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deLIVER: Direct Acting Antiviral Effects on the Liver (deLIVER)

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ClinicalTrials.gov Identifier: NCT02938013
Recruitment Status : Active, not recruiting
First Posted : October 19, 2016
Last Update Posted : June 18, 2019
Sponsor:
Information provided by (Responsible Party):
Johns Hopkins University

Brief Summary:
Open-label, partially-randomized plasma and liver sampling study to assess hepatitis C virus (HCV) kinetics during treatment with two (Sofosbuvir/Velpatasvir) or three (Sofosbuvir/Velpatasvir/Voxilaprevir) direct acting antivirals (DAAs)

Condition or disease Intervention/treatment Phase
HCV Coinfection Liver Disease HIV Drug: Sofosbuvir/Velpatasvir/Voxilaprevir [SOF/VEL/VOX] Drug: Sofosbuvir/Velpatasvir (SOF/VEL) Phase 4

Detailed Description:

Primary Objective: The primary objective is to estimate the 1-week change in the proportion of HCV-infected hepatocytes in participants with HCV monoinfection and HIV/HCV coinfection on therapy with two or three DAAs with different mechanisms of action using single cell laser microdissection (scLCM).

Secondary Objectives:

Estimate the change over the first week in plasma HCV RNA in subjects with HCV monoinfected and HIV/HCV coinfected participants on therapy with two or three DAAs

Estimate the 1 week change in the amount of HCV RNA per infected hepatocyte using scLCM on liver biopsy specimens, obtained just prior to treatment initiation (pre-treatment), and after the first week of DAA therapy.

Estimate the change in the proportion of HCV-infected hepatocytes that express interferon-stimulated genes (ISGs) within the first week of DAA therapy using scLCM.

Measure the change in expression of ISGs in non-parenchymal intrahepatic immune cells (Kupffer cells, plasmacytoid dendritic cells) within the first week of DAA therapy using scLCM.

Exploratory Objectives:

Estimate the 1 week change in expression of ISGs from peripheral blood mononucleated cells (PBMCs) within the first week of DAA+ribavirin (RBV) therapy using scLCM.

Compare sequence(s) of HCV protease, nonstructural protein 5A (NS5A), and nonstructural protein 5B (NS5B) depending on the peripheral sequence) of intrahepatic HCV RNA in single cells and bulk tissue, before and during week 1 of DAA+RBV therapy.

Estimate the week 1 change in the sizes and numbers of HCV-infected clusters on DAA therapy to test whether clearance of HCV-infected hepatocytes occurs in spatially random patterns or within specific clusters.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 15 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: deLIVER: Direct Acting Antiviral Effects on the Liver
Actual Study Start Date : January 2017
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : June 2020

Resource links provided by the National Library of Medicine

Drug Information available for: Sofosbuvir

Arm Intervention/treatment
Experimental: Group A
Non-Randomized: Monoinfected Sofosbuvir/Velpatasvir/Voxilaprevir SOF/VEL/VOX days 0-7 Paired liver biopsy at days 0 and 7. SOF/VEL days 8 (week 2) through 84 (week 12). Post-treatment follow up through week 12.
Drug: Sofosbuvir/Velpatasvir/Voxilaprevir [SOF/VEL/VOX]
antiviral therapy for HCV

Experimental: Group B
Randomized: HIV/HCV coinfected; Sofosbuvir/Velpatasvir/Voxilaprevir SOF/VEL/VOX days 0 through 7, Paired liver biopsy days 0 and 7. SOF/VEL days 8 (week 2) through 84 (week 12). Post-treatment follow up through week 12.
Drug: Sofosbuvir/Velpatasvir/Voxilaprevir [SOF/VEL/VOX]
antiviral therapy for HCV

Active Comparator: Group C
Random Assignment of arm: Co-infection Sofosbuvir/Velpatasvir (SOF/VEL) days 0 through 7 and Paired liver biopsy days 0 and 7. SOF/VEL on day 8 (week 2) through 84 (week 12) . Post-Treatment follow up through week 12
Drug: Sofosbuvir/Velpatasvir (SOF/VEL)
antiviral therapy for HCV




Primary Outcome Measures :
  1. Change in the proportion of HCV-infected hepatocytes measured in liver tissue obtained by liver biopsy at day 0 (pre-treatment) and at day 7 of antiviral therapy [ Time Frame: Pre-treatment, Day 7 ]

    One week after treatment with direct-acting antivirals, the decline in intrahepatic and intracellular HCV RNA will be greater in patients treated with an non-structural 3 (NS3) protease inhibitor in combination with inhibitors of NS5A and NS5B compared to those treated with the latter two inhibitors alone.

