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

HIV Infections Clinical Trial

Official title:

A Phase II Randomized Study of the Virologic and Immunologic Effects of d4T vs Zidovudine Plus d4T vs Zidovudine Plus Ddl in HIV-Infected Patients With CD4 Cell Counts Between 300-600/mm3 and Greater Than 12 Weeks Zidovudine Experience

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT00001063
• Other study ID #: ACTG 290
• Secondary ID: 11266
• Status: Completed
• Phase: Phase 2
• Est. completion date: November 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 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.

Description:

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 200
• Est. completion date: November 1997
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• HIV Infections

Intervention

Drug:
• Stavudine

• Zidovudine

• Didanosine

Locations

Country	Name	City	State
Puerto Rico	Puerto Rico-AIDS CRS	San Juan
Puerto Rico	San Juan City Hosp. PR NICHD CRS	San Juan
United States	University of Colorado Hospital CRS	Aurora	Colorado
United States	Beth Israel Deaconess Med. Ctr., ACTG CRS	Boston	Massachusetts
United States	Bmc Actg Crs	Boston	Massachusetts
United States	Massachusetts General Hospital ACTG CRS	Boston	Massachusetts
United States	SUNY Downstate Med. Ctr., Children's Hosp. at Downstate NICHD CRS	Brooklyn	New York
United States	SUNY - Buffalo, Erie County Medical Ctr.	Buffalo	New York
United States	Cook County Hosp. CORE Ctr.	Chicago	Illinois
United States	Northwestern University CRS	Chicago	Illinois
United States	Rush Univ. Med. Ctr. ACTG CRS	Chicago	Illinois
United States	Weiss Memorial Hosp.	Chicago	Illinois
United States	Univ. of Cincinnati CRS	Cincinnati	Ohio
United States	The Ohio State Univ. AIDS CRS	Columbus	Ohio
United States	Univ. of Hawaii at Manoa, Leahi Hosp.	Honolulu	Hawaii
United States	Indiana Univ. School of Medicine, Infectious Disease Research Clinic	Indianapolis	Indiana
United States	Indiana Univ. School of Medicine, Wishard Memorial	Indianapolis	Indiana
United States	Methodist Hosp. of Indiana	Indianapolis	Indiana
United States	Univ. of Florida Jacksonville NICHD CRS	Jacksonville	Florida
United States	UCLA CARE Center CRS	Los Angeles	California
United States	Univ. of Miami AIDS CRS	Miami	Florida
United States	Hennepin County Med. Ctr., Div. of Infectious Diseases	Minneapolis	Minnesota
United States	University of Minnesota, ACTU	Minneapolis	Minnesota
United States	Tulane Hemophilia Treatment Ctr.	New Orleans	Louisiana
United States	Stanford CRS	Palo Alto	California
United States	Univ. of Rochester ACTG CRS	Rochester	New York
United States	St. Louis ConnectCare, Infectious Diseases Clinic	Saint Louis	Missouri
United States	Washington U CRS	Saint Louis	Missouri
United States	Ucsd, Avrc Crs	San Diego	California
United States	Ucsf Aids Crs	San Francisco	California
United States	University of Washington AIDS CRS	Seattle	Washington
United States	Harbor-UCLA Med. Ctr. CRS	Torrance	California
United States	Children's National Med. Ctr., ACTU	Washington	District of Columbia

Sponsors (2)

Lead Sponsor	Collaborator
National Institute of Allergy and Infectious Diseases (NIAID)	Bristol-Myers Squibb

Countries where clinical trial is conducted

United States,  Puerto Rico, 

References & Publications (6)

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

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

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)

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. Epub 2000 Jul 6. — View Citation

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)

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)