Treatment Success and Failure in HIV-Infected Subjects Receiving Indinavir in Combination With Nucleoside Analogs: A Rollover Study for ACTG 320

Sponsor

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

Overall Status

Completed

CT.gov ID

NCT00000885

Collaborator

(none)

440

Enrollment

Locations

8.3

Patients Per Site

Study Details

Study Description

Brief Summary

Group A:

To compare the time to confirmed virologic failure (2 consecutive plasma HIV-RNA concentrations of 500 copies/ml or more) between the treatment arms: abacavir (ABC) or placebo in combination with zidovudine (ZDV), lamivudine (3TC), and indinavir (IDV). To evaluate the safety and tolerability of these treatment arms. [AS PER AMENDMENT 06/16/99: To compare the time to confirmed treatment failure, permanent discontinuation of treatment, or death between the treatment arms.] [AS PER AMENDMENT 12/27/01: Groups B, C, and D completed follow-up on March 4, 1999. Therefore, only information pertinent to Group A is applicable.]

Group B:

To compare the proportion of patients who achieve plasma HIV-1 RNA concentrations below 500 copies/ml, as assessed by the standard Roche Amplicor assay at Week 16, or to compare the absolute changes in plasma HIV-1 RNA concentrations at Week 16 across the treatment arms: ABC or approved nucleoside analogs and nelfinavir (NFV) or placebo in combination with efavirenz (EFV) and adefovir dipivoxil. To compare the safety and tolerability of these treatment arms.

Group C:

To monitor plasma HIV-1 RNA trajectory over time and determine the time to a confirmed plasma HIV-1 RNA concentration above 2,000 copies/ml on 2 consecutive determinations for patients treated with ZDV or stavudine (d4T) plus 3TC and IDV.

Group D:

To evaluate plasma HIV-1 RNA responses at Weeks 16 and 48. To evaluate the safety and tolerability of the treatment arms: ABC, EFV, adefovir dipivoxil, and NFV.

This study explores new treatment options for ACTG 320 enrollees (and, if needed, a limited number of non-ACTG 320 volunteers) who have been receiving ZDV (or d4T) plus 3TC and IDV and are currently exhibiting a range of virologic responses. By dividing the study into the corresponding, nonsequential cohorts (Groups A, B, C, D), different approaches to evaluating virologic success, i.e., undetectable plasma HIV-1 RNA levels, and virologic failure, i.e., plasma HIV-1 RNA levels of 500 copies/ml or more [AS PER AMENDMENT 12/27/01: 200 copies/ml or more], are explored while maintaining long-term follow-up of ACTG 320 patients. [AS PER AMENDMENT 12/27/01: Groups B, C, and D completed follow-up on March 4, 1999. Therefore, only information pertinent to Group A is applicable. This study will examine the question of whether intensification of therapy can prolong the virologic benefit in individuals whose plasma HIV-1 RNA concentrations have been below the limits of assay detection on ZDV (or d4T) plus 3TC plus IDV.]

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: Indinavir sulfate Drug: Abacavir sulfate Drug: Nelfinavir mesylate Drug: Efavirenz Drug: Levocarnitine Drug: Adefovir dipivoxil Drug: Lamivudine Drug: Stavudine Drug: Zidovudine Drug: Didanosine	Phase 2

Detailed Description

This study explores new treatment options for ACTG 320 enrollees (and, if needed, a limited number of non-ACTG 320 volunteers) who have been receiving ZDV (or d4T) plus 3TC and IDV and are currently exhibiting a range of virologic responses. By dividing the study into the corresponding, nonsequential cohorts (Groups A, B, C, D), different approaches to evaluating virologic success, i.e., undetectable plasma HIV-1 RNA levels, and virologic failure, i.e., plasma HIV-1 RNA levels of 500 copies/ml or more [AS PER AMENDMENT 12/27/01: 200 copies/ml or more], are explored while maintaining long-term follow-up of ACTG 320 patients. [AS PER AMENDMENT 12/27/01: Groups B, C, and D completed follow-up on March 4, 1999. Therefore, only information pertinent to Group A is included. This study will examine the question of whether intensification of therapy can prolong the virologic benefit in individuals whose plasma HIV-1 RNA concentrations have been below the limits of assay detection on ZDV (or d4T) plus 3TC plus IDV.]

Rollover patients from ACTG 320 are given enrollment priority and permitted to enroll in all 4 study groups; non-ACTG patients are permitted to enroll in Groups A and B if accrual objectives are not met with ACTG 320 patients.

