The Effectiveness of Three Drug Combinations in HIV-Infected Patients Who Have Taken Zidovudine for More Than 12 Weeks

NCT ID: NCT00001063

Last Updated: 2021-11-04

Study Results

Results pending

The study team has not published outcome measurements, participant flow, or safety data for this trial yet. Check back later for updates.

Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

200 participants

Study Classification

INTERVENTIONAL

Study Completion Date

1997-11-30

Brief Summary

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To compare the effect of stavudine (d4T) alone or with zidovudine (AZT) versus didanosine (ddI) alone or with AZT on CD4 counts, HIV RNA levels, and viral load in HIV-infected patients \[AS PER AMENDMENT 3/21/97: To compare the effects of d4T alone versus ddI alone versus AZT plus ddI\]. To compare the safety of d4T/AZT. AS PER AMENDMENT 3/21/97: To evaluate the pharmacokinetic interactions of AZT and d4T both at an extracellular and intracellular level.

Although AZT and ddI can delay the advancement of HIV disease, the benefit of either of these drugs has proven to be only temporary. d4T, a new nucleoside analog with a favorable toxicity profile and demonstrated activity against HIV, offers an additional therapeutic option. It is reasonably assumed that the benefit of an antiretroviral agent in terms of delaying clinical disease progression is directly related to its ability to achieve and sustain viral suppression; thus, this study measures effects on viral load and CD4 count.

Detailed Description

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Although AZT and ddI can delay the advancement of HIV disease, the benefit of either of these drugs has proven to be only temporary. d4T, a new nucleoside analog with a favorable toxicity profile and demonstrated activity against HIV, offers an additional therapeutic option. It is reasonably assumed that the benefit of an antiretroviral agent in terms of delaying clinical disease progression is directly related to its ability to achieve and sustain viral suppression; thus, this study measures effects on viral load and CD4 count.

Patients are randomized in a blinded fashion to receive AZT or placebo in combination with open-label d4T or ddI for up to 48 weeks. AS PER AMENDMENT 3/21/97: The study is now composed of three arms: open-label d4T versus open-label ddI plus blinded AZT placebo versus blinded AZT plus open-label ddI. Patients originally assigned to the d4T + AZT arm, which was closed 10/96, will be given the option of discontinuing AZT and remaining on d4T monotherapy or discontinuing all study drugs. In addition, all study participants will be asked to participate in a pharmacology substudy.

Conditions

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HIV Infections

Keywords

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Didanosine Drug Therapy, Combination AIDS-Related Complex Zidovudine Stavudine

Study Design

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Primary Study Purpose

TREATMENT

Interventions

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Stavudine

Intervention Type DRUG

Zidovudine

Intervention Type DRUG

Didanosine

Intervention Type DRUG

Eligibility Criteria

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Inclusion Criteria

Concurrent Medication:

Required for patients whose CD4 count falls below 200 cells/mm3:

* PCP prophylaxis with TMP/SMX, aerosolized pentamidine, or dapsone.

Allowed:

* Atovaquone, IV pentamidine, trimethoprim-dapsone, clindamycin-primaquine, trimetrexate, or TMP/SMX for acute PCP.
* Topical antifungals, clotrimazole, ketoconazole, fluconazole, and amphotericin B for mucosal and esophageal candidiasis.
* Itraconazole.
* Amphotericin B.
* Rifabutin.
* Isoniazid.
* Pyrazinamide.
* Clofazimine.
* Clarithromycin.
* Azithromycin.
* Ethambutol.
* Amikacin.
* Ciprofloxacin.
* Ofloxacin.
* Pyrimethamine.
* Sulfadiazine.
* Clindamycin.
* Ganciclovir.
* G-CSF.
* Acyclovir (up to 1000 mg/day).
* Erythropoietin.
* Antibiotics for bacterial infections.
* Antipyretics.
* Analgesics.
* Antiemetics.
* Rifampin.

Concurrent Treatment:

Allowed:

* Local radiation therapy.

Patients must have:

* HIV infection.
* CD4 count 300-600 cells/mm3.
* More than 12 weeks (was 24 weeks, AMENDED 3/31/96) of total prior AZT ( \> 500 mg/day without serious adverse event). Subjects must be actively taking ZDV for at least 4 continuous weeks up to the time of study entry.
* No prior or current history of AIDS.
* No active opportunistic infection.
* Life expectancy of at least 2 years.
* Consent of patient and parent or guardian if less than 18 years of age.

NOTE:

* Protocol is approved for prisoner enrollment.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

* Malignancy requiring systemic cytotoxic chemotherapy.
* Serious underlying medical condition other than HIV that would reduce life expectancy to \< 2 years.

Concurrent Medication:

Excluded:

* Antiretrovirals other than study drugs.
* Foscarnet.

Patients with the following prior conditions are excluded:

* Unexplained temperature \>= 38.5 C for 7 days or chronic diarrhea (\>= three stools daily) for 15 days, if occurring within 30 days prior to study entry.
* History of acute or chronic pancreatitis.
* History of grade 2 or higher peripheral neuropathy.
* History of grade 3 or worse intolerance to 500-600 mg/day AZT.

