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Study of Protease Inhibitor and/or Non-Nucleoside Reverse Transcriptase Inhibitor With Dual Nucleosides in Initial Therapy of HIV Infection


N/A
13 Years
N/A
Not Enrolling
Both
HIV Infections

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Trial Information

Study of Protease Inhibitor and/or Non-Nucleoside Reverse Transcriptase Inhibitor With Dual Nucleosides in Initial Therapy of HIV Infection


Highly active antiretroviral therapy, though effective in the suppression of HIV
proliferation, is often complicated by difficulties with adherence and drug toxicity.
Various combinations of highly active antiretroviral therapy exist; all have proved
efficacious in related trials. The question addressed in this trial is which combination of
antiretroviral "cocktails" provides the single greatest advantage in preventing the spread
of HIV in the body. In effect, which therapy provides the greatest benefit with the fewest
complications.

Step 1: Patients are randomized to 1 of 6 arms:

Arm A: didanosine (ddI), stavudine (d4T), efavirenz (EFV), and nelfinavir (NFV) placebo.

Arm B: ddI, d4T, EFV placebo, and NFV. Arm C: lamivudine (3TC)/zidovudine (ZDV), EFV, and
NFV placebo. Arm D: 3TC/ZDV, EFV placebo, and NFV. Arm E: ddI, d4T, EFV, and NFV. Arm F:
3TC/ZDV, EFV, and NFV. Patients with virologic failure on 2 successive measurements or
study-drug intolerance discontinue their randomized study therapy and proceed to Step 2. [AS
PER AMENDMENT 7/5/00: Patients must switch regimens as soon as possible after confirmation
of virologic failure to prevent development of drug resistance.]

Step 2:

Arm A: Patients receive treatment as in Arm D of Step 1. Arm B: Patients receive treatment
as in Arm C of Step 1. Arm C: Patients receive treatment as in Arm B of Step 1. Arm D:
Patients receive treatment as in Arm A of Step 1. Arms A, B, C, and D: Patients who fail
Step 2 treatment proceed to Step 3. Arms E and F: Patients with virologic failure on Step 1
proceed immediately to Step 3.

Step 3 (salvage therapy):

Arm A, B, C, and D: Patients receive indinavir (IDV), amprenavir (APV), ddI, and hydroxyurea
(HU).

[AS PER AMENDMENT 7/5/00: Patients now receive treatment on Regimen 1, 2, 3, 4, 5, or 6.
Regimen 1 consists of IDV, ritonavir (RTV), ddI, and HU. Regimen 2 consists of APV, RTV,
ddI, and HU. Regimen 3 consists of IDV, RTV, abacavir (ABC), and 3TC/ZDV. Regimen 4 consists
of APV, RTV, ABC, and 3TC/ZDV. Regimen 5 consists of IDV, RTV, ABC, d4T, and 3TC. Regimen 6
consists of APV, RTV, ABC, d4T, and 3TC.] Arm E: Patients receive IDV, APV, and 3TC/ZDV. [AS
PER AMENDMENT 7/5/00: Patients now receive treatment on Regimen 7 or 8. Regimen 7 consists
of IDV, RTV, and 3TC/ZDV. Regimen 8 consists of APV, RTV, and 3TC/ZDV.] Arm F: Patients
receive IDV, APV, ddI, and d4T. [AS PER AMENDMENT 7/5/00: Patients now receive treatment on
Regimen 9 or 10. Regimen 9 consists of IDV, RTV, ddI, and d4T. Regimen 10 consists of APV,
RTV, ddI, and d4T.] [AS PER AMENDMENT 7/5/00: Patients already enrolled in Step 3 before
site registration to Version 4.0 of this protocol have the option of receiving 1 of the
appropriate new Step 3 regimens as outlined above or staying on their originally assigned
Step 3 therapy.] [AS PER AMENDMENT 3/21/01: If virologic failure on Step 1 or 2 is
confirmed, then HIV-1 RNA genotype resistance testing (in real-time, if possible) is
performed. Patients receive 1 of the Step 3 drug regimens based on the results of the
resistance testing.] Patients may co-enroll in metabolic, pharmacologic, immunologic, or
adherence substudies.

Inclusion Criteria


Inclusion Criteria

Concurrent Medication:

[Required: AS PER AMENDMENT 7/5/00:

- Chemoprophylaxis for Pneumocystis carinii pneumonia if CD4+ cell count is less than
or equal to 200 cells/mm3.]

