Clinical trial NCT00000903: Addition of Efavirenz or Nelfinavir to a Lamivudine/Zidovudine/Indinavir HIV Treatment Regimen
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 type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: HIV Infections
Keywords: Drug Therapy, Combination
Zidovudine
HIV Protease Inhibitors
Lamivudine
Indinavir
RNA, Viral
Reverse Transcriptase Inhibitors
Nelfinavir
efavirenz
Lead sponsor: National Institute of Allergy and Infectious Diseases (NIAID)
Sponsor class: NIH
First posted: 2001-08-31
Enrollment: 444
Sex: ALL
Minimum age (years): 13
Standard ages: CHILD
ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Primary purpose: TREATMENT

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.

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 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.\]

Primary outcomes:
Secondary outcomes:
Other outcomes:
Locations:
city: Birmingham
country: United States
facility: Alabama Therapeutics CRS
state: Alabama
city: Los Angeles
country: United States
facility: USC CRS
state: California
city: Los Angeles
country: United States
facility: UCLA CARE Center CRS
state: California
city: Palo Alto
country: United States
facility: Stanford CRS
state: California
city: San Diego
country: United States
facility: Ucsd, Avrc Crs
state: California
city: San Francisco
country: United States
facility: Ucsf Aids Crs
state: California
city: San Jose
country: United States
facility: Santa Clara Valley Med. Ctr.
state: California
city: San Mateo
country: United States
facility: San Mateo County AIDS Program
state: California
city: San Rafael
country: United States
facility: Marin County Dept. of Health & Human Services, HIV/AIDS Program & Specialty Clinic
state: California
city: Torrance
country: United States
facility: Harbor-UCLA Med. Ctr. CRS
state: California
city: Aurora
country: United States
facility: University of Colorado Hospital CRS
state: Colorado
city: Washington
country: United States
facility: Howard University Hosp., Div. of Infectious Diseases, ACTU
state: District of Columbia
city: Miami
country: United States
facility: Univ. of Miami AIDS CRS
state: Florida
city: Atlanta
country: United States
facility: The Ponce de Leon Ctr. CRS
state: Georgia
city: Honolulu
country: United States
facility: Queens Med. Ctr.
state: Hawaii
city: Honolulu
country: United States
facility: Univ. of Hawaii at Manoa, Leahi Hosp.
state: Hawaii
city: Chicago
country: United States
facility: Northwestern University CRS
state: Illinois
city: Chicago
country: United States
facility: Cook County Hosp. CORE Ctr.
state: Illinois
city: Chicago
country: United States
facility: Rush Univ. Med. Ctr. ACTG CRS
state: Illinois
city: Chicago
country: United States
facility: Weiss Memorial Hosp.
state: Illinois
city: Indianapolis
country: United States
facility: Indiana Univ. School of Medicine, Wishard Memorial
state: Indiana
city: Indianapolis
country: United States
facility: Indiana Univ. School of Medicine, Infectious Disease Research Clinic
state: Indiana
city: Indianapolis
country: United States
facility: Methodist Hosp. of Indiana
state: Indiana
city: Iowa City
country: United States
facility: Univ. of Iowa Healthcare, Div. of Infectious Diseases
state: Iowa
city: New Orleans
country: United States
facility: Tulane Med. Ctr. - Charity Hosp. of New Orleans, ACTU
state: Louisiana
city: Baltimore
country: United States
facility: Johns Hopkins Adult AIDS CRS
state: Maryland
city: Boston
country: United States
facility: Beth Israel Deaconess Med. Ctr., ACTG CRS
state: Massachusetts
city: Minneapolis
country: United States
facility: University of Minnesota, ACTU
state: Minnesota
city: St Louis
