Clinical trial NCT04382404: Treatment of Chronic Hepatitis C During Pregnancy With Sofosbuvir/Velpatasvir
Official title: Phase 1 Pharmacokinetic Trial of Sofosbuvir/Velpatasvir in Pregnant Women With Chronic Hepatitis C Virus Infection
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Hepatitis C, Chronic
Keywords: pregnancy
Lead sponsor: University of Pittsburgh
Sponsor class: OTHER
Collaborators: name: Gilead Sciences
name: Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
First posted: 2020-05-11
Enrollment: 11
Sex: FEMALE
Minimum age (years): 18
Maximum age (years): 39
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: Open-label, single arm
Primary purpose: TREATMENT

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.

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:

  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

Primary outcomes:
measure: Maximum Concentration of Velpatasvir in Maternal Plasma
timeFrame: Up to 9 weeks from initiation of treatment
measure: Maximum Concentration of Sofosbuvir in Maternal Plasma
timeFrame: Up to 9-weeks from initiation of treatment
measure: Maximum Concentration of GS-331007 in Maternal Plasma
timeFrame: Up to 9 weeks from initiation of treatment
measure: Area Under the Maternal Plasma Concentration Versus Time Curve of Velpatasvir
timeFrame: Up to 9 weeks from initiation of treatment
measure: Area Under the Maternal Plasma Concentration Versus Time Curve of Sofosbuvir
timeFrame: Up to 9 weeks from initiation of treatment
measure: Area Under the Maternal Plasma Concentration Versus Time Curve of GS-331007
timeFrame: Up to 9 weeks from initiation of treatment
Secondary outcomes:
measure: Intracellular Concentration of GS-461203 From Maternal Peripheral Blood Mononuclear Cells at 3 Weeks
timeFrame: Approximately 3 weeks from initiation of treatment
measure: Intracellular Concentration of GS-461203 From Maternal Peripheral Blood Mononuclear Cells at 6 Weeks
timeFrame: Approximately 6 weeks from initiation of treatment
measure: Intracellular Concentration of GS-461203 From Maternal Peripheral Blood Mononuclear Cells at 9 Weeks
timeFrame: Approximately 9 weeks from initiation of treatment
measure: Intracellular Concentration of GS-461203 From Dried Maternal Blood Spots at 3 Weeks
timeFrame: Approximately 3 weeks from initiation of treatment
measure: Intracellular Concentration of GS-461203 From Dried Maternal Blood Spots at 6 Weeks
timeFrame: Approximately 6 weeks from initiation of treatment
measure: Intracellular Concentration of GS-461203 From Dried Maternal Blood Spots at 9 Weeks
timeFrame: Approximately 9 weeks from initiation of treatment
measure: Quantity of Hepatitis C Virus in Maternal Plasma After Completion of Velpatasvir and Sofosbuvir Treatment
timeFrame: Approximately 24 weeks from initiation of treatment
measure: Number of Maternal and Infant Participants That Experience Adverse Events Related to Sofosbuvir/Velpatasvir
timeFrame: Up to 16 weeks from initiation of treatment or 12 months from delivery
measure: Maternal Gestational Age at Delivery
timeFrame: Up to 16 weeks from treatment initiation (at delivery)
measure: Infant Weight at Delivery
timeFrame: Up to 16 weeks from treatment initiation (at delivery)
measure: Frequency of Delivery Modes for Maternal Participants
timeFrame: Up to 16 weeks from treatment initiation (at delivery)
measure: Number of Infant Participants With Congenital Anomalies
timeFrame: Up to 12 months from delivery
measure: Weight of Infant Participant at 1 to 3 Months
timeFrame: Approximately 3 months from delivery
measure: Weight of Infant Participant at 6 Months
timeFrame: Approximately 6 months from delivery
measure: Weight of Infant Participant at 12 Months
timeFrame: Approximately 12 months from delivery
measure: Length of Infant Participant at 1 to 3 Months
timeFrame: Approximately 3 months from delivery
measure: Length of Infant Participant at 6 Months
timeFrame: Approximately 6 months from delivery
measure: Length of Infant Participant at 12 Months
timeFrame: Approximately 12 months from delivery
measure: Head Circumference of Infant Participant at 1 to 3 Months
timeFrame: Approximately 3 months from delivery
measure: Head Circumference of Infant Participant at 6 Months
timeFrame: Approximately 6 months from delivery
measure: Head Circumference of Infant Participant at 12 Months
timeFrame: Approximately 12 months from delivery
measure: Quantity of Hepatitis C Virus in Infant Plasma at Birth
timeFrame: Up to 16 weeks from treatment initiation (at delivery)
measure: Quantity of Hepatitis C Virus in Infant Plasma at 1 to 3 Months
timeFrame: Approximately 3 months from delivery
measure: Quantity of Hepatitis C Virus in Infant Plasma at 6 Months
timeFrame: Approximately 6 months from delivery
measure: Quantity of Hepatitis C Virus in Infant Plasma at 12 Months
timeFrame: Approximately 12 months from delivery
measure: Number of Infant Participants Referred for Early Neurological Development Intervention
timeFrame: Approximately 12 months from delivery
measure: Percentage of Unbound Sofosbuvir Measured in Maternal Plasma
timeFrame: Approximately 9 weeks from initiation of maternal treatment
measure: Percentage of Unbound Velpatasvir Measured in Maternal Plasma
timeFrame: Approximately 9 weeks from initiation of maternal treatment
Other outcomes:
Locations:
city: Pittsburgh
country: United States
facility: University of Pittsburgh, Magee Womens Hospital
state: Pennsylvania
Study officials:
affiliation: University of Pittsburgh
name: Catherine Chappell, MD, MSc
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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
citation: 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.
citation: 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.
citation: 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.
citation: 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.
citation: 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.