Addition of Efavirenz or Nelfinavir to a Lamivudine/Zidovudine/Indinavir HIV Treatment Regimen

Sponsor

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

Overall Status

Completed

CT.gov ID

NCT00000903

Collaborator

(none)

444

Enrollment

Locations

8.9

Patients Per Site

Study Details

Study Description

Brief Summary

To compare time to a virologic failure (first of 2 consecutive plasma HIV RNA levels greater than or equal to 200 copies/ml at or after Week 24) of each 4-drug regimen vs the 3-drug regimen. To determine the safety, tolerance, and virologic benefits of either nelfinavir (NFV) or efavirenz (EFV) with indinavir/lamivudine/zidovudine (IDV/3TC/ZDV) vs IDV/3TC/ZDV alone, in the treatment of patients with advanced HIV disease who have received limited or no prior antiretroviral therapy.

Prior ACTG studies have shown that the 3-drug combination regimen (IDV/ZDV/3TC) resulted in improved clinical outcomes and therefore may prolong the effects of therapy. The enhanced effects seen with combination therapies are likely related to a greater suppression of RNA replication and alterations in resistance patterns. Due to the progressive success of combination regimens, it is possible that more potent regimens will further enhance viral suppression and provide more durable treatment responses. In light of the additive suppression of HIV replication determined by pharmacological, immunological, and virological results, nelfinavir (NFV) as an addition to IDV/ZDV/3TC will be evaluated. Based on the potency of nonnucleoside reverse transcriptase inhibitors (NNRTIs) to suppress viral replication and the effectiveness of 3-drug regimens containing NNRTIs, efavirenz (EFV) will also be evaluated as an addition to IDV/ZDV/3TC.

Condition or Disease	Intervention/Treatment	Phase
HIV Infections	Drug: Indinavir sulfate Drug: Lamivudine/Zidovudine Drug: Nelfinavir mesylate Drug: Efavirenz	Phase 3

Detailed Description

Patients with HIV infection, CD4 cell count less than or equal to 200 cells/mm3 or plasma HIV RNA greater than or equal to 100,000 copies/ml, and limited (no prior 3TC, NNRTI, or protease inhibitor) or no prior antiretroviral treatment are randomized to 1 of 3 arms. Patients are stratified by CD4 cell count (less than or equal to 50 cells/mm3 vs greater than 50 cells/mm3), HIV-1 RNA copy number (less than or equal to 40,000 copies/ml vs greater than 40,000 copies/ml), and prior antiretroviral therapy (no therapy vs any therapy), and then randomly assigned to 1 of 3 treatment arms:

Arm 1: 3TC plus ZDV plus IDV. Arm 2: 3TC plus ZDV plus IDV plus EFV. Arm 3: 3TC plus ZDV plus IDV plus NFV. Patients are followed for at least 72 weeks [AS PER AMENDMENT 2/16/99: 96 weeks] beyond the enrollment of the last patient. Patients who experience virologic relapse will have the option of continuing randomized study medications, switching to Step 2 treatment, switching to another ACTG study, or seeking best available therapy for the remaining weeks of the study. Step 2 treatment consists of abacavir or 2 NNRTIs plus efavirenz plus amprenavir or another protease inhibitor. [AS PER AMENDMENT 4/3/00: Optimally, Step 2 treatment regimens should contain 3 or 4 drugs to which the virus is susceptible. If this is not possible, a drug to which the virus is partially susceptible is acceptable, but a drug to which the virus is resistant should not be included.]

Study Design

Study Type:

Interventional

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase III Randomized, Controlled Trial of Efavirenz (EFV) or Nelfinavir (NFV) in Combination With Fixed-Dose Combination Lamivudine/Zidovudine (3TC/ZDV) and Indinavir (IDV) in HIV-Infected Subjects With Less Than or Equal to 200 CD4 Cells/mm3 or Greater Than or Equal to 80,000 HIV RNA Copies/ml in Plasma

Actual Study Completion Date :

Jul 1, 2001

Outcome Measures

Primary Outcome Measures

Eligibility Criteria

Criteria

Ages Eligible for Study:

13 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria

Concurrent Medication:

Allowed:

Chemoprophylaxis for Pneumocystis carinii pneumonia.
Topical and oral antifungal agents (except for oral ketoconazole and itraconazole).
All antibiotics as clinically indicated (unless otherwise excluded).
Treatment, maintenance, or chemoprophylaxis with approved agents for opportunistic infections as clinically indicated (unless otherwise excluded).
Systemic corticosteroids for 21 days or less for acute problems.
Recombinant erythropoietin (rEPO) and granulocyte colony-stimulating factor (G-CSF, filgrastim).
Regularly prescribed medications such as antipyretics, analgesics, allergy medications, antidepressants, sleep medications, oral contraceptives, megestrol acetate, testosterone.
Alternative therapies such as vitamins. Patients should report the use of these therapies.
[AS PER AMENDMENT 2/16/99: Rifabutin can be administered at a reduced dose.]
[AS PER AMENDMENT 4/3/00: Systemic cytotoxic chemotherapy. Study team should be notified.]
[AS PER AMENDMENT 4/3/00: Expanded access and compassionate use drugs are allowed as part of Step 2 treatment only.]