[Suggested as an alternative agent for chemoprophylaxis against Mycobacterium avium
complex:

- Azithromycin.]

[Allowed: AS PER AMENDMENT 7/5/00:

- Topical and oral antifungal agents. Oral itraconazole may be administered
concurrently with IDV if the dose of IDV is reduced to 600 mg every 8 hours.

- Treatment, maintenance, or chemoprophylaxis for opportunistic infections, as
clinically indicated unless otherwise prohibited by the protocol.

- All antibiotics, as clinically indicated unless otherwise prohibited by the protocol.

- Systemic corticosteroid use for 21 days or less for acute problems, as medically
indicated.

- Recombinant erythropoietin (rEPO, epoetin alfa, Epogen, epoetin beta, Marogen),
granulocyte colony-stimulating factor (G-CSF, filgrastim, Neupogen), and
granulocyte-macrophage colony-stimulating factor (GM-CSF, Regramostim).

- Regularly prescribed medications, such as antipyretics, analgesics, allergy
medications, antidepressants, sleep medications, oral contraceptives, megestrol
acetate (Megace), testosterone, or any other medications, as medically indicated
unless otherwise prohibited by the protocol. NOTE: Due to the possibility that study
medications may alter the effectiveness of oral contraceptives or depoprogesterone,
these agents must not be used as the sole form of birth control, because the role of
some study medications on the effectiveness of these methods has not yet been
established.

- Alternative therapies, such as vitamins.

- Medications requiring low gastric pH if not administered at the same time as buffered
ddI. Patients taking these agents should do so at least 2 hours before ddI.]

- Vaccinations, if administered at least 2 weeks prior to an HIV RNA viral load
evaluation.

[Allowed with caution: AS PER AMENDMENT 7/5/00:

- Oral ketoconazole with IDV.

Medications that interact with PIs as substrates, inhibitors, or inducers, including, but
not limited to:

- allopurinol, alprazolam, amitriptyline, atorvastatin, bupropion, carbamazepine,
cerivastatin, chlorpheniramine, chlorpromazine, chlorzoxazone, cimetidine,
clarithromycin, clofibrate, clorazepate, clozapine, codeine, dapsone, desipramine,
diazepam, diltiazem, disopyramide, encainide, erythromycin, estazolam, estrogens and
progesterones, fluoxetine, flurazepam, fluvastatin, glucocorticoids, hypericum
perforatum (St. John's wort), imipramine, isoniazid, itraconazole, ketoconazole,
labetalol, lamotrigine, lidocaine, lovastatin, mexiletine, morphine, naloxone,
nefazodone, nifedipine, nortriptyline, opioids, oxazepam, pentazocine, phenobarbital,
phenytoin, promethazine, propofol, propranolol and other beta blockers, sildenafil,
simvastatin, temazepam, T3 (thyroid hormone), warfarin, valproic acid, and zolpidem.

- Drugs with high protein-binding properties, nephrotoxic drugs, and opiate agonists
(e.g., methadone or buprenorphine).]

NOTE:

- Refer to package insert for potential drug interactions with IDV, RTV, NFV, or APV
that may require therapeutic drug monitoring and/or adjustment of concomitant
medications.]

[Allowed with extreme caution:

- AS PER AMENDMENT 7/5/00:

ddI, as clinically indicated in patients with known risk factors, including, but not
limited to, alcohol abuse, morbid obesity, hypertriglyceridemia, cholelithiasis,
endoscopic retrograde cholangiopancreatography, use of medications known to cause
pancreatitis (e.g., pentamidine) and use of medications known or thought to increase
exposure to ddI (e.g., HU, allopurinol).]

Concurrent Treatment:

[Allowed:

- AS PER AMENDMENT 7/5/00:

Acupuncture and visualization techniques.]

Patients must have:

- HIV infection, as documented by any licensed ELISA test kit and confirmed by either
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.

- Plasma HIV-1 RNA of 500 copies/ml or more, confirmed by the Roche Amplicor assay only
and performed within 60 days [AS PER AMENDMENT 5/5/99:

- 70 days] of study entry by any certified laboratory.

- Inclusion laboratory parameters, documented within 14 days prior to study entry (see
lab values).

[AS PER AMENDMENT 9/9/99:

- Co-enrollment on ACTG A5005s (Metabolism Substudy) is required for patients enrolling
under Version 3.0 of ACTG 384.]

Risk Behavior:

[Allowed with caution:

- AS PER AMENDMENT 7/5/00:

Alcoholic beverages.]

