- ICH GCP
- US Clinical Trials Registry
- Clinical Trial NCT02347345
Immunologic Effects of HCV Therapy With HARVONI in HCV Genotype 1 Chronically Mono-infected Active and Former IDUs
The Immunologic Effects of HCV Therapy With Fixed Dose Combination Ledipasvir/Sofosbuvir (HARVONI) in HCV Genotype 1 Chronically Mono-infected Active and Former IDUs.
Study Overview
Status
Conditions
Intervention / Treatment
Detailed Description
This group of multidisciplinary investigators has discovered increased levels of immune activation among HIV-1-uninfected active injection drug users (IDUs) when compared to non-IDU controls . The vast majority (80%) are also infected with HCV.
Active injectors have high levels of immune activation as measured by sCD14, CD8 co-expression of CD38 and HLA-DR, as well as Type 1 cytokines.
Within months of ceasing injecting, there are observable decreases in some parameters however in general they remain elevated when compared to non-injecting healthy volunteers.
As approximately 80% of these subjects are HCV infected and viremic, these results are confounded as to the cause of the observed increased levels of markers of immune activation- active injection or chronic Hepatitis C. Until recently HCV treatment required the use of IFN which has immunomodulatory activity which would cause perturbations in the markers of immune activation. However the development of direct acting agents (DAA) to treat HCV has revolutionized therapy. In this trial the investigators will employ the once daily FDC formulation of sofosbuvir and ledipasvir to assess changes in markers of immune activation during therapy.
There have been multiple clinical trials of FDC LDV-SOF in patients with Genotype 1 HCV. When taken once daily for 12 weeks, sustained virologic response rates have been very high with response rates nearing 99% in most studies with a 12-week course of therapy.
Common adverse events associated with FDC LDV-SOF in ION-1 include fatigue (21%), headache (25%), nausea (11%), insomnia (8%), asthenia (7%), diarrhea (11%), rash (7%), irritibility (7%), cough (3%), and pruritis (5%).
Ledipasvir undergoes minimal metabolism and expectations are that this medication will have few clinically significant drug-drug interactions. In general, sofosbuvir is considered to have relatively few clinically significant drug-drug interactions, but coadministration of sofosbuvir with the following medications is not recommended because these medications may significantly lower sofosbuvir levels:
Anticonvulsants: carbamazepine, oxycarbazepine, phenobarbital, and phenytoin Antimycobacterials: rifabutin, rifampin, rifapentine Herbal Supplements: St. John's wort HIV Protease Inhibitors: tipranavir-ritonavir Antiarrhythmic Drugs : amiodarone (Cordarone®, Nexterone®, Pacerone®)
Participants will be provided with a 12-week course of FDC LDV-SOF which will provide a near 99% likelihood of a SVR in participants who are adherent to therapy with low likelihood of significant adverse events and drug-drug interactions.
In treating HCV effectively the investigators will measure changes in immune activation and gene expression that accompany HCV treatment.
Study Type
Enrollment (Actual)
Phase
- Phase 4
Contacts and Locations
Study Locations
-
-
New York
-
New York, New York, United States, 10021
- Rockefeller University Hospital
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-
Participation Criteria
Eligibility Criteria
Ages Eligible for Study
Accepts Healthy Volunteers
Genders Eligible for Study
Description
Inclusion Criteria:
- Ability to give written informed consent in English
- Age≥18 and ≤55
- HCV antibody positive
- HCV RNA >1,000 copies/mL plasma
- HCV treatment naive
- HCV genotype 1a or 1b or mixed type 1
- AST, ALT <10x ULN
- Direct bilirubin <3.0
- Platelet count >50,000
- Creatinine clearance >30mL/min as estimated by Cockroft Gault
- Hemoglobin >10 if female, >11 if male
- Albumin > 2.8
- INR<2.0
- If Group A: urine dip for opiates + and active injection drug use of heroin defined as injecting at least 3 times per week.
- If Group B then no IDU for at least 4 months and a negative urine for opiates at screening.
- Venous access for phlebotomy
- Willingness to agree to effective contraception during the course of the study.
If Group C: - negative urine for opiates at screening
- no recreational drug use for at least 2 years (excluding marijuana)
- HIV, HCV and HBV uninfected
Exclusion Criteria:
- HIV infection
- Chronic infection with Hepatitis B
- Uncompensated cirrhosis
Required use of:
Anticonvulsants: carbamazepine, oxycarbazepine, phenobarbital, and phenytoin
Antimycobacterials: rifabutin, rifampin, rifapentine
Herbal Supplements: St. John's wort
HIV Protease Inhibitors: tipranavir-ritonavir
Antiarrhythmic Drugs: amiodarone (Cordarone, Nexterone, Pacerone)
- Any medical condition that in the opinion of the investigator would interfere with study participation and medical adherence
Pregnancy/breast feeding
-
Study Plan
How is the study designed?