GROUP A:

Patients with screening plasma HIV-1 RNA concentrations below 500 copies/ml are randomized to 1 of 2 treatment arms and stratified according to their participation in ACTG 320 (original randomization to IDV versus open-label IDV). The 2 treatment arms are as follows:

ARM A1: IDV plus ZDV (or d4T) plus 3TC plus ABC. ARM A2: IDV plus ZDV (or d4T) plus 3TC plus ABC placebo. Patients who achieve a plasma HIV-1 RNA level of 500 copies/ml or more on 2 consecutive determinations may continue their assigned arm in a blinded fashion, or seek the best alternative therapy selected by the local investigator or primary care physician.

GROUP B:

Nonnucleoside reverse transcriptase inhibitor (NNRTI)-naive patients with plasma HIV-1 RNA plasma concentrations of 500 copies/ml or more are randomized to 1 of 4 treatment arms and stratified by plasma HIV-1 RNA concentrations (above versus below 15,000 RNA copies/ml) and participation in ACTG 320 (original randomization to IDV versus open-label IDV). The treatment arms are as follows:

ARM B1: ABC plus EFV plus adefovir dipivoxil plus NFV. ARM B2: ABC plus EFV plus adefovir dipivoxil plus NFV placebo. ARM B3: 2 nucleoside reverse transcriptase inhibitors (NRTIs) (or 1 if 2 not tolerated) (chosen from ZDV, 3TC, d4T, or didanosine [ddI]) plus EFV plus adefovir dipivoxil plus NFV.

ARM B4: 2 NRTIs (or 1 if 2 not tolerated) (chosen from ZDV, 3TC, d4T, or ddI) plus EFV plus adefovir dipivoxil plus NFV placebo.

GROUP C:

NNRTI-naive patients with plasma HIV-1 RNA concentrations of 500-2,000 copies/ml at screening may elect to be randomized to a treatment arm in Group B or continue with their current ACTG 320 regimen as follows:

ARM C: ZDV (or d4T) plus 3TC plus IDV. Patients who elect this treatment are randomized in Group B if their plasma HIV-1 RNA concentrations are confirmed to be above 2,000 copies.

GROUP D:

NNRTI-experienced, ACTG 320 patients with screening plasma HIV-1 RNA concentrations of 500 copies/ml or more receive open-label treatment as follows:

ARM D: ABC plus EFV plus adefovir dipivoxil plus NFV. [AS PER AMENDMENT 06/29/98: Enrollment to Group B is closed to accrual. Group A patients with HIV-1 RNA of 200 copies/ml or more on 2 consecutive determinations may continue their assigned treatment or seek best alternative antiretroviral therapy, which may include access to ABC. Group B patients with plasma HIV-1 RNA of 500 copies/ml or more may continue their assigned treatment or seek best available antiretroviral therapy, which may include access to ABC, EFV, and adefovir dipivoxil with L-carnitine supplementation. Group C patients with HIV-1 RNA levels above 2,000 copies/ml and Group D patients with levels above 500 copies/ml may no longer be randomized to a treatment arm in Group B. Such patients may continue their assigned treatment or seek best available therapy, which may include access to therapy as per Group B patients.] [AS PER AMENDMENT 06/16/99: Study treatment for Groups B, C, and D has been completed. Group A patients with a confirmed plasma HIV-2 endpoint who remain on study may have access to ABC while on study.] [AS PER AMENDMENT 12/27/01: With Version 4.0 of the protocol, many of the metabolic assessments and the cardiovascular risk assessment will be repeated, and a self-reported questionnaire of body shape changes will be added. In addition, an investigation of the effect of long-term IDV on pyuria/hematuria is added, as well as a study of HIV-1 RNA in peripheral blood mononuclear cells (PBMCs).]

Study Design

Study Type:

Interventional

Masking:

Double

Primary Purpose:

Treatment

Official Title:

A Phase II Study of the Prolongation of Virologic Success (ACTG 372A) and Options for Virologic Failure (ACTG B/C/D) in HIV-Infected Subjects Receiving Indinavir in Combination With Nucleoside Analogs: A Rollover Study for ACTG 320

Actual Study Completion Date :

Jun 1, 2003

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

16 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria

Concurrent Medication:

Required:

Chemoprophylaxis for Pneumocystis carinii pneumonia for all patients with a CD4 cell count of 200 cells/mm3 or less.

