Safety and Efficacy Study Comparing Raltegravir to a Protease Inhibitor in Treatment-naïve, HIV/Hepatitis C Drug Users

NCT01105611 | Unknown Phase 4 DMC

• 2 other identifiers: CB-2010-012010-018326-39
• Study Type: interventional
• Target: 40
• Locations: 1 country
• Sites: 2

Brief Summary

The purpose of this study is to compare how safe, tolerable, and effective a novel drug, raltegravir, is to a commonly used combination, atazanavir/ritonavir, as initial treatment in HIV/Hepatitis C co-infected injecting drug users on a methadone program.

Conditions

HIV Infections; Hepatitis C

Keywords

HIV; Hepatitis C; Co-infection; Intravenous drug users; Treatment-naïve; Methadone

Outcome Measures

Primary Outcomes (10)

• Incidence of grade 3-4 liver function test (LFT) elevations

  4 weeks

• Incidence of grade 3-4 liver function test (LFT) elevations

  12 weeks

• Incidence of grade 3-4 liver function test (LFT) elevations

  24 weeks

• Incidence of grade 3-4 liver function test (LFT) elevations

  36 weeks

• Incidence of grade 3-4 liver function test (LFT) elevations

  48 weeks

• Incidence of grade 3-4 liver function test (LFT) elevations

  60 weeks

• Incidence of grade 3-4 liver function test (LFT) elevations

  72 weeks

• Incidence of grade 3-4 liver function test (LFT) elevations

  84 weeks

• Incidence of grade 3-4 liver function test (LFT) elevations

  96 weeks

• Viral suppression

  Viral suppression is defined as HIV-1 RNA less than 50 copies per mL

  24 weeks

Secondary Outcomes (7)

• Viral suppression

  48 weeks

• Immunologic response

  96 weeks

• Overall safety in patients with mild to moderate hepatic impairment

  48 weeks

• Outpatient retention rates

  96 weeks

• QTc interval changes

  4 weeks

Study Arms (2)

Raltegravir

EXPERIMENTAL

Raltegravir in combination with Tenofovir/Emtricitabine

Drug: Raltegravir

Atazanavir/Ritonavir

ACTIVE COMPARATOR

Atazanavir 300mg orally once daily with Ritonavir 100mg orally once daily; together with combination of Tenofovir/Emtricitabine

Drug: Atazanavir/Ritonavir

Interventions

Raltegravir DRUG

400mg orally twice daily. Number of cycles: unless toxicity or treatment failure occurs, there will be no anticipated treatment discontinuation.

Also known as: Isentress™

Raltegravir

Atazanavir/Ritonavir DRUG

Atazanavir 300mg orally once daily boosted with Ritonavir orally 100mg once daily. Number of cycles: unless toxicity or treatment failure occurs, there will be no anticipated treatment discontinuation.

Also known as: Reyataz™ (Atazanavir), Norvir™ (Ritonavir)

Atazanavir/Ritonavir

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Male or Female Patients Age ≥ 18 years old.
• Naïve to antiretroviral treatment.
• Subject must be willing and able to understand and provide written, informed consent prior to participation in the study.
• Subjects must be on concurrent methadone maintenance therapy.
• Documented HIV infection (antibody positive).
• Documented Hepatitis C co-infection (PCR positive).
• HIV RNA \> 5,000.
• Indication for starting ART according to guidelines.
• Documented resistance profile taken at baseline and includes investigational medicinal products.
• Females may be eligible for enrolment in the study if she is of:
• Non-childbearing potential; or, Child-bearing potential females must have a negative pregnancy test at initial screening and agree to an acceptable barrier and/or hormonal method of contraception; Sterilization

You may not qualify if:

• Subject is in the initial acute phase of a CDC Clinical Category C infection at Baseline. Subjects may be enrolled provided they are receiving treatment for such infections and are clinically improving at the Baseline visit.
• Concurrent treatment with an investigational drug or participation in another clinical trial.
• Use of an investigational drug within 4 weeks or 5 half-lives, whichever is longer, preceding the first dose of investigational medicinal product.
• Subject is, in the opinion of the investigator, unable to complete the study dosing period and protocol evaluations and assessments.
• Subject has evidence of genotypic (as defined by the current ANRS AC-11 algorithm) resistance to raltegravir, atazanavir and ritonavir at screening.
• Patients with alcohol and drug use problems that in the view of investigator will compromise participation in the study.
• Elevated alanine aminotransferase (ALT) \> 5 times upper limit of normal (ULN)
• Subjects with severe hepatic impairment (Child-Pugh score \> 9).
• Subjects receiving treatment for HCV.
• Subjects with concurrent HBV infection.
• Subject is pregnant or breast feeding.
• Subject suffers from any serious medical condition which would compromise the safety of the subject.
• Subject has a pre-existing mental, physical, or substance abuse disorder that may interfere with the subject's ability to comply with the dosing schedule and protocol evaluations and assessments.
• Subject has a condition or disorder which may interfere with drug absorption or render the subject unable to take oral medication.
• Subject has any acute laboratory abnormality at screening, which, in the opinion of the Investigator, would preclude the subject's participation in the study of an investigational compound. Any verified Grade 4 laboratory abnormality would exclude a subject from study participation.

