A Randomized, Double-Blind, Four-Arm Study Comparing Combination Nucleoside, Alternating Nucleoside, and Triple-Drug Therapy for the Treatment of Advanced HIV Disease (CD4 <= 50/mm3)

• Sponsor: National Institute of Allergy and Infectious Diseases (NIAID) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00000781
• Collaborator: Bristol-Myers Squibb (Industry), Glaxo Wellcome (Industry)
• Enrollment: 1,292
• Locations: 96
• Patients Per Site: 13.5

Study Details

Study Description

Brief Summary

To determine the relative clinical efficacy of zidovudine ( AZT ) plus didanosine (ddI), AZT plus zalcitabine ( ddC ), AZT alternating monthly with ddI, and AZT/ddI plus nevirapine in HIV-infected patients with advanced disease.

The rapid emergence of resistant HIV strains has been observed in patients receiving monotherapy with a nucleoside analog or non-nucleoside reverse transcriptase inhibitor. Use of combination therapy with two nucleoside drugs or convergent combination therapy with two nucleosides and a non-nucleoside RT inhibitor may minimize the evolution of these resistant HIV strains. Since toxicity is a major problem in patients with advanced disease who are receiving combination nucleoside therapy, alternating the two drugs may provide a way of retaining several benefits of combination therapy while minimizing the increased toxicity.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: Nevirapine; Drug: Zidovudine; Drug: Zalcitabine; Drug: Didanosine	Phase 2

Detailed Description

The rapid emergence of resistant HIV strains has been observed in patients receiving monotherapy with a nucleoside analog or non-nucleoside reverse transcriptase inhibitor. Use of combination therapy with two nucleoside drugs or convergent combination therapy with two nucleosides and a non-nucleoside RT inhibitor may minimize the evolution of these resistant HIV strains. Since toxicity is a major problem in patients with advanced disease who are receiving combination nucleoside therapy, alternating the two drugs may provide a way of retaining several benefits of combination therapy while minimizing the increased toxicity.

Patients are randomized to receive either AZT/ddC, AZT/ddI, AZT alternating monthly with ddI, or AZT/ddI/nevirapine. Patients are evaluated at week 0 and every 4 weeks thereafter for 2 years. Pharmacologic, virologic, and macroneurologic substudies will be conducted. Patients who are already enrolled on protocol ACTG 193 will be given the option of continuing on their originally assigned ACTG 193 therapy for an additional 6 months or undergoing re-randomization to one of the four treatment arms on ACTG 193A.

Study Design

• Study Type: Interventional
• Masking: Double
• Primary Purpose: Treatment
• Official Title: A Randomized, Double-Blind, Four-Arm Study Comparing Combination Nucleoside, Alternating Nucleoside, and Triple-Drug Therapy for the Treatment of Advanced HIV Disease (CD4 <= 50/mm3)
• Actual Study Completion Date: Sep 1, 1996

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

• Ages Eligible for Study: 13 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria

Concurrent Medication:

Required:

• PCP prophylaxis.

Allowed:

• Erythropoietin maintenance.

• G-CSF and GM-CSF.

• Prophylaxis for Mycobacterium avium intracellulare.

• Antifungal prophylaxis or treatment with specific drugs.

• Maintenance therapy for opportunistic infection.

• Over-the-counter medications or alternative therapies such as vitamins and herbs.

• Antibiotics as clinically indicated.

• Steroids for < 21 days for acute problems.

• Antipyretics, analgesics, allergy medication, antidepressants, sleep medications, oral contraceptives, or other appropriate medications.

Concurrent Treatment:

Allowed:

• Radiation therapy for cutaneous Kaposi's sarcoma.

• Acupuncture.

Patients must have:

• Documented HIV infection.

• CD4 count <= 50 cells/mm3.

• Either no prior nucleoside therapy OR a history of prior nucleoside therapy in the absence of high-grade intolerance.

• Life expectancy of at least 6 months.

• Consent of parent or guardian if < 18 years of age.

• Normal chest x-ray at baseline or within 6 months prior to study entry in the absence of new pulmonary or cardiac symptoms (per 12/28/94 amendment).

NOTE:

• Patients who withdrew from protocol ACTG 193 therapy prior to activation of ACTG 193A are not eligible.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

• Abnormal baseline chest x-ray.

• New pulmonary or cardiac symptoms.

• Psychological or emotional problems sufficient to prevent compliance with study medication.

Concurrent Medication:

Excluded:

• Systemic chemotherapy for malignancy.