Allowed:

Treatment, maintenance, or chemoprophylaxis, including topical and/or oral antifungal agents unless otherwise excluded by the protocol.
All antibiotics as clinically indicated, unless otherwise excluded in the protocol.
Systemic corticosteroid use for 21 days or less for acute problems as medically indicated. Chronic corticosteroid use is not permitted, unless it is within physiologic replacement levels. Study team must be contacted in these instances.
rEPO and G-CSF as medically indicated.
Regularly prescribed medications such as [AS PER AMENDMENT 06/29/98: alternative, FDA-approved antiretrovirals not supplied by the study] [AS PER AMENDMENT 12/27/01: or unapproved antiretrovirals available by expanded access (when permanently discontinued from randomized study treatment)], antipyretics, analgesics, allergy medications, antidepressants, sleep medications, oral contraceptives, megestrol acetate, testosterone, or any other medications not otherwise excluded by the protocol, as medically indicated.
[AS PER AMENDMENT 12/27/01: Supplemental and] alternative therapies such as vitamins, acupuncture, and visualization techniques.

Recommended as an alternative agent for chemoprophylaxis against Mycobacterium avium complex for patients randomized to EFV in Group B or D:

clarithromycin or azithromycin.

Patients must have:

HIV-1 infection as documented by any licensed ELISA test kit and confirmed by either a Western Blot, HIV culture, HIV antigen, plasma HIV-1 RNA, or a second antibody test by a method other than ELISA at any time prior to study entry.

Non-ACTG patients:

Documented CD4 cell count of 200 cells/mm3 or less at the time of initiation of ZDV (or d4T) plus 3TC plus IDV.
Signed, informed consent from a parent or legal guardian for patients under 18 years of age.

Prior Medication:

Required:

Non-ACTG 320 patients:

At least 3 months prior therapy with ZDV (or d4T) plus 3TC plus IDV and continued receipt of ZDV (or d4T) plus 3TC plus IDV until enrollment. IDV and 3TC must have been initiated concurrently.

ACTG patients:

Randomization to the ZDV (or d4T) plus 3TC plus IDV combination arm or receipt of open-label prior to unblinding and maintenance of that treatment as participation in ACTG 320.

Group D:

Prior NNRTI-exposure.

Exclusion Criteria

Co-existing Condition:

Patients with the following conditions and symptoms are excluded:

Unexplained temperature above 38.5 C for any 7 days or chronic diarrhea, defined as more than 3 liquid stools per day persisting for 15 days, within 30 days prior to study treatment.
AIDS-related malignancy, other than minimal Kaposi's sarcoma that requires systemic chemotherapy. Minimal Kaposi's sarcoma is defined as 5 or fewer cutaneous lesions and no visceral disease or tumor-associated edema that does not require systemic therapy.
Documented or suspected acute hepatitis within 30 days prior to study entry, irrespective of laboratory values.

Concurrent Medication:

Excluded:

All antiretroviral therapies other than study [AS PER AMENDMENT 06/16/99: provided] medications, [AS PER AMENDMENT 06/16/99: unless approved by the protocol chairs] [AS PER AMENDMENT 12/27/01: while on original randomized treatment.]
Rifabutin and rifampin.
Investigational agents without specific approval from the protocol chair.
Systemic cytotoxic chemotherapy.
Oral ketoconazole and itraconazole. NOTE: Itraconazole may be permitted for Group B and Group D patients if fluconazole is not an option.
Terfenadine, astemizole, cisapride, triazolam, midazolam, amiodarone, quinine, ergot derivatives, isotretinoin, [AS PER AMENDMENT 12/27/01: pimozide, St.John's Wort, and milk thistle.]
[AS PER AMENDMENT 12/27/01: Concomitant use of lovastatin or simvastatin is not recommended because of potential drug interactions. Pravastatin or atorvastatin may be used after consultation with the Study Team.]

To be avoided:

Herbal medications.

Prior Medication:

Excluded:

Any prior protease inhibitor therapy other than indinavir.
Interferons, interleukins, or HIV vaccines within 30 days prior to study entry.
Any experimental therapy within 30 days prior to study entry.
Rifampin, rifabutin, ketoconazole, or itraconazole within 14 days of study entry.

Non-ACTG patients:

Acute therapy for an infection or other medical illness within 14 days prior to study therapy.
NNRTI therapy prior to study entry (with the exception of Group D).
Recombinant erythropoietin (rEPO), granulocyte colony-stimulating factor (G-CSF, filgrastim), or granulocyte-macrophage colony-stimulating factor (GM-CSF, sargramostim) within 30 days prior to study entry.

