Eight Weeks Sofosbovir/Ledipasvir in HCV Infected Children Aged 4 to 10 Years

Hepatitis C, Chronic Clinical Trial

Official title:

Sofosbovir/Ledipasvir in HCV Infected Children Aged From 4 to 10 Years

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03764345
• Other study ID #: Sof-Led-HCV-Ped
• Status: Completed
• Phase: N/A
• Start date: December 6, 2018
• Est. completion date: July 2, 2019

Study information

• Verified date: September 2019
• Source: National Liver Institute, Egypt
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Recently the era of direct-acting antiviral drugs for hepatitis C treatment has changed the world map of HCV. Results in adults are promising. FDA approved only two drugs in the pediatric age group 12 to 17 years. Younger children are still on the wait list for treatment. The current study aimed to treat children aged between 3 and 12 years with half the adult dose of Sofosbuvir/Ledipasvir combination (Heterosofir).

Description:

The WHO has declared hepatitis C a global health problem, with ∼ 3% of the world's population (roughly 170-200 million individuals) infected with HCV. Egypt has the highest prevalence of HCV in the world, ranging from 6 to 28%, with an average of ∼ 13.8% in the general population. Ap-proximately 90% of Egyptian HCV isolates belong to a single subtype, 4a.

Hepatitis C virus (HCV) is a major cause of chronic liver disease and a prin-cipal reason for liver transplant; approximately 170 million people worldwide are chronically infected. There is general consensus that HCV elimination is associated with strong and sustained CD4+ and CD8+ T cell res-ponses that target multiple epitopes within the different HCV proteins, however, they are not maintained in patients who develop chronic disease . A variety of factors purportedly contribute to the dimi-nished T cell responses observed in chronically infected patients, including an im-paired dendritic cell (DC) function.

The successful development of direct-acting antivirals (DAAs) that are active against hepatitis C virus has transformed chronic hepatitis C infection from a con-dition requiring complex therapies with unsatisfactory outcomes to one that can be easily treated with few contraindications and side-effects. Since 2011, the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) have approved eight oral DAA regimens for the treatment of adults with chronic hepatitis C. Investigation into DAAs for children has been slower.

For adolescents aged 12-17 years, the safety and efficacy of the fixed-dose combination sofosbuvir and ledipasvir for genotype 1 or 4 infection and of combination sofosbuvir plus ribavirin for genotype 2 or 3 infection have been described in full-length articles.

A recent study explored the safety and efficacy of combination sofosbuvirplus ribavirin in Pakistani children (aged 5-18 years) with hepatitis C virus genotype 1, 2, or 3 infection. Further results have been presented as ab-stracts for the fixed-dose combination sofosbuvir and ledipasvir in children aged 6-11 years for the fixed-dose combination ombitasvir, pari-taprevir, and ritonavir with or without dasabuvir and with or without ribavirin in adolescents aged 12-17 years with genotype 1 or 4 infection and for combination sofosbuvir plus daclatasvir with or without ribavirin in Egyp-tian adolescents aged 12-17 years with genotype 4 infection.

Dendritic cells are professional antigen presenting cells characterized by a po-tent capacity to elicit primary T cell responses. Two major subsets of DC can be identified from human peripheral blood: plasmacytoid (p) DC and conventional or myeloid (m) DC. Each subset represents 0.3-0.5% of the normal human peripheral blood mononuclear cell (PBMC) population.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: July 2, 2019
• Est. primary completion date: July 2, 2019
• Accepts healthy volunteers: No
• Gender: All
• Age group: 3 Years to 12 Years

Eligibility

Inclusion Criteria:

• Children with chronic HCV

• age 3- 12 y old

• weight 17- 35kg

• Basal HCV viremia less than 6.8 log IU/mL

• Treatment-naive

• No cirrhosis

Exclusion Criteria:

• Patients with dual HBV and HCV infection or associated with chronic hepatitis other than chronic HCV

• age below 3 years or above 12 years

• body weight less than 17 or more than 35 Kg

• HCV/HIV coinfection.