Prior Medication:

Excluded:

(within 30 days prior to study entry)

* Prior ddI, ddC, 3TC or d4T (more than 2 weeks total).
* Non-nucleoside reverse transcriptase inhibitor or protease inhibitor.
* Biologic response modifiers such as interferon and IL-2.
* Other experimental therapy.
Minimum Eligible Age

12 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No

Sponsors

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Bristol-Myers Squibb

INDUSTRY

Sponsor Role collaborator

National Institute of Allergy and Infectious Diseases (NIAID)

NIH

Sponsor Role lead

Responsible Party

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Responsibility Role SPONSOR

Principal Investigators

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Havlir D

Role: STUDY_CHAIR

Richman D

Role: STUDY_CHAIR

Pollard R

Role: STUDY_CHAIR

Friedland G

Role: STUDY_CHAIR

Locations

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UCLA CARE Center CRS

Los Angeles, California, United States

Site Status

Stanford CRS

Palo Alto, California, United States

Site Status

Ucsd, Avrc Crs

San Diego, California, United States

Site Status

Ucsf Aids Crs

San Francisco, California, United States

Site Status

Harbor-UCLA Med. Ctr. CRS

Torrance, California, United States

Site Status

University of Colorado Hospital CRS

Aurora, Colorado, United States

Site Status

Children's National Med. Ctr., ACTU

Washington D.C., District of Columbia, United States

Site Status

Univ. of Florida Jacksonville NICHD CRS

Jacksonville, Florida, United States

Site Status

Univ. of Miami AIDS CRS

Miami, Florida, United States

Site Status

Univ. of Hawaii at Manoa, Leahi Hosp.

Honolulu, Hawaii, United States

Site Status

Northwestern University CRS

Chicago, Illinois, United States

Site Status

Cook County Hosp. CORE Ctr.

Chicago, Illinois, United States

Site Status

Rush Univ. Med. Ctr. ACTG CRS

Chicago, Illinois, United States

Site Status

Weiss Memorial Hosp.

Chicago, Illinois, United States

Site Status

Indiana Univ. School of Medicine, Infectious Disease Research Clinic

Indianapolis, Indiana, United States

Site Status

Indiana Univ. School of Medicine, Wishard Memorial

Indianapolis, Indiana, United States

Site Status

Methodist Hosp. of Indiana

Indianapolis, Indiana, United States

Site Status

Tulane Hemophilia Treatment Ctr.

New Orleans, Louisiana, United States

Site Status

Massachusetts General Hospital ACTG CRS

Boston, Massachusetts, United States

Site Status

Bmc Actg Crs

Boston, Massachusetts, United States

Site Status

Beth Israel Deaconess Med. Ctr., ACTG CRS

Boston, Massachusetts, United States

Site Status

Hennepin County Med. Ctr., Div. of Infectious Diseases

Minneapolis, Minnesota, United States

Site Status

University of Minnesota, ACTU

Minneapolis, Minnesota, United States

Site Status

St. Louis ConnectCare, Infectious Diseases Clinic

St Louis, Missouri, United States

Site Status

Washington U CRS

St Louis, Missouri, United States

Site Status

SUNY Downstate Med. Ctr., Children's Hosp. at Downstate NICHD CRS

Brooklyn, New York, United States

Site Status

SUNY - Buffalo, Erie County Medical Ctr.

Buffalo, New York, United States

Site Status

Univ. of Rochester ACTG CRS

Rochester, New York, United States

Site Status

Univ. of Cincinnati CRS

Cincinnati, Ohio, United States

Site Status

The Ohio State Univ. AIDS CRS

Columbus, Ohio, United States

Site Status

University of Washington AIDS CRS

Seattle, Washington, United States

Site Status

San Juan City Hosp. PR NICHD CRS

San Juan, , Puerto Rico

Site Status

Puerto Rico-AIDS CRS

San Juan, , Puerto Rico

Site Status

Countries

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United States Puerto Rico

References

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d4T+AZT--unexpected CD4 drop seen in study. AIDS Treat News. 1996 Dec 20;(No 261):1.

Reference Type BACKGROUND
PMID: 11364024 (View on PubMed)

Shaefer M, Hardy WD, Shaker-Irwin L, Williams V, Maude C, Thommes J, Graham N. HIV viral load response in subjects switched from zidovudine (ZDV)-containing to stavudine (D4T)-containing regimens in the Pacific Oaks Population Study (POPS). Int Conf AIDS. 1998;12:57 (abstract no 12228)

Reference Type BACKGROUND

Havlir DV, Friedland G, Pollard R, Tierney C, Smeaton L, Fox L, Richman DD. Combination zidovudine (ZDV) and stavudine (d4T) therapy versus other nucleosides: report of two randomized trials (ACTG 290 and 298). Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:79 (abstract no 2)

Reference Type BACKGROUND

Cadman J. 2, 4, 6, 8, who's afraid to phosphorylate? GMHC Treat Issues. 1998 Feb;12(2):6-8.

Reference Type BACKGROUND
PMID: 11365218 (View on PubMed)

Havlir DV, Tierney C, Friedland GH, Pollard RB, Smeaton L, Sommadossi JP, Fox L, Kessler H, Fife KH, Richman DD. In vivo antagonism with zidovudine plus stavudine combination therapy. J Infect Dis. 2000 Jul;182(1):321-5. doi: 10.1086/315683. Epub 2000 Jul 6.

Reference Type BACKGROUND
PMID: 10882616 (View on PubMed)

Sommadossi JP, Zhou XJ, Moore J, Havlir DV, Friedland G, Tierney C, Smeaton L, Fox L, Richman D, Pollard R. Impairment of stavudine (d4T) phosphorylation in patients receiving a combination of zidovudine (ZDV) and d4T (ACTG 290). Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:79 (abstract no 3)

Reference Type BACKGROUND

Other Identifiers

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11266

Identifier Type: REGISTRY

Identifier Source: secondary_id

ACTG 290

Identifier Type: -

Identifier Source: org_study_id