Clinical trial NCT00001063: The Effectiveness of Three Drug Combinations in HIV-Infected Patients Who Have Taken Zidovudine for More Than 12 Weeks
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: Didanosine
Drug Therapy, Combination
AIDS-Related Complex
Zidovudine
Stavudine
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
Collaborators: name: Bristol-Myers Squibb
First posted: 2001-08-31
Enrollment: 200
Sex: ALL
Minimum age (years): 12
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief 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.

Detailed 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.

Eligibility criteria: 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.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: Palo Alto
country: United States
facility: Stanford CRS
state: California
city: San Diego
country: United States
facility: Ucsd, Avrc Crs
state: California
city: San Francisco
country: United States
facility: Ucsf Aids Crs
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Med. Ctr. CRS
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Washington
country: United States
facility: Children's National Med. Ctr., ACTU
state: District of Columbia
city: Jacksonville
country: United States
facility: Univ. of Florida Jacksonville NICHD CRS
state: Florida
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS
state: Florida
city: Honolulu
country: United States
facility: Univ. of Hawaii at Manoa, Leahi Hosp.
state: Hawaii
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Chicago
country: United States
facility: Cook County Hosp. CORE Ctr.
state: Illinois
city: Chicago
country: United States
facility: Rush Univ. Med. Ctr. ACTG CRS
state: Illinois
city: Chicago
country: United States
facility: Weiss Memorial Hosp.
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ. School of Medicine, Infectious Disease Research Clinic
state: Indiana
city: Indianapolis
country: United States
facility: Indiana Univ. School of Medicine, Wishard Memorial
state: Indiana
city: Indianapolis
country: United States
facility: Methodist Hosp. of Indiana
state: Indiana
city: New Orleans
country: United States
facility: Tulane Hemophilia Treatment Ctr.
state: Louisiana
city: Boston
country: United States
facility: Massachusetts General Hospital ACTG CRS
state: Massachusetts
city: Boston
country: United States
facility: Bmc Actg Crs
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS
state: Massachusetts
city: Minneapolis
country: United States
facility: Hennepin County Med. Ctr., Div. of Infectious Diseases
state: Minnesota
city: Minneapolis
country: United States
facility: University of Minnesota, ACTU
state: Minnesota
city: Saint Louis
country: United States
facility: St. Louis ConnectCare, Infectious Diseases Clinic
state: Missouri
city: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: Brooklyn
country: United States
facility: SUNY Downstate Med. Ctr., Children's Hosp. at Downstate NICHD CRS
state: New York
city: Buffalo
country: United States
facility: SUNY - Buffalo, Erie County Medical Ctr.
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS
state: Ohio
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS
state: Ohio
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
city: San Juan
country: Puerto Rico
facility: San Juan City Hosp. PR NICHD CRS
city: San Juan
country: Puerto Rico
facility: Puerto Rico-AIDS CRS
Study officials:
name: Havlir D
role: STUDY_CHAIR
name: Richman D
role: STUDY_CHAIR
name: Pollard R
role: STUDY_CHAIR
name: Friedland G
role: STUDY_CHAIR
References:
citation: d4T+AZT--unexpected CD4 drop seen in study. AIDS Treat News. 1996 Dec 20;(No 261):1.
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)
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)
citation: Cadman J. 2, 4, 6, 8, who's afraid to phosphorylate? GMHC Treat Issues. 1998 Feb;12(2):6-8.
citation: 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.
citation: 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)