TITLE:A RANDOMIZED, DOUBLE-BLIND, PHASE III STUDY OF INDINAVIR SULFATE (IDV) WITH OPEN-LABEL ZIDOVUDINE (ZDV) OR STAVUDINE (D4T) AND LAMIVUDINE (3TC) IN SUBJECTS WITH HIV INFECTION WITH CD4 CELL COUNTS 200 CELLS/mm3 AND 3 MONTHS OF PRIOR ZDV EXPERIENCE

DESIGN: Phase III, randomized, double-blind trial of Indinavir Sulfate (IDV) with open-label ZDV (or d4T for ZDV intolerant subjects) and 3TC™, with the option to adjust the double nucleoside analog combination utilizing ZDV, 3TC™, d4T and ddI in the event of nucleoside analog related toxicities or disease progression short of a primary study endpoint. This study is designed to determine the clinical efficacy of IDV in subjects with advanced HIV disease who have received prior antiretroviral therapy.

NOTE: For the purposes of this study, ZDV intolerance at pre-entry will be defined as a documented history of signs, symptoms or laboratory abnormalities that prevented a subject from tolerating a minimum of 300 mg/day of ZDV. Furthermore, subjects tolerant to ZDV @ 300-400 mg/day (but who are not tolerant to higher doses) will be randomized to d4T + 3TC™ + IDV/placebo. Subjects tolerant to ZDV @ 500-600 mg/day will be randomized to ZDV + 3TC™ + IDV/placebo.

SAMPLE SIZE: A total of 1,750 subjects will be enrolled over approximately 9 months.

POPULATION: HIV-infected subjects who have a CD4 cell count 200 cells/mm³ and 3 months of cumulative ZDV therapy.

STRATIFICATION: Subjects will be stratified by CD4 cell count: 50 cells/mm³ versus > 50 cells/mm³. Forty percent of the subjects will be enrolled in the 50 CD4 cells/mm³ stratum, and the remaining 60% will be enrolled in the > 50 CD4 cells/mm³ stratum.

REGIMEN: Subjects will be randomized to one of two treatment arms and followed for 48 weeks beyond the enrollment of the last subject:

ARM I Open-label ZDV 200mg TID or d4T 40mg BID* + open-label 3TC™ 150mg BID + IDV placebo TID (q8h)

versus

ARM II Open-label ZDV 200mg TID or d4T 40mg BID* + open-label 3TC™ 150mg BID + IDV 800mg TID (q8h)

• To determine the clinical efficacy of IDV when given in combination with ZDV or d4T and 3TC™ vs. ZDV or d4T plus 3TC™, as measured by the time to an AIDS-defining event or death, whichever occurs first.
  
  
• To determine the safety of IDV when given in combination with ZDV or d4T and 3TC™ vs. ZDV or d4T plus 3TC™.
  
  

• To determine the survival benefits of IDV when given in combination with ZDV or d4T and 3TC™ vs. ZDV or d4T plus 3TC™.
  
  
• To determine the efficacy of IDV when given in combination with ZDV or d4T and 3TC™ vs. ZDV or d4T plus 3TC™ with respect to:
  
  

  The short-term CD4 cell count changes at Weeks 4 and 8;
  
  The long-term CD4 cell count changes at Week 40;
  
  The longitudinal CD4 cell count profile during study treatment;
  
  The short- and long-term CD8 cell count changes.

• To determine the efficacy of IDV when given in combination with ZDV or d4T and 3TC™ vs. ZDV or d4T plus 3TC™, as measured by changes in weight and quality of life measures.
  
  
• To determine the degree of clinical treatment effect that is explained by short- and long-term changes in levels of plasma-associated HIV-1 RNA between intercurrent illness and the magnitude and duration of changes in viral load, and identification of factors associated with viral load increases during specific types of acute illness.

• HIV-1 infection as documented by any licensed ELISA test kit and confirmed by either Western blot, HIV culture, HIV antigen, plasma HIV RNA or a second antibody test by a method other than ELISA at any time prior to study entry.
• A CD4 cell count < or = 200 cells/mm³ within 60 days prior to study entry, as measured by an ACTG-certified laboratory.
• Six months or more of cumulative ZDV therapy, either alone or in combination regimens, at any time prior to study entry.
• Previous exposure to d4T, ddI or ddC, either alone or in combination at any time before study entry is allowed.
• A Karnofsky status > or = 70 within 14 days prior to study entry.
• The following laboratory parameters within 14 days prior to study entry:
  • Hemoglobin > or = 9.1 gm/dL for men and > or = 8.9 gm/dL for women;
  • Absolute neutrophil count > or = 1000 cells/mm³;
  • Platelet count > or = 65,000 platelets/mm³;
  • Bilirubin < or = 1.5 ´ the upper limit of normal (ULN);
  • AST (SGOT)/ALT (SGPT) < or = 5.0 ´ ULN;
  • Creatinine < or = 2.0 ´ ULN;
  • Total serum amylase < or = 1.5 ´ ULN (if the total serum amylase is > 1.5 ´ ULN, pancreatic amylase or lipase must be < or = 1.5 ´ ULN).
• Age > or = 18 years.
• Ability and willingness to give written informed consent.
• Both men and women will be included.
• All women of childbearing potential must practice adequate birth control to prevent pregnancy while receiving study medications and for 3 months thereafter. NOTE: Due to the possibility that IDV 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. Women of childbearing potential must have a negative serum b-HCG within 14 days prior to study entry.

• Acute therapy for an infection or other medical illnesses within 14 days prior to study entry.
• Unexplained temperature > 38.5°C for any 7 days, or chronic diarrhea defined as > three liquid stools per day persisting for 15 days, within 30 days prior to study entry.
• A malignancy which requires systemic therapy other than minimal Kaposi's sarcoma.
• Subjects with minimal Kaposi's sarcoma, defined as <5 cutaneous lesions and no visceral disease or tumor-associated edema, will be allowed to enroll as long as they do not require systemic therapy for Kaposi's sarcoma.
• A history of acute or chronic pancreatitis.
• Proven or suspected acute hepatitis within 30 days prior to study entry, even if AST (SGOT) and ALT (SGPT) are < or = 5.0 ´ ULN.
• A history of > or = Grade 2 bilateral peripheral neuropathy within 60 days prior to study entry.
• The following medications:
  • > 1 week of cumulative 3TC™ therapy at any time prior to study entry;
  • any prior protease inhibitor therapy;
  • erythropoietin, G-CSF or GM-CSF within 30 days prior to study entry;
  • non-nucleoside RT inhibitors, interferons, interleukins or HIV vaccines within 30 days prior to study entry;
  • any experimental therapy within 30 days prior to study entry;
  • rifampin or rifabutin within 14 days of study entry or at anytime while on study.
  • Intolerance to 600 mg/day of ZDV defined as any grade toxicity which resulted in a dose reduction or termination of ZDV.
• Pregnancy or breast feeding.
• A history of nephrolithiasis IS NOT an exclusion criterion.