Sponsors & Collaborators

• St. James's Hospital, Ireland: lead

Study Sites (2)

Department of Genitourinary Medicine and Infectious Diseases, St. James's Hospital

Dublin, Ireland

RECRUITING

Mater Misericordiae University Hospital

Dublin, Ireland

NOT YET RECRUITING

Related Publications (26)

• Markowitz M, Nguyen BY, Gotuzzo E, Mendo F, Ratanasuwan W, Kovacs C, Prada G, Morales-Ramirez JO, Crumpacker CS, Isaacs RD, Campbell H, Strohmaier KM, Wan H, Danovich RM, Teppler H; Protocol 004 Part II Study Team. Sustained antiretroviral effect of raltegravir after 96 weeks of combination therapy in treatment-naive patients with HIV-1 infection. J Acquir Immune Defic Syndr. 2009 Nov 1;52(3):350-6. doi: 10.1097/QAI.0b013e3181b064b0.

  PMID: 19648823 BACKGROUND

• Lennox JL, DeJesus E, Lazzarin A, Pollard RB, Madruga JV, Berger DS, Zhao J, Xu X, Williams-Diaz A, Rodgers AJ, Barnard RJ, Miller MD, DiNubile MJ, Nguyen BY, Leavitt R, Sklar P; STARTMRK investigators. Safety and efficacy of raltegravir-based versus efavirenz-based combination therapy in treatment-naive patients with HIV-1 infection: a multicentre, double-blind randomised controlled trial. Lancet. 2009 Sep 5;374(9692):796-806. doi: 10.1016/S0140-6736(09)60918-1. Epub 2009 Aug 3.

  PMID: 19647866 BACKGROUND

• O'Connor PG, Selwyn PA, Schottenfeld RS. Medical care for injection-drug users with human immunodeficiency virus infection. N Engl J Med. 1994 Aug 18;331(7):450-9. doi: 10.1056/NEJM199408183310707. No abstract available.

  PMID: 8035842 BACKGROUND

• Waldrop-Valverde D, Valverde E. Homelessness and psychological distress as contributors to antiretroviral nonadherence in HIV-positive injecting drug users. AIDS Patient Care STDS. 2005 May;19(5):326-34. doi: 10.1089/apc.2005.19.326.

  PMID: 15916495 BACKGROUND

• Lucas GM, Cheever LW, Chaisson RE, Moore RD. Detrimental effects of continued illicit drug use on the treatment of HIV-1 infection. J Acquir Immune Defic Syndr. 2001 Jul 1;27(3):251-9. doi: 10.1097/00126334-200107010-00006.

  PMID: 11464144 BACKGROUND

• Lucas GM, Griswold M, Gebo KA, Keruly J, Chaisson RE, Moore RD. Illicit drug use and HIV-1 disease progression: a longitudinal study in the era of highly active antiretroviral therapy. Am J Epidemiol. 2006 Mar 1;163(5):412-20. doi: 10.1093/aje/kwj059. Epub 2006 Jan 4.

  PMID: 16394200 BACKGROUND

• Lucas GM, Mullen BA, Weidle PJ, Hader S, McCaul ME, Moore RD. Directly administered antiretroviral therapy in methadone clinics is associated with improved HIV treatment outcomes, compared with outcomes among concurrent comparison groups. Clin Infect Dis. 2006 Jun 1;42(11):1628-35. doi: 10.1086/503905. Epub 2006 Apr 28.

  PMID: 16652321 BACKGROUND

• Graham CS, Baden LR, Yu E, Mrus JM, Carnie J, Heeren T, Koziel MJ. Influence of human immunodeficiency virus infection on the course of hepatitis C virus infection: a meta-analysis. Clin Infect Dis. 2001 Aug 15;33(4):562-9. doi: 10.1086/321909. Epub 2001 Jul 6.

