Treatment of Chronic Hepatitis C During Pregnancy With Sofosbuvir/Velpatasvir

Phase 1 Pharmacokinetic Trial of Sofosbuvir/Velpatasvir in Pregnant Women With Chronic Hepatitis C Virus Infection

A single-arm, single-center, open label Phase 1 study of a 12-week course of Sofosbuvir (SOF)/Velpatasvir (VEL) in 10 HCV-infected pregnant women 1 that will evaluate the plasma pharmacokinetic parameters of SOF/VEL administered during pregnancy and compare them to those of a historical cohort of nonpregnant women.

Study Overview

• Status: Completed
• Conditions: Hepatitis C, Chronic
• Intervention / Treatment: Drug: Sofosbuvir-Velpatasvir Drug Combination

Detailed Description

A single-arm, single-center, open label Phase 1 study of a 12-week course of SOF/VEL in 10 HCV-infected pregnant women. Treatment will be initiated during the second trimester, reducing the risk of SOF/VEL exposure during organogenesis and ensuring treatment completion by delivery, minimizing the risk of perinatal transmission. The study will be completed in 10 or 11 visits (7 maternal visits, delivery visit and 3 infant visits) which should align with prenatal and postpartum visits. Patients will be screened between 14+0 and 22+6 weeks of gestation confirmed by ultrasound by the time of their enrollment visit who are known to have chronic HCV infection. An HCV RNA level to confirm the patient is actively infected with HCV as well as an HCV genotype will be obtained. A full laboratory evaluation of liver function will be obtained to evaluate for renal failure and decompensated cirrhosis. A Hepatitis B Virus (HBV) panel will be performed to test all patients for evidence of current or prior HBV infection before initiation of HCV treatment. If the inclusion and exclusion criteria are met, the patient will be enrolled into the study between 23+0 and 25+6 weeks' gestation and initiated on a 12 week course of SOF/VEL. Systemic exposure of both VEL and SOF (SOF and inactive metabolite GS-331007) and intracellular SOF (GS-461203) will be assessed by pharmacokinetic sampling at 3, 6, and 9 weeks after first dose. HCV RNA viral load will be assessed at 12 weeks after completion of SOF/VEL treatment. Pregnancy and delivery outcomes will be collected prospectively. Neonatal outcomes will be assessed at birth, 8 weeks, 6 months and 12 months. HCV RNA viral load will be obtained at birth (as available), 1 to 3 months, at 6 months and then again at 12 months only if negative viral loads are not documented at 1 to 3 and 6 months. Neurodevelopmental assessments will be obtained at 6 months and 12 months.

• Study Type: Interventional
• Enrollment (Actual): 11
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Pennsylvania
    • Pittsburgh, Pennsylvania, United States, 15213
      • University of Pittsburgh, Magee Womens Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 39 years (Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Able and willing to provide written informed consent and take part in the study -procedures
• Able and willing to provide adequate locator information
• Chronic hepatitis C viral (HCV) infection, defined as a positive HCV test at least 6 months prior to screening
• Detectable HCV RNA viral load at Screening
• Desired pregnancy at 23 + 0 to 25 + 6 weeks' gestation at enrollment with gestational dating confirmed by ultrasound
• Singleton gestation with no known fetal abnormalities
• Documented negative Hepatitis B (HB) testing for current infection (negative HB serum antigen test) or previous infection (negative anti-HB Core) performed at the screening visit
• Negative HIV testing at the screening visit
• Per participant report at screening and enrollment, agrees not to participate in other research studies involving drugs or medical devices for the duration of study participation

Exclusion Criteria:

• Participant report of any of the following at screening or enrollment:

  1. Previous treatment for Hepatitis C virus with sofosbuvir or a non-structural protein 5A inhibitor
  2. Use of any medications contraindicated with concurrent use of velpatasvir or sofosbuvir according to the most current Epclusa package insert
  3. Plans to relocate away from the study site area in the next 1 year and 4 months and unable/unwilling to return for study visits
  4. Current sexual partner is known to be infected with HIV or Hepatitis B virus
  5. History of cirrhosis documented or reported by previous liver biopsy or liver imaging tests
• Reports participating in any other research study involving drugs or medical devices within 60 days or less prior to enrollment
• Clinically significant and habitual non-therapeutic drug abuse, not including marijuana, as determined by Protocol Chair
• At Screening or Enrollment, as determined by the Protocol Chair, any significant uncontrolled active or chronic cardiovascular, renal, liver (such as evidence of decompensated cirrhosis by ascites, encephalopathy, or variceal hemorrhage), hematologic, neurologic, gastrointestinal, psychiatric, endocrine, respiratory, immunologic disorder or infectious disease (other than Hepatitis C)
• Has a high risk of preterm birth defined as a history of spontaneous preterm birth at less than 34 weeks of gestation or a shortened cervical length of less than 20 millimeters

