Virologic and Immunologic Activity of Continued Lamivudine (3TC) vs Delavirdine (DLV) in Combination With Indinavir (IDV) and Zidovudine (ZDV) or Stavudine (d4T) in 3TC-Experienced Subjects

Sponsor

National Institute of Allergy and Infectious Diseases (NIAID) (NIH)

Overall Status

Completed

CT.gov ID

NCT00000882

Collaborator

(none)

300

Enrollment

Locations

9.7

Patients Per Site

Study Details

Study Description

Brief Summary

To compare the proportion of patients in the 2 zidovudine (ZDV)-containing arms who have a plasma HIV RNA concentration below the limit of detection (defined as 500 copies/ml or less) at Weeks 20 and 24 [AS PER AMENDMENT 8/24/98: HIV RNA concentration below the limit of detection is now defined as 200 copies/ml or less]. To compare the safety and tolerability of the different treatment regimens. To compare the decrease in plasma HIV-1 RNA and the change in CD4 count from baseline to the average of Weeks 20 and 24 [AS PER AMENDMENT 12/19/97: and to the average of Weeks 44 and 48; AS PER AMENDMENT 8/24/98: and the average of Weeks 88 and 96] in the 2 ZDV-containing arms. To study the emergence of resistance to ZDV, lamivudine (3TC), stavudine (d4T), delavirdine (DLV), and indinavir (IDV) in treated patients. To correlate the antiviral and immunologic activity and emergence of drug resistance with pharmacologic parameters of study drugs. To delineate the pharmacokinetic interactions of IDV and DLV. [AS PER AMENDMENT 12/19/97: To delineate the possible development of cellular resistance to nucleoside analogs and the consequences of switching nucleoside study drugs on intracellular phosphorylation.] To document rates and patterns of adherence over the course of the study, from day of randomization through 48 weeks. [AS PER AMENDMENT 8/24/98: To define long-term durability of the virologic activity of the different treatment regimens, as defined by the proportion of patients with plasma HIV-1 RNA levels that remains below the limit of detection. To define long-term tolerability of the different treatment regimens.] Although a change in reverse transcriptase (RT) inhibitors is recommended when adding or changing protease inhibitors in a treatment regimen, the choice of available RT inhibitors is often limited by prior exposure, toxicity, or pharmacologic interaction with the protease inhibitors. This study addresses the question of whether to continue 3TC or substitute the nonnucleoside reverse transcriptase inhibitor (NNRTI) DLV when adding IDV to therapy for patients previously treated with ddI or d4T plus 3TC who have greater than 500 copies/ml of plasma HIV-1 RNA. Although the activity of DLV as monotherapy or in combination with nucleoside reverse transcriptase inhibitors is of limited duration due to rapid emergence of resistance, it is possible that DLV will contribute significantly to the activity of 3-drug regimens that include a new RT inhibitor plus a protease inhibitor.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: Indinavir sulfate Drug: Delavirdine mesylate Drug: Lamivudine Drug: Stavudine Drug: Zidovudine	Phase 2

Detailed Description

Although a change in reverse transcriptase (RT) inhibitors is recommended when adding or changing protease inhibitors in a treatment regimen, the choice of available RT inhibitors is often limited by prior exposure, toxicity, or pharmacologic interaction with the protease inhibitors. This study addresses the question of whether to continue 3TC or substitute the nonnucleoside reverse transcriptase inhibitor (NNRTI) DLV when adding IDV to therapy for patients previously treated with ddI or d4T plus 3TC who have greater than 500 copies/ml of plasma HIV-1 RNA. Although the activity of DLV as monotherapy or in combination with nucleoside reverse transcriptase inhibitors is of limited duration due to rapid emergence of resistance, it is possible that DLV will contribute significantly to the activity of 3-drug regimens that include a new RT inhibitor plus a protease inhibitor.

Patients with greater than 500 HIV-1 RNA copies/ml are randomized to 3 treatment arms as follows:

Arm I: d4T + ZDV placebo + DLV + IDV Arm II: ZDV + d4T placebo + 3TC + IDV Arm III: ZDV + d4T placebo + DLV + IDV Treatment on all arms is given for 24 weeks. [AS PER AMENDMENT 12/19/97: The study is no longer partially blinded, and placebo agents are no longer given; treatment duration is now 48 weeks.] [AS PER AMENDMENT 8/24/98: study duration is now 96 weeks.] Rollover patients from ACTG 306 with greater than 500 HIV-1 RNA copies/ml previously assigned to ZDV/3TC are nonrandomly assigned to Arm I; those previously assigned to ddI/3TC or d4T/3TC are randomized to Arm II or III. Non-rollover patients are randomized to Arm II or III. Rollover patients from ACTG 306 with 500 HIV-1copies/ml or less continue on their previously assigned regimen [AS PER AMENDMENT 12/19/98: current regimen must be ZDV/3TC, ddI/3TC, or d4T/3TC.] for the study duration or until an increase occurs. If this increase occurs, patients previously assigned to ZDV/3TC are nonrandomly assigned to Arm I for the remaining study weeks, while those previously assigned to either ddI/3TC or d4T/3TC are randomized to Arm II or III for the remaining study weeks. Patients who received ddI/d4T or ddI/3TC in ACTG 306 are stratified by whether patients received monotherapy or combination therapy during the first 24 weeks [AS PER AMENDMENT 12/19/97: 48 weeks]; [ AS PER AMENDMENT 8/24/98: 96 weeks.] of ACTG 306.