  PMID: 11462196 BACKGROUND

• Kassahun K, McIntosh I, Cui D, Hreniuk D, Merschman S, Lasseter K, Azrolan N, Iwamoto M, Wagner JA, Wenning LA. Metabolism and disposition in humans of raltegravir (MK-0518), an anti-AIDS drug targeting the human immunodeficiency virus 1 integrase enzyme. Drug Metab Dispos. 2007 Sep;35(9):1657-63. doi: 10.1124/dmd.107.016196. Epub 2007 Jun 25.

  PMID: 17591678 BACKGROUND

• Iwamoto M, Wenning LA, Petry AS, Laethem M, De Smet M, Kost JT, Merschman SA, Strohmaier KM, Ramael S, Lasseter KC, Stone JA, Gottesdiener KM, Wagner JA. Safety, tolerability, and pharmacokinetics of raltegravir after single and multiple doses in healthy subjects. Clin Pharmacol Ther. 2008 Feb;83(2):293-9. doi: 10.1038/sj.clpt.6100281. Epub 2007 Aug 22.

  PMID: 17713476 BACKGROUND

• Furlan V, Demirdjian S, Bourdon O, Magdalou J, Taburet AM. Glucuronidation of drugs by hepatic microsomes derived from healthy and cirrhotic human livers. J Pharmacol Exp Ther. 1999 May;289(2):1169-75.

  PMID: 10215701 BACKGROUND

• Iwamoto M, Hanley WD, Petry AS, Friedman EJ, Kost JT, Breidinger SA, Lasseter KC, Robson R, Lunde NM, Wenning LA, Stone JA, Wagner JA. Lack of a clinically important effect of moderate hepatic insufficiency and severe renal insufficiency on raltegravir pharmacokinetics. Antimicrob Agents Chemother. 2009 May;53(5):1747-52. doi: 10.1128/AAC.01194-08. Epub 2009 Feb 17.

  PMID: 19223645 BACKGROUND

• Le Tiec C, Barrail A, Goujard C, Taburet AM. Clinical pharmacokinetics and summary of efficacy and tolerability of atazanavir. Clin Pharmacokinet. 2005;44(10):1035-50. doi: 10.2165/00003088-200544100-00003.

  PMID: 16176117 BACKGROUND

• Perloff ES, Duan SX, Skolnik PR, Greenblatt DJ, von Moltke LL. Atazanavir: effects on P-glycoprotein transport and CYP3A metabolism in vitro. Drug Metab Dispos. 2005 Jun;33(6):764-70. doi: 10.1124/dmd.104.002931. Epub 2005 Mar 11.

  PMID: 15764714 BACKGROUND

• Friis-Moller N, Sabin CA, Weber R, d'Arminio Monforte A, El-Sadr WM, Reiss P, Thiebaut R, Morfeldt L, De Wit S, Pradier C, Calvo G, Law MG, Kirk O, Phillips AN, Lundgren JD; Data Collection on Adverse Events of Anti-HIV Drugs (DAD) Study Group. Combination antiretroviral therapy and the risk of myocardial infarction. N Engl J Med. 2003 Nov 20;349(21):1993-2003. doi: 10.1056/NEJMoa030218.

  PMID: 14627784 BACKGROUND

• DAD Study Group; Friis-Moller N, Reiss P, Sabin CA, Weber R, Monforte Ad, El-Sadr W, Thiebaut R, De Wit S, Kirk O, Fontas E, Law MG, Phillips A, Lundgren JD. Class of antiretroviral drugs and the risk of myocardial infarction. N Engl J Med. 2007 Apr 26;356(17):1723-35. doi: 10.1056/NEJMoa062744.

  PMID: 17460226 BACKGROUND

• Ehret GB, Voide C, Gex-Fabry M, Chabert J, Shah D, Broers B, Piguet V, Musset T, Gaspoz JM, Perrier A, Dayer P, Desmeules JA. Drug-induced long QT syndrome in injection drug users receiving methadone: high frequency in hospitalized patients and risk factors. Arch Intern Med. 2006 Jun 26;166(12):1280-7. doi: 10.1001/archinte.166.12.1280.

  PMID: 16801510 BACKGROUND

• Krantz MJ, Lewkowiez L, Hays H, Woodroffe MA, Robertson AD, Mehler PS. Torsade de pointes associated with very-high-dose methadone. Ann Intern Med. 2002 Sep 17;137(6):501-4. doi: 10.7326/0003-4819-137-6-200209170-00010.