Design Details
- Primary Purpose: Treatment
- Allocation: Non-Randomized
- Interventional Model: Parallel Assignment
- Masking: None (Open Label)
Arms and Interventions
Participant Group / Arm |
Intervention / Treatment |
---|---|
Active Comparator: Active injection drug use (IDU)
In active IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill orally daily x 12 weeks
|
Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill daily x 12 weeks
Other Names:
|
Active Comparator: Former injection drug use (former IDU)
In former IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill orally daily x 12 weeks
|
Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill daily x 12 weeks
Other Names:
|
No Intervention: Healthy volunteers
HIV, HCV and HBV negative, never injected drugs, no recreational drugs for at least 2 years (does not include marijuana) and negative urine screen for opiates at the screening visit.
|
What is the study measuring?
Primary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
sCD14 (ng/mL)
Time Frame: 24 weeks
|
Marker of immune activation as measured by levels of soluble CD14.
Note that the levels of sCD14 were only measured at baseline in the Healthy Volunteers group and therefore there are no data for weeks 4, 12, or 24 entered.
|
24 weeks
|
Secondary Outcome Measures
Outcome Measure |
Measure Description |
Time Frame |
---|---|---|
Virologic Response to Therapy as Measured by HCV RNA
Time Frame: 24 weeks
|
HCV RNA levels in plasma (IU/mL)
|
24 weeks
|
Gene Expression Profiles
Time Frame: 24 weeks
|
Gene expression profiles in PBMC will be determined using RNA Seq
|
24 weeks
|
Collaborators and Investigators
Sponsor
Collaborators
Investigators
- Principal Investigator: Martin Markowitz, MD, ADARC/Rockefeller University
Publications and helpful links
General Publications
- Kowdley KV, Gordon SC, Reddy KR, Rossaro L, Bernstein DE, Lawitz E, Shiffman ML, Schiff E, Ghalib R, Ryan M, Rustgi V, Chojkier M, Herring R, Di Bisceglie AM, Pockros PJ, Subramanian GM, An D, Svarovskaia E, Hyland RH, Pang PS, Symonds WT, McHutchison JG, Muir AJ, Pound D, Fried MW; ION-3 Investigators. Ledipasvir and sofosbuvir for 8 or 12 weeks for chronic HCV without cirrhosis. N Engl J Med. 2014 May 15;370(20):1879-88. doi: 10.1056/NEJMoa1402355. Epub 2014 Apr 10.
- Lawitz E, Poordad FF, Pang PS, Hyland RH, Ding X, Mo H, Symonds WT, McHutchison JG, Membreno FE. Sofosbuvir and ledipasvir fixed-dose combination with and without ribavirin in treatment-naive and previously treated patients with genotype 1 hepatitis C virus infection (LONESTAR): an open-label, randomised, phase 2 trial. Lancet. 2014 Feb 8;383(9916):515-23. doi: 10.1016/S0140-6736(13)62121-2. Epub 2013 Nov 5. Erratum In: Lancet. 2014 Mar 8;383(9920):870.
- Gane EJ, Deray G, Liaw YF, Lim SG, Lai CL, Rasenack J, Wang Y, Papatheodoridis G, Di Bisceglie A, Buti M, Samuel D, Uddin A, Bosset S, Trylesinski A. Telbivudine improves renal function in patients with chronic hepatitis B. Gastroenterology. 2014 Jan;146(1):138-146.e5. doi: 10.1053/j.gastro.2013.09.031. Epub 2013 Sep 22.
Study record dates
Study Major Dates
Study Start (Actual)
Primary Completion (Actual)
Study Completion (Actual)
Study Registration Dates
First Submitted
First Submitted That Met QC Criteria
First Posted (Estimate)
Study Record Updates
Last Update Posted (Actual)
Last Update Submitted That Met QC Criteria
Last Verified
More Information
Terms related to this study
Keywords
Additional Relevant MeSH Terms
- Digestive System Diseases
- RNA Virus Infections
- Virus Diseases
- Infections
- Blood-Borne Infections
- Communicable Diseases
- Liver Diseases
- Flaviviridae Infections
- Hepatitis, Viral, Human
- Hepatitis
- Hepatitis C
- Anti-Infective Agents
- Antiviral Agents
- Sofosbuvir
- Ledipasvir, sofosbuvir drug combination
- Ledipasvir
Other Study ID Numbers
- MMA-0874
- 5R01DA033777 (U.S. NIH Grant/Contract)
Plan for Individual participant data (IPD)
Plan to Share Individual Participant Data (IPD)?
This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.
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