Caution should be taken in the consumption of alcoholic beverages with study medications.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Univ of Alabama at Birmingham	Birmingham	Alabama	United States	35294
2	Univ of Southern California / LA County USC Med Ctr	Los Angeles	California	United States	900331079
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	Harbor UCLA Med Ctr	Torrance	California	United States	90502
8	Univ of Colorado Health Sciences Ctr	Denver	Colorado	United States	80262
9	Georgetown Univ Hosp	Washington	District of Columbia	United States	20037
10	Howard Univ	Washington	District of Columbia	United States	20059
11	Univ of Miami School of Medicine	Miami	Florida	United States	331361013
12	Emory Univ	Atlanta	Georgia	United States	30308
13	Queens Med Ctr	Honolulu	Hawaii	United States	96816
14	Univ of Hawaii	Honolulu	Hawaii	United States	96816
15	Northwestern Univ Med School	Chicago	Illinois	United States	60611
16	Cook County Hosp	Chicago	Illinois	United States	60612
17	Rush Presbyterian - Saint Luke's Med Ctr	Chicago	Illinois	United States	60612
18	Louis A Weiss Memorial Hosp	Chicago	Illinois	United States	60640
19	Indiana Univ Hosp	Indianapolis	Indiana	United States	462025250
20	Division of Inf Diseases/ Indiana Univ Hosp	Indianapolis	Indiana	United States	46202
21	Methodist Hosp of Indiana / Life Care Clinic	Indianapolis	Indiana	United States	46202
22	Univ of Iowa Hosp and Clinic	Iowa City	Iowa	United States	52242
23	Tulane Univ School of Medicine	New Orleans	Louisiana	United States	70112
24	Johns Hopkins Hosp	Baltimore	Maryland	United States	21287
25	Harvard (Massachusetts Gen Hosp)	Boston	Massachusetts	United States	02114
26	Boston Med Ctr	Boston	Massachusetts	United States	02118
27	Beth Israel Deaconess - West Campus	Boston	Massachusetts	United States	02215
28	Beth Israel Deaconess Med Ctr	Boston	Massachusetts	United States	02215
29	Univ of Minnesota	Minneapolis	Minnesota	United States	55455
30	St Louis Regional Hosp / St Louis Regional Med Ctr	Saint Louis	Missouri	United States	63112
31	Univ of Nebraska Med Ctr	Omaha	Nebraska	United States	681985130
32	SUNY / Erie County Med Ctr at Buffalo	Buffalo	New York	United States	14215
33	Beth Israel Med Ctr	New York	New York	United States	10003
34	Bellevue Hosp / New York Univ Med Ctr	New York	New York	United States	10016
35	Chelsea Ctr	New York	New York	United States	10021
36	Cornell Univ Med Ctr	New York	New York	United States	10021
37	St Vincent's Hosp / Mem Sloan-Kettering Cancer Ctr	New York	New York	United States	10021
38	Mount Sinai Med Ctr	New York	New York	United States	10029
39	Univ of Rochester Medical Center	Rochester	New York	United States	14642
40	Univ of North Carolina	Chapel Hill	North Carolina	United States	275997215
41	Carolinas Med Ctr	Charlotte	North Carolina	United States	28203
42	Duke Univ Med Ctr	Durham	North Carolina	United States	27710
43	Moses H Cone Memorial Hosp	Greensboro	North Carolina	United States	27401
44	Univ of Cincinnati	Cincinnati	Ohio	United States	452670405
45	Univ of Kentucky Lexington	Cincinnati	Ohio	United States	45267
46	MetroHealth Med Ctr	Cleveland	Ohio	United States	441091998
47	Ohio State Univ Hosp Clinic	Columbus	Ohio	United States	432101228
48	Julio Arroyo	West Columbia	South Carolina	United States	29169
49	Univ of Tennessee / E Tennessee Comprehensive Hemophilia Ctr	Knoxville	Tennessee	United States	37920
50	Vanderbilt Univ Med Ctr	Nashville	Tennessee	United States	37203
51	Univ of Texas Galveston	Galveston	Texas	United States	775550435
52	Univ Texas Health Science Ctr / Univ Texas Med School	Houston	Texas	United States	77030
53	Univ of Puerto Rico	San Juan		Puerto Rico	009365067