Interleukin-2 Plus Antiretroviral Therapy for HIV-Infected Patients With Low CD4+ Counts (SILCAAT Study)

NCT00013611 | Completed Phase 3 Results DMC

• 2 other identifiers: 0303M4496101-I-0126
• Study Type: interventional
• Target: 1,695
• Locations: 1 country
• Sites: 1

Brief Summary

This study will examine whether interleukin-2 (IL-2) plus antiretroviral therapy (ART) slows HIV disease progression in patients with low CD4+ T cell counts compared with patients taking ART alone. CD4+ T cells are a subset of lymphocytes-white blood cells that are part of the body's immune system. IL-2 is a protein that is naturally produced by lymphocytes. Given in intermittent cycles, IL-2 can raise CD4+ T cell counts in some HIV-infected patients taking antiretroviral drugs. This study will examine whether the increase in CD4+ T cells lowers the risk of AIDS-related illnesses and death. HIV-infected patients 18 years of age and older with a viral load under 10,000 copies per milliliter and a CD4+ T cell count between 50 and 299 cells per cubic millimeter who are taking antiretroviral therapy and who have not previously received IL-2 therapy may be eligible for this study. Candidates will be screened with a medical history, physical examination, and blood and urine tests. Participation in the study will be from 4.5 to 6 years, depending on what point in the duration of the study the individual patient is enrolled. Patients will be randomly assigned to receive IL-2 plus ART or ART alone. All participants will be advised individually about the best ART regimen for them. Patients in the IL-2 treatment group will be taught how to self-inject IL-2 under the skin (similar to insulin injections). They will inject IL-2 twice a day for 5 days every 8 weeks for the first year (until week 49 of the study). From week 49 on they may receive 5-day cycles of IL-2 every 4 months when needed to maintain CD4+ T cell count elevations. An extra cycle may be given 2 months after the week 49 follow-up visit (see follow-up schedule below), depending on their CD4+ T cell count. Patients whose cell counts have not increased after 12 to 16 months of IL-2 treatment will discuss with the doctor the possibility of stopping IL-2. Those who do stop IL-2 treatment will be asked to remain in the study for follow-up evaluations. All patients will be followed in the clinic every 2 months for the first year of the study (weeks 1, 9, 17, 25, 33, 41 and 49) and every 4 months during years 2-6 for a brief history and physical exam, urine and blood tests, return of diary cards (record of drug side effects) and medication review. During the visits from the second year on, patients will also be asked about their ability to do certain ordinary tasks, such as taking care of themselves; ...

Conditions

HIV Infection

Keywords

HIV; Proleukin; IL-2; Adult; HAART; Treatment Experienced

Outcome Measures

Primary Outcomes (1)

• New or Recurrent Disease Progression Events, as Defined, or Death.

  Number of participants with fatal or non-fatal AIDS-related opportunistic disease or death from any cause. AIDS-related opportunistic disease includes CDC Category C 1993 definition plus the following diseases: Aspergillosis, invasive; Bartonellosis; Chagas disease of the CNS; Herpes zoster, multidermal; Leishmaniasis, visceral; Lymphoma, Hodgkin's; Microsporidiosis (\> 1 month's duration); Nocardiosis; Penicillium marneffti, disseminated; Pneumocystis carinii, extrapulmonary; Rhodococcus equi disease.

  From randomization to date last known to be alive or November 15, 2008, whichever is earlier

Secondary Outcomes (5)

• All-cause Mortality

  From randomization to date last known to be alive or November 15, 2008, whichever is earlier

• New or Recurrent Disease Progression Events

  From randomization to date last known to be alive or November 15, 2008, whichever is earlier

• Grade 4 Clinical Events

  From randomization to date last known to be alive or November 15, 2008, whichever is earlier

• CD4+ Cell Count

  Every 4 months from randomization through date last known to be alive or November 15, 2008, whichever was earliest .

• New or Recurrent Serious Disease Progression Events or Death

  From randomization to date last known to be alive or November 15, 2008, whichever is earlier

Study Arms (2)

Antiretroviral therapy alone

NO INTERVENTION

Proleukin plus antiretroviral therapy

EXPERIMENTAL

Drug: Proleukin

Interventions

Proleukin DRUG

Recombinant IL-2 was given at a dose of 4.5 MIU twice daily subcutaneously for 5 consecutive days every 8 weeks, in addition to antiretroviral therapy, for 6 cycles. After the first 6 cycles, additional cycles were given to either achieve or maintain the patient's CD4+ cell count goal.

