Sofosbuvir/Velpatasvir Treatment of Chronic Hepatitis C During Pregnancy

Study Overview
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Brief Summary
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This is a multicenter, single arm study of Sofosbuvir/Velpatasvir (SOF/VEL) for treatment of chronic hepatitis C infection during pregnancy. Treatment will be initiated during the second or third trimester in approximately 100 pregnant people. Maternal participants will take one SOF/VEL tablet once daily for 12 weeks (84 days) and followed until 12 weeks after treatment completion (postpartum). Infants will be followed from birth until one year of age. The primary objectives are to evaluate the sustained virologic response 12 weeks after completion of SOF/VEL treatment (SVR12) in participants treated during pregnancy and to evaluate impact of antenatal treatment with SOF/VEL on the gestational age at delivery.

Detailed Description
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This is a phase 4, multicenter study, single arm study of Sofosbuvir/Velpatasvir (SOF/VEL) for treatment of chronic hepatitis C infection during pregnancy. Participants will be screened between 12+0 and 29+6 weeks of gestation confirmed by ultrasound. HCV RNA level to confirm the patient has active infection will be obtained. Laboratory evaluation of liver function will be obtained, to evaluate for renal insufficiency, decompensated cirrhosis and baseline elevations of lipase and creatine kinase. Hepatitis B virus (HBV) antigen will be performed to look for evidence of active HBV infection. Medical history and demographic information will also be collected at screening. If the inclusion and exclusion criteria are met, the patient will be enrolled into the study between 20+0 and 30+0 weeks' gestation and initiate a 12-week course of a fixed-dose combination tablet of sofosbuvir 400 mg and velpatasvir 100 mg. Maternal participants will take one SOF/VEL tablet once daily for 12 weeks (84 days). The study will be completed in 8 or 9 visits (6 maternal visits and 3 infant visits). The primary endpoints are 1) maternal HCV RNA PCR 12 weeks after completion of SOF/VEL treatment (HCV RNA PCR below the lower limit of quantification will be considered evidence of SVR12) and 2) preterm delivery (spontaneous and iatrogenic) prior to 37 weeks' gestation. The secondary endpoints are 1) Maternal safety defined as maternal adverse events and pregnancy and delivery outcomes (stillbirth or intrauterine fetal demise, intrapartum hemorrhage, postpartum hemorrhage, hypertensive disorders of pregnancy, gestational diabetes, intrauterine growth restriction, cholestasis of pregnancy, severe maternal morbidity (defined by CDC), maternal admission to the intensive care unit, maternal death), 2) composite neonatal/Infant safety endpoints defined as severe neonatal morbidity with admission to neonatal intensive care unit and stratified by perinatal preterm (<37 weeks) (including fetal or neonatal death, severe bronchopulmonary dysplasia (grade 3) intraventricular hemorrhage grades III-IV, necrotizing enterocolitis (proven - Bell Stage 2A or greater), periventricular leukomalacia, retinopathy of prematurity stage III-V, or proven sepsis (early or late)) and perinatal term (>= 37 weeks) (including fetal or neonatal death, respiratory support , Apgar score ≤ 3 at 5 minutes, hypoxic ischemic encephalopathy, seizure, infection (sepsis or pneumonia), birth trauma, meconium aspiration syndrome, intracranial or subgaleal hemorrhage, or hypotension requiring vasopressor support). Other secondary endpoints are admission to the neonatal intensive care unit, neonatal death, major malformations, defined as structural abnormalities with medical, surgical or cosmetic importance, weight, length, and head circumference at birth (by exam or chart review), 8 weeks, six months and 12 months, neurodevelopmental assessments at 6 months and 12 months by Ages & Stages Questionnaires®, and infant HCV RNA PCR viral load at 8 weeks, 6 months and 12 months.

Official Title
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Safety, Tolerability, and Outcomes of Velpatasvir/SofosbuviR in Treatment of Chronic Hepatitis C Virus During Pregnancy (STORC)

Conditions
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Hepatitis C, Chronic, Pregnancy; Infection

Intervention / Treatment
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* Drug: Sofosbuvir/Velpatasvir 400 MG-100 MG Oral Tablet


