 2017 Aug;67(2):370-398. doi: 10.1016/j.jhep.2017.03.021. Epub 2017 Apr 18.

  PMID: 28427875 RESULT

• Zampino R, Boemio A, Sagnelli C, Alessio L, Adinolfi LE, Sagnelli E, Coppola N. Hepatitis B virus burden in developing countries. World J Gastroenterol. 2015 Nov 14;21(42):11941-53. doi: 10.3748/wjg.v21.i42.11941.

  PMID: 26576083 RESULT

• European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018 Jul;69(1):182-236. doi: 10.1016/j.jhep.2018.03.019. Epub 2018 Apr 5. No abstract available.

  PMID: 29628281 RESULT

• Yuen MF, Chen DS, Dusheiko GM, Janssen HLA, Lau DTY, Locarnini SA, Peters MG, Lai CL. Hepatitis B virus infection. Nat Rev Dis Primers. 2018 Jun 7;4:18035. doi: 10.1038/nrdp.2018.35.

  PMID: 29877316 RESULT

• Terrault NA, Lok ASF, McMahon BJ, Chang KM, Hwang JP, Jonas MM, Brown RS Jr, Bzowej NH, Wong JB. Update on prevention, diagnosis, and treatment of chronic hepatitis B: AASLD 2018 hepatitis B guidance. Hepatology. 2018 Apr;67(4):1560-1599. doi: 10.1002/hep.29800. No abstract available.

  PMID: 29405329 RESULT

• Wang YJ, Yang L, Zuo JP. Recent developments in antivirals against hepatitis B virus. Virus Res. 2016 Feb 2;213:205-213. doi: 10.1016/j.virusres.2015.12.014. Epub 2015 Dec 28.

  PMID: 26732483 RESULT

• Wong GL, Seto WK, Wong VW, Yuen MF, Chan HL. Review article: long-term safety of oral anti-viral treatment for chronic hepatitis B. Aliment Pharmacol Ther. 2018 Mar;47(6):730-737. doi: 10.1111/apt.14497. Epub 2018 Jan 22.

  PMID: 29359487 RESULT

• de Fraga RS, Van Vaisberg V, Mendes LCA, Carrilho FJ, Ono SK. Adverse events of nucleos(t)ide analogues for chronic hepatitis B: a systematic review. J Gastroenterol. 2020 May;55(5):496-514. doi: 10.1007/s00535-020-01680-0. Epub 2020 Mar 17.

  PMID: 32185517 RESULT

• Liborio AB, Andrade L, Pereira LV, Sanches TR, Shimizu MH, Seguro AC. Rosiglitazone reverses tenofovir-induced nephrotoxicity. Kidney Int. 2008 Oct;74(7):910-8. doi: 10.1038/ki.2008.252. Epub 2008 Jun 18.

  PMID: 18563054 RESULT

• Birkus G, Hitchcock MJ, Cihlar T. Assessment of mitochondrial toxicity in human cells treated with tenofovir: comparison with other nucleoside reverse transcriptase inhibitors. Antimicrob Agents Chemother. 2002 Mar;46(3):716-23. doi: 10.1128/AAC.46.3.716-723.2002.

  PMID: 11850253 RESULT

• Kohler JJ, Hosseini SH, Hoying-Brandt A, Green E, Johnson DM, Russ R, Tran D, Raper CM, Santoianni R, Lewis W. Tenofovir renal toxicity targets mitochondria of renal proximal tubules. Lab Invest. 2009 May;89(5):513-9. doi: 10.1038/labinvest.2009.14. Epub 2009 Mar 9.

  PMID: 19274046 RESULT

• Rodriguez-Novoa S, Labarga P, Soriano V, Egan D, Albalater M, Morello J, Cuenca L, Gonzalez-Pardo G, Khoo S, Back D, Owen A. Predictors of kidney tubular dysfunction in HIV-infected patients treated with tenofovir: a pharmacogenetic study. Clin Infect Dis. 2009 Jun 1;48(11):e108-16. doi: 10.1086/598507.

  PMID: 19400747 RESULT

• Lampertico P, Chan HL, Janssen HL, Strasser SI, Schindler R, Berg T. Review article: long-term safety of nucleoside and nucleotide analogues in HBV-monoinfected patients. Aliment Pharmacol Ther. 2016 Jul;44(1):16-34. doi: 10.1111/apt.13659. Epub 2016 May 19.

  PMID: 27198929 RESULT

• Grant PM, Cotter AG. Tenofovir and bone health. Curr Opin HIV AIDS. 2016 May;11(3):326-32. doi: 10.1097/COH.0000000000000248.