Also known as: recombinanat interleukin-2, rIL-2

Proleukin plus antiretroviral therapy

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Subjects are eligible for this study if they have been on greater than or equal to 2 ART for greater than or equal to 4 months prior to randomization, with no change in the type of ART received during this 4-month period of time. For subjects who receive only 2 ART, at least one of these two medications should be a protease inhibitor (PI). Subjects are not eligible if ART is discontinued for a cumulative period of 7 or more days during the 4 months prior to randomization.
• Subjects with documented HIV-1 infection. Acceptable documentation consists of either of the following:
• Positive HIV-1 ELISA test and Western Blot;
• Detectable plasma viral load measurement (greater than 500 RNA copies/mL using an ultrasensitive bDNA or PCR test or greater than 1500 RNA copies/mL using a non-ultrasensitive bDNA or PCR test).
• CD4+ T cell counts: mean of 2 points obtained within 4 calendar months of randomization greater than or equal to 50 and less than 300 cells/mm(3). The first CD4+ count should be the most recent documented historical value and should be greater than or equal to 50 and less than 300 cells/mm(3); the second point should be pre-study visit 1.
• Viral load less than 10,000 copies/mL, at 2 time points within 4 calendar months of randomization. The first viral load should be the most recent documented historical value and should be less than 10,000 copies/mL; the second time point should be pre-study visit 1.
• Karnofsky performance status greater than or equal to 80%.
• Age greater than or equal to 18 years old.
• Women of childbearing potential must have a negative urine or serum pregnancy test within 28 days prior to randomization. They must also understand that if they are randomized to the IL-2 group, they must practice effective contraception during their first 2 years of study participation. Pregnancy is discouraged among IL-2 recipients, but if an IL-2 recipient wishes to become pregnant after two years of trial participation she must alert the investigator prior to interruption of contraception. The potential for risk to the fetus must be carefully discussed with the subject before contraception is interrupted. Effective contraception will be continued for at least 24 hours following the interruption of IL-2 therapy. IL-2 will be held throughout the period of time during which the subject is not practicing effective birth control, throughout the pregnancy, and throughout any period of breast feeding. If oral contraceptive therapy is resumed after a period of interruption, IL-2 dosing will be delayed for 1 month following the reinstatement of oral contraceptive therapy. The subject must have a negative pregnancy test result prior to dosing with IL-2 after a lapse in effective contraception.
• The following laboratory criteria must be fulfilled within 28 days of enrollment in the study:
• Serum AST of less than or equal to 5 times upper limit of normal range (ULN);
• Serum bilirubin less than or equal 2 times ULN (patients with Gilbert's syndrome or protease inhibitor-induced hyperbilirubinemia must have a serum bilirubin less than or equal to five times ULN);
• Less than 2 + proteinuria;
• Serum creatinine less than or equal to 1.5 times ULN;
• Absolute neutrophil count greater than or equal to 1000 cells/mm(3);

You may not qualify if:

• Certain AIDS-defining illnesses. These conditions include:
• Patients with no prior history of AIDS-defining events are eligible for SILCAAT;
• Patients with a prior medical history of one or more of the following AIDS-defining events are eligible only under the condition specified below:
• Lymphoma (other than lymphoma of the brain): Patients with a history of successfully treated lymphoma are eligible, provided full remission was obtained at least 5 years prior to randomization. Full remission (or complete response) is defined as the absence of clinically detectable disease with normalization of any previously abnormal radiographic studies, and bone marrow examination. Patients with bone marrow positive lymphoma prior to chemotherapy must have had two repeat bone marrow examinations negative for lymphoma after chemotherapy at least 12 months prior to randomization.
• Esophageal candidiasis; Patients with a prior history of successfully treated esophageal candidiasis are eligible if they have been free of clinical symptoms in the absence of antifungal suppressive therapy for at least 12 months prior to randomization. Documentation of a negative endoscopy should ideally be on record.
• Invasive cervical cancer: Patients with a prior history of invasive cervical cancer are eligible if complete local cure of the cancer has been documented at least 5 years prior to randomization and there has been no evidence of metastatic disease at any time.
• Kaposi's sarcoma: Patients are eligible if mucocutaneous lesions have been resolved or clinically stable for at least 12 months prior to randomization. Subjects with a history of visceral KS are excluded.
• Mycobacterium tuberculosis or M. kansasii: Patients are eligible if clinical resolution of disease occurred at least 12 months prior to randomization and previously abnormal imaging studies have been normal, or stable after improvement, for at least 12 months prior to randomization. Documentation of microbiologic cure should ideally be on record. Therapy for tuberculosis or M. kansasii must have been completed at least 12 months prior to randomization.
• Pneumocystis carinii pneumonia (PCP): Patients are eligible if clinical resolution of the disease occurred at least 12 months prior to randomization and previously abnormal imaging studies have been normal, or stable after improvement, for at least 12 months prior to randomization.
• Recurrent pneumonia: Patients are eligible if there has been no evidence of pneumonia within 12 months prior to randomization.
• Recurrent Salmonella septicemia: Patients are eligible if there has been no evidence of Salmonella septicemia within 12 months prior to randomization.
• Wasting syndrome due to HIV: Patients are eligible for enrollment in SILCAAT if they have had a stable or increasing weight for at least 12 months prior to randomization.
• Toxoplasmosis of the brain: Patients are eligible if their disease has been clinically resolved for at least 12 months prior to randomization. In addition, these patients must have a MRI or contrast CT scan of the brain performed within 1 month prior to randomization showing no sign of active disease.
• Chronic intestinal cryptosporidiosis and chronic intestinal isosporiasis (greater than 1 month duration): Patients are eligible if their disease has been clinically resolved and they have been off specific therapy for at least 12 months prior to randomization. In addition, these patients must have at least one stool specimen documenting clearance of parasitic infection obtained within 1 month prior to randomization.
• Patients with a history of any other AIDS-defining conditions as listed in the CDC 1993 Case Definition are not eligible for SILCAAT.

