Clinical Trial: A Comparative Study of a Combination of Zidovudine, Didanosine, and Double-Blinded Nevirapine Versus a Combination of Zidovudine and Didanosine

This study has been completed.

Sponsors and Collaborators: National Institute of Allergy and Infectious Diseases (NIAID)
Bristol-Myers Squibb
Glaxo Wellcome
Information provided by: National Institute of Allergy and Infectious Diseases (NIAID)

Purpose

To assess the safety and toxicity of zidovudine (AZT)/didanosine (ddI) versus AZT/ddI combined with nevirapine in HIV-infected patients, and to obtain preliminary anti-HIV activity data using immunologic and virologic markers. Previous in vitro studies suggest that HIV that has already developed resistance to AZT and ddI is less able to develop resistance to nevirapine, a non-nucleoside reverse transcriptase inhibitor. Thus, convergent combination therapy with these three drugs in HIV-infected patients may prove more effective.

Condition Treatment or Intervention Phase
HIV Infections
 Drug: Nevirapine
 Drug: Zidovudine
 Drug: Didanosine
Phase II

MedlinePlus related topics:  AIDS

Study Type: Interventional
Study Design: Treatment, Double-Blind, Pharmacokinetics Study

Further Study Details: 

Expected Total Enrollment:  400

Previous in vitro studies suggest that HIV that has already developed resistance to AZT and ddI is less able to develop resistance to nevirapine, a non-nucleoside reverse transcriptase inhibitor. Thus, convergent combination therapy with these three drugs in HIV-infected patients may prove more effective.

Patients are randomized to receive AZT/ddI plus either nevirapine or placebo daily for 48 weeks, with possible extension for at least 12 weeks. At eight participating sites, ACTG 808 and 809 will be conducted as virologic and pharmacokinetic substudies.

Eligibility

Ages Eligible for Study:  13 Years and above,  Genders Eligible for Study:  Both

Criteria

Inclusion Criteria

Concurrent Medication: Required:

  • PCP prophylaxis for patients with CD4 count < 200 cells/mm3 or a prior history of PCP.

Allowed:

  • Trimethoprim with sulfamethoxazole or dapsone, intravenous pentamidine, atovaquone, primaquine-clindamycin or trimetrexate for acute PCP.
  • Topical antifungals, clotrimazole, ketoconazole, fluconazole, and amphotericin B for treatment of mucosal and esophageal candidiasis.
  • Prophylaxis or therapy for opportunistic infections, as indicated, with other medications such as itraconazole, isoniazid, pyrazinamide, clofazimine, clarithromycin, azithromycin, ethambutol, amikacin, ciprofloxacin, ofloxacin, pyrimethamine, sulfadiazine, and clindamycin.
  • Maintenance therapy for opportunistic infections as long as patients have been on a stable dosage regimen for 1 month prior to study entry.
  • Ganciclovir for CMV retinitis or gastrointestinal disease as long as patients have been on a stable dose for at least 1 month prior to study entry with no grade 3 or 4 neutropenia or dependence on G-CSF.
  • Acyclovir (<= 1000 mg/day) for maintenance of herpes simplex virus infections.
  • Erythropoietin or G-CSF if clinically indicated.
  • Antibiotics for bacterial infections unless specifically excluded.
  • Rifampin or rifabutin.
  • Symptomatic treatments such as antipyretics, analgesics, and antiemetics.

Concurrent Treatment: Allowed:

Prior Medication: Required:

  • At least 6 months of prior cumulative nucleoside therapy with AZT, ddI, or ddC, given as monotherapy or in combination.

Patients must have:

  • Prior or current documentation of HIV seropositivity by ELISA confirmed by Western blot, positive HIV antigen, or positive HIV culture, or a second antibody test by a method other than ELISA.
  • CD4 count <= 350 cells/mm3.
  • Prior cumulative nucleoside therapy of >= 6 months.
  • Consent of parent or guardian if less than 18 years of age.

Exclusion Criteria

Concurrent Medication: Excluded:

  • Antiretroviral therapies other than study medications.
  • Systemic corticosteroids given consecutively for > 21 days.
  • Induction or maintenance with foscarnet.
  • Systemic cytotoxic chemotherapy for a malignancy.
  • Erythromycin.
  • Coumadin/warfarin.
  • Phenytoin or phenobarbital.
  • Amoxicillin/clavulanate acid (Augmentin) or ticarcillin/clavulanate acid (Timentin).