  PMID: 12230351 BACKGROUND

• Katchman AN, McGroary KA, Kilborn MJ, Kornick CA, Manfredi PL, Woosley RL, Ebert SN. Influence of opioid agonists on cardiac human ether-a-go-go-related gene K(+) currents. J Pharmacol Exp Ther. 2002 Nov;303(2):688-94. doi: 10.1124/jpet.102.038240.

  PMID: 12388652 BACKGROUND

• Anson BD, Ackerman MJ, Tester DJ, Will ML, Delisle BP, Anderson CL, January CT. Molecular and functional characterization of common polymorphisms in HERG (KCNH2) potassium channels. Am J Physiol Heart Circ Physiol. 2004 Jun;286(6):H2434-41. doi: 10.1152/ajpheart.00891.2003. Epub 2004 Feb 19.

  PMID: 14975928 BACKGROUND

• Anson BD, Weaver JG, Ackerman MJ, Akinsete O, Henry K, January CT, Badley AD. Blockade of HERG channels by HIV protease inhibitors. Lancet. 2005 Feb 19-25;365(9460):682-6. doi: 10.1016/S0140-6736(05)17950-1.

  PMID: 15721475 BACKGROUND

• Ly T, Ruiz ME. Prolonged QT interval and torsades de pointes associated with atazanavir therapy. Clin Infect Dis. 2007 Mar 15;44(6):e67-8. doi: 10.1086/511875. Epub 2007 Feb 1.

  PMID: 17304444 BACKGROUND

• Josephson F, Bertilsson L, Bottiger Y, Flamholc L, Gisslen M, Ormaasen V, Sonnerborg A, Diczfalusy U. CYP3A induction and inhibition by different antiretroviral regimens reflected by changes in plasma 4beta-hydroxycholesterol levels. Eur J Clin Pharmacol. 2008 Aug;64(8):775-81. doi: 10.1007/s00228-008-0492-8. Epub 2008 May 6.

  PMID: 18458892 BACKGROUND

• Gallagher DP, Kieran J, Sheehan G, Lambert J, Mahon N, Mallon PW. Ritonavir-boosted atazanavir, methadone, and ventricular tachycardia: 2 case reports. Clin Infect Dis. 2008 Aug 1;47(3):e36-8. doi: 10.1086/589869.

  PMID: 18558878 BACKGROUND

• Nordin C, Kohli A, Beca S, Zaharia V, Grant T, Leider J, Marantz P. Importance of hepatitis C coinfection in the development of QT prolongation in HIV-infected patients. J Electrocardiol. 2006 Apr;39(2):199-205. doi: 10.1016/j.jelectrocard.2005.09.001. Epub 2005 Nov 28.

  PMID: 16580420 BACKGROUND

• Iwamoto M, Kost JT, Mistry GC, Wenning LA, Breidinger SA, Marbury TC, Stone JA, Gottesdiener KM, Bloomfield DM, Wagner JA. Raltegravir thorough QT/QTc study: a single supratherapeutic dose of raltegravir does not prolong the QTcF interval. J Clin Pharmacol. 2008 Jun;48(6):726-33. doi: 10.1177/0091270008318007. Epub 2008 Apr 25.

  PMID: 18441333 BACKGROUND

MeSH Terms

Conditions

HIV Infections; Hepatitis C; Coinfection

Interventions

Raltegravir Potassium; atazanavir, ritonavir drug combination; Atazanavir Sulfate; Ritonavir

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases; Hepatitis, Viral, Human; Flaviviridae Infections; Hepatitis; Liver Diseases; Digestive System Diseases

Intervention Hierarchy (Ancestors)

Pyrrolidinones; Pyrrolidines; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyridines; Oligopeptides; Peptides; Amino Acids, Peptides, and Proteins; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles

Study Officials

• Colm Bergin, MD, FRCPI

  Department of Genitourinary Medicine and Infectious Diseases, St. James's Hospital, Dublin, Ireland

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Colm Bergin, MD, FRCPI

CONTACT

+35314162507; cbergin@stjames.ie

James Woo, MB, MRCPI

CONTACT

+353868108086; wooj@tcd.ie

Study Design

• Study Type: interventional
• Phase: phase 4
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: April 14, 2010
• First Posted: April 16, 2010
• Study Start: August 1, 2010
• Primary Completion: December 1, 2012
• Study Completion: December 1, 2012
• Last Updated: July 21, 2011

Record last verified: 2010-03

Locations

IE (2)