country: United States
facility: St. Louis ConnectCare, Infectious Diseases Clinic
state: Missouri
city: St. Louis
country: United States
facility: Washington U CRS
state: Missouri
city: Omaha
country: United States
facility: Univ. of Nebraska Med. Ctr., Durham Outpatient Ctr.
state: Nebraska
city: Buffalo
country: United States
facility: SUNY - Buffalo, Erie County Medical Ctr.
state: New York
city: New York
country: United States
facility: Beth Israel Med. Ctr., ACTU
state: New York
city: New York
country: United States
facility: Cornell CRS
state: New York
city: New York
country: United States
facility: Beth Israel Med. Ctr. (Mt. Sinai)
state: New York
city: New York
country: United States
facility: Cornell University A2201
state: New York
city: New York
country: United States
facility: NY Univ. HIV/AIDS CRS
state: New York
city: New York
country: United States
facility: Weill Med. College of Cornell Univ., The Cornell CTU
state: New York
city: Rochester
country: United States
facility: Univ. of Rochester ACTG CRS
state: New York
city: Chapel Hill
country: United States
facility: Unc Aids Crs
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas HealthCare System, Carolinas Med. Ctr.
state: North Carolina
city: Durham
country: United States
facility: Duke Univ. Med. Ctr. Adult CRS
state: North Carolina
city: Greensboro
country: United States
facility: Regional Center for Infectious Disease, Wendover Medical Center CRS
state: North Carolina
city: Cincinnati
country: United States
facility: Univ. of Cincinnati CRS
state: Ohio
city: Cleveland
country: United States
facility: Case CRS
state: Ohio
city: Cleveland
country: United States
facility: MetroHealth CRS
state: Ohio
city: Columbus
country: United States
facility: The Ohio State Univ. AIDS CRS
state: Ohio
city: Philadelphia
country: United States
facility: Hosp. of the Univ. of Pennsylvania CRS
state: Pennsylvania
city: Seattle
country: United States
facility: University of Washington AIDS CRS
state: Washington
city: San Juan
country: Puerto Rico
facility: Puerto Rico-AIDS CRS
Study officials:
name: Margaret Fischl
role: STUDY_CHAIR
name: Ann Collier
role: STUDY_CHAIR
name: Judith Feinberg
role: STUDY_CHAIR
name: Stefano Vella
role: STUDY_CHAIR
References:
citation: Fischl MA, Ribaudo HJ, Collier AC, Erice A, Giuliano M, Dehlinger M, Eron JJ Jr, Saag MS, Hammer SM, Vella S, Morse GD, Feinberg JE, Demeter LM, Eshleman SH; Adult AIDS Clinical Trials Group 388 Study Team. A randomized trial of 2 different 4-drug antiretroviral regimens versus a 3-drug regimen, in advanced human immunodeficiency virus disease. J Infect Dis. 2003 Sep 1;188(5):625-34. doi: 10.1086/377311. Epub 2003 Aug 15.
citation: Demeter LM, Ribaudo HJ, Erice A, Eshleman SH, Hammer SM, Hellmann NS, Fischl MA; AIDS Clinical Trials Group Protocol 388. HIV-1 drug resistance in subjects with advanced HIV-1 infection in whom antiretroviral combination therapy is failing: a substudy of AIDS Clinical Trials Group Protocol 388. Clin Infect Dis. 2004 Aug 15;39(4):552-8. doi: 10.1086/422518. Epub 2004 Jul 30.
citation: DiCenzo R, Forrest A, Fischl MA, Collier A, Feinberg J, Ribaudo H, DiFrancecso R, Morse GD; AIDS Clinical Trials Group 388/733/5060 Study Team. Pharmacokinetics of indinavir and nelfinavir in treatment-naive, human immunodeficiency virus-infected subjects. Antimicrob Agents Chemother. 2004 Mar;48(3):918-23. doi: 10.1128/AAC.48.3.918-923.2004.
citation: Lok JJ, Hunt PW, Collier AC, Benson CA, Witt MD, Luque AE, Deeks SG, Bosch RJ. The impact of age on the prognostic capacity of CD8+ T-cell activation during suppressive antiretroviral therapy. AIDS. 2013 Aug 24;27(13):2101-10. doi: 10.1097/QAD.0b013e32836191b1.