Patients with the following prior conditions are excluded:

  • History of pancreatitis.
  • History of intolerance to 500 or 600 mg/day AZT or to 400 mg/day ddI tablets or 500 mg/day ddI sachets.
  • History of grade 2 or worse peripheral neuropathy.

Prior Medication: Excluded at any time: Prior non-nucleoside reverse transcriptase inhibitors (NVP; L697,611; TIBO; atevirdine).

Excluded within 14 days prior to study entry:

  • Acute treatment for a serious infection or any opportunistic infection.
  • Biologic response modifiers such as interferon and IL-2.
  • Erythromycin.
  • Coumadin/warfarin.
  • Phenytoin or phenobarbital.
  • Ticarcillin/clavulanate acid (Timentin) or amoxicillin/clavulanate acid (Augmentin).

Location Information


Alabama
      Univ of Alabama at Birmingham, Birmingham,  Alabama,  35294,  United States

California
      Univ of California / San Diego Treatment Ctr, San Diego,  California,  921036325,  United States

      San Francisco Gen Hosp, San Francisco,  California,  941102859,  United States

      San Francisco AIDS Clinic / San Francisco Gen Hosp, San Francisco,  California,  941102859,  United States

      Summitt Med Ctr / San Francisco Gen Hosp, Oakland,  California,  94609,  United States

      Univ of Southern California / LA County USC Med Ctr, Los Angeles,  California,  900331079,  United States

      Highland Gen Hosp / San Francisco Gen Hosp, Oakland,  California,  946021018,  United States

Colorado
      Univ of Colorado Health Sciences Ctr, Denver,  Colorado,  80262,  United States

Florida
      Univ of Miami School of Medicine, Miami,  Florida,  331361013,  United States

Illinois
      Northwestern Univ Med School, Chicago,  Illinois,  60611,  United States

      Rush Presbyterian - Saint Luke's Med Ctr, Chicago,  Illinois,  60612,  United States

      Cook County Hosp, Chicago,  Illinois,  60612,  United States

Indiana
      Indiana Univ Hosp, Indianapolis,  Indiana,  462025250,  United States

Iowa
      Univ of Iowa Hosp and Clinic, Iowa City,  Iowa,  52242,  United States

Massachusetts
      Harvard (Massachusetts Gen Hosp), Boston,  Massachusetts,  02114,  United States

      Beth Israel Deaconess Med Ctr, Boston,  Massachusetts,  02215,  United States

      Beth Israel Deaconess - West Campus, Boston,  Massachusetts,  02215,  United States

      Boston Med Ctr, Boston,  Massachusetts,  02118,  United States

Minnesota
      Univ of Minnesota, Minneapolis,  Minnesota,  55455,  United States

      St Paul Ramsey Med Ctr, St. Paul,  Minnesota,  55101,  United States

      Hennepin County Med Clinic, Minneapolis,  Minnesota,  55415,  United States

Nebraska
      Univ of Nebraska Med Ctr, Omaha,  Nebraska,  681985130,  United States

New York
      Montefiore Drug Treatment Ctr / Bronx Municipal Hosp, Bronx,  New York,  10461,  United States

      Montefiore Family Health Ctr / Bronx Municipal Hosp, Bronx,  New York,  10461,  United States

      Samaritan Village Inc / Bronx Municipal Hosp, Bronx,  New York,  10461,  United States

      Mem Sloan - Kettering Cancer Ctr, New York,  New York,  10021,  United States

      Mount Sinai Med Ctr, New York,  New York,  10029,  United States

      Jack Weiler Hosp / Bronx Municipal Hosp, Bronx,  New York,  10465,  United States

      Cornell Univ Med Ctr, New York,  New York,  10021,  United States

      Bronx Municipal Hosp Ctr/Jacobi Med Ctr, Bronx,  New York,  10461,  United States

      Montefiore Med Ctr / Bronx Municipal Hosp, Bronx,  New York,  10467,  United States

      Beth Israel Med Ctr, New York,  New York,  10003,  United States

      City Hosp Ctr at Elmhurst / Mount Sinai Hosp, Elmhurst,  New York,  11373,  United States

      Saint Clare's Hosp and Health Ctr, New York,  New York,  10019,  United States

      North Central Bronx Hosp / Bronx Municipal Hosp, Bronx,  New York,  10467,  United States

      Comprehensive Health Care Ctr / Bronx Municipal Hosp, Bronx,  New York,  10461,  United States