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 through 45 years (inclusive) at screening Able and willing to provide written informed consent and take part in the study procedures Able and willing to provide adequate locator information, defined as at least two other alternate contacts HCV antibody seropositivity with detectable HCV RNA viral load at screening Chronic HCV infection of at least 6 months by laboratory report or participant reported medical history as determined by the site PI, or if duration of HCV cannot be determined then the participant can be enrolled if there is no clinical evidence of acute hepatitis C infection (defined by CDC as presence of jaundice or total bilirubin >/= 3.0 mg/dL or ALT >200IU/L) Singleton pregnancy at 20 + 0 to 30 + 0 weeks' gestation at enrollment with gestational dating confirmed by ultrasound Having a comprehensive anatomy scan with no evidence of major structural abnormalities as defined by the CDC birth surveillance toolkit (https://www.cdc.gov/ncbddd/birthdefects/surveillancemanual/chapters/chapter-4/chapter4-1.html) or an anomaly that would significantly impact delivery timing or neonatal outcomes as determined by the Protocol Safety Review Team (PSRT) prior to enrollment Documented negative Hepatitis B testing for current infection (negative HBsAg test) prior to enrollment If living with HIV, must be on antiretroviral therapy with HIV viral load <50 copies/mL on the most recent HIV viral load test within 30 days before enrollment and agree to continue antiretroviral therapy throughout study participation If taking acid-suppressant medication(s), willing and able to either discontinue administration during the 12-week period of study treatment or to follow specific dosing instructions for concomitant use with SOF/VEL Per participant report at screening and enrollment, agrees not to participate in other research studies involving investigational medications or investigational medical devices for the duration of study participation (does not include duration of infant participation). Note: maternal participants can participate in research studies that include standard of care medications. Exclusion Criteria: Participant report of any of the following at screening or enrollment: Previous DAA treatment for HCV (prior interferon-based treatment is acceptable) without documentation of SVR12 (HCV RNA below the lower limit of quantification at least 24 weeks after DAA initiation) Use of any medications contraindicated with concurrent use of velpatasvir or sofosbuvir according to the most current EPCLUSA® package insert30 Plans to relocate away from the study site area in the next 16 months and unable/unwilling to return for study visits History of cirrhosis documented or reported by previous liver biopsy, imaging tests or on at least 2 noninvasive laboratory tests of fibrosis, including compensated cirrhosis Reports participating in any other research study involving investigational medications or investigational medical devices within 60 days or less prior to enrollment (does not include research studies involving standard of care medications) Known fetal chromosomal abnormality prior to enrollment (confirmed by chorionic villus sampling or amniocentesis) Clinically significant and habitual non-therapeutic drug use, not including marijuana, as determined by site PI at screening and enrollment At screening and enrollment, as determined by site PI, any significant, uncontrolled, active or chronic cardiovascular, renal, liver, hematologic, neurologic, gastrointestinal, psychiatric, endocrine, respiratory, immunologic disorder or infectious disease other than HCV (or HIV as outlined in eligibility criteria) Any of the following laboratory abnormalities at screening: Aspartate aminotransferase (AST) or alanine transaminase (ALT) greater than 10 times the upper limit of normal Hemoglobin less than 9 g/dL Platelet count less than 90,000 per mm3 International normalized ratio (INR) > 1.5 Creatinine greater than 1.4 If living with HIV, CD4 count less than 200 cells/mm3 within 6 months of enrollment. Any other condition that, in the opinion of the site PI/designee, would preclude appropriate informed consent, make study participation unsafe, complicate interpretation of study outcome data, or otherwise interfere with achieving study objectives.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Female