• Acute or induction therapy for opportunistic infection.

• Antiretroviral drugs other than study drugs.

• Biological response modifiers.

• Erythromycin, phenytoin, phenobarbital, warfarin, or coumadin.

Patients with the following prior conditions are excluded:

• History of recurrent grade 3 or greater toxicity to AZT, ddI, or ddC on two or more occasions.

• Evidence of active pulmonary disease within 6 months prior to study entry.

• History of grade 3 or worse peripheral neuropathy.

• History of acute or chronic pancreatitis.

Prior Medication:

Excluded:

• Prior nevirapine.

Excluded within 7 days prior to study entry:

• Acute therapy for opportunistic infection (maintenance therapy is permitted).

• Acute systemic therapy for a nonopportunistic infection or other medical condition.

• Antiretroviral drugs other than AZT, ddI, or ddC.

• Biological response modifiers.

• d4T therapy.

• Nucleosides other than those used in the study.

• Antibiotics containing clavulanate potassium.

Prior Treatment:

Excluded:

• More than 4 units of blood in a 30-day period.

Active alcohol or drug abuse.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Univ of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Children's Hosp of Los Angeles	Los Angeles	California	United States	90027
3	Univ of Southern California / LA County USC Med Ctr	Los Angeles	California	United States	900331079
4	Huntington Memorial Hosp / Children's Hosp of Los Angeles	Pasadena	California	United States	91105
5	Univ of California / San Diego Treatment Ctr	San Diego	California	United States	921036325
6	San Francisco AIDS Clinic / San Francisco Gen Hosp	San Francisco	California	United States	941102859
7	San Francisco Gen Hosp	San Francisco	California	United States	941102859
8	Stanford at Kaiser / Kaiser Permanente Med Ctr	San Francisco	California	United States	94115
9	Santa Clara Valley Med Ctr / AIDS Community Rsch Consortium	San Jose	California	United States	951282699
10	San Mateo AIDS Program / Stanford Univ	Stanford	California	United States	943055107
11	Stanford Univ Med Ctr	Stanford	California	United States	943055107
12	Olive View Med Ctr	Sylmar	California	United States	91342
13	Harbor UCLA Med Ctr	Torrance	California	United States	90502
14	Denver Dept of Health and Hosps	Denver	Colorado	United States	80262
15	Mountain States Reg Hemo Ctr / Univ of Colorado	Denver	Colorado	United States	80262
16	Rose Med Ctr	Denver	Colorado	United States	80262
17	Univ of Colorado Health Sciences Ctr	Denver	Colorado	United States	80262
18	Yale Univ / New Haven	New Haven	Connecticut	United States	065102483
19	HIV Ctr - District of Columbia Gen Hosp	Washington	District of Columbia	United States	200072197
20	Whitman - Walker Clinic / Georgetown Univ Med Ctr	Washington	District of Columbia	United States	200072197
21	Georgetown Univ Med Ctr	Washington	District of Columbia	United States	20007
22	George Washington Univ / Hershey Med Ctr	Washington	District of Columbia	United States	20037
23	Howard Univ	Washington	District of Columbia	United States	20059
24	Univ of Miami School of Medicine	Miami	Florida	United States	331361013
25	Univ of South Florida	Tampa	Florida	United States	33612
26	Univ of Hawaii	Honolulu	Hawaii	United States	96816
27	Northwestern Univ Med School	Chicago	Illinois	United States	60611
28	Cook County Hosp	Chicago	Illinois	United States	60612
29	Rush Presbyterian - Saint Luke's Med Ctr	Chicago	Illinois	United States	60612
30	Louis A Weiss Memorial Hosp	Chicago	Illinois	United States	60640
31	Indiana Univ Hosp	Indianapolis	Indiana	United States	462025250
32	Methodist Hosp of Indiana / Life Care Clinic	Indianapolis	Indiana	United States	46202
33	Univ of Louisville / East Tennesee Comprehensive Hem Ctr	Louisville	Kentucky	United States	40202
34	Harvard (Massachusetts Gen Hosp)	Boston	Massachusetts	United States	02114
35	Boston Med Ctr	Boston	Massachusetts	United States	02118
36	Beth Israel Deaconess - West Campus	Boston	Massachusetts	United States	02215
37	Worcester Memorial Hosp / Med Ctr of Cntrl MA-Memorial	Worcester	Massachusetts	United States	01605
38	Hennepin County Med Clinic	Minneapolis	Minnesota	United States	55415
39	Univ of Minnesota	Minneapolis	Minnesota	United States	55455
40	St Paul Ramsey Med Ctr	Saint Paul	Minnesota	United States	55101
