Treatment of Chronic Hepatitis C During Pregnancy With Sofosbuvir/Velpatasvir

Phase 1

Completed

Conditions: Hepatitis C, Chronic

Interventions: Drug: Sofosbuvir-Velpatasvir Drug Combination

Registration Number: NCT04382404

Lead Sponsor: Catherine Anne Chappell

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.

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.

Recruitment & Eligibility

Status: COMPLETED

Sex: Female

Target Recruitment: 11

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 & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Sofosbuvir-Velpatasvir	Sofosbuvir-Velpatasvir Drug Combination	Sofosbuvir-Velpatasvir

Primary Outcome Measures

Name	Time	Method
Maximum Concentration of Velpatasvir in Maternal Plasma	Up to 9 weeks from initiation of treatment	Maximum concentration of Velpatasvir measured in maternal plasma samples. Plasma samples were obtained pre-dose and at 0.5-, 1-, 2-, 3-, 4-, 5-, 8-, and 12- and 24 hours post-dose at the 3- and 9-week visits after treatment initiation. At the 6-week visit, a single convenience blood sample was collected.
Maximum Concentration of Sofosbuvir in Maternal Plasma	Up to 9-weeks from initiation of treatment	Maximum concentration of Sofosbuvir measured in maternal plasma samples. Plasma samples were obtained pre-dose and at 0.5-, 1-, 2-, 3-, 4-, 5-, 8-, and 12- and 24 hours post-dose at the 3- and 9-week visits after treatment initiation. At the 6-week visit, a single convenience blood sample was collected.
Maximum Concentration of GS-331007 in Maternal Plasma	Up to 9 weeks from initiation of treatment	Maximum concentration of GS-331007, an inactive metabolite of Sofosbuvir, measured in maternal plasma samples. Plasma samples were obtained pre-dose and at 0.5-, 1-, 2-, 3-, 4-, 5-, 8-, and 12- and 24 hours post-dose at the 3- and 9-week visits after treatment initiation. At the 6-week visit, a single convenience blood sample was collected.
Area Under the Maternal Plasma Concentration Versus Time Curve of Velpatasvir	Up to 9 weeks from initiation of treatment	Area under the maternal plasma concentration of Velpatasvir versus time curve tau of the dosing interval. Plasma samples were obtained pre-dose and at 0.5-, 1-, 2-, 3-, 4-, 5-, 8-, and 12- and 24 hours post-dose at the 3- and 9-week visits after treatment initiation.
Area Under the Maternal Plasma Concentration Versus Time Curve of Sofosbuvir	Up to 9 weeks from initiation of treatment	Area under the maternal plasma concentration of Sofosbuvir versus time curve tau of the dosing interval. Plasma samples were obtained pre-dose and at 0.5-, 1-, 2-, 3-, 4-, 5-, 8-, and 12- and 24 hours post-dose at the 3- and 9-week visits after treatment initiation.
Area Under the Maternal Plasma Concentration Versus Time Curve of GS-331007	Up to 9 weeks from initiation of treatment	Area under the maternal plasma concentration of GS-331007 versus time curve tau of the dosing interval; GS-331007 is an inactive metabolite of Sofosbuvir. Plasma samples were obtained pre-dose and at 0.5-, 1-, 2-, 3-, 4-, 5-, 8-, and 12- and 24 hours post-dose at the 3- and 9-week visits after treatment initiation.

