Clinical trial NCT00000803: A Phase II Double-Blind Study of Delavirdine Mesylate ( U-90152 ) in Combination With Zidovudine ( AZT ) and/or Didanosine ( ddI ) Versus AZT and ddI Combination Therapy
Official title: A Phase II Double-Blind Study of Delavirdine Mesylate ( U-90152 ) in Combination With Zidovudine ( AZT ) and/or Didanosine ( ddI ) Versus AZT and ddI Combination Therapy
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: HIV Infections
Keywords: Didanosine
Drug Therapy, Combination
Acquired Immunodeficiency Syndrome
AIDS-Related Complex
Antiviral Agents
Zidovudine
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-08-31
Enrollment: 471
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

Brief summary: To determine the safety and anti-HIV activity of delavirdine mesylate ( U-90152 ) in combination with zidovudine ( AZT ) and/or didanosine ( ddI ) versus AZT/ddI combination.

U-90152 has demonstrated anti-HIV activity. Since the combination of this drug with either AZT or ddI has synergistic inhibitory activity against HIV-1 in vitro, and triple therapy appears to have greater inhibitory activity against HIV-1 in vitro than dual therapy, the use of U-90152 in combination with AZT and/or ddI may improve the benefits of these drugs in persons with HIV disease.

Detailed description: U-90152 has demonstrated anti-HIV activity. Since the combination of this drug with either AZT or ddI has synergistic inhibitory activity against HIV-1 in vitro, and triple therapy appears to have greater inhibitory activity against HIV-1 in vitro than dual therapy, the use of U-90152 in combination with AZT and/or ddI may improve the benefits of these drugs in persons with HIV disease.

Patients are randomized to receive U-90152/AZT/ddI, U-90152/AZT, U-90152/ddI, or AZT/ddI for 48 weeks.

Eligibility criteria: Inclusion Criteria

Concurrent Medication:

Required:

* PCP prophylaxis for patients with CD4 count \<= 200 cells/mm3.

Allowed:

* Topical antifungal agents.
* Oral ketoconazole, fluconazole, and itraconazole for candidiasis or disseminated fungal infections.
* Isoniazid, ethambutol, pyrazinamide, clofazimine, ciprofloxacin, and clarithromycin for acute or maintenance therapy for mycobacterial disease (also clarithromycin for MAC prophylaxis).
* Acute or maintenance therapy for toxoplasmosis.
* Acute or maintenance therapy with acyclovir (no more than 1000 mg/day) for herpes simplex virus infection.
* rEPO and rG-CSF.
* Antibiotics for bacterial infections (except rifampin and rifabutin).
* Antipyretics, analgesics, nonsteroidal anti-inflammatory agents, antiemetics, and methadone.

Concurrent Treatment:

Allowed for cutaneous Kaposi's sarcoma:

* Localized radiation therapy.
* Limited intralesional therapy.

Patients must have:

* HIV infection.
* CD4 count 100 - 500 cells/mm3.
* Prior cumulative monotherapy of \<= 6 months (may have taken either AZT or ddI, but not both) OR no prior antiretroviral therapy.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

* Malignancy (other than basal or squamous cell carcinoma of the skin, Stage 1 or 2 cervical intraepithelial neoplasia, or minimal Kaposi's sarcoma).
* Considered to be unlikely to comply with study requirements.

Concurrent Medication:

Excluded:

* Antiretroviral therapies and biologic response modifiers (except for study medications, rEPO, and rG-CSF).
* Rifampin.
* Rifabutin.
* Terfenadine.
* Astemizole.
* Loratadine.
* Quinidine.
* Digitoxin.
* Systemic corticosteroids for more than 21 consecutive days.
* Foscarnet.
* Systemic cytotoxic chemotherapy for a malignancy.

Patients with the following prior conditions are excluded:

* History of intolerance to AZT at \<= 600 mg/day or ddI at \<= 400 mg/day or discontinuation of either drug for toxicity.
* History of intolerance to trifluoperazine or piperazine citrate (per amendment).
* History of pancreatitis.
* History of grade 2 or worse peripheral neuropathy.
* Unexplained temperature \>= 38.5 C on any 7 days within the past 30 days.
* Chronic diarrhea on any 15 days during the past 30 days.

Prior Medication:

Excluded:

* Prior foscarnet as induction or maintenance therapy.
* Prior U-90152.
* Prior ddC or d4T.
* Prior AZT/ddI in combination or taken separately at different times.
* Prior non-nucleoside reverse transcriptase inhibitors (nevirapine, atevirdine, etc.).
* Prior protease inhibitors (although patients from ACTG 282 are eligible).
* HIV-1 vaccine within the past 21 days.
* Acute treatment for a serious infection or for any opportunistic infection within the past 14 days.

