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Hepatitis C InfectionPhase 1/2NCT01185028

A Safety and Tolerability Study of Nitazoxanide in HIV-HCV Treatment Failures

A Phase 1/2 study testing Nitazoxanide With Pegylated Interferon And Ribavirin in people with Hepatitis C Infection and HIV Infection, run by National Institutes of Health Clinical Center (CC) at 4 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial summary

Background: Chronic hepatitis C (CHC) is a major health problem that particularly affects individuals with human immunodeficiency virus (HIV) infection, and can lead to cirrhosis and liver failure. Read more about this study

Who is it for?
Ages 18 to 99 years
Conditions the study is for
Hepatitis C Infection, HIV Infection
What is being tested?
Nitazoxanide With Pegylated Interferon And Ribavirin
Could I receive a placebo?
No, everyone receives an active treatment
How many people
8 participants
Where
4 sitesUnited States
Study dates
Aug 2010to Oct 2011
Phase
Phase 1/2
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 99 years
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

None listed.

Who cannot join

  • A participant will be ineligible to participate on this study if any of the following criteria are met:
  • A participant cannot be on other experimental therapies (including expanded access/compassionate use of antiretrovirals) for 28 days prior to Day -28 and during his/her participation in this protocol.
  • Mixed genotypes (e.g., 1 \& 2, 1 \& 3,1 \& 4). Mixed genotype 1a/1b will be enrolled.
  • Has any other known, or clinically suspected, cause of liver disease, including active hepatitis B.
  • For participants with cirrhosis, a Child Turcotte Pugh score > 7, or Child's B or C cirrhosis.
  • Has a prothrombin time International Normalized Ratio (PT-INR) > 2 and is not on chronic anti-coagulation medications, or has a history of hemophilia.
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  • Has had an organ transplantation other than cornea or hair.
  • Has an estimated creatinine clearance (estimated glomerular flow rate) < 50 mL/min.
  • For a participant with higher than 20 ng/mL of alpha-fetoprotein, a negative ultrasound or computerized tomography scan to rule out hepatoma is required for enrollment.
  • Has any neoplastic disease EXCEPT for (1) Kaposi's sarcoma not requiring systemic chemotherapy, (2) any non-metastatic skin cancer that has been resected or (3) non-metastatic cervical or anal cancer that has been resected.
  • Has evidence of severe cardiac disease (greater than or equal to Grade 3 congestive cardiac failure, symptomatic coronary artery disease, significant arrhythmias, or uncontrolled hypertension) despite intervention or medical therapy.
  • Has evidence of severe chronic pulmonary disease with functional impairment or a DLCO (diffusing capacity of the lung for carbon monoxide) less than or equal to 70% at baseline.
  • Has a severe psychiatric disorder that would interfere with the adherence to protocol requirements, and that is not stably treated with risk of decompensation.
  • Has evidence of autoimmune disorders including inflammatory bowel diseases, psoriasis, and optic neuritis.
  • Has evidence of an uncontrolled seizure disorder defined as more than 1 episode of generalized seizure within the past year.
  • Has chronic pancreatitis.
  • Has severe retinopathy, as determined by the ophthalmologist.
  • Has any hemoglobinopathy (e.g., Thalassemia, sickle cell disease).
  • Is currently taking didanosine or d4T as part of antiretroviral regimen.
  • If total bilirubin is greater than 1.5 mg/dL then direct bilirubin can be no more than 70% of the total, up to a direct bilirubin of 2.0 mg/dL.
  • Concurrent use of any immunosuppressive therapy, including systemic steroids (prednisone equivalent of > 10 mg/day) for a duration of 6 weeks or more within 6 months prior to enrollment. Inhaled steroids will be allowed, even with ritonavir.
  • Has active systemic infections other than HCV and HIV.
  • Has a hepatic mass suggestive of hepatocellular carcinoma as detected by ultrasound scan, dual-phase computerized tomography, or magnetic resonance imaging.
  • Has evidence of moderate or heavy alcohol use (> 50 grams/day), or substance abuse, within the past 6 months that potentially could interfere with participant compliance. (Urine toxicology will be completed at screening.)
  • Currently uses warfarin, ganciclovir, isoniazid, pyrazinamide, rifabutin, rifampin/rifampicin, thalidomide, or theophylline.
  • Has a history of esophageal or gastric varices.
  • Has any systemic illness that will make it unlikely that the participant will be able to return for the required study visits.
  • Has evidence of gastrointestinal malabsorption, chronic nausea, or vomiting.
  • The participant is the male partner of a pregnant woman and does not always use a condom during intercourse.
  • Women who are pregnant.
  • Women who are breast-feeding.
  • Has a hypersensitivity to NTZ, interferon products, or ribavirin.
  • Has ingested silymarin (milk thistle), s-adenosylmethionine (SAM-e), glycyrrhizin, Sho-saiko-to (SST), or other herbal supplements that may be either liver beneficial or toxic, within 28 days prior to Day -28.