Study Design

Study Type:

Interventional

Primary Purpose:

Treatment

Official Title:

Virologic and Immunologic Activity of Continued Lamivudine (3TC) vs Delavirdine (DLV) in Combination With Indinavir (IDV) and Zidovudine (ZDV) or Stavudine (d4T) in 3TC-Experienced Subjects

Actual Primary Completion Date :

May 1, 1999

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

12 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria

Concurrent Medication:

Required:

Patients completing ACTG 306 who remain on blinded therapy through the extension period or
Patients on stable (6 months or greater) ddI/3TC or d4T/3TC combination therapy who have plasma HIV-1 levels higher than 500 copies/ml by the Amplicor HIV-1 Monitor Assay.

Allowed following contact with Protocol Pharmacologist:

Diltiazem, nifedipine, phenytoin, and warfarin.

Patients must have:

Absolute CD4 count of 200 cells/mm3 or greater.
HIV-1 RNA levels greater than 500 copies/ml by the Amplicor HIV-1 Monitor assay. NOTE:
This is a requirement for those receiving study medication. [AS PER AMENDMENT 12/19/97:
HIV-1 infection must be documented by any licensed ELISA test kit and confirmed by either Western blot, HIV culture, HIV antigen, plasma HIV RNA, or a second antibody test by a method other than ELISA at any time prior to entry.]
Signed, informed consent from a parent or legal guardian for patients under 18 years of age.
Life expectancy of at least 24 weeks.

Exclusion Criteria

Co-existing Condition:

Patients with the following symptoms or conditions are excluded:

Unexplained temperature of 38.5 C or higher for 7 consecutive days, or chronic diarrhea defined as more than 3 liquid stools per day persisting for 15 days, within 30 days prior to study entry.
Proven or suspected acute hepatitis within 30 days prior to study entry.
Malignancy that requires systemic chemotherapy. NOTE:Patients with minimal Kaposi's sarcoma (KS) fewer than 5 cutaneous lesions and no visceral disease or tumor-associated edema) are allowed to enroll provided that they do not require systemic therapy.

Concurrent Medication:

Excluded:

Concurrent ZDV (for patients other than those rolling over from ACTG 306).
Any experimental antiretroviral agents or other experimental therapies.
Acute therapy for an infection or other medical illnesses within 14 days prior to study entry.
Recombinant erythropoietin (rEPO), G-CSF, or GM-CSF within 30 days prior to study entry.
Interferons, interleukins, or HIV vaccines within 30 days prior to study entry.
Rifampin, rifabutin, cisapride, triazolam, midazolam, terfenadine, astemizole, or loratadine, within 14 days prior to study entry.

Patients with the following prior conditions are excluded:

History of acute or chronic pancreatitis.
History of Grade 2 or higher bilateral peripheral neuropathy. [AS PER AMENDMENT 12/19/97: Patients with Grade 2 or 3 peripheral neuropathy due to current use of ddI/3TC or d4T/3TC and who have a screening viral load above 500 copies/ml are eligible as they will be randomized to a regimen that does not contain an agent associated with peripheral neuropathy toxicity.]

Prior Medication:

Excluded:

Prior NNRTI or protease inhibitor therapy.
Prior ZDV (for patients other than those rolling over from ACTG 306).
Previous induction or maintenance therapy with foscarnet.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Univ of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Univ of California / San Diego Treatment Ctr	San Diego	California	United States	921036325
3	Stanford at Kaiser / Kaiser Permanente Med Ctr	San Francisco	California	United States	94115
4	Santa Clara Valley Med Ctr / AIDS Community Rsch Consortium	San Jose	California	United States	951282699
5	San Mateo AIDS Program / Stanford Univ	Stanford	California	United States	943055107
6	Stanford Univ Med Ctr	Stanford	California	United States	943055107
7	Univ of Colorado Health Sciences Ctr	Denver	Colorado	United States	80262
8	Univ of Miami School of Medicine	Miami	Florida	United States	331361013
9	Queens Med Ctr	Honolulu	Hawaii	United States	96816
10	Univ of Hawaii	Honolulu	Hawaii	United States	96816
11	Northwestern Univ Med School	Chicago	Illinois	United States	60611
12	Cook County Hosp	Chicago	Illinois	United States	60612
13	Rush Presbyterian - Saint Luke's Med Ctr	Chicago	Illinois	United States	60612
14	Louis A Weiss Memorial Hosp	Chicago	Illinois	United States	60640
15	Indiana Univ Hosp	Indianapolis	Indiana	United States	462025250
16	State of MD Div of Corrections / Johns Hopkins Univ Hosp	Baltimore	Maryland	United States	212052196
17	Johns Hopkins Hosp	Baltimore	Maryland	United States	21287
18	Beth Israel Deaconess - West Campus	Boston	Massachusetts	United States	02215
19	St Louis Regional Hosp / St Louis Regional Med Ctr	St Louis	Missouri	United States	63112
20	SUNY / Erie County Med Ctr at Buffalo	Buffalo	New York	United States	14215
21	Beth Israel Med Ctr	New York	New York	United States	10003
22	Univ of Rochester Medical Center	Rochester	New York	United States	14642
23	Univ of North Carolina	Chapel Hill	North Carolina	United States	275997215
24	Carolinas Med Ctr	Charlotte	North Carolina	United States	28203
25	Moses H Cone Memorial Hosp	Greensboro	North Carolina	United States	27401
26	MetroHealth Med Ctr	Cleveland	Ohio	United States	441091998
27	Ohio State Univ Hosp Clinic	Columbus	Ohio	United States	432101228
28	Univ of Pennsylvania at Philadelphia	Philadelphia	Pennsylvania	United States	19104
29	Julio Arroyo	West Columbia	South Carolina	United States	29169
30	Univ of Washington	Seattle	Washington	United States	981224304
31	Univ of Puerto Rico	San Juan		Puerto Rico	009365067