Allowed with caution:

[AS PER AMENDMENT 4/3/00: Viagra (sildenafil citrate) at a reduced dose unless otherwise approved by the protocol chair.]
[AS PER AMENDMENT 4/3/00: Lovastatin or simvastatin with PIs is not recommended. Caution should be exercised with the use of all other statins when used concomitantly with PIs.]

Concurrent Treatment:

Allowed:

Alternative therapies such as acupuncture and visualization techniques. Patients should report use of these therapies.

Patients must have:

Documented HIV-1 infection.
CD4 count less than or equal to 200 cells/mm3 or a plasma HIV RNA greater than or equal to 100,000 copies/ml [AS PER AMENDMENT 2/16/99:
80,000 copies/ml] within 60 days prior to entry.
Other lab values performed within 14 days prior to entry.

Prior Medication:

Allowed:

Zidovudine (ZDV), didanosine (ddI), stavudine (d4T), or zalcitabine (ddC) therapy alone or in combination any time prior to study entry.

Exclusion Criteria

Concurrent Medication:

Excluded:

All antiretroviral therapies other than study medications. [AS PER AMENDMENT 4/3/00: Compassionate use and expanded access drugs are allowed as part of Step 2 treatment.]
Investigational drugs without specific approval from the Study Chair. [AS PER AMENDMENT 4/3/00: Compassionate use and expanded access drugs are allowed as part of Step 2 treatment.]
Systemic cytotoxic chemotherapy. [AS PER AMENDMENT 4/3/00: Systemic cytotoxic chemotherapy is allowed. Study team should be notified.]
Alprazolam, amiodarone, astemizole, bepridil, bupropion, cisapride, clorazepate, clozapine, diazepam, encainide, ergot alkaloids and derivatives of ergot alkaloids, estazolam, flecainide, flurazepam, itraconazole , ketoconazole, meperidine, midazolam, piroxicam, propafenone, propoxyphene, quinidine, rifabutin, rifampin, terfenadine, triazolam, or zolpidem. [AS PER AMENDMENT 2/16/99: Amiodarone, astemizole, cisapride, ergot alkaloids or drugs containing derivatives of ergot alkaloids, itraconazole, midazolam, triazolam, quinidine, rifampin, terfenadine.] [AS PER AMENDMENT 4/3/00: Amiodarone, astemizole, bepridil, cisapride, ergot alkaloids and derivatives of ergot alkaloids, Hypericum perforatum (St. John's wort), itraconazole, midazolam, quinidine, rifampin, terfenadine, triazolam.]
Vitamin E supplements. [AS PER AMENDMENT 4/3/00: Multivitamins containing vitamin E are allowed.]

Avoided:

Herbal medications. Patients should report use.

Patients with the following prior conditions are excluded:

Acute therapy for an infection or other medical illnesses within 14 days prior to study entry. [AS PER AMENDMENT 2/16/99: Acute therapy for a serious infection or other serious medical illnesses that are potentially life-threatening and require systemic therapy and/or hospitalization within 14 days of study entry.]

Prior Medication:

Excluded within 30 days prior to entry:

More than 1 day experience with lamivudine (3TC), nonnucleoside reverse transcriptase inhibitor, or protease inhibitor.
Erythropoietin, G-CSF, or GM-CSF.
Interferons, interleukins, HIV vaccines, or any experimental therapy.

Excluded within 14 days prior to entry:

Alprazolam (Xanax), amiodarone (Cordarone), astemizole (Hismanal), bepridil (Vascor), bupropion (Wellbutrin, Zyban), cisapride (Propulsid), clorazepate (Tranxene), clozapine (Clozaril), diazepam (Valium), encainide (Enkaid), ergot alkaloids or drugs containing derivatives of ergot alkaloids, estazolam (ProSom), flecainide (Tambocor), flurazepam (Dalmane), itraconazole (Sporanox), ketoconazole (Nizoral), meperidine (Demerol), midazolam (Versed), piroxicam (Feldene), propafenone (Rythmol), propoxyphene (Darvon, Darvocet), quinidine, rifabutin (Mycobutin), rifampin (Rifadin, Rifamate, Rifater, Rimactane), terfenadine (Seldane), triazolam (Halcion), or zolpidem (Ambien). [AS PER AMENDMENT 2/16/99: Agents excluded within 14 days prior to entry are now as follows:
amiodarone, astemizole, cisapride, ergot alkaloids or drugs containing derivatives of ergot alkaloids, itraconazole, midazolam, quinidine, rifampin, terfenadine, and triazolam.