• Has any of the following laboratory abnormalities at screening:

  1. Aspartate aminotransferase or alanine transaminase greater than 10 times the upper limited of normal
  2. Hemoglobin less than 9g/dL
  3. Platelet count less than 90,000 per mm3
  4. International normalized ratio > 1.5
  5. Creatinine greater than 1.4
• Has any other condition that, in the opinion of the investigator or designee, would preclude informed consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving study objectives

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Sofosbuvir-Velpatasvir	Drug: Sofosbuvir-Velpatasvir Drug Combination; One pill once a day for 12 weeks; Other Names: Epclusa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum Concentration of Velpatasvir in Plasma	Maximum concentration of Velpatasvir measured in plasma samples	Approximately 3 months
Maximum Concentration of Sofosbuvir in Plasma	Maximum concentration of Sofosbuvir measured in plasma samples	Approximately 3 months
Maximum Concentration of GS-331007 in Plasma	Maximum concentration of GS-331007, an inactive metabolite of Sofosbuvir, measured in plasma samples	Approximately 3 months
Area Under the Plasma Concentration Versus Time Curve of Velpatasvir	Area under the plasma concentration versus time curve of Velpatasvir	Approximately 3 months
Area Under the Plasma Concentration Versus Time Curve of Sofosbuvir	Area under the plasma concentration versus time curve of Sofosbuvir	Approximately 3 months
Area Under the Plasma Concentration Versus Time Curve of GS-331007	Area under the plasma concentration versus time curve of GS-331007, an inactive metabolite of Sofosbuvir	Approximately 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Intracellular Concentration of GS-461203 from Peripheral Blood Mononuclear Cells	Intracellular concentration of GS-461203, the active form of Sofosbuvir, from peripheral blood mononuclear cells	Approximately 3 months
Intracellular Concentration of GS-461203 from Dried Blood Spots	Intracellular concentration of GS-461203, the active form of Sofosbuvir, from dried blood spots	Approximately 3 months
Percentage of Unbound Velpatasvir measured in Plasma	Percentage of unbound Velpatasvir out of total Velpatasvir, unbound and protein-bound, measured in plasma	Approximately 3 months
Percentage of Unbound Sofosbuvir measured in Plasma	Percentage of unbound Sofosbuvir out of total Sofosbuvir, unbound and protein-bound, measured in plasma	Approximately 3 months
Quantity of Hepatitis C Virus in Plasma After Completion of Velpatasvir and Sofosbuvir Treatment	Quantity of Hepatitis C RNA measured in plasma measured after completion of Velpatasvir and Sofosbuvir treatment regimen	Approximately 6 months
Number of Participants That Experience Adverse Events Related to Sofosbuvir/Velpatasvir	Number of maternal and infant participants that experience an adverse event that is deemed related to Sofosbuvir/Velpatasvir by a study physician	Approximately 6 months
Gestational Age at Delivery	Gestational age at delivery determined by medical record review	Approximately 6 months
Infant Weight at Delivery	Infant birth weight determined by medical record review	Approximately 6 months
Frequency of Delivery Modes	Frequency of delivery modes (spontaneous vaginal, assisted vaginal, cesarean section) determined by medical record review	Approximately 6 months
Number of Infant Participants with Congenital Anomalies	Number of infant participants with congenital anomalies determined by medical record review	Approximately 6 months
-Weight of Infant Participant	Weight of infant participant measured at 1-3 months, 6 months, and 12 months	Approximately 12 months
Length of Infant Participant	Length of infant participant measured at 1-3 months, 6 months, and 12 months	Approximately 12 months
Head Circumference of Infant Participant	Head circumference of infant participant measured at 1-3 months, 6 months, and 12 months	Approximately 12 months
Quantity of Hepatitis C Virus in Infant Plasma	-Quantity of Hepatitis C viral RNA measured in infant plasma will be assessed at birth, 1-3 months, 6 months, and 12 months	Approximately 12 months
Number of Infant Participants Referred for Early Neurological Development Intervention	Number of infant participants referred for early intervention based on neurological development assessments (Bayley's scores)	Approximately 12 months
Number of Infant Participants with Any Neurological Development Score Less than 6	Number of infant participants with a Bayley's score of less than 6 on either cognitive, motor or language development assessments; Bayley's score ranges from 1 (extremely low) to 19 (very superior)	Approximately 12 months

Collaborators and Investigators

• Sponsor: Catherine Anne Chappell
• Collaborators: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD); Gilead Sciences
• Investigators: Principal Investigator: Catherine Chappell, MD, MSc, University of Pittsburgh