  PMID: 26859637 RESULT

• Fontana RJ. Side effects of long-term oral antiviral therapy for hepatitis B. Hepatology. 2009 May;49(5 Suppl):S185-95. doi: 10.1002/hep.22885.

  PMID: 19399802 RESULT

• Fong TL, Lee BT, Tien A, Chang M, Lim C, Ahn A, Bae HS. Improvement of bone mineral density and markers of proximal renal tubular function in chronic hepatitis B patients switched from tenofovir disoproxil fumarate to tenofovir alafenamide. J Viral Hepat. 2019 May;26(5):561-567. doi: 10.1111/jvh.13053. Epub 2019 Jan 16.

  PMID: 30576085 RESULT

• Grigsby IF, Pham L, Mansky LM, Gopalakrishnan R, Carlson AE, Mansky KC. Tenofovir treatment of primary osteoblasts alters gene expression profiles: implications for bone mineral density loss. Biochem Biophys Res Commun. 2010 Mar 26;394(1):48-53. doi: 10.1016/j.bbrc.2010.02.080. Epub 2010 Feb 18.

  PMID: 20171173 RESULT

• Masia M, Padilla S, Robledano C, Lopez N, Ramos JM, Gutierrez F. Early changes in parathyroid hormone concentrations in HIV-infected patients initiating antiretroviral therapy with tenofovir. AIDS Res Hum Retroviruses. 2012 Mar;28(3):242-6. doi: 10.1089/AID.2011.0052. Epub 2011 Jul 19.

  PMID: 21639815 RESULT

• Mingione A, Maruca K, Chiappori F, Pivari F, Brasacchio C, Quirino T, Merelli I, Soldati L, Bonfanti P, Mora S. High parathyroid hormone concentration in tenofovir-treated patients are due to inhibition of calcium-sensing receptor activity. Biomed Pharmacother. 2018 Jan;97:969-974. doi: 10.1016/j.biopha.2017.11.037. Epub 2017 Nov 7.

  PMID: 29136775 RESULT

• Havens PL, Kiser JJ, Stephensen CB, Hazra R, Flynn PM, Wilson CM, Rutledge B, Bethel J, Pan CG, Woodhouse LR, Van Loan MD, Liu N, Lujan-Zilbermann J, Baker A, Kapogiannis BG, Gordon CM, Mulligan K; Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) 063 Study Team. Association of higher plasma vitamin D binding protein and lower free calcitriol levels with tenofovir disoproxil fumarate use and plasma and intracellular tenofovir pharmacokinetics: cause of a functional vitamin D deficiency? Antimicrob Agents Chemother. 2013 Nov;57(11):5619-28. doi: 10.1128/AAC.01096-13. Epub 2013 Sep 3.

  PMID: 24002093 RESULT

• Childs KE, Fishman SL, Constable C, Gutierrez JA, Wyatt CM, Dieterich DT, Mullen MP, Branch AD. Short communication: Inadequate vitamin D exacerbates parathyroid hormone elevations in tenofovir users. AIDS Res Hum Retroviruses. 2010 Aug;26(8):855-9. doi: 10.1089/aid.2009.0308.

  PMID: 20672993 RESULT

• Noe S, Heldwein S, Wiese C, Pascucci R, von Krosigk A, Schabaz F, Jonsson-Oldenbuettel C, Jaeger H, Wolf E. Tenofovir Disoproxil Fumarate Is Associated with a Set-Point Variation in the Calcium-Parathyroid Hormone-Vitamin D Axis: Results from a German Cohort. Adv Pharmacol Sci. 2018 Dec 31;2018:6069131. doi: 10.1155/2018/6069131. eCollection 2018.

  PMID: 30687401 RESULT

• Havens PL, Stephensen CB, Hazra R, Flynn PM, Wilson CM, Rutledge B, Bethel J, Pan CG, Woodhouse LR, Van Loan MD, Liu N, Lujan-Zilbermann J, Baker A, Kapogiannis BG, Mulligan K; Adolescent Medicine Trials Network (ATN) for HIV/AIDS Interventions 063 study team. Vitamin D3 decreases parathyroid hormone in HIV-infected youth being treated with tenofovir: a randomized, placebo-controlled trial. Clin Infect Dis. 2012 Apr;54(7):1013-25. doi: 10.1093/cid/cir968. Epub 2012 Jan 19.

