Hepatitis CPhase 4NCT02347345
Immunologic Effects of HCV Therapy With HARVONI in HCV Genotype 1 Chronically Mono-infected Active and Former IDUs
A Phase 4 study testing Harvoni (Fixed dose combination ledipasvir/sofosbuvir) in people with Hepatitis C, run by Rockefeller University at 1 site in United States.
Trial summary
The investigator's hypothesis is that active injectors will show a partial reduction in markers of immune activation with HCV therapy whereas non-injectors will show a more significant reduction in these markers, and will exhibit levels of immune activation that approach that seen in similarly studied healthy… Read more about this study
- Who is it for?
- Ages 18 to 55 yearsHealthy volunteers can take part
- Conditions the study is for
- Hepatitis C
- What is being tested?
- Harvoni (Fixed dose combination ledipasvir/sofosbuvir)
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 34 participants
- Where
- 1 siteUnited States
- Study dates
- 15 Nov 2016to 15 Nov 2016
- Phase
- Phase 4
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- All sexes
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Show all 20Show fewer
- 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
Who cannot join
- HIV infection
- Chronic infection with Hepatitis B
- Uncompensated cirrhosis
- Required use of:
- Anticonvulsants: carbamazepine, oxycarbazepine, phenobarbital, and phenytoin
- Antimycobacterials: rifabutin, rifampin, rifapentine
Show all 12Show fewer
- 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
- -
Trial locations and contacts
1 site in 1 country.
United States1 site
Rockefeller University Hospital
New York, New York, 10021
About this study
Official title: The Immunologic Effects of HCV Therapy With Fixed Dose Combination Ledipasvir/Sofosbuvir (HARVONI) in HCV Genotype 1 Chronically Mono-infected Active and Former IDUs.
The investigator's hypothesis is that active injectors will show a partial reduction in markers of immune activation with HCV therapy whereas non-injectors will show a more significant reduction in these markers, and will exhibit levels of immune activation that approach that seen in similarly studied healthy volunteers.This is based on observations that this group of investigators have made. They have shown that individuals who inject drugs have high level of immune activation in blood and tissue. Immune activation or chronic inflammation has been associated with accelerated aging, cardiovascular, renal and liver disease as well as CNS dysfunction. It remains unclear whether increased levels of immune activation are due to non-sterile injection of drugs, chronic infection with Hepatitis C, chronic opiate use, or perhaps combinations of all 3. To understand the potential contribution of infection with Hepatitis C the investigators will compare levels of immune activation pre- and post treatment with an all oral, one pill once daily, interferon sparing treatment of HCV in 2 groups of chronically HCV infected patients- one actively injecting with drugs and the other free of injection for at least 4 months. Immune activation comparisons will also include non-injecting healthy volunteers.
Read the 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.
- Conditions
- Hepatitis C
- Being tested
- Harvoni (Fixed dose combination ledipasvir/sofosbuvir)
- Keywords
- HCV, injection drug use
- Medical subject headings
- Hepatitis C
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
Harvoni (Fixed dose combination ledipasvir/sofosbuvir)Drug
Also called Fixed dose combination ledipasvir/sofosbuvir
Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill daily x 12 weeks
| Study group | Role | What they receive |
|---|---|---|
| Active injection drug use (IDU) | Active comparator | In active IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill orally daily x 12 weeks Receives: Drug: Harvoni (Fixed dose combination ledipasvir/sofosbuvir) |
| Former injection drug use (former IDU) | Active comparator | In former IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill orally daily x 12 weeks Receives: Drug: Harvoni (Fixed dose combination ledipasvir/sofosbuvir) |
| Healthy volunteers | No intervention | 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 being measured
The primary outcome is the main question the study is designed to answer.
sCD14 (ng/mL)
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.
Measured: 24 weeks
Secondary outcomes (2)
Virologic Response to Therapy as Measured by HCV RNA
HCV RNA levels in plasma (IU/mL)
Measured: 24 weeks
Gene Expression Profiles
Gene expression profiles in PBMC will be determined using RNA Seq
Measured: 24 weeks
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jan 2015 (estimated)
- Study start15 Nov 2016
- Primary completion15 Nov 2016
- Study completion15 Nov 2016
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (3)Papers the sponsor has linked to this study.
- Other trials for Hepatitis CStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 4
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Enrolment
- 34 participants (actual)
Sponsor and investigators
- Lead sponsor
- Rockefeller University
- Sponsor type
- University, hospital or other
- Collaborators
- National Institute on Drug Abuse (NIDA)
- Responsible party
- Principal investigator, Martin Markowitz, Rockefeller University
- Investigators
- Martin Markowitz, MD, Principal investigator, ADARC/Rockefeller University
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02347345
- Sponsor's protocol ID
- MMA-0874
- Other IDs
- 5R01DA033777
- Status last verified
- Jul 2019
- First submitted
- 15 Jan 2015
- Last updated
- 13 Aug 2019
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- No
- Individual data sharing
- No
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.
PubMed 24720702Lawitz 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.