Publications and helpful links

General Publications

• Gilbert EM, Darin KM, Scarsi KK, McLaughlin MM. Antiretroviral Pharmacokinetics in Pregnant Women. Pharmacotherapy. 2015 Sep;35(9):838-55. doi: 10.1002/phar.1626. Epub 2015 Aug 21.
• Chappell CA, Krans EE, Bunge KE, Macio IS, Bogen D, Scarsi KK, Meyn LA, Hillier SL. A Phase 1 Study of Ledipasvir/Sofosbuvir in Pregnant Women with Hepatitis C Virus. In: Conferences on Retroviruses and Opportunistic Infections; 2010 Mar 4-7; Seattle, WA; Abstract 87
• Ward RM, Varner MW. Principles of Pharmacokinetics in the Pregnant Woman and Fetus. Clin Perinatol. 2019 Jun;46(2):383-398. doi: 10.1016/j.clp.2019.02.014. Epub 2019 Mar 30.
• MacBrayne CE, Kiser JJ. Pharmacologic Considerations in the Treatment of Hepatitis C Virus in Persons With HIV. Clin Infect Dis. 2016 Jul 15;63 Suppl 1(Suppl 1):S12-23. doi: 10.1093/cid/ciw220. Erratum In: Clin Infect Dis. 2016 Sep 1;63(5):715.
• Kirby BJ, Symonds WT, Kearney BP, Mathias AA. Pharmacokinetic, Pharmacodynamic, and Drug-Interaction Profile of the Hepatitis C Virus NS5B Polymerase Inhibitor Sofosbuvir. Clin Pharmacokinet. 2015 Jul;54(7):677-90. doi: 10.1007/s40262-015-0261-7.
• Feld JJ, Jacobson IM, Hezode C, Asselah T, Ruane PJ, Gruener N, Abergel A, Mangia A, Lai CL, Chan HL, Mazzotta F, Moreno C, Yoshida E, Shafran SD, Towner WJ, Tran TT, McNally J, Osinusi A, Svarovskaia E, Zhu Y, Brainard DM, McHutchison JG, Agarwal K, Zeuzem S; ASTRAL-1 Investigators. Sofosbuvir and Velpatasvir for HCV Genotype 1, 2, 4, 5, and 6 Infection. N Engl J Med. 2015 Dec 31;373(27):2599-607. doi: 10.1056/NEJMoa1512610. Epub 2015 Nov 16.
• Foster GR, Afdhal N, Roberts SK, Brau N, Gane EJ, Pianko S, Lawitz E, Thompson A, Shiffman ML, Cooper C, Towner WJ, Conway B, Ruane P, Bourliere M, Asselah T, Berg T, Zeuzem S, Rosenberg W, Agarwal K, Stedman CA, Mo H, Dvory-Sobol H, Han L, Wang J, McNally J, Osinusi A, Brainard DM, McHutchison JG, Mazzotta F, Tran TT, Gordon SC, Patel K, Reau N, Mangia A, Sulkowski M; ASTRAL-2 Investigators; ASTRAL-3 Investigators. Sofosbuvir and Velpatasvir for HCV Genotype 2 and 3 Infection. N Engl J Med. 2015 Dec 31;373(27):2608-17. doi: 10.1056/NEJMoa1512612. Epub 2015 Nov 17.
• Society for Maternal-Fetal Medicine (SMFM). Electronic address: pubs@smfm.org; Hughes BL, Page CM, Kuller JA. Hepatitis C in pregnancy: screening, treatment, and management. Am J Obstet Gynecol. 2017 Nov;217(5):B2-B12. doi: 10.1016/j.ajog.2017.07.039. Epub 2017 Aug 4.

Helpful Links

• Food and Drug Administration. Epclusa Package Insert.

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2020
• Primary Completion (Actual): October 16, 2023
• Study Completion (Actual): October 16, 2023

Study Registration Dates

• First Submitted: February 16, 2020
• First Submitted That Met QC Criteria: May 6, 2020
• First Posted (Actual): May 11, 2020

Study Record Updates

• Last Update Posted (Actual): December 26, 2023
• Last Update Submitted That Met QC Criteria: December 18, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Keywords: pregnancy
• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; RNA Virus Infections; Virus Diseases; Infections; Blood-Borne Infections; Communicable Diseases; Disease Attributes; Liver Diseases; Flaviviridae Infections; Hepatitis, Viral, Human; Enterovirus Infections; Picornaviridae Infections; Hepatitis, Chronic; Chronic Disease; Hepatitis; Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Anti-Infective Agents; Antiviral Agents; Sofosbuvir; Sofosbuvir-velpatasvir drug combination; Velpatasvir
• Other Study ID Numbers: STUDY19100377; R21HD101996 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Data requests can be submitted by email to the Principal Investigator
• IPD Sharing Time Frame: Immediately after the primary manuscript for the study is published. Information will be available for an indefinite period of time.
• IPD Sharing Access Criteria: Data requests submitted by email will be reviewed by the Principal Investigator on a case by case basis.
• IPD Sharing Supporting Information Type: STUDY_PROTOCOL; SAP; ICF; CSR

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No