Addition of Efavirenz or Nelfinavir to a Lamivudine/Zidovudine/Indinavir HIV Treatment Regimen
Information source: National Institute of Allergy and Infectious Diseases (NIAID)
Information obtained from ClinicalTrials.gov on June 20, 2008
Link to the current ClinicalTrials.gov record.
Condition(s) targeted: HIV Infections
Intervention: Indinavir sulfate (Drug); Lamivudine/Zidovudine (Drug); Nelfinavir mesylate (Drug); Efavirenz (Drug)
Phase: Phase 3
Status: Completed
Sponsored by: National Institute of Allergy and Infectious Diseases (NIAID) Official(s) and/or principal investigator(s):
Margaret Fischl, Study Chair
Ann Collier, Study Chair
Judith Feinberg, Study Chair
Stefano Vella, Study Chair
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.
Clinical Details
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
Study design: Treatment, Open Label, Safety Study
Detailed description:
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.
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.]
Eligibility
Minimum age: 13 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
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.]
Locations and Contacts
Spedali Civili - Carosi, Brescia, Italy
Univ of Puerto Rico, San Juan 009365067, Puerto Rico
Univ of Alabama at Birmingham, Birmingham, Alabama 35294, United States
VA Hosp at San Diego / Pediatrics, San Diego, California 92161, United States
San Francisco Gen Hosp, San Francisco, California 941102859, United States
San Francisco AIDS Clinic / San Francisco Gen Hosp, San Francisco, California 941102859, United States
Stanford Univ Med Ctr, Stanford, California 943055107, United States
UCLA CARE Ctr, Los Angeles, California 90095, United States
Univ of Southern California / LA County USC Med Ctr, Los Angeles, California 900331079, United States
Harbor UCLA Med Ctr, Torrance, California 90502, United States
Santa Clara Valley Med Ctr / AIDS Community Rsch Consortium, San Jose, California 951282699, United States
Willow Clinic, Menlo Park, California 94025, United States
Kaiser Permanente LAMC, Los Angeles, California 90027, United States
Univ of Colorado Health Sciences Ctr, Denver, Colorado 80262, United States
Howard Univ, Washington, District of Columbia 20059, United States
Georgetown Univ Hosp, Washington, District of Columbia 20037, United States
Univ of Miami School of Medicine, Miami, Florida 331361013, United States
Emory Univ, Atlanta, Georgia 30308, United States
Queens Med Ctr, Honolulu, Hawaii 96816, United States
Univ of Hawaii, Honolulu, Hawaii 96816, United States
Northwestern Univ Med School, Chicago, Illinois 60611, United States
Rush Presbyterian - Saint Luke's Med Ctr, Chicago, Illinois 60612, United States
Cook County Hosp, Chicago, Illinois 60612, United States
Louis A Weiss Memorial Hosp, Chicago, Illinois 60640, United States
Indiana Univ Hosp, Indianapolis, Indiana 462025250, United States
Methodist Hosp of Indiana / Life Care Clinic, Indianapolis, Indiana 46202, United States
Division of Inf Diseases/ Indiana Univ Hosp, Indianapolis, Indiana 46202, United States
Univ of Iowa Hosp and Clinic, Iowa City, Iowa 52242, United States
Charity Hosp / Tulane Univ Med School, New Orleans, Louisiana 70112, United States
Tulane Univ School of Medicine, New Orleans, Louisiana 70112, United States
Johns Hopkins Hosp, Baltimore, Maryland 21287, United States
State of MD Div of Corrections / Johns Hopkins Univ Hosp, Baltimore, Maryland 212052196, United States
Beth Israel Deaconess - West Campus, Boston, Massachusetts 02215, United States
Univ of Minnesota, Minneapolis, Minnesota 55455, United States
St Louis Regional Hosp / St Louis Regional Med Ctr, St. Louis, Missouri 63112, United States
Univ of Nebraska Med Ctr, Omaha, Nebraska 681985130, United States
Univ of Rochester Medical Center, Rochester, New York 14642, United States
Bellevue Hosp / New York Univ Med Ctr, New York, New York 10016, United States
Mount Sinai Med Ctr, New York, New York 10029, United States
Cornell Univ Med Ctr, New York, New York 10021, United States
SUNY / Erie County Med Ctr at Buffalo, Buffalo, New York 14215, United States
Beth Israel Med Ctr, New York, New York 10003, United States
Chelsea Ctr, New York, New York 10021, United States
Carolinas Med Ctr, Charlotte, North Carolina 28203, United States
Univ of North Carolina, Chapel Hill, North Carolina 275997215, United States
Moses H Cone Memorial Hosp, Greensboro, North Carolina 27401, United States
Duke Univ Med Ctr, Durham, North Carolina 27710, United States
Case Western Reserve Univ, Cleveland, Ohio 44106, United States
Univ of Cincinnati, Cincinnati, Ohio 452670405, United States
Ohio State Univ Hosp Clinic, Columbus, Ohio 432101228, United States
MetroHealth Med Ctr, Cleveland, Ohio 441091998, United States
Univ of Kentucky Lexington, Cincinnati, Ohio 45267, United States
Univ of Pennsylvania at Philadelphia, Philadelphia, Pennsylvania 19104, United States
Julio Arroyo, West Columbia, South Carolina 29169, United States
Univ of Texas Galveston, Galveston, Texas 775550435, United States
Univ of Washington, Seattle, Washington 981224304, United States
Additional Information
Click here for more information about indinavir sulfate Click here for more information about nelfinavir mesylate Click here for more information about efavirenz Click here for more information about lamivudine/zidovudine
Ending date: January 1999
Last updated: June 23, 2005
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