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Clinical Trial Details — Status: Completed

Administrative data

NCT number NCT05313477
Other study ID # Si 1045/2020
Secondary ID
Status Completed
Phase Phase 4
First received
Last updated
Start date May 1, 2022
Est. completion date November 30, 2023

Study information

Verified date February 2024
Source Mahidol University
Contact n/a
Is FDA regulated No
Health authority
Study type Interventional

Clinical Trial 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.


Description:

Hepatitis B virus is a global public health problem. This infection leads to chronic hepatitis, cirrhosis and liver cancer. According to past statistics, infection with hepatitis B virus is a common cause of hepatocellular carcinoma about 60% in East-Asia and Africa and about 20% in Western countries. About 350-400 million people are infected worldwide. Infection with hepatitis B virus is also an important factor of death in 1million patients per year. 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. Nowadays, the recommendation of nucleot(s)ide prefers Tenofovir disoproxil fumarate (TDF), Tenofovir Alafenamide (TAF) and Entecavir (ETV) than Lamivudine, Adefovir and Telbivudine due to high potency and low resistance rate Tenofovir disoproxil fumarate (TDF) is one of nucleotide analogue that inhibits reverse transcriptase in HBV replication process. However, long-term TDF therapy may have side effects especially nephrotoxicity. The proposed mechanisms of nephrotoxicity of TDF are cumulative of TDF at proximal tubule of kidney leads to mitochondrial toxicity, downregulation of sodium-phosphorus cotransporter, sodium/ hydrogen exchanger 3 and aquaporin 2, decreased endothelial nitric oxide-synthase (eNOS) and renal vasoconstriction results in tubulopathy in renal proximal tubule, increase of phosphate loss in urine and increase od serum creatinine. Moreover, TDF also affects to decrease bone mineral density (BMD) that related with renal phosphate loss, loss of osteoblast function, high parathyroid hormone level regardless of vitamin D level and high fibroblast growth factor 23 (FGF23) leads to worsen in bone mineralization Vitamin D has a protective effect and indicate for osteoporosis treatment. The chronic hepatitis B infected patients with vitamin D deficiency may have a poor prognosis in hepatic fibrosis and high HBV DNA level. 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.


Recruitment information / eligibility

Status Completed
Enrollment 64
Est. completion date November 30, 2023
Est. primary completion date August 31, 2023
Accepts healthy volunteers Accepts Healthy Volunteers
Gender All
Age group 18 Years to 70 Years
Eligibility Inclusion Criteria: - 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 Exclusion Criteria: - 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

Study Design


Intervention

Drug:
Ergocalciferol Capsules
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
Calcium carbonate
1000mg of Calcium carbonate daily

Locations

Country Name City State
Thailand Faculty of Medicine, Siriraj Hospital Bangkok

Sponsors (1)

Lead Sponsor Collaborator
Mahidol University

Country where clinical trial is conducted

Thailand, 

References & Publications (32)

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- — View Citation

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: — View Citation

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. — View Citation

European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; 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 — View Citation

European Association for the Study of the Liver. Electronic address: easloffice@easloffice.eu; European Association for the Study of the Liver. EASL Clinical Practice Guidelines: Management of hepatocellular carcinoma. J Hepatol. 2018 Jul;69(1):182-236. d — View Citation

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. — View Citation

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. — View Citation

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

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: 10.1 — View Citation

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 Intervent — View Citation

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 Intervent — View Citation

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 — View Citation

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 Intervent — View Citation

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. — View Citation

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 — View Citation

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. — View Citation

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 — View Citation

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. — View Citation

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/A — View Citation

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 Pharmac — View Citation

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 Coh — View Citation

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. d — View Citation

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. — View Citation

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. — View Citation

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 — View Citation

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 Indi — View Citation

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 — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

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. — View Citation

* Note: There are 32 references in allClick here to view all references

Outcome

Type Measure Description Time frame Safety issue
Primary Change in serum parathyroid hormone Change from the baseline in serum parathyroid hormone as assessed by Electrochemiluminescent immunoassay (ECLIA) 48weeks
Secondary Change in bone mineral density Change from the baseline in bone mineral density as assessed by Dual-energy X-ray absorptiometry (DXA) 48weeks
Secondary Renal function changes Change from the baseline in renal function (eGFR) based on creatinine as assessed by Enzymatic method 48weeks
Secondary Change in renal phosphate loss Change from the baseline in the tubular reabsorption of phosphate (TRP) as renal phosphate loss depended on serum creatinine, urine creatine (assessed by enzymatic method) and serum phosphate, urine phosphate (assessed by modification of the classical phosphomolybdate method by Fiske and Subbarow) 48weeks
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