SYNOPSIS
Purpose:
The purpose of this study is to compare the effects of subcutaneous recombinant interleukin-2 (SC rIL-2) and no SC rIL-2 on disease progression and death over a 5-year follow-up period in patients with HIV-1 infection and absolute CD4+ cell counts of >300/mm3 who are taking combination antiretroviral therapy.
Design:
International, phase III, open-label, randomized trial.
Sample Size:
The total sample size is 4,000 patients. 2,000 patients will be randomized to SC rIL-2 therapy and 2,000 patients will be randomized to no SC rIL-2 over a 2-year period. With this enrollment period, and proposed follow-up to a common closing date 4 years after the last patient is randomized, the average follow-up will be 5 years. During this planned follow-up, it is estimated that 320 patients will develop a primary endpoint.
Inclusion Criteria:
1. Documentation of HIV-1 infection by any licensed ELISA test and confirmed by a second method (e.g. Western Blot); or any one of the following at any time: detectable HIV p24 antigen, quantifiable plasma HIV RNA, or detectable proviral DNA.
2. Absolute CD4+ cell count of > 300/mm3 within 45 days prior to randomization. (For patients who are status post-splenectomy, also a CD4+ cell percentage > 20%.)
3. No evidence of active clinical disease for at least one year, in the judgement of the clinician, for any AIDS-defining illness (category C., CDC, 1993) or any of the following conditions: extrapulmonary Pneumocystis carinii disease; multi-dermatomal Herpes zoster (>10 lesions in a non-contiguous site); American trypanosomiasis (Chagas disease) of the CNS; Penicillium marneffii disease; visceral leishmaniasis; non-Hodgkin’s lymphoma of any cell-type; Hodgkin’s lymphoma; bartonellosis; microsporidiosis (> 1 month’s duration); nocardiosis; invasive aspergillosis; or Rhodococcus equi disease.
4. Age > 18 years.
5. Laboratory values (within 45 days prior to randomization):
a. AST or ALT £ 5 X the upper limit of normal (ULN).
b. Total or direct bilirubin £ 2 X ULN (Patients with hyperbilirubinemia due to Gilbert's syndrome
or indinavir therapy may have a serum bilirubin up to 5 X ULN.)
c. Creatinine £ 2.0 mg/dL (177 µmol/L).
d. Platelet count > 50,000/mm3.
6. on or initiating combination antiretroviral therapy at the time of randomization. Antiretroviral
therapy can include agents (approved and investigational) administered through routine care or through participation in clinical trials or expanded access programs.
7. Signed informed consent form.
Exclusion Criteria:
1. Prior rIL-2 therapy.
2. Concurrent malignancy requiring cytotoxic chemotherapy.
3. Use of systemic corticosteroids, immunosuppressants, or cytotoxic agents within 45 days prior
to study randomization.
4. Any CNS abnormality that requires ongoing treatment with antiseizure medication.
5. Current or historical autoimmune/inflammatory diseases including:
a. Inflammatory bowel disease (Crohn’s disease, ulcerative colitis)
b. Psoriasis
c. Optic neuritis, or
d.Any autoimmune/inflammatory diseases with potentially life-threatening complications
6. Pregnancy (For women of childbearing potential, a negative pregnancy test, serum or urine, is
required within 14 days prior to randomization.)
7. Breastfeeding
Study Treatment:
Eligible patients will be randomized to receive SC rIL-2 therapy or no SC rIL-2. Recombinant IL-2 at a dose of 7.5 MIU twice daily will be given SC for 5 consecutive days every 8 weeks for at least three cycles. Thus, during the first 6 months of follow-up, all patients randomized to SC rIL-2 will receive three cycles of SC rIL-2 unless toxicities or other contraindications develop. After the first three cycles, additional cycles will be given at the discretion of each patient’s physician. As a guideline, patients who enter with a CD4+ count < 500 cells/mm3 will be encouraged to receive additional cycles of therapy to maintain their CD4+ level > twice baseline; those entering with CD4+ > 500 cells/mm3, will be encouraged to receive additional cycles of therapy to maintain their CD4+ > 1000 cells/mm3 as long as possible.SC rIL-2 therapy may not be given more frequently than every 6 weeks.
Procedures:
The timing of randomization should be planned to ensure that patients assigned to the SC rIL-2 group will begin their first cycle of treatment within 2 weeks after the date of randomization. For patient management during each cycle of treatment, selected serum chemistries and hematology measures and side effects will be monitored, although not reported centrally except for grade 4 toxicities. Reasons for dosage modification and/or cycle interruption will be reported. Every 4
months CD4+ cell counts, plasma HIV RNA quantitations, changes in HIV treatments, and diagnoses will be reported for patients in both treatment groups. Grade 4 signs and symptoms,
disease progression events, and deaths will be reported immediately following site awareness.
Primary Endpoint:
The primary endpoint will be a new or recurrent disease progression event as defined in Appendix B, including death.
Secondary Outcome Measures:
1. New or recurrent serious disease progression events, including death. A serious disease progression event is considered one of the following: progressive multifocal leukoencephalopathy
(PML), lymphoma, Kaposi’s sarcoma (visceral), AIDS dementia complex (ADC) stage II or
higher, toxoplasmosis, histoplasmosis (systemic), cryptococcosis (systemic), disseminated Mycobacterium avium complex (MAC) disease, wasting syndrome, and cytomegalovirus (CMV) disease.These events are associated with an increased risk of death and evidence of advanced immunodeficiency.
2. All-cause mortality.
3. New (non-recurrent) disease progression event, including death.
4. Absolute CD4+ cell counts and percent CD4+ of lymphocytes.
5. Plasma HIV RNA levels.
6. Changes in antiretroviral treatment.
7. Grade 4 signs and symptoms.
8. Pattern of use of prophylaxes for opportunistic infections.
9. Hepatic, metabolic and cardiac conditions.
From ESPRIT PROTOCOL 001, Version 2.0, 15 December, 2000
Updated: 13 Dec 2005