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A Randomized, Phase II, Placebo Controlled Trial of Abacavir (ABC, 1592U89) in Combination With Open-Label Indinavir Sulfate (IDV) and Efavirenz (EFV, DMP-266) in HIV-Infected Subjects With Nucleoside Analog Experience: A Rollover Study for ACTG 320

Phase 2
16 Years
Not Enrolling
HIV Infections

Thank you

Trial Information

A Randomized, Phase II, Placebo Controlled Trial of Abacavir (ABC, 1592U89) in Combination With Open-Label Indinavir Sulfate (IDV) and Efavirenz (EFV, DMP-266) in HIV-Infected Subjects With Nucleoside Analog Experience: A Rollover Study for ACTG 320

Therapeutically, there is a need to explore potent alternative therapy for patients who have
received, or are currently receiving, a double nucleoside analog combination including
lamivudine (3TC), a regimen that was proven to be clinically inferior to indinavir (IDV)
when combined with zidovudine/3TC in study ACTG 320. In order to produce and maintain a
maximal antiviral response, all patients in this study will receive 2 or 3 potent, new
agents; ABC, a nucleoside analog, EFV, a non-nucleoside reverse transcriptase inhibitor
(NNRTI), and IDV, a protease inhibitor. Virologically, the major question this protocol
seeks to answer is how prior 3TC exposure in a dual nucleoside regimen influences the
response to subsequent treatment. It is unclear whether it is best to add a protease
inhibitor either 1) an NNRTI at 1 of 2 doses, or 2) an NNRTI at 1 of 2 doses plus a new
nucleoside analog to achieve plasma HIV RNA levels that are below the limits of detection.

Prior to randomization, patients are stratified by CD4 cell count (cells/mm3): less than or
equal to 50 versus greater than 50 and by ACTG 320 participation: enrolled versus not
enrolled. Patients with greater than 50 CD4 cells/mm3 are randomized to 1 of 4 treatment
arms (Arms I, II, III, or IV) and patients with less than or equal to 50 CD4 cells/mm3 are
randomized to 1 of 2 treatment arms (Arms I and II). All patients will be followed for 48
weeks beyond the enrollment of the last patient. The regimens for the treatment arms are as
follows: Arm I - indinavir (IDV) plus EFV plus ABC placebo bid, Arm II - IDV (higher dose)
plus EFV (lower dose) plus ABC, Arm III - IDV plus EFV plus ABC placebo, and Arm IV - IDV
(higher dose) plus EFV (lower dose) plus ABC. If 15 week data indicates this is a reasonable
dosing regimen, the sample size in Arms III and IV will be expanded to include additional
patients with a CD4 count greater than 50 cells/mm3 and allow for equal enrollment across
all 4 treatment arms. Those patients who roll over from ACTG 320 will be assigned to receive
open-label treatment on Arm II and evaluated independently of the 4 treatment arms listed

[AS PER AMENDMENT 8/27/97: Patients with 2 consecutive HIV RNA measurements at least 500
copies/ml at week 16 or anytime thereafter are given the option to receive open-label
treatment with IDV plus EFV plus ABC, or to seek the best available therapy outside of the
study. NOTE: Patients who choose the open-label combination may take other prescribed
nucleoside analogs provided outside the study.] [AS PER AMENDMENT 12/17/97: It is strongly
recommended that patients who reach a confirmed endpoint and elect to receive open-label
therapy consider adding additional approved (and novel, if possible) antiretroviral agents
to their open-label regimen.] [AS PER AMENDMENT 1/12/98: Patients who choose the open-label
combination may receive other approved antiretrovirals obtained outside the study provided
the ACTG 368 team approves the combination.] [AS PER AMENDMENT 8/7/98: Subjects will take
study medications for a maximum of 96 weeks, depending on their time of study enrollment.]
[AS PER AMENDMENT 3/10/99: A 24-week extension, which will end July 30, 1999, has been added
to the study. The extension applies to subjects currently on blinded Step 1 treatment, on
open-labeled Step 2, or on study but off treatment. Subjects are to be unblinded in their
study treatment and followed for the remainder of the extension. Subjects continue on their
current study drug schedule. Subjects on blinded IDV plus EFV who, upon unblinding (not
failure) decide to add prescription ABC to their regimen, will be considered off study
treatment and will be followed for the duration of the extension; those already registered
on Step 2 will continue their Step 2 therapy. Any subject who does not wish to continue on
the study extension will be unblinded to their original randomized regimen. Subjects who
experience virologic failure during the extension should seek best available treatment
following current recommendations to use as many approved, novel antiretroviral agents as
possible. The new drug regimen may incorporate any or all of the study drugs.]

Inclusion Criteria

Inclusion Criteria

Concurrent Medication:


- Chemoprophylaxis for Pneumocystis carinii pneumonia is required for all patients who
have a CD4 cell count <= 200 cells/mm3.

- Topical and/or oral antifungal agents are permitted except for oral ketoconazole.

