A Study of Three Treatment Combinations Using Zidovudine Plus Lamivudine Plus Indinavir in HIV-Infected Patients

HIV Infections Clinical Trial

Official title:

A Prospective Randomized Double-Blind Trial of Three Maintenance Regimens for HIV-Infected Subjects Receiving Induction Therapy With Zidovudine, Lamivudine and Indinavir

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00001084
• Other study ID #: ACTG 343
• Secondary ID: 11314
• Status: Completed
• Phase: Phase 2
• Est. completion date: December 1997

Study information

• Verified date: October 2021
• Source: National Institute of Allergy and Infectious Diseases (NIAID)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

To compare the proportion of patients who sustain suppression of plasma HIV RNA to undetectable levels [AS PER AMENDMENT 09/19/97: below 200 copies/mL by Roche UltraSensitive assay] among the 3 regimens during the maintenance phase.

The objective of antiretroviral therapy is to reduce HIV replication, preserve immunologic function and delay the development of HIV-related complications. In patients administered potent antiretroviral regimens, HIV RNA levels are reduced below 500 copies/ml of plasma and below the level of detection of commercially available assays. This protocol attempts to learn if a less intensive regimen can successfully sustain viral suppression after induction with a triple-drug regimen. The study also addresses whether HIV can be eradicated in patients following prolonged treatment with induction and maintenance regimens.

Description:

The objective of antiretroviral therapy is to reduce HIV replication, preserve immunologic function and delay the development of HIV-related complications. In patients administered potent antiretroviral regimens, HIV RNA levels are reduced below 500 copies/ml of plasma and below the level of detection of commercially available assays. This protocol attempts to learn if a less intensive regimen can successfully sustain viral suppression after induction with a triple-drug regimen. The study also addresses whether HIV can be eradicated in patients following prolonged treatment with induction and maintenance regimens.

All patients will receive open label induction therapy with zidovudine (ZDV), lamivudine (3TC) and indinavir (IDV) for 6 months. Following the 6 month induction phase, patients with undetectable plasma HIV RNA at weeks 16, 20 and 24 will enter the maintenance phase [blinded maintenance phase AS PER AMENDMENT 09/19/97] and be randomized to one of three maintenance regimens, i.e., either continued ZDV/3TC/IDV (control), or ZDV/3TC/IDV placebo or ZDV placebo/3TC placebo/IDV. Prior to randomization, patients are stratified according to entry HIV RNA level (greater than or equal to 30,000 or less than 30,000 copies/ml) and by prior ZDV therapy (at least 7 days or less than 7 days). After 12 months [AS PER AMENDMENT 09/19/97: 18 months] of maintenance therapy, treatment will be withdrawn at 6-month intervals in randomly-selected patients who have achieved undetectable HIV RNA. AS PER 09/19/97 AMENDMENT: After 18 months of blinded maintenance therapy, treatment is unblinded for patients whose HIV RNA levels remain detectable. Such patients receive optimal therapy, either continuing the protocol regimen or initiating alternative therapy.

AS PER AMENDMENT 2/27/98: An interim review conducted in January, 1998 demonstrated that the strategy of less intensive antiviral therapy after 6 months of IDV/3TC/ZDV induction therapy is less effective than continuation of triple drug therapy except for ZDV-naive patients assigned to ZDV/3TC. Therefore, the maintenance phase of this study has been discontinued.

Patients currently on blinded maintenance are unblinded immediately and have the option of reinitiating open-label triple therapy with IDV/3TC/ZDV or discontinuing study treatment. Patients currently on induction may register for continued open-label triple therapy or may discontinue study treatment. This amendment allows treatment extension so that subjects may receive open-label triple therapy until May 31, 1998. At that time, a rollover protocol or another modification with a longer period of drug supply may become available. Patients who choose to go off treatment are followed until May 31, 1998.

AS PER AMENDMENT 04/23/98: This study will now provide treatment with open-label ZDV/3TC/IDV until August 1, 1998. A rollover protocol or another 343 protocol modification with a longer period of drug supply may become available, but this cannot be guaranteed.

AS PER AMENDMENT 06/19/98: This study will now provide treatment with open-label ZDV/3TC/IDV until either November 1, 1998 or until 3 months after the rollover study (A5025) is available to the study sites (whichever comes first).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 500
• Est. completion date: December 1997
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

Inclusion Criteria

Patients must have:

• Documented HIV infection.

• A CD4 cell count >= 200 cells/mm3 within 90 days prior to study entry.