Excluded within the past 30 days:

* Interferon or interleukin.
* Rifampin.
* Rifabutin.
* Terfenadine.
* Astemizole.
* Loratadine.
* Recombinant EPO or G-CSF.
* Hydroxyurea.
* SPV-30.
* Any other investigational drug.

Active drug or alcohol use.

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS
state: Alabama
city: Los Angeles
country: United States
facility: USC 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: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Washington
country: United States
facility: Howard University Hosp., Div. of Infectious Diseases, ACTU
state: District of Columbia
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS
state: Florida
city: Honolulu
country: United States
facility: Queens Med. Ctr.
state: Hawaii
city: Honolulu
country: United States
facility: Univ. of Hawaii at Manoa, Leahi Hosp.
state: Hawaii
city: Indianapolis
country: United States
facility: Indiana Univ. School of Medicine, Infectious Disease Research Clinic
state: Indiana
city: Indianapolis
country: United States
facility: Methodist Hosp. of Indiana
state: Indiana
city: Baltimore
country: United States
facility: Johns Hopkins Adult AIDS CRS
state: Maryland
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 - East Campus A0102 CRS
state: Massachusetts
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota, ACTU
state: Minnesota
city: Saint Louis
country: United States
facility: Washington U CRS
state: Missouri
city: Saint Louis
country: United States
facility: St. Louis ConnectCare, Infectious Diseases Clinic
state: Missouri
city: Buffalo
country: United States
facility: SUNY - Buffalo, Erie County Medical Ctr.
state: New York
city: New York
country: United States
facility: Cornell University A2201
state: New York
city: New York
country: United States
facility: Beth Israel Med. Ctr. (Mt. Sinai)
state: New York
city: New York
country: United States
facility: Memorial Sloan-Kettering Cancer Ctr.
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS
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: Cleveland
country: United States
facility: Case CRS
state: Ohio
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS
state: Ohio
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS
state: Pennsylvania
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
city: San Juan
country: Puerto Rico
facility: Puerto Rico-AIDS CRS
Study officials:
name: Friedland G
role: STUDY_CHAIR
name: Fischl MA
role: STUDY_CHAIR
name: Pollard R
role: STUDY_CHAIR
References:
citation: Griffit B, Morse G, Demeter L, Bassett R, Hughes M, Friedland G. Relationship between delavirdine (DLV) plasma levels, HIV RNA responses and DLV resistance during combination therapy with zidovudine (ZDV), and didanosine (ddI). Int Conf AIDS. 1998;12:52 (abstract no 12206)
citation: Freimuth WW, Chuang-Stein CJ, Greenwald CA, Wathen LK, Edge-Padbury BA, Cox SR, Daenzer CL, Wang Y, Carberry PA. Delavirdine (DLV) combined with zidovudine (ZDV) or didanosine (ddI) produces sustained reduction in viral burden and increases in CD4 count in early and advanced HIV-1 infection. Int Conf AIDS. 1996 Jul 7-12;11(1):22 (abstract no MoB295)
citation: Nokta M, Turk P. Partial restoration of HIV specific neutralizing activity (NA) of HIV infected patients receiving antiretrovial therapy: DDI/delaviridine (DLV), AZT/DLV, DDI/AZT or DDI/AZT/DLV. Int Conf AIDS. 1998;12:516 (abstract no 31108)
citation: Friedland GH, Pollard R, Griffith B, Hughes M, Morse G, Bassett R, Freimuth W, Demeter L, Connick E, Nevin T, Hirsch M, Fischl M. Efficacy and safety of delavirdine mesylate with zidovudine and didanosine compared with two-drug combinations of these agents in persons with HIV disease with CD4 counts of 100 to 500 cells/mm3 (ACTG 261). ACTG 261 Team. J Acquir Immune Defic Syndr. 1999 Aug 1;21(4):281-92. doi: 10.1097/00126334-199908010-00005.
citation: Demeter LM, Meehan PM, Morse G, Gerondelis P, Dexter A, Berrios L, Cox S, Freimuth W, Reichman RC. HIV-1 drug susceptibilities and reverse transcriptase mutations in patients receiving combination therapy with didanosine and delavirdine. J Acquir Immune Defic Syndr Hum Retrovirol. 1997 Feb 1;14(2):136-44. doi: 10.1097/00042560-199702010-00006.