Secondary Outcome Measures

Name	Time	Method
Percentage of Unbound Sofosbuvir Measured in Maternal Plasma	Approximately 9 weeks from initiation of maternal treatment	Percentage of Sofosbuvir not bound to protein out of total protein- unbound and bound Sofosbuvir measured in maternal plasma samples. Plasma samples were obtained pre-dose and at 0.5-, 1-, 2-, 3-, 4-, 5-, 8-, and 12- and 24 hours post-dose at the 3- and 9-week visits after treatment initiation. At the 6-week visit, a single convenience blood sample was collected.
Percentage of Unbound Velpatasvir Measured in Maternal Plasma	Approximately 9 weeks from initiation of maternal treatment	Percentage of Velpatasvir not bound to protein out of total protein- unbound and bound Velpatasvir measured in maternal plasma samples. Plasma samples were obtained pre-dose and at 0.5-, 1-, 2-, 3-, 4-, 5-, 8-, and 12- and 24 hours post-dose at the 3- and 9-week visits after treatment initiation. At the 6-week visit, a single convenience blood sample was collected.
Intracellular Concentration of GS-461203 From Maternal Peripheral Blood Mononuclear Cells at 3 Weeks	Approximately 3 weeks from initiation of treatment	Intracellular concentration of GS-461203, the active form of Sofosbuvir, from maternal peripheral blood mononuclear cells measured 3 weeks after initiation of treatment
Intracellular Concentration of GS-461203 From Maternal Peripheral Blood Mononuclear Cells at 6 Weeks	Approximately 6 weeks from initiation of treatment	Intracellular concentration of GS-461203, the active form of Sofosbuvir, from maternal peripheral blood mononuclear cells measured 6 weeks after initiation of treatment
Intracellular Concentration of GS-461203 From Maternal Peripheral Blood Mononuclear Cells at 9 Weeks	Approximately 9 weeks from initiation of treatment	Intracellular concentration of GS-461203, the active form of Sofosbuvir, from maternal peripheral blood mononuclear cells measured 9 weeks after initiation of treatment
Intracellular Concentration of GS-461203 From Dried Maternal Blood Spots at 3 Weeks	Approximately 3 weeks from initiation of treatment	Intracellular concentration of GS-461203, the active form of Sofosbuvir, from dried maternal blood spots measured 3 weeks after initiation of treatment
Intracellular Concentration of GS-461203 From Dried Maternal Blood Spots at 6 Weeks	Approximately 6 weeks from initiation of treatment	Intracellular concentration of GS-461203, the active form of Sofosbuvir, from dried maternal blood spots measured 6 weeks after initiation of treatment
Intracellular Concentration of GS-461203 From Dried Maternal Blood Spots at 9 Weeks	Approximately 9 weeks from initiation of treatment	Intracellular concentration of GS-461203, the active form of Sofosbuvir, from dried maternal blood spots measured 9 weeks after initiation of treatment
Quantity of Hepatitis C Virus in Maternal Plasma After Completion of Velpatasvir and Sofosbuvir Treatment	Approximately 24 weeks from initiation of treatment	Quantity of Hepatitis C RNA in maternal plasma measured at least 12 weeks after completion of Velpatasvir and Sofosbuvir treatment regimen
Number of Maternal and Infant Participants That Experience Adverse Events Related to Sofosbuvir/Velpatasvir	Up to 16 weeks from initiation of treatment or 12 months from delivery	Number of maternal and infant participants that experience an adverse event that is deemed related to Sofosbuvir/Velpatasvir by a study physician
Maternal Gestational Age at Delivery	Up to 16 weeks from treatment initiation (at delivery)	Maternal gestational age at delivery determined by medical record review
Infant Weight at Delivery	Up to 16 weeks from treatment initiation (at delivery)	Infant birth weight determined by medical record review
Frequency of Delivery Modes for Maternal Participants	Up to 16 weeks from treatment initiation (at delivery)	Frequency of delivery modes (spontaneous and assisted vaginal, scheduled and emergent cesarean section) for maternal participants determined by medical record review
Number of Infant Participants With Congenital Anomalies	Up to 12 months from delivery	Number of infant participants with congenital anomalies determined by medical record review for up to 12 months of age.
Weight of Infant Participant at 1 to 3 Months	Approximately 3 months from delivery	Weight of infant participant measured at 1 to 3 months of age
Weight of Infant Participant at 6 Months	Approximately 6 months from delivery	Weight of infant participant measured at 6 months of age
Weight of Infant Participant at 12 Months	Approximately 12 months from delivery	Weight of infant participant measured at 12 months of age
Length of Infant Participant at 1 to 3 Months	Approximately 3 months from delivery	Length of infant participant measured at 1 to 3 months of age
Length of Infant Participant at 6 Months	Approximately 6 months from delivery	Length of infant participant measured at 6 months of age
Length of Infant Participant at 12 Months	Approximately 12 months from delivery	Length of infant participant measured at 12 months of age
Head Circumference of Infant Participant at 1 to 3 Months	Approximately 3 months from delivery	Head circumference of infant participant measured at 1 to 3 months of age
Head Circumference of Infant Participant at 6 Months	Approximately 6 months from delivery	Head circumference of infant participant measured at 6 months of age
Head Circumference of Infant Participant at 12 Months	Approximately 12 months from delivery	Head circumference of infant participant measured at 12 months of age
Quantity of Hepatitis C Virus in Infant Plasma at Birth	Up to 16 weeks from treatment initiation (at delivery)	Quantity of Hepatitis C viral RNA measured in infant plasma assessed at birth
Quantity of Hepatitis C Virus in Infant Plasma at 1 to 3 Months	Approximately 3 months from delivery	Quantity of Hepatitis C viral RNA measured in infant plasma assessed at 1 to 3 months of age
Quantity of Hepatitis C Virus in Infant Plasma at 6 Months	Approximately 6 months from delivery	Quantity of Hepatitis C viral RNA measured in infant plasma assessed at 6 months of age
Quantity of Hepatitis C Virus in Infant Plasma at 12 Months	Approximately 12 months from delivery	Quantity of Hepatitis C viral RNA measured in infant plasma assessed at 12 months of age
Number of Infant Participants Referred for Early Neurological Development Intervention	Approximately 12 months from delivery	Number of infant participants referred for early intervention based on neurological development assessments using Bayley Scales of Infant and Toddler Development. Infant participants with a Bayley's score of less than 6 on either cognitive, motor or language development assessments indicates an infant at risk for delayed development; Bayley's score ranges from 1 (extremely low) to 19 (very superior)