Treatment of Chronic Hepatitis C During Pregnancy With Sofosbuvir/Velpatasvir

Study Overview
=================
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.

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

Conditions
-----------------
Hepatitis C, Chronic

Intervention / Treatment
-----------------
* Drug: Sofosbuvir-Velpatasvir Drug Combination


Participation Criteria
=================
Eligibility 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: Previous treatment for Hepatitis C virus with sofosbuvir or a non-structural protein 5A inhibitor Use of any medications contraindicated with concurrent use of velpatasvir or sofosbuvir according to the most current Epclusa package insert 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 Current sexual partner is known to be infected with HIV or Hepatitis B virus 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: Aspartate aminotransferase or alanine transaminase greater than 10 times the upper limited of normal Hemoglobin less than 9g/dL Platelet count less than 90,000 per mm3 International normalized ratio > 1.5 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 39 Years

Sexes Eligible for Study
-----------------
Female

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: Open-label, single arm
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sofosbuvir-Velpatasvir<br>Sofosbuvir-Velpatasvir | Drug: Sofosbuvir-Velpatasvir Drug Combination<br>* One pill once a day for 12 weeks<br>* 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 | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
pregnancy