Trial locations and contacts

4 sites in 1 country.

United States4 sites
  • National Institutes of Health Clinical Center, 9000 Rockville Pike

    Bethesda, Maryland, 20892

  • Family Medical and Counseling Services, SE

    Washington D.C., District of Columbia

  • Unity Health Care/Walker Jones, NE

    Washington D.C., District of Columbia

  • Whitman Walker Clinic, NW

    Washington D.C., District of Columbia

Other trials in United States

About this study

Official title: An Open-Label Safety and Tolerability Study of Nitazoxanide, Pegylated-Interferon Alfa 2a and Ribavirin in HIV/HCV Co-Infected Genotype 1 Prior Treatment Relapsers and Non-Responders

Background:

  • Chronic hepatitis C (CHC) is a major health problem that particularly affects individuals with human immunodeficiency virus (HIV) infection, and can lead to cirrhosis and liver failure. Standard treatment for people with HIV and CHC is a 48-week course of pegylated-interferon alfa 2a (peg-IFN) and ribavirin (RBV), but better treatments are needed for those who either do not respond to the drugs or who relapse after treatment.
  • Nitazoxanide has been approved by the Food and Drug Administration primarily to treat diarrhea caused by parasites, and it has been studied in the treatment of CHC infection. However, it has not been tested in persons infected with HIV and CHC co-infection. Researchers are interested in determining whether nitazoxanide is a safe and tolerable treatment for CHC in individuals with HIV.
Read more

Objectives:

  • To assess the safety and tolerability of using nitazoxanide to treat chronic hepatitis C infection in individuals with HIV who have not responded to standard treatment for hepatitis C.

Eligibility:

  • Individuals at least 18 years of age who have been diagnosed with both HIV and chronic hepatitis C, and who have either not responded to or relapsed after previous hepatitis C treatment.

Design:

  • Participants will be screened with a physical examination and medical history; blood and urine tests; imaging studies; possible heart, lung, and psychological tests; and a liver biopsy if one has not been done in the past 3 years.
  • Participants will receive nitazoxanide, the medication being studied, to take by mouth for 4 weeks, and will provide blood samples during this time.
  • After 4 weeks, participants will receive the first dose of peg-IFN and RBV. Participants will have weekly injections of peg-IFN and continue to take nitazoxanide and RBV by mouth for 48 weeks. Individuals who are slow to respond to this combined CHC treatment (nitazoxanide, peg-IFN, and RBV) by week 12 will continue to have the combined treatment for an extended period, a total of 72 weeks.
  • Participants will have study visits to provide blood samples and have other tests two times in the first month of combined treatment, and then at months 2, 3, 4, 7, 10, 13, 19; and month 25 only in participants slow to respond to combined treatment.
  • Some participants who are on specific HIV treatment regimens may enroll in a substudy that will require three separate 12-hour visits for repeated blood samples and other tests during the initial 4-week nitazoxanide treatment.
Read the detailed description

Chronic hepatitis C (CHC) viral infection is a major health problem affecting 130-170 million worldwide, and 2.7-3.9 million in the US, more than 3 times those with HIV infection. One-third of persons with HIV have CHC, a more rapid progression to cirrhosis and liver failure, with liver disease as one of the leading causes of mortality.

Standard treatment, pegylated-interferon (IFN) alfa and ribavirin (RBV), has an efficacy, sustained virologic response (SVR), of less than 50% in those with HCV genotype 1 (GT 1); and only about 25% of those with HIV-HCV GT1 co-infection. SVR is even lower in those retreated, who were prior treatment relapsers or non-responders; few published studies exist, especially in those with HIV. Improved therapy is imperative given increasing morbidity and mortality and the proportion of persons who are relapsers or non-responders. Newer and promising anti-HCV therapies, directly acting antivirals (DAA), are in development. However, only 2 are in Phase 3 clinical trials and most remain far from FDA approval.