Sponsors & Collaborators

• University of Minnesota: lead
• National Institute of Allergy and Infectious Diseases (NIAID): collaborator

Study Sites (1)

National Institutes of Health Clinical Center, 9000 Rockville Pike

Bethesda, Maryland, 20892, United States

Location

Related Publications (5)

• Bernstein ZP, Porter MM, Gould M, Lipman B, Bluman EM, Stewart CC, Hewitt RG, Fyfe G, Poiesz B, Caligiuri MA. Prolonged administration of low-dose interleukin-2 in human immunodeficiency virus-associated malignancy results in selective expansion of innate immune effectors without significant clinical toxicity. Blood. 1995 Nov 1;86(9):3287-94.

  PMID: 7579429 BACKGROUND

• Autran B, Carcelain G, Li TS, Blanc C, Mathez D, Tubiana R, Katlama C, Debre P, Leibowitch J. Positive effects of combined antiretroviral therapy on CD4+ T cell homeostasis and function in advanced HIV disease. Science. 1997 Jul 4;277(5322):112-6. doi: 10.1126/science.277.5322.112.

  PMID: 9204894 BACKGROUND

• Davey RT Jr, Chaitt DG, Piscitelli SC, Wells M, Kovacs JA, Walker RE, Falloon J, Polis MA, Metcalf JA, Masur H, Fyfe G, Lane HC. Subcutaneous administration of interleukin-2 in human immunodeficiency virus type 1-infected persons. J Infect Dis. 1997 Apr;175(4):781-9. doi: 10.1086/513971.

  PMID: 9086130 BACKGROUND

• Nordell AD, McKenna M, Borges AH, Duprez D, Neuhaus J, Neaton JD; INSIGHT SMART, ESPRIT Study Groups; SILCAAT Scientific Committee. Severity of cardiovascular disease outcomes among patients with HIV is related to markers of inflammation and coagulation. J Am Heart Assoc. 2014 May 28;3(3):e000844. doi: 10.1161/JAHA.114.000844.

  PMID: 24870935 DERIVED

• INSIGHT-ESPRIT Study Group; SILCAAT Scientific Committee; Abrams D, Levy Y, Losso MH, Babiker A, Collins G, Cooper DA, Darbyshire J, Emery S, Fox L, Gordin F, Lane HC, Lundgren JD, Mitsuyasu R, Neaton JD, Phillips A, Routy JP, Tambussi G, Wentworth D. Interleukin-2 therapy in patients with HIV infection. N Engl J Med. 2009 Oct 15;361(16):1548-59. doi: 10.1056/NEJMoa0903175.

  PMID: 19828532 DERIVED

MeSH Terms

Conditions

HIV Infections

Interventions

aldesleukin

Condition Hierarchy (Ancestors)

Blood-Borne Infections; Communicable Diseases; Infections; Sexually Transmitted Diseases, Viral; Sexually Transmitted Diseases; Lentivirus Infections; Retroviridae Infections; RNA Virus Infections; Virus Diseases; Genital Diseases; Urogenital Diseases; Immunologic Deficiency Syndromes; Immune System Diseases

Results Point of Contact

• Title: Gary Collins, M.S.
• Organization: University of Minnesota

gary-c@ccbr.umn.edu

612-626-9006

Study Officials

• James D Neaton, PhD

  University of Minnesota

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 3
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER

Study Record Dates

• First Submitted: March 24, 2001
• First Posted: March 26, 2001
• Study Start: March 1, 2001
• Primary Completion: January 1, 2007
• Study Completion: January 1, 2007
• Last Updated: August 8, 2011
• Results First Posted: December 13, 2010

Record last verified: 2011-08

Locations

US (1)