• Patients with HCV infection and HCC.

• Patients with HCV infection and underlying cardiac comorbidities

• Decompensated patients with HCV

• Hypoalbuminemia of < 3.5g/dL.

• International normalised ratio (INR) >2.

• Advanced fibrosis scoring by transient elastography (F 4 broScan)

• Any concomitant malignancy.

• Parents' refusal for participation of their children in the study.

Related Conditions & MeSH terms

• Children, Only
• Hepatitis C
• Hepatitis C, Chronic

Intervention

Drug:
• Sofosbovir/Lepipasvir (200/45mg) tablet (Heterosofir)
Patients receive oral daily dose of Sofosbovir/Ledipasvir (200/45mg) daily for 8 weeks

Locations

Country	Name	City	State
Egypt	Pediatric Hepatology, Gastroenterology and Nutrition Department, National Liver Institute, Menoufia University	Shebin El-Koom	Menofiya

Sponsors (1)

Lead Sponsor	Collaborator
National Liver Institute, Egypt

Country where clinical trial is conducted

Egypt, 

References & Publications (14)

Balistreri WF, Murray KF, Rosenthal P, Bansal S, Lin CH, Kersey K, Massetto B, Zhu Y, Kanwar B, German P, Svarovskaia E, Brainard DM, Wen J, Gonzalez-Peralta RP, Jonas MM, Schwarz K. The safety and effectiveness of ledipasvir-sofosbuvir in adolescents 12-17 years old with hepatitis C virus genotype 1 infection. Hepatology. 2017 Aug;66(2):371-378. doi: 10.1002/hep.28995. Epub 2017 Jun 19. — View Citation

Deuffic-Burban S, Mohamed MK, Larouze B, Carrat F, Valleron AJ. Expected increase in hepatitis C-related mortality in Egypt due to pre-2000 infections. J Hepatol. 2006 Mar;44(3):455-61. Epub 2005 Sep 15. — View Citation

El-Sayed M, Hassany M, Asem N. A pilot study for safety and efficacy of 12 weeks sofosbuvir plus daclatasvir with or without ribavirin in Egyptian adoles-cents with chronic hepatitis C virus Infection. Journal of Hepatology 2017,66:S178

El-Serag HB. Hepatocellular carcinoma and hepatitis C in the United States. Hepatology. 2002 Nov;36(5 Suppl 1):S74-83. Review. — View Citation

Gowans EJ, Jones KL, Bharadwaj M, Jackson DC. Prospects for dendritic cell vaccination in persistent infection with hepatitis C virus. J Clin Virol. 2004 Aug;30(4):283-90. Review. — View Citation

Hashmi MA, Cheema HA. Effectiveness and Safety of Sofosbuvir in Treatment-NäiveChildren with Hepatitis C Infection. J Coll Physicians Surg Pak. 2017 Jul;27(7):423-426. doi: 2657. — View Citation

Indolfi G, Serranti D, Resti M. Direct-acting antivirals for children and adolescents with chronic hepatitis C. Lancet Child Adolesc Health. 2018 Apr;2(4):298-304. doi: 10.1016/S2352-4642(18)30037-3. Epub 2018 Feb 24. Review. — View Citation

Kamal SM, Madwar MA, Peters T, Fawzy R, Rasenack J. Interferon therapy in patients with chronic hepatitis C and schistosomiasis. J Hepatol. 2000 Jan;32(1):172-4. — View Citation

Murray KF, Balistreri W, Bansal S, Whitworth S, Evans H, Gonzalez-Peralta R, et al. Ledipasvir/sofosbuvir±ribavirin for 12 or 24 weeks is safe and effective in children 6-11 years old with chronic hepatitis C infection. Journal of Hepatology 2017,66:S57-S58

O'Doherty U, Peng M, Gezelter S, Swiggard WJ, Betjes M, Bhardwaj N, Steinman RM. Human blood contains two subsets of dendritic cells, one immunologically mature and the other immature. Immunology. 1994 Jul;82(3):487-93. — View Citation