North Carolina
      Carolinas Med Ctr, Charlotte,  North Carolina,  28203,  United States

      Univ of North Carolina, Chapel Hill,  North Carolina,  275997215,  United States

      Moses H Cone Memorial Hosp, Greensboro,  North Carolina,  27401,  United States

      Wake County Dept of Health, Raleigh,  North Carolina,  27610,  United States

Ohio
      Univ of Cincinnati, Cincinnati,  Ohio,  452670405,  United States

Pennsylvania
      Univ of Pennsylvania at Philadelphia, Philadelphia,  Pennsylvania,  19104,  United States

      Thomas Jefferson Univ Hosp, Philadelphia,  Pennsylvania,  191075098,  United States

      Girard Med Ctr, Philadelphia,  Pennsylvania,  191046073,  United States

Study chairs or principal investigators

D'Aquila R,  Study Chair
Hirsch M,  Study Chair

More Information

Click here for more information about Zidovudine

Click here for more information about Didanosine

Click here for more information about Nevirapine

Publications

D'Aquila RT, Hughes MD, Johnson VA, Fischl MA, Sommadossi JP, Liou SH, Timpone J, Myers M, Basgoz N, Niu M, Hirsch MS. Nevirapine, zidovudine, and didanosine compared with zidovudine and didanosine in patients with HIV-1 infection. A randomized, double-blind, placebo-controlled trial. National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators. Ann Intern Med. 1996 Jun 15;124(12):1019-30.

Dusek A, Hall D, Lamson M, Myers M. Once-daily dosing of nevirapine: a retrospective, cross-study analysis. Int Conf AIDS. 1998;12:85 (abstract no 12360)

Leigh Brown AJ, D'Aquila RT, Johnson VA, Kuritzkes DR, Richman DD. Baseline sequence clusters predict response to combination therapy in ACTG 241. Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:211 (abstract no 704)

Fiscus SA, Welles SL, Spector SA, Lathey JL. Length of incubation time for human immunodeficiency virus cultures. J Clin Microbiol. 1995 Jan;33(1):246-7.

D'Aquila RT, Sutton L, Savara A, Hughes MD, Johnson VA. CCR5/delta(ccr5) heterozygosity: a selective pressure for the syncytium-inducing human immunodeficiency virus type 1 phenotype. NIAID AIDS Clinical Trials Group Protocol 241 Virology Team. J Infect Dis. 1998 Jun;177(6):1549-53.

[No authors listed] Virus sidesteps convergent therapy. GMHC Treat Issues. 1995 Jan;9(1):6. No abstract available.

Precious H, Leigh Brown AJ, Gunthard HF, Wong JK, D'Aquila RT, Johnson VA, Kuritzkes DR, Richman DD. A multiple regression model predicting response to combination therapy from baseline sequence data identifies amino acid sites not previously associated with resistance. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:69 (abstract no 14)

Zhou XJ, Sheiner LB, D'Aquila RT, Hughes MD, Hirsch MS, Fischl MA, Johnson VA, Myers M, Sommadossi JP. Population pharmacokinetics of nevirapine, zidovudine, and didanosine in human immunodeficiency virus-infected patients. The National Institute of Allergy and Infectious Diseases AIDS Clinical Trials Group Protocol 241 Investigators. Antimicrob Agents Chemother. 1999 Jan;43(1):121-8.

Hall D, Robinson P, Cort S, Kohlbrenner V, Leitz G, Myers M. Duration of effect of nevirapine (NVP), a cross-trial analysis of three controlled studies. Conf Retroviruses Opportunistic Infect. 1996 Jan 28-Feb 1;3rd:79

Hughes MD, Johnson VA, Hirsch MS, Bremer JW, Elbeik T, Erice A, Kuritzkes DR, Scott WA, Spector SA, Basgoz N, Fischl MA, D'Aquila RT. Monitoring plasma HIV-1 RNA levels in addition to CD4+ lymphocyte count improves assessment of antiretroviral therapeutic response. ACTG 241 Protocol Virology Substudy Team. Ann Intern Med. 1997 Jun 15;126(12):929-38.

Study ID Numbers:  ACTG 241
Record last reviewed:  December 1994
Last Updated:  April 7, 2005
Record first received:  November 2, 1999
ClinicalTrials.gov Identifier:  NCT00000770
Health Authority: United States: Federal Government
ClinicalTrials.gov processed this record on 2005-04-08


Source: ClinicalTrials.gov
Cache Date: April 9, 2005

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