Exclusion Criteria

Co-existing Condition:

Patients with the following condition are excluded:

AIDS-related malignancy other than minimal Kaposi's sarcoma.

Concurrent Medication:

[Excluded:

- AS PER AMENDMENT 7/5/00:

- Chronic systemic corticosteroids.

- For Steps 1 and 2, all antiretroviral therapies other than study medications. For
step 3, contact the team to discuss potential addition or substitution with off-study
antiretroviral medications.

- Investigational drugs without specific approval from the study chairs.

- Neurotoxic and pancreatotoxic drugs.

- Systemic cytotoxic chemotherapy.

- Amiodarone, astemizole, bepridil, cisapride, cholestyramine, ergot and ergot
derivatives, flecainide, ganciclovir, interferon alfa, midazolam (unless used for
sedation on ACTG 723), pimozide, propafenone, propoxyphene, quinidine, ribavirin,
rifampin, sucralfate, terfenadine, and triazolam.

- Rifabutin for patients on RTV in Step 3 and for patients on Steps 1 and 2 because of
the contradictory effects of EFV and NFV on plasma rifabutin levels. If a patient on
Step 1 or 2 requires treatment with rifabutin after coming on the study, the team
must be notified.

- Alpha tocopherol (vitamin E) supplementation since vitamin E is contained in the soft
gelatin capsule formulation of APV.

- ddI concurrently with IV pentamidine.

- Herbal medications.]

Patients with the following prior conditions are excluded:

- Pancreatitis within 3 years of study entry.

- Current peripheral neuropathy grade 2 or greater or history of peripheral neuropathy
grade 3 or greater.

- Documented or suspected acute hepatitis within 30 days prior to study entry.

- Unexplained temperature above 38.5 C for any 7 days or chronic diarrhea (defined as
more than 3 liquid stools per day persisting for more than 15 days) within 30 days
prior to study entry.

- Any previous hypersensitivity to study drugs or their components.

Prior Medication:

Excluded:

- Receipt within 30 days of erythropoietin, G-CSF, or GM-CSF.

- Treatment within 14 days of study entry with any of the following:

- amiodarone, astemizole, cisapride, ergot or ergot derivatives, ketoconazole,
midazolam, propoxyphene, quinidine, rifampin, terfenidine, or triazolam.

- Prior antiretroviral therapy for 7 days or more, including protease inhibitors (PIs),
nucleoside reverse transcriptase inhibitors (NRTIs), and nonnucleoside reverse
transcriptase inhibitors (NNRTIs). [AS PER AMENDMENT 5/5/99:

- Systemic ketoconazole or itraconazole, intravenous pentamidine, and rifabutin are
prohibited. Midazolam is allowed for sedation in patients participating on ACTG 723.]

- Any vaccination within 14 days prior to study entry.

- Any immunomodulator or investigational therapy within 30 days prior to study entry.

[AS PER AMENDMENT 5/5/99:

- 6. Rifabutin is discouraged.]

Prior Treatment:

Excluded:

- Acute therapy for an infection or other medical illness within 14 days prior to study
entry.

[AS PER AMENDMENT 5/5/99:

- Acute therapy for a serious infection or other serious medical illness that is
potentially life-threatening and requires systemic therapy and/or hospitalization
within 14 days of study entry. Patients with Pneumocystis carinii pneumonia must have
completed acute therapy at least 7 days prior to entry and be clinically stable.
Patients with other serious infection or serious medical illness who must continue
chronic therapy must have completed at least 14 days of therapy prior to entry and be
clinically stable. Patients with all other infections or medical illnesses must have
completed therapy, or at least 14 days of maintenance therapy, prior to entry and be
clinically stable (restrictions do not apply to oral and vaginal candidiasis,
mucocutaneous herpes simplex infection, and minor skin conditions).]

Risk Behavior:

Excluded:

- Possible current substance abuse that could prevent compliance with the study
medication.