    2.2 One week after treatment with direct-acting antivirals, the decline in intrahepatic and intracellular HCV RNA quantity will be greater in persons with HCV compared to those with HIV/HCV coinfection.



Secondary Outcome Measures :
  1. Change over the first week in plasma HCV RNA [ Time Frame: Pre-treatment, up to 1 week ]
    plasma HCV RNA levels will be assessed by Real-Time Polymerase Chain Reaction (PCR) reported as international units (IU) per milliliter of blood

  2. Change in the proportion of HCV-infected hepatocytes that express interferon-stimulated genes (ISGs) within the first week of DAA therapy using scLCM. [ Time Frame: Pre-treatment, up to 1 week ]
    ISGs are interferon stimulated genes and will be measured in hepatocytes from the liver biopsy

  3. Change in expression of ISGs in non-parenchymal intrahepatic immune cells (Kupffer cells, plasmacytoid dendritic cells) within the first week of DAA therapy using scLCM. [ Time Frame: Pre-treatment, up to 1 week ]
    ISGs are interferon stimulated genes and will be measured in non-parenchymal cells in the liver tissue obtained from the liver biopsy

  4. Change in the amount of HCV RNA per infected hepatocyte using scLCM on liver biopsy specimens, obtained just prior to treatment initiation (pre-treatment), and after the first week of DAA therapy. [ Time Frame: Pre-treatment, after first week ]
    HCV RNA levels in individual hepatocytes will be assessed by Real-Time Polymerase Chain Reaction (PCR) reported as international units per hepatocyte



Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years to 70 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

- Ability and willingness of participant to provide written informed consent. 2. Men and women age ≥18 to ≤70 years at study entry 3. Body mass index (BMI) ≥ 18 kg/m2 4. HCV RNA ≥ 10,000 IU/mL at Screening 5. HCV genotype 1a at Screening 6. Chronic HCV infection (≥ 6 months) documented by prior medical history 7. HCV treatment-naïve with no prior treatment with any interferon (IFN), RBV, or approved or experimental HCV-specific DAA

8. Absence of cirrhosis as defined as transient elastography (FibroScan®) liver stiffness measurement < 12.5 kilopascal (kPa) within 6 months of screening 9. The following laboratory values obtained within 42 days prior to study entry.

  • Hemoglobin > 10 g/dL for men and > 9 g/dL for women
  • Platelet count ≥90,000/mm3
  • International normalized ratio (INR) ≤1.5
  • Calculated creatinine clearance (CrCl) ≥ 30 mL/min
  • Alanine aminotransferase (ALT) and aspartate aminotransferase level ≤ 10 x upper limit of the normal range (ULN)
  • Total bilirubin <3 mg/dL and Direct bilirubin ≤1.5 x ULN
  • Albumin ≥3.5 g/dL
  • CD4+ cell count ≥200 cells/microliter (uL) and CD4+ cell percentage ≥14% within 42 days of study entry at any US laboratory that has a Clinical Laboratory Improvement Amendments (CLIA) certification [HIV seropositive participants only]
  • HIV RNA < 400 copies/mL prior to study entry by any US laboratory that has a CLIA certification or its equivalent [HIV seropositive participants only] 10. On a qualifying antiretroviral therapy (ART) regimen for at least 14 weeks prior to entry/day0 [HIV seropositive participants only]
  • HIV antiretroviral (ARV) agents allowed in this study include combinations of nucleos(t)ide reverse transcriptase inhibitors emtricitabine, lamivudine, tenofovir alafenamide or disoproxil fumarate, abacavir PLUS
  • Raltegravir, OR
  • Dolutegravir OR
  • Rilpivirine

Fixed dose combinations are permitted including emtricitabine/tenofovir alafenamide (Descovy®), emtricitabine/ tenofovir disoproxil fumarate (Truvada®), emtricitabine/tenofovir alafenamide/rilpivirine (Odefsey®), emtricitabine/ tenofovir disoproxil fumarate/rilpivirine (Complera®) lamivudine/abacavir (Epzicom®), lamivudine/abacavir/dolutegravir (Triumeq®).

