Treatment of Chronic Hepatitis C During Pregnancy With Sofosbuvir/Velpatasvir

• ClinicalTrials.gov Identifier: NCT04382404
• Recruitment Status: Active, not recruiting
• First Posted: May 11, 2020
• Last Update Posted: January 9, 2023
• Sponsor: Catherine Anne Chappell
• Collaborators: Gilead Sciences; Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
• Information provided by (Responsible Party): Catherine Anne Chappell, University of Pittsburgh

Study Description

Brief Summary:

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.

Condition or disease	Intervention/treatment	Phase
Hepatitis C, Chronic	Drug: Sofosbuvir-Velpatasvir Drug Combination	Phase 1

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 10 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Open-label, single arm
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Phase 1 Pharmacokinetic Trial of Sofosbuvir/Velpatasvir in Pregnant Women With Chronic Hepatitis C Virus Infection
• Actual Study Start Date: October 22, 2020
• Estimated Primary Completion Date: December 30, 2023
• Estimated Study Completion Date: December 30, 2023

Arms and Interventions

Arm	Intervention/treatment
Experimental: Sofosbuvir-Velpatasvir; Sofosbuvir-Velpatasvir	Drug: Sofosbuvir-Velpatasvir Drug Combination; One pill once a day for 12 weeks; Other Name: Epclusa

Outcome Measures

Primary Outcome Measures :

1. Maximum Concentration of Velpatasvir in Plasma [ Time Frame: Approximately 3 months ]
   Maximum concentration of Velpatasvir measured in plasma samples
2. Maximum Concentration of Sofosbuvir in Plasma [ Time Frame: Approximately 3 months ]
   Maximum concentration of Sofosbuvir measured in plasma samples
3. Maximum Concentration of GS-331007 in Plasma [ Time Frame: Approximately 3 months ]
   Maximum concentration of GS-331007, an inactive metabolite of Sofosbuvir, measured in plasma samples
4. Area Under the Plasma Concentration Versus Time Curve of Velpatasvir [ Time Frame: Approximately 3 months ]
   Area under the plasma concentration versus time curve of Velpatasvir
5. Area Under the Plasma Concentration Versus Time Curve of Sofosbuvir [ Time Frame: Approximately 3 months ]
   Area under the plasma concentration versus time curve of Sofosbuvir
6. Area Under the Plasma Concentration Versus Time Curve of GS-331007 [ Time Frame: Approximately 3 months ]
   Area under the plasma concentration versus time curve of GS-331007, an inactive metabolite of Sofosbuvir

Secondary Outcome Measures :

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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

United States, Pennsylvania

University of Pittsburgh, Magee Womens Hospital

Pittsburgh, Pennsylvania, United States, 15213

Sponsors and Collaborators

Catherine Anne Chappell

Gilead Sciences

Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)

Investigators

• Principal Investigator: Catherine Chappell, MD, MSc; University of Pittsburgh

More Information

Additional Information:

Food and Drug Administration. Epclusa Package Insert. 

Publications:

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.

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.

• Responsible Party: Catherine Anne Chappell, Assistant Professor, University of Pittsburgh
• ClinicalTrials.gov Identifier: NCT04382404
• Other Study ID Numbers: STUDY19100377; R21HD101996 ( U.S. NIH Grant/Contract )
• First Posted: May 11, 2020
• Last Update Posted: January 9, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• Plan Description: Data requests can be submitted by email to the Principal Investigator
• Supporting Materials: Study Protocol; Statistical Analysis Plan (SAP); Informed Consent Form (ICF); Clinical Study Report (CSR)
• Time Frame: Immediately after the primary manuscript for the study is published. Information will be available for an indefinite period of time.
• Access Criteria: Data requests submitted by email will be reviewed by the Principal Investigator on a case by case basis.

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Keywords provided by Catherine Anne Chappell, University of Pittsburgh:

pregnancy

Additional relevant MeSH terms:

Hepatitis A; Hepatitis C; Hepatitis C, Chronic; Hepatitis; Liver Diseases; Digestive System Diseases; Hepatitis, Viral, Human; Virus Diseases; Infections; Enterovirus Infections; Picornaviridae Infections; RNA Virus Infections; Blood-Borne Infections; Communicable Diseases; Flaviviridae Infections; Hepatitis, Chronic; Sofosbuvir; Sofosbuvir-velpatasvir drug combination; Velpatasvir; Antiviral Agents; Anti-Infective Agents