  PMID: 22267714 RESULT

• Saeedi R, Mojebi-Mogharar A, Sandhu SK, Dubland JA, Ford JA, Yousefi M, Pudek M, Holmes DT, Erb SR, Peter Kwan W, Kendler DL, Yoshida EM. Lamivudine, Entecavir, or Tenofovir Treatment of Hepatitis B Infection: Effects on Calcium, Phosphate, FGF23 and Indicators of Bone Metabolism. Ann Hepatol. 2017 March-April;16(2):207-214. doi: 10.5604/16652681.1231577.

  PMID: 28233741 RESULT

• Havens PL, Hazra R, Stephensen CB, Kiser JJ, Flynn PM, Wilson CM, Rutledge B, Bethel J, Pan CG, Woodhouse LR, Van Loan MD, Liu N, Lujan-Zilbermann J, Baker A, Kapogiannis BG, Gordon CM, Mulligan K; Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) 063 study team. Vitamin D3 supplementation increases fibroblast growth factor-23 in HIV-infected youths treated with tenofovir disoproxil fumarate. Antivir Ther. 2014;19(6):613-8. doi: 10.3851/IMP2755. Epub 2014 Feb 17.

  PMID: 24535626 RESULT

• Reid IR, Bolland MJ, Grey A. Effects of vitamin D supplements on bone mineral density: a systematic review and meta-analysis. Lancet. 2014 Jan 11;383(9912):146-55. doi: 10.1016/S0140-6736(13)61647-5. Epub 2013 Oct 11.

  PMID: 24119980 RESULT

• Reid IR. Vitamin D Effect on Bone Mineral Density and Fractures. Endocrinol Metab Clin North Am. 2017 Dec;46(4):935-945. doi: 10.1016/j.ecl.2017.07.005. Epub 2017 Sep 29.

  PMID: 29080644 RESULT

• Hoan NX, Tong HV, Song LH, Meyer CG, Velavan TP. Vitamin D deficiency and hepatitis viruses-associated liver diseases: A literature review. World J Gastroenterol. 2018 Jan 28;24(4):445-460. doi: 10.3748/wjg.v24.i4.445.

  PMID: 29398866 RESULT

• Overton ET, Chan ES, Brown TT, Tebas P, McComsey GA, Melbourne KM, Napoli A, Hardin WR, Ribaudo HJ, Yin MT. Vitamin D and Calcium Attenuate Bone Loss With Antiretroviral Therapy Initiation: A Randomized Trial. Ann Intern Med. 2015 Jun 16;162(12):815-24. doi: 10.7326/M14-1409.

  PMID: 26075752 RESULT

• Havens PL, Stephensen CB, Van Loan MD, Schuster GU, Woodhouse LR, Flynn PM, Gordon CM, Pan CG, Rutledge B, Harris DR, Price G, Baker A, Meyer WA 3rd, Wilson CM, Hazra R, Kapogiannis BG, Mulligan K; Adolescent Medicine Trials Network for HIV/AIDS Interventions (ATN) 109 Study Team. Vitamin D3 Supplementation Increases Spine Bone Mineral Density in Adolescents and Young Adults With Human Immunodeficiency Virus Infection Being Treated With Tenofovir Disoproxil Fumarate: A Randomized, Placebo-Controlled Trial. Clin Infect Dis. 2018 Jan 6;66(2):220-228. doi: 10.1093/cid/cix753.

  PMID: 29020329 RESULT

MeSH Terms

Conditions

Hepatitis B, Chronic

Interventions

Ergocalciferols; Calcium Carbonate

Condition Hierarchy (Ancestors)

Hepatitis B; Blood-Borne Infections; Communicable Diseases; Infections; Hepadnaviridae Infections; DNA Virus Infections; Virus Diseases; Hepatitis, Viral, Human; Hepatitis, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cholestenes; Cholestanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds; Sterols; Vitamin D; Secosteroids; Membrane Lipids; Lipids; Calcium Compounds; Inorganic Chemicals; Carbonates; Carbonic Acid; Carbon Compounds, Inorganic; Minerals

Study Officials

• Watcharasak Chotiyaputta, Asso Prof

  Mahidol University

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: Associate professor, Faculty of Medicine, Siriraj Hospital

Study Record Dates

• First Submitted: March 7, 2022
• First Posted: April 6, 2022
• Study Start: May 1, 2022
• Primary Completion: August 31, 2023
• Study Completion: November 30, 2023
• Last Updated: September 5, 2024

Record last verified: 2024-09

Data Sharing

• IPD Sharing: Will not share

Locations

TH (1)