11. Women of childbearing potential must have a negative serum pregnancy test at Screening and a negative urine pregnancy test on Day 0 prior to liver biopsy 12. All participants must agree not to participate in a conception process (e.g., active attempt to become pregnant or to impregnate, sperm donation, in vitro fertilization).

13. If participating in sexual activity that could lead to pregnancy, the participant (men and women) must also agree to use two reliable methods of contraception simultaneously while receiving study treatment and for 30 days after stopping study treatment.

A combination of TWO of the following contraceptives MUST be used appropriately:

  • Condoms (male or female) with or without a spermicidal agent
  • Diaphragm or cervical cap with spermicide
  • intrauterine device (IUD) 14. Participants who are not of reproductive potential (women who have been post-menopausal for at least 24 consecutive months or have undergone hysterectomy, bilateral tubal ligation, and/or bilateral oophorectomy or men who have documented azoospermia) are eligible without requiring the use of contraceptives. Acceptable documentation of sterilization and menopause is specified below.

Written or oral documentation communicated by clinician or clinician's staff of one of the following:

• Physician report/letter

  • Laboratory report of azoospermia
  • Follicle stimulating hormone-release factor (FSH) measurement elevated into the menopausal range as established by the reporting laboratory.

    15. Participants must be able to adhere to dosing instructions for study drug administration and able to complete the study schedule of assessments, in the opinion of the investigator.

Exclusion Criteria:

  • Breastfeeding. 2. Known allergy/sensitivity or any hypersensitivity to components of study drugs or their formulation.

    3. Acute or serious illness requiring systemic treatment and/or hospitalization within 42 days prior to study entry.

    4. Active hepatitis B infection (positive HBsAg) within 42 days prior to study entry.

    5. History of decompensated liver disease (including but not limited to encephalopathy, variceal bleeding, or ascites) prior to study entry.

    6. Any cause of liver disease other than chronic HCV infection, including but not limited to the following:

    • Hemochromatosis
    • Alpha-1 antitrypsin deficiency
    • Wilson's disease
    • Autoimmune hepatitis
    • Alcoholic liver disease
    • Drug-related liver disease 7. Uncontrolled or active depression or other psychiatric disorder within 24 weeks prior to study entry that in the opinion of the investigator might preclude adherence to study requirements.

      8. Active drug or alcohol use or dependence that, in the opinion of the investigator, would interfere with adherence to study requirements.

      9. Serious illness including uncontrolled seizure disorders, active coronary artery disease within 24 weeks prior to study entry, or other chronic medical conditions that in the opinion of the investigator might preclude completion of the protocol.

      10. Presence of active or acute AIDS-defining opportunistic infections within 12 weeks prior to study entry.

      11. Active or history of malignancy within 2 years prior to study entry other than basal cell carcinoma of the skin and/or cutaneous Kaposi's sarcoma (KS) and/or cervical or anal dysplasia or carcinoma in situ.

      12. Clinically significant abnormal EKG, or EKG with QT interval corrected for heart rate (QTc) using Fridericia's correction formula (QTcF) >450 msec within 42 days of study entry.

      13. Infection with any HCV genotype other than genotype 1a, or mixed genotype infection any time prior to study entry.

      14. History of major organ transplantation with an existing functional graft any time prior to study entry.

      15. History of acquired or hereditary bleeding disorder (e.g., hemophilia, warfarin use) or any other cause of or tendency toward excessive bleeding time prior to study entry.

      16. Gastrointestinal disorder or post-operative condition that could interfere with the absorption of the study drug 17. Difficulty with blood collection and/or poor venous access for the purposes of phlebotomy


Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02938013


Locations
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United States, Maryland
Johns Hopkins Hospital : The John G. Bartlett Specialty Practice
Baltimore, Maryland, United States, 21287
Sponsors and Collaborators
Johns Hopkins University
Investigators
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Principal Investigator: Mark Sulkowski, M.D. Johns Hopkins University

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Responsible Party: Johns Hopkins University
ClinicalTrials.gov Identifier: NCT02938013     History of Changes
Other Study ID Numbers: IRB00110677
First Posted: October 19, 2016    Key Record Dates
Last Update Posted: June 18, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: Undecided

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

Additional relevant MeSH terms:
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Liver Diseases
Coinfection
Digestive System Diseases
Infection
Virus Diseases
Parasitic Diseases
Antiviral Agents
Sofosbuvir
Velpatasvir
Sofosbuvir-velpatasvir drug combination
Anti-Infective Agents