PubMed 24209977Gane 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.
PubMed 24067879
Study at a glance
From the registry record, last updated by the sponsor on 13 Aug 2019. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- The Immunologic Effects of HCV Therapy With Fixed Dose Combination Ledipasvir/Sofosbuvir (HARVONI) in HCV Genotype 1 Chronically Mono-infected Active and Former IDUs.
- ClinicalTrials.gov ID
- NCT02347345
- Acronym / sponsor ID
- MMA-0874
- Conditions
- Hepatitis C
- Keywords
- HCV, injection drug use
- Phase
- Phase 4
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 34 participants (actual)
- Lead sponsor
- Rockefeller UniversityUniversity, hospital or other
- Collaborators
- National Institute on Drug Abuse (NIDA)
- Study start
- 15 Nov 2016 (actual)
- Primary completion
- 15 Nov 2016 (actual)
- Study completion
- 15 Nov 2016 (actual)
- First posted
- 27 Jan 2015 (estimated)
- Results
- Posted 13 Aug 2019
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
The investigator's hypothesis is that active injectors will show a partial reduction in markers of immune activation with HCV therapy whereas non-injectors will show a more significant reduction in these markers, and will exhibit levels of immune activation that approach that seen in similarly studied healthy volunteers.This is based on observations that this group of investigators have made. They have shown that individuals who inject drugs have high level of immune activation in blood and tissue. Immune activation or chronic inflammation has been associated with accelerated aging, cardiovascular, renal and liver disease as well as CNS dysfunction. It remains unclear whether increased levels of immune activation are due to non-sterile injection of drugs, chronic infection with Hepatitis C, chronic opiate use, or perhaps combinations of all 3. To understand the potential contribution of infection with Hepatitis C the investigators will compare levels of immune activation pre- and post treatment with an all oral, one pill once daily, interferon sparing treatment of HCV in 2 groups of chronically HCV infected patients- one actively injecting with drugs and the other free of injection for at least 4 months. Immune activation comparisons will also include non-injecting healthy volunteers.
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 design
- Primary purpose
- Treatment
- Allocation
- Non-randomised
- Intervention model
- Parallel groups
- Masking
- None (open label)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| Active injection drug use (IDU) | Active comparator | Drug: Harvoni (Fixed dose combination ledipasvir/sofosbuvir)In active IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill orally daily x 12 weeks |
| Former injection drug use (former IDU) | Active comparator | Drug: Harvoni (Fixed dose combination ledipasvir/sofosbuvir)In former IDU, Harvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill orally daily x 12 weeks |
| Healthy volunteers | No intervention | –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. |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (20 listed)
- 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
Key exclusion criteria (12 listed)
- HIV infection
- Chronic infection with Hepatitis B
- Uncompensated cirrhosis
- Required use of:
- Anticonvulsants: carbamazepine, oxycarbazepine, phenobarbital, and phenytoin
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| Harvoni (Fixed dose combination ledipasvir/sofosbuvir)Also: Fixed dose combination ledipasvir/sofosbuvirHarvoni (Fixed dose combination ledipasvir/sofosbuvir), one pill daily x 12 weeks | Drug | Active injection drug use (IDU), Former injection drug use (former IDU) |
Primary outcome
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.
2 secondary outcomes
Virologic Response to Therapy as Measured by HCV RNA
Time frame: 24 weeks
Gene Expression Profiles
Time frame: 24 weeks
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 13 Aug 2019.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 24720702Kowdley 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.
- Results publication: PubMed 24209977Lawitz 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.
- Results publication: PubMed 24067879Gane 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.
- Individual participant dataSharing planned: No
Related trials for Hepatitis C
RecruitingObservational study
Evaluation of Patients With Liver Disease
Hepatitis D, Hepatitis C
Not yet recruitingObservational study
Elimination of Hepatitis C Virus Among Users of Substances
Hepatitis C in Substance Users
Not yet recruiting
Clinical Study to Evaluate the Performance of the INSTI® HCV Antibody Test for CLIA-Waived Use
HCV Infection
Not yet recruiting
Study to Evaluate the Performance of the INSTI® HCV Antibody Test for Point-of-Care Use in Individuals at Risk for HCV Infection or Presenting With Signs or Symptoms of HCV Infection
HCV Infection
Active, not recruitingPhase 4
People With CHC Who Achieved a Sustained Virological Response Following Therapy With Direct Acting Antiviral Agents
Diabetes Mellitus, Hepatitis C, Chronic
Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Martin Markowitz, MD principal investigator
ADARC/Rockefeller University
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 4 study testing Harvoni (Fixed dose combination ledipasvir/sofosbuvir) in people with Hepatitis C, run by Rockefeller University at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 20 inclusion and 12 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 13 Aug 2019. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 4 studies take place after a treatment is approved, to learn more about its long-term benefits and risks in everyday use.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
Yes. Results are posted in the registry (first posted 13 Aug 2019). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
sCD14 (ng/mL) (time frame: 24 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02347345, which also lists 3 linked publications.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 13 Aug 2019.