• Plasma HIV RNA >= 1000 copies/ml within 90 days prior to study entry.

Exclusion Criteria

Co-existing Condition:

Patients with any of the following conditions or symptoms are excluded:

• A malignancy that requires systemic chemotherapy.

Concurrent Medication:

Excluded:

• Oral ketoconazole (Nizoral), terfenadine (Seldane), astemizole (Hismanal), cisapride (Propulsid), triazolam (Halcion) or midazolam (Versed).

• All antiretroviral therapies other than study medications.

• Rifabutin and rifampin.

• Investigational drugs and vaccines.

• Systemic cytotoxic chemotherapy.

• Interferon, interleukins, GM-CSF and HIV vaccines.

Patients with any of the following prior conditions are excluded:

• Unexplained temperature > 38.5 degrees C for any 7 days within 30 days prior to study entry.

• Chronic diarrhea as defined as > 3 liquid stools per day persisting for 15 days within 30 days prior to study entry.

• Proven or suspected acute hepatitis within 30 days prior to study entry, even if AST and ALT are <= 5.0 X ULN (upper limit of normal).

• A history of >= Grade 2 bilateral peripheral neuropathy within 60 days prior to study entry.

• A history of intolerance to 300 mg/day of ZDV defined as any toxicity requiring a dose reduction or termination of ZDV.

Prior Medication:

Excluded:

• Acute therapy for an infection or other medical illness within 14 days prior to study entry.

• Any prior therapy with 3TC or experimental drug 1592.

• More than 2 weeks of lifetime exposure to protease inhibitor therapy; any exposure within 14 days prior to study entry.

• Interferons, interleukins, GM-CSF or HIV vaccines within 30 days prior to study entry.

• Any experimental therapy (drugs or vaccines) within 30 days prior to study entry.

• Rifampin or rifabutin within 14 days prior to study entry.

• Systemic cytotoxic chemotherapy within 30 days prior to study entry.

• Oral ketoconazole (Nizoral), terfenadine (Seldane), astemizole (Hismanal), cisapride (Propulsid), triazolam (Halcion) or midazolam (Versed).

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• Indinavir sulfate

• Lamivudine

• Stavudine

• Zidovudine

Locations

Country	Name	City	State
United States	Emory Univ	Atlanta	Georgia
United States	Johns Hopkins Hosp	Baltimore	Maryland
United States	State of MD Div of Corrections / Johns Hopkins Univ Hosp	Baltimore	Maryland
United States	Beth Israel Deaconess - West Campus	Boston	Massachusetts
United States	Harvard (Massachusetts Gen Hosp)	Boston	Massachusetts
United States	Univ of North Carolina	Chapel Hill	North Carolina
United States	Carolinas Med Ctr	Charlotte	North Carolina
United States	Cook County Hosp	Chicago	Illinois
United States	Northwestern Univ Med School	Chicago	Illinois
United States	Univ of Cincinnati	Cincinnati	Ohio
United States	Case Western Reserve Univ	Cleveland	Ohio
United States	MetroHealth Med Ctr	Cleveland	Ohio
United States	Ohio State Univ Hosp Clinic	Columbus	Ohio
United States	Univ of Colorado Health Sciences Ctr	Denver	Colorado
United States	Univ of Texas Galveston	Galveston	Texas
United States	Moses H Cone Memorial Hosp	Greensboro	North Carolina
United States	Queens Med Ctr	Honolulu	Hawaii
United States	Univ of Hawaii	Honolulu	Hawaii
United States	Division of Inf Diseases/ Indiana Univ Hosp	Indianapolis	Indiana
United States	Indiana Univ Hosp	Indianapolis	Indiana
United States	Univ of Iowa Hosp and Clinic	Iowa City	Iowa
United States	Univ of Southern California / LA County USC Med Ctr	Los Angeles	California
United States	Univ of Miami School of Medicine	Miami	Florida
United States	Hennepin County Med Clinic	Minneapolis	Minnesota
United States	Univ of Minnesota	Minneapolis	Minnesota
United States	Tulane Med Ctr Hosp	New Orleans	Louisiana
United States	Tulane Univ School of Medicine	New Orleans	Louisiana
United States	Bellevue Hosp / New York Univ Med Ctr	New York	New York
United States	Beth Israel Med Ctr	New York	New York
United States	Mem Sloan - Kettering Cancer Ctr	New York	New York
United States	Mount Sinai Med Ctr	New York	New York
United States	Saint Clare's Hosp and Health Ctr	New York	New York
United States	Univ of Nebraska Med Ctr	Omaha	Nebraska
United States	Univ of Rochester Medical Center	Rochester	New York
United States	St Louis Regional Hosp / St Louis Regional Med Ctr	Saint Louis	Missouri
United States	St Paul Ramsey Med Ctr	Saint Paul	Minnesota
United States	Univ of California / San Diego Treatment Ctr	San Diego	California
United States	San Francisco Gen Hosp	San Francisco	California
United States	Stanford at Kaiser / Kaiser Permanente Med Ctr	San Francisco	California
United States	Santa Clara Valley Med Ctr / AIDS Community Rsch Consortium	San Jose	California
United States	Univ of Washington	Seattle	Washington
United States	San Mateo AIDS Program / Stanford Univ	Stanford	California
United States	Stanford Univ Med Ctr	Stanford	California
United States	Harbor UCLA Med Ctr	Torrance	California
United States	Julio Arroyo	West Columbia	South Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)

