Safety and Efficacy Trial of Subcutaneously Administered Serostim® in the Treatment of Human Immunodeficiency Virus-Associated Adipose Redistribution Syndrome (HARS)

This study is a Phase