41	St Louis Regional Hosp / St Louis Regional Med Ctr	Saint Louis	Missouri	United States	63112
42	Univ of Nebraska Med Ctr	Omaha	Nebraska	United States	681985130
43	Dartmouth - Hitchcock Med Ctr / Med Ctr Cntrl Massachusetts	Lebanon	New Hampshire	United States	03756
44	Robert Wood Johnson Med School / Hershey Med Ctr	New Brunswick	New Jersey	United States	08903
45	Univ of Medicine & Dentistry of New Jersey / Univ Hosp	Newark	New Jersey	United States	071032714
46	Adirondack Med Ctr at Saranac Lake	Albany	New York	United States	122083479
47	Albany Med College / Division of HIV Medicine A158	Albany	New York	United States	122083479
48	Mid - Hudson Care Ctr	Albany	New York	United States	122083479
49	Bronx Municipal Hosp Ctr/Jacobi Med Ctr	Bronx	New York	United States	10461
50	Comprehensive Health Care Ctr / Bronx Municipal Hosp	Bronx	New York	United States	10461
51	Montefiore Drug Treatment Ctr / Bronx Municipal Hosp	Bronx	New York	United States	10461
52	Montefiore Family Health Ctr / Bronx Municipal Hosp	Bronx	New York	United States	10461
53	Samaritan Village Inc / Bronx Municipal Hosp	Bronx	New York	United States	10461
54	Jack Weiler Hosp / Bronx Municipal Hosp	Bronx	New York	United States	10465
55	Montefiore Med Ctr / Bronx Municipal Hosp	Bronx	New York	United States	10467
56	Montefiore Med Ctr Adolescent AIDS Program	Bronx	New York	United States	10467
57	North Central Bronx Hosp / Bronx Municipal Hosp	Bronx	New York	United States	10467
58	Bronx Veterans Administration / Mount Sinai Hosp	Bronx	New York	United States	10468
59	SUNY / Health Sciences Ctr at Brooklyn	Brooklyn	New York	United States	112032098
60	SUNY / Erie County Med Ctr at Buffalo	Buffalo	New York	United States	14215
61	City Hosp Ctr at Elmhurst / Mount Sinai Hosp	Elmhurst	New York	United States	11373
62	North Shore Univ Hosp	Manhasset	New York	United States	11030
63	Beth Israel Med Ctr	New York	New York	United States	10003
64	Bellevue Hosp / New York Univ Med Ctr	New York	New York	United States	10016
65	Saint Clare's Hosp and Health Ctr	New York	New York	United States	10019
66	Cornell Univ Med Ctr	New York	New York	United States	10021
67	Mem Sloan - Kettering Cancer Ctr	New York	New York	United States	10021
68	Mount Sinai Med Ctr / Hemophilia Treatment Ctr	New York	New York	United States	10029
69	Mount Sinai Med Ctr	New York	New York	United States	10029
70	Columbia Presbyterian Med Ctr	New York	New York	United States	100323784
71	Harlem Hosp Ctr	New York	New York	United States	10037
72	Univ of Rochester Medical Center	Rochester	New York	United States	14642
73	SUNY / State Univ of New York	Syracuse	New York	United States	13210
74	Univ of North Carolina	Chapel Hill	North Carolina	United States	275997215
75	Moses H Cone Memorial Hosp	Greensboro	North Carolina	United States	27401
76	Univ of Cincinnati	Cincinnati	Ohio	United States	452670405
77	Univ of Kentucky Lexington	Cincinnati	Ohio	United States	45267
78	Case Western Reserve Univ	Cleveland	Ohio	United States	44106
79	MetroHealth Med Ctr	Cleveland	Ohio	United States	441091998
80	Columbus Children's Hosp	Columbus	Ohio	United States	432052696
81	Med College of Ohio	Toledo	Ohio	United States	43699
82	Milton S Hershey Med Ctr	Hershey	Pennsylvania	United States	170330850
83	Saint Michael's Med Ctr / Milton S Hershey Med Ctr	Hershey	Pennsylvania	United States	170330850
84	Girard Med Ctr	Philadelphia	Pennsylvania	United States	191046073
85	Univ of Pennsylvania at Philadelphia	Philadelphia	Pennsylvania	United States	19104
86	Thomas Jefferson Univ Hosp	Philadelphia	Pennsylvania	United States	191075098
87	Med Univ of South Carolina / UNC	Charleston	South Carolina	United States	29425
88	Julio Arroyo	West Columbia	South Carolina	United States	29169
89	Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr	Knoxville	Tennessee	United States	37920
90	Meharry Med College	Nashville	Tennessee	United States	37203
91	Univ of Texas Galveston	Galveston	Texas	United States	775550435
92	Univ Texas Health Science Ctr / Univ Texas Med School	Houston	Texas	United States	77030
93	Univ of Washington	Seattle	Washington	United States	981224304
94	Northern Wisconsin Hemophilia Ctr / Saint Vincent's Hosp	Green Bay	Wisconsin	United States	54301
95	Great Lakes Hemophilia Foundation	Wauwatosa	Wisconsin	United States	532130127
96	Univ of Puerto Rico	San Juan		Puerto Rico	009365067