- Treatment, maintenance or chemoprophylaxis with approved agents for opportunistic
infections as clinically indicated, except for rifabutin.

- All antibiotics as clinically indicated.

- Systemic corticosteroid use for <= 21 days for acute problems is permitted as
medically indicated; chronic systemic corticosteroid use is not permitted, unless it
is within physiologic replacement levels.

- Recombinant erythropoietin and granulocyte colony-stimulating factor are permitted as
medically indicated.

- Regularly prescribed medications such as antipyretics, analgesics, allergy
medications (except for terfenadine (Seldane) and astemizole (Hismanal)),
antidepressants, sleep medications, oral contraceptives, megestrol acetate,
testosterone or any other medications are permitted as medically indicated.


- Due to the possibility that EFV or ABC may alter the effectiveness of oral
contraceptives or depo-progesterone, oral contraceptives or depo-progesterone must
not be used as the sole form of birth control. [AS PER AMENDMENT 8/7/98: adequate
birth control is hormonal plus barrier method or two barrier methods].

- Alternative therapies such as vitamins, acupuncture, and visualization techniques
will be permitted. Herbal medications should be avoided. Patients should report the
use of these therapies; alternative therapies will be recorded. [AS PER AMENDMENT
8/7/98: Due to the likelihood of IDV increasing the concentrations of sildenafil
(Viagra) when coadministered, it is suggested that subjects who use viagra take the
lowest dose (25 mg, i.e., half the typical dose).]

Both NIAID ACTG 320 participants and non-ACTG 320 patients must have:

- Documented HIV-1 infection.

- Written informed consent from parent or legal guardian for those patients < 18 years

Non-ACTG 320 patients must have:

- Documented CD4 cell count <= 200 cells/mm3 at the time of initiation of ZDV (or d4T)
plus 3TC therapy [AS PER AMENDMENT 12/17/97:

- Documented CD4 cell count <= 250 cells/mm3 within 3 months of initiation of ZDV (or
d4T) plus 3TC therapy].

Prior Medication:


For ACTG 320 patients:

- Patients must have participated in ACTG 320 with original randomization to the
double-nucleoside combination arm, and maintenance of that treatment
(on-study/on-treatment in ACTG 320) until enrollment into ACTG 368.

For non-ACTG 320 patients:

- Greater than or equal to 3 months [2 months AS PER AMENDMENT 12/17/97] of therapy
with ZDV (or d4T) + 3TC and receiving ZDV (or d4T) + 3TC at the time of entry.

Exclusion Criteria

Co-existing Condition:

Non-ACTG 320 patients with the following symptoms and conditions are excluded:

Malignancy that requires systemic therapy other than minimal Kaposi's sarcoma.


- Minimal Kaposi's sarcoma, defined as <= 5 cutaneous lesions and no visceral disease
or tumor-associated edema, allowed, provided systemic therapy not required.

Non-ACTG 320 patients with the following prior conditions or symptoms are excluded:

- Unexplained temperature > 38.5 degrees C for 7 consecutive days.

- Chronic diarrhea defined as > 3 liquid stools per day persisting for 15 days, within
30 days prior to entry.

- Proven or suspected acute hepatitis within 30 days prior to entry, even if AST (SGOT)
and ALT (SGPT) are <= 5 X ULN.

Concurrent Medication: Excluded:

- All antiretroviral therapies other then study medications.

- Rifabutin and rifampin.

- Investigational drugs without specific approval from the protocol chair.

- Systemic cytotoxic chemotherapy.

- Oral ketoconazole (Nizoral), terfenadine (Seldane), astemizole (Hismanal), cisapride
(Propulsid), triazolam (Halcion), and midazolam (Versed).

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

- Itraconazole.

Prior Medication: Excluded: For ACTG 320 patients:

- Those who opted to receive open-label IDV while on ACTG 320, or if they switched to
open label IDV during the study.

For non-ACTG 320 patients:

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

- Prior protease inhibitor therapy.

- Prior NNRTI therapy (approved or experimental).

- Erythropoietin, G-CSF or GM-CSF within 30 days prior to entry.

- Interferons, interleukins or HIV vaccines within 30 days prior to entry.

- Any experimental therapy within 30 days prior to entry.

- Rifampin or rifabutin within 14 days prior to entry.

Type of Study:


Study Design:

Endpoint Classification: Safety Study, Masking: Open Label, Primary Purpose: Treatment

Principal Investigator

Squires KE

Investigator Role:

Study Chair


United States: Federal Government

Study ID:

ACTG 368



Start Date:

Completion Date:

September 1999

Related Keywords:

  • HIV Infections
  • Placebos
  • HIV-1
  • Drug Therapy, Combination
  • HIV Protease Inhibitors
  • Indinavir
  • RNA, Viral
  • Reverse Transcriptase Inhibitors
  • Anti-HIV Agents
  • Viral Load
  • efavirenz
  • HIV Infections
  • Acquired Immunodeficiency Syndrome



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