Country where clinical trial is conducted

United States, 

References & Publications (10)

Bowersox J. ACTG 343: three drugs better than two for maintaining HIV suppression. NIAID AIDS Agenda. 1998 Mar:1-2, 10-1. — View Citation

Gulick RM, Mellors J, Havlir D, Eron J, Gonzalez C, McMahon D, Richman D, Valentine F, Rooney J, Jonas L, Meibohm A, Emini E, Chodakewitz J. Potent and sustained antiretroviral activity of indinavir (IDV), zidovudine (ZDV) and lamivudine (3TC). Int Conf AIDS. 1996 Jul 7-12;11(Program Supplement):19 (abstract no ThB931)

Günthard HF, Havlir DV, Fiscus S, Zhang ZQ, Eron J, Mellors J, Gulick R, Frost SD, Brown AJ, Schleif W, Valentine F, Jonas L, Meibohm A, Ignacio CC, Isaacs R, Gamagami R, Emini E, Haase A, Richman DD, Wong JK. Residual human immunodeficiency virus (HIV) Type 1 RNA and DNA in lymph nodes and HIV RNA in genital secretions and in cerebrospinal fluid after suppression of viremia for 2 years. J Infect Dis. 2001 May 1;183(9):1318-27. Epub 2001 Apr 10. — View Citation

Havlir DV, Bassett R, Levitan D, Gilbert P, Tebas P, Collier AC, Hirsch MS, Ignacio C, Condra J, Günthard HF, Richman DD, Wong JK. Prevalence and predictive value of intermittent viremia with combination hiv therapy. JAMA. 2001 Jul 11;286(2):171-9. — View Citation

Havlir DV, Hirsch M, Collier A, Marschner I, Bassett R, Tebas P, Ioannidis J, Richman DD. Randomized trial of indinavir (IDV) vs. zidovudine (ZDV)/lamivudine (3TC) vs IDV/ZDV/3TC maintenance therapy after induction IDV/ZDV/3TC therapy. Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:225 (abstract no LB16)

Havlir DV, Marschner IC, Hirsch MS, Collier AC, Tebas P, Bassett RL, Ioannidis JP, Holohan MK, Leavitt R, Boone G, Richman DD. Maintenance antiretroviral therapies in HIV-infected subjects with undetectable plasma HIV RNA after triple-drug therapy. AIDS Clinical Trials Group Study 343 Team. N Engl J Med. 1998 Oct 29;339(18):1261-8. — View Citation

Maenza JR. ACTG 343: (why) we can't relax our grip on viral suppression. Hopkins HIV Rep. 1998 May;10(3):10. — View Citation

O'Brien TR, McDermott DH, Ioannidis JP, Carrington M, Murphy PM, Havlir DV, Richman DD. Effect of chemokine receptor gene polymorphisms on the response to potent antiretroviral therapy. AIDS. 2000 May 5;14(7):821-6. — View Citation

Seth A, Markee J, Ap S, Sevin A, Hoering A, Hirsch M, Collier A, Letvin N, McElrath MJ. Alterations in T cell phenotype and antigen-specific cytotoxicity in patients receiving three anti-retroviral agents (ACTG protocol 343). Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:132 (abstract no 340)

Zhou XJ, Havlir DV, Richman DD, Acosta EP, Hirsch M, Collier AC, Tebas P, Sommadossi JP; AIDS Clinical Trials Study 343 Investigators. Plasma population pharmacokinetics and penetration into cerebrospinal fluid of indinavir in combination with zidovudine and lamivudine in HIV-1-infected patients. AIDS. 2000 Dec 22;14(18):2869-76. — View Citation