Type of Study:

Interventional

Study Design:

Endpoint Classification: Pharmacokinetics Study, Masking: Double-Blind, Primary Purpose: Treatment

Principal Investigator

Robert Shafer

Investigator Role:

Study Chair

Authority:

United States: Federal Government

Study ID:

ACTG 384

NCT ID:

NCT00000919

Start Date:

Completion Date:

November 2002

Related Keywords:

  • HIV Infections
  • HIV Protease Inhibitors
  • Reverse Transcriptase Inhibitors
  • Anti-HIV Agents
  • Viral Load
  • HIV Infections
  • Acquired Immunodeficiency Syndrome

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Location

San Francisco Gen HospSan Francisco, California  941102859
Mem Sloan - Kettering Cancer CtrNew York, New York  10021
Univ of Rochester Medical CenterRochester, New York  14642
Julio ArroyoWest Columbia, South Carolina  29169
UCLA CARE CtrLos Angeles, California  90095
Univ of California / San Diego Treatment CtrSan Diego, California  921036325
San Francisco AIDS Clinic / San Francisco Gen HospSan Francisco, California  941102859
Harbor UCLA Med CtrTorrance, California  90502
Univ of Colorado Health Sciences CtrDenver, Colorado  80262
Univ of Miami School of MedicineMiami, Florida  331361013
Rush Presbyterian - Saint Luke's Med CtrChicago, Illinois  60612
Northwestern Univ Med SchoolChicago, Illinois  60611
Indiana Univ HospIndianapolis, Indiana  462025250
Tulane Univ School of MedicineNew Orleans, Louisiana  70112
Harvard (Massachusetts Gen Hosp)Boston, Massachusetts  02114
Beth Israel Deaconess - West CampusBoston, Massachusetts  02215
Boston Med CtrBoston, Massachusetts  02118
Univ of MinnesotaMinneapolis, Minnesota  55455
SUNY / Erie County Med Ctr at BuffaloBuffalo, New York  14215
Cornell Univ Med CtrNew York, New York  10021
Mount Sinai Med CtrNew York, New York  10029
Univ of North CarolinaChapel Hill, North Carolina  275997215
Duke Univ Med CtrDurham, North Carolina  27710
Ohio State Univ Hosp ClinicColumbus, Ohio  432101228
Milton S Hershey Med CtrHershey, Pennsylvania  170330850
Univ of WashingtonSeattle, Washington  98105
Charity Hosp / Tulane Univ Med SchoolNew Orleans, Louisiana  70112
St Louis Regional Hosp / St Louis Regional Med CtrSt Louis, Missouri  63112
Univ of Alabama at BirminghamBirmingham, Alabama  35294
Univ of Southern California / LA County USC Med CtrLos Angeles, California  900331079
Cook County HospChicago, Illinois  60612
Univ of Iowa Hosp and ClinicIowa City, Iowa  52242
Univ of Nebraska Med CtrOmaha, Nebraska  681985130
Beth Israel Med CtrNew York, New York  10003
Carolinas Med CtrCharlotte, North Carolina  28203
Moses H Cone Memorial HospGreensboro, North Carolina  27401
Univ of CincinnatiCincinnati, Ohio  452670405
Univ of Pennsylvania at PhiladelphiaPhiladelphia, Pennsylvania  19104
Santa Clara Valley Med Ctr / AIDS Community Rsch ConsortiumSan Jose, California  951282699
Stanford Univ Med CtrStanford, California  943055107
San Mateo AIDS Program / Stanford UnivStanford, California  943055107
Howard UnivWashington, District of Columbia  20059
Univ of HawaiiHonolulu, Hawaii  96816
Methodist Hosp of Indiana / Life Care ClinicIndianapolis, Indiana  46202
Columbia Presbyterian Med CtrNew York, New York  100323784
Univ of Kentucky LexingtonCincinnati, Ohio  45267
MetroHealth Med CtrCleveland, Ohio  441091998
Case Western Reserve UnivCleveland, Ohio  44106
Univ of Texas GalvestonGalveston, Texas  775550435
Georgetown Univ HospWashington, District of Columbia  20037
Emory UnivAtlanta, Georgia  30308
Emory Hemo Comp Evaluation Clinic / East TN Comp Hemo CtrAtlanta, Georgia  303652225
Division of Inf Diseases/ Indiana Univ HospIndianapolis, Indiana  46202
Tulane Med Ctr HospNew Orleans, Louisiana  70112
State of MD Div of Corrections / Johns Hopkins Univ HospBaltimore, Maryland  212052196
Manhattan Veterans Administration / New York Univ Med CtrNew York, New York  10016
Willow ClinicMenlo Park, California  94025
Univ of Pittsburgh Med CtrPittsburgh, Pennsylvania  15213
Chelsea CtrNew York, New York  10021
Marin County Specialty ClinicSan Rafael, California  94903
St Mary's Hosp (Univ of Rochester/Infectious Diseases)Rochester, New York  14642
Akron City HospitalAkron, Ohio  44304
Philadelphia Veterans Administration Med CtrPhiladelphia, Pennsylvania  19104