Schulze Zur Wiesch J, Ciuffreda D, Lewis-Ximenez L, Kasprowicz V, Nolan BE, Streeck H, Aneja J, Reyor LL, Allen TM, Lohse AW, McGovern B, Chung RT, Kwok WW, Kim AY, Lauer GM. Broadly directed virus-specific CD4+ T cell responses are primed during acute hepatitis C infection, but rapidly disappear from human blood with viral persistence. J Exp Med. 2012 Jan 16;209(1):61-75. doi: 10.1084/jem.20100388. Epub 2012 Jan 2. — View Citation

Takaki A, Wiese M, Maertens G, Depla E, Seifert U, Liebetrau A, Miller JL, Manns MP, Rehermann B. Cellular immune responses persist and humoral responses decrease two decades after recovery from a single-source outbreak of hepatitis C. Nat Med. 2000 May;6(5):578-82. — View Citation

Thorne C, Indolfi G, Turkova A, Giaquinto C, Nastouli E. Treating hepatitis C virus in children: time for a new paradigm. J Virus Erad. 2015 Jul 1;1(3):203-5. Review. — View Citation

Wirth S, Rosenthal P, Gonzalez-Peralta RP, Jonas MM, Balistreri WF, Lin CH, Hardikar W, Kersey K, Massetto B, Kanwar B, Brainard DM, Shao J, Svarovskaia E, Kirby B, Arnon R, Murray KF, Schwarz KB. Sofosbuvir and ribavirin in adolescents 12-17 years old with hepatitis C virus genotype 2 or 3 infection. Hepatology. 2017 Oct;66(4):1102-1110. doi: 10.1002/hep.29278. Epub 2017 Aug 26. — View Citation

* Note: There are 14 references in all — Click here to view all references

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Treatment safety-1 Alanine transaminase serum level	Alanine transaminase serum level	8 weeks
Other	Treatment safety-2 Aspartate transaminase serum level	Aspartate transaminase serum level	8 weeks
Other	Treatment safety-2 Degree of liver fibrosis	Liver Stiffness measurement before and after end of therapy	8 weeks
Other	Treatment tolerability-1 Patient height	measurement of Height	20 weeks
Other	Treatment tolerability-2 Body weight	measurement of weight	20 weeks
Primary	Side effect 1 Number of patients with fatigue	Number of patients with fatigue	8 weeks
Primary	Side effect 2 Number of patients with Headache	Number of patients with Headache	8 weeks
Primary	Side effect 3 Number of patients with nausea	Number of patients with nausea	8 weeks
Primary	Side effect 4 Number of patients with diarrhea	Number of patients with diarrhea	8 weeks
Primary	Side effect 5 Number of patients with insomnia	Number of patients with insomnia	8 weeks
Primary	Side effect 6 Number of patients with weakness	Number of patients with weakness	8 weeks
Primary	Side effect 7 Number of patients with bradycardia	Number of patients with bradycardia	8 weeks
Primary	Side effect 8 Number of patients with cough	Number of patients with cough	8 weeks
Primary	Side effect 9 Number of patients with myalgia	Number of patients with myalgia	8 weeks
Primary	Side effect 10 Number of patients with dysapnea	Number of patients with dysapnea	8 weeks
Primary	Side effect 11 Number of patients with irritability	Number of patients with irritability	8 weeks
Primary	Side effect 12 Number of patients with dizziness	Number of patients with dizziness	8 weeks
Primary	Side effect 13 Number of patients with depression	Number of patients with depression	8 weeks
Primary	Side effect 14 Number of patients with skin rash	Number of patients with skin rash	8 weeks
Secondary	HCV-RNA PCR by the end of therapy	HCV-RNA PCR at week 8	8 weeks
Secondary	HCV-RNA PCR after 20 weeks for SVR	HCV-RNA PCR at week 20	20 weeks