An oral agent, nitazoxanide (NTZ), with broad in vitro anti-microbial activity and a good safety profile, has higher efficacy rates in treatment na ve participants mono-infected with HCV GT 1 or 4. There have not been studies in HIV co-infected persons, nor pharmacokinetic (PK) studies in liver or renal disease. In vitro studies suggest that NTZ has both a direct suppressive effect on HCV replication, as well as a sensitizing effect on IFN-mediated suppression of HCV replication, yet the exact mechanism of action giving rise to higher SVR rates is not well understood.

This is an open-label study in 35 HIV-HCV GT 1 co infected persons, prior relapsers (n=25) or non-responders (n=10) after a full course of IFN and RBV therapy. Participants will receive 4 weeks of NTZ lead-in therapy, followed by NTZ/peg-IFN/RBV triple combination therapy for an additional 48 weeks. Slow responders will receive 72 weeks of triple therapy after the 4-week NTZ lead-in.

The primary endpoint is safety and tolerability of NTZ. Secondary endpoints are exploratory: (1) efficacy rate estimation, (2) viral dynamics assessment, and determination of predictive response, (3) pharmacologic level assessment, (4) indirect mechanistic action evaluation of NTZ through virologic response, and, (5) IFN-stimulated genetic expression evaluation and determination of predictive response. There will be a sub-study evaluating the PK of NTZ in a group of 10 participants who are on a ritonavir-based HIV antiretroviral regimen.

Being tested
Nitazoxanide With Pegylated Interferon And Ribavirin
Keywords
Chronic HCV, HCV Treatment Nonresponders, HCV Treatment Relapsers, HIV-HCV Co-Infection, Nitazoxanide, Hepatitis C
Medical subject headings
Hepatitis C, HIV Infections

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Nitazoxanide With Pegylated Interferon And RibavirinDrug

    Nitazoxanide 500mg po bid for 4 wks followed by peg-IFN/Ribavirin/nitazoxanide for 48 weeks

Study groups in NCT01185028
Study groupRoleWhat they receive
Nitazoxanide With Pegylated Interferon And RibavirinExperimentalNitazoxanide 500mg po bid for 4 wks followed by peg-IFN/Ribavirin/nitazoxanide for 48 weeks
Receives: Drug: Nitazoxanide With Pegylated Interferon And Ribavirin

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Number of Participants With Adverse Events

    Adverse events determined and evaluated by patient reporting and the DAIDS toxicity table.

    Measured: 1 year and 2 months

Secondary outcomes (2)
  1. Sustained Viral Response Rate

    Proportion of participants that are HCV negative 6 months after treatment completion

    Measured: 1 year and 2 mos

  2. Tolerability of Study Drug Measured as Discontinuation.

    Proportion of individuals that discontinued study drug due to intolerability.

    Measured: 1 year and 2 mos

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted19 Aug 2010 (estimated)
  2. Study startAug 2010
  3. Primary completionOct 2011
  4. Study completionOct 2011

Resources

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 1/2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
8 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01185028
Sponsor's protocol ID
100183
Other IDs
10-CC-0183
Status last verified
May 2013
First submitted
18 Aug 2010
Last updated
5 Oct 2021

Publications

  • Seeff LB, Buskell-Bales Z, Wright EC, Durako SJ, Alter HJ, Iber FL, Hollinger FB, Gitnick G, Knodell RG, Perrillo RP, et al. Long-term mortality after transfusion-associated non-A, non-B hepatitis. The National Heart, Lung, and Blood Institute Study Group. N Engl J Med. 1992 Dec 31;327(27):1906-11. doi: 10.1056/NEJM199212313272703.

    PubMed 1454085
  • Seeff LB. Natural history of chronic hepatitis C. Hepatology. 2002 Nov;36(5 Suppl 1):S35-46. doi: 10.1053/jhep.2002.36806.

    PubMed 12407575
  • Staples CT Jr, Rimland D, Dudas D. Hepatitis C in the HIV (human immunodeficiency virus) Atlanta V.A. (Veterans Affairs Medical Center) Cohort Study (HAVACS): the effect of coinfection on survival. Clin Infect Dis. 1999 Jul;29(1):150-4. doi: 10.1086/520144.

    PubMed 10433578

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing Nitazoxanide With Pegylated Interferon And Ribavirin in people with Hepatitis C Infection and HIV Infection, run by National Institutes of Health Clinical Center (CC) at 4 sites 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 0 inclusion and 33 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 5 Oct 2021. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 4 sites 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 combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

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 15 May 2013). 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?

Number of Participants With Adverse Events (time frame: 1 year and 2 months). 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 NCT01185028, 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 5 Oct 2021.

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