Note:

Rifabutin can be administered at a reduced dose of 150 mg/day.]

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alabama Therapeutics CRS	Birmingham	Alabama	United States	35294
2	USC CRS	Los Angeles	California	United States	900331079
3	UCLA CARE Center CRS	Los Angeles	California	United States	90095
4	Stanford CRS	Palo Alto	California	United States
5	Ucsd, Avrc Crs	San Diego	California	United States	92161
6	Ucsf Aids Crs	San Francisco	California	United States	941102859
7	Santa Clara Valley Med. Ctr.	San Jose	California	United States	951282699
8	San Mateo County AIDS Program	San Mateo	California	United States
9	Marin County Dept. of Health & Human Services, HIV/AIDS Program & Specialty Clinic	San Rafael	California	United States
10	Harbor-UCLA Med. Ctr. CRS	Torrance	California	United States	90502
11	University of Colorado Hospital CRS	Aurora	Colorado	United States	80262
12	Howard University Hosp., Div. of Infectious Diseases, ACTU	Washington	District of Columbia	United States	20059
13	Univ. of Miami AIDS CRS	Miami	Florida	United States	331361013
14	The Ponce de Leon Ctr. CRS	Atlanta	Georgia	United States	30308
15	Queens Med. Ctr.	Honolulu	Hawaii	United States	96816
16	Univ. of Hawaii at Manoa, Leahi Hosp.	Honolulu	Hawaii	United States	96816
17	Northwestern University CRS	Chicago	Illinois	United States	60611
18	Cook County Hosp. CORE Ctr.	Chicago	Illinois	United States	60612
19	Rush Univ. Med. Ctr. ACTG CRS	Chicago	Illinois	United States	60612
20	Weiss Memorial Hosp.	Chicago	Illinois	United States	60640
21	Indiana Univ. School of Medicine, Wishard Memorial	Indianapolis	Indiana	United States	462025250
22	Indiana Univ. School of Medicine, Infectious Disease Research Clinic	Indianapolis	Indiana	United States	46202
23	Methodist Hosp. of Indiana	Indianapolis	Indiana	United States	46202
24	Univ. of Iowa Healthcare, Div. of Infectious Diseases	Iowa City	Iowa	United States	52242
25	Tulane Med. Ctr. - Charity Hosp. of New Orleans, ACTU	New Orleans	Louisiana	United States	70112
26	Johns Hopkins Adult AIDS CRS	Baltimore	Maryland	United States	21287
27	Beth Israel Deaconess Med. Ctr., ACTG CRS	Boston	Massachusetts	United States	02215
28	University of Minnesota, ACTU	Minneapolis	Minnesota	United States	55455
29	St. Louis ConnectCare, Infectious Diseases Clinic	St Louis	Missouri	United States	63112
30	Washington U CRS	St. Louis	Missouri	United States
31	Univ. of Nebraska Med. Ctr., Durham Outpatient Ctr.	Omaha	Nebraska	United States	681985130
32	SUNY - Buffalo, Erie County Medical Ctr.	Buffalo	New York	United States	14215
33	Beth Israel Med. Ctr., ACTU	New York	New York	United States	10003
34	Cornell CRS	New York	New York	United States	10021
35	Beth Israel Med. Ctr. (Mt. Sinai)	New York	New York	United States	10029
36	Cornell University A2201	New York	New York	United States
37	NY Univ. HIV/AIDS CRS	New York	New York	United States
38	Weill Med. College of Cornell Univ., The Cornell CTU	New York	New York	United States
39	Univ. of Rochester ACTG CRS	Rochester	New York	United States	14642
40	Unc Aids Crs	Chapel Hill	North Carolina	United States	275997215
41	Carolinas HealthCare System, Carolinas Med. Ctr.	Charlotte	North Carolina	United States	28203
42	Duke Univ. Med. Ctr. Adult CRS	Durham	North Carolina	United States	27710
43	Regional Center for Infectious Disease, Wendover Medical Center CRS	Greensboro	North Carolina	United States	27401
44	Univ. of Cincinnati CRS	Cincinnati	Ohio	United States	452670405
45	Case CRS	Cleveland	Ohio	United States	44106
46	MetroHealth CRS	Cleveland	Ohio	United States	441091998
47	The Ohio State Univ. AIDS CRS	Columbus	Ohio	United States	432101228
48	Hosp. of the Univ. of Pennsylvania CRS	Philadelphia	Pennsylvania	United States	19104
49	University of Washington AIDS CRS	Seattle	Washington	United States	981224304
50	Puerto Rico-AIDS CRS	San Juan		Puerto Rico	009365067