Sponsors and Collaborators

• National Institute of Allergy and Infectious Diseases (NIAID)
• Bristol-Myers Squibb
• Glaxo Wellcome

Investigators

• Study Chair: Henry WK,
• Study Chair: Kahn JO,
• Study Chair: Balfour HH,

Study Documents (Full-Text)

None provided.

More Information

Publications

• Coplan P, Nikas A, Saah A, Nessly M, Doll L, Leavitt R, Benson J, Guess H. No association observed between indinavir therapy for HIV/AIDS and myocardial infarction in 4 clinical trials with 2,825 subjects. Conf Retroviruses Opportunistic Infect. 1999 Jan 31-Feb 4;6th:191 (abstract no 658)
• Erice A, Tierney C, Balfour HH Jr, Liou S, Kahn JO, Henry WK. Virologlc effect of therapy with reverse transcriptase inhibitors (RTIs) in patients with AIDS and less than 50 CD4+ T cells per mm(3): a substudy of ACTG 193a. Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:204 (abstract no 662)
• Henry K, Erice A, Tierney C, Balfour HH Jr, Fischl MA, Kmack A, Liou SH, Kenton A, Hirsch MS, Phair J, Martinez A, Kahn JO. A randomized, controlled, double-blind study comparing the survival benefit of four different reverse transcriptase inhibitor therapies (three-drug, two-drug, and alternating drug) for the treatment of advanced AIDS. AIDS Clinical Trial Group 193A Study Team. J Acquir Immune Defic Syndr Hum Retrovirol. 1998 Dec 1;19(4):339-49.
• Henry K, Tierney C, Kahn J, Balfour H, Jiang Q, Kmack A, Fischl M. A randomized, double-blind, placebo-controlled study comparing combination nucleoside and triple therapy for the treatment of advanced HIV disease (CD4 less than or equal to 50/mm(3)). Conf Retroviruses Opportunistic Infect. 1997 Jan 22-26;4th:207 (abstract no LB6)
• Price RW, Yiannoutsos C, Zaborski L, Kmack A, Henry K, Tierney C, Clifford D. Neurological substudies of ACTG protocol 193A: quantitative neurological performance measures and treatment outcomes. Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:176 (abstract no 516)
• Price RW, Yiannoutsos CT, Clifford DB, Zaborski L, Tselis A, Sidtis JJ, Cohen B, Hall CD, Erice A, Henry K. Neurological outcomes in late HIV infection: adverse impact of neurological impairment on survival and protective effect of antiviral therapy. AIDS Clinical Trial Group and Neurological AIDS Research Consortium study team. AIDS. 1999 Sep 10;13(13):1677-85.
• Robinson P, Cotton D, Curry R, Henry K, Hall D, Myers M. Analysis of nevirapine (NVP) effect on clinical endpoints (CEs) of HIV progression or death in ACTG trial 193A. Conf Retroviruses Opportunistic Infect. 1998 Feb 1-5;5th:210 (abstract no 700)

• Responsible Party: National Institute of Allergy and Infectious Diseases (NIAID)
• ClinicalTrials.gov Identifier: NCT00000781
• Other Study ID Numbers: ACTG 193A; 11169
• First Posted: Aug 31, 2001
• Last Update Posted: Nov 4, 2021
• Last Verified: Oct 1, 2021

• Keywords provided by National Institute of Allergy and Infectious Diseases (NIAID): Zalcitabine; Didanosine; Drug Therapy, Combination; Acquired Immunodeficiency Syndrome; Zidovudine; Nevirapine
• Additional relevant MeSH terms: HIV Infections; Acquired Immunodeficiency Syndrome; Zidovudine; Nevirapine; Didanosine; Zalcitabine

Study Results

No Results Posted as of Nov 4, 2021