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sofosbuvir/Velpatasvir<br>Sofosbuvir/Velpatasvir 400 MG-100 MG Oral Tablet, one tablet taken once daily for 84 days | Drug: Sofosbuvir/Velpatasvir 400 MG-100 MG Oral Tablet<br>* One Sofosbuvir/Velpatasvir 400 MG-100 MG Oral Tablet taken once daily for 84 days.<br>* Other names: Epclusa;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of maternal participants with sustained virologic response after completion of SOF/VEL treatment (SVR12) | Number of maternal participants with plasma level of HCV RNA PCR that is below the lower limit of quantification after completion of SOF/VEL treatment | Approximately 12 weeks | 
| Number of maternal participants that deliver prior to 37 weeks' gestation | Number of maternal participants that deliver (spontaneous and iatrogenic) prior to 37 weeks' gestation | Approximately 28 weeks | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of maternal participants that experience an adverse event that is deemed related to Sofosbuvir/Velpatasvir | Number of maternal participants that experience an adverse event that is deemed related to Sofosbuvir/Velpatasvir by a study physician | Approximately six months | 
| Number of infants that experience an adverse event that is deemed related to Sofosbuvir/Velpatasvir | Number of infant participants that experience an adverse event that is deemed related to Sofosbuvir/Velpatasvir by a study physician | Approximately six months | 
| Number of maternal participants whose pregnancy results in a stillbirth or intrauterine fetal demise | Number of maternal participants whose pregnancy results in a stillbirth or intrauterine fetal demise | Approximately 28 weeks | 
| Number of maternal participants that experience intrapartum hemorrhage | Number of maternal participants that experience intrapartum hemorrhage | Approximately 28 weeks | 
| Number of maternal participants that experience postpartum hemorrhage | Number of maternal participants that experience postpartum hemorrhage | Approximately 28 weeks | 
| Number of maternal participants that experience a hypertensive disorder of pregnancy | Number of maternal participants that experience a hypertensive disorder of pregnancy (gestational hypertension, pre-eclampsia with and without severe features, eclampsia) | Approximately 28 weeks | 
| Number of maternal participants that develop gestational diabetes | Number of maternal participants that develop gestational diabetes | Approximately 28 weeks | 
| Number of maternal participants that experience cholestasis of pregnancy | Number of maternal participants that experience cholestasis of pregnancy | Approximately 28 weeks | 
| Number of maternal participants that experience intrauterine growth restriction | Number of maternal participants that experience intrauterine growth restriction | Approximately 28 weeks | 
| Number of maternal participants that develop severe maternal morbidity | Number of maternal participants that develop severe maternal morbidity, as defined by the Centers for Disease Control | Approximately 28 weeks | 
| Number of maternal participants that are admitted to the intensive care unit | Number of maternal participants that are admitted to the intensive care unit | Approximately 28 weeks | 
| Number of maternal deaths | Number of maternal deaths | Approximately 28 weeks | 
| Number of preterm neonates (<37 weeks) admitted to the neonatal intensive care unit for severe neonatal morbidity | Perinatal preterm (<37 weeks) composite outcome defined as fetal or neonatal death, or admission to the neonatal intensive care unit for severe bronchopulmonary dysplasia (grade 3), intraventricular hemorrhage grades III-IV, necrotizing enterocolitis (proven - Bell Stage 2A or greater), periventricular leukomalacia, retinopathy of prematurity stage III-V, or proven sepsis (early or late) | Approximately 4 weeks | 
| Number of term neonates (>=37 weeks) admitted to the neonatal intensive care unit for severe neonatal morbidity | Perinatal term (<37 weeks) composite outcome defined as fetal or neonatal death, or admission to the neonatal intensive care unit for respiratory support, Apgar score ≤ 3 at 5 minutes, hypoxic ischemic encephalopathy, seizure, infection (sepsis or pneumonia), birth trauma, meconium aspiration syndrome, intracranial or subgaleal hemorrhage, or hypotension requiring vasopressor support | Approximately 4 weeks | 
| Number of neonates admitted to the neonatal intensive care unit | Number of neonates admitted to the neonatal intensive care unit | Approximately 4 weeks | 
| Number of neonatal deaths | Number of neonatal deaths | Approximately 4 weeks | 
| Number of neonates with major malformations | Number of neonates with major malformations, defined as structural abnormalities with medical, surgical or cosmetic importance. | Approximately 4 weeks | 
| Weight of infant participant at 8 Weeks | Weight of infant participant measured at 8 weeks (by exam or chart review) | Approximately 8 weeks | 
| Weight of infant participant at 6 months | Weight of infant participant measured at 6 months (by exam or chart review) | Approximately 6 months | 
| Weight of infant participant at 12 months | Weight of infant participant measured at 12 months (by exam or chart review) | Approximately 12 months | 
| Length of infant participant at 8 weeks | Length of infant participant measured at 8 weeks (by exam or chart review) | Approximately 8 weeks | 
| Length of infant participant at 6 months | Length of infant participant measured at 6 months (by exam or chart review) | Approximately 6 months | 
| Length of infant participant at 12 months | Length of infant participant measured at 12 months (by exam or chart review) | Approximately 12 months | 
| Head circumference of infant participant at 8 weeks | Head circumference of infant participant measured at 8 weeks (by exam or chart review) | Approximately 8 weeks | 
| Head circumference of infant participant at 6 months | Head circumference of infant participant measured at 6 months (by exam or chart review) | Approximately 6 months | 
| Head circumference of infant participant at 12 months | Head circumference of infant participant measured at 12 months (by exam or chart review) | Approximately 12 months | 
| Number of Infant Participants with Any Neurological Development Score Less than 6 at 6 months | Number of infant participants with a Bayley's score of less than 6 on either cognitive, motor or language development assessments evaluated at 6 months; Bayley's score ranges from 1 (extremely low) to 19 (very superior) | Approximately 6 months | 
| Number of Infant Participants with Any Neurological Development Score Less than 6 at 12 months | Number of infant participants with a Bayley's score of less than 6 on either cognitive, motor or language development assessments evaluated at 12 months; Bayley's score ranges from 1 (extremely low) to 19 (very superior) | Approximately 12 months | 
| Number of infant participants with with plasma level of HCV RNA PCR viral load that is below the lower limit of quantification at 8 weeks | Number of infant participants with with plasma level of HCV RNA PCR viral load that is below the lower limit of quantification at 8 weeks | Approximately 8 weeks | 
| Number of infant participants with with plasma level of HCV RNA PCR viral load that is below the lower limit of quantification at 6 months | Number of infant participants with with plasma level of HCV RNA PCR viral load that is below the lower limit of quantification at 6 months | Approximately 6 months | 
| Number of infant participants with with plasma level of HCV RNA PCR viral load that is below the lower limit of quantification at 12 months | Number of infant participants with with plasma level of HCV RNA PCR viral load that is below the lower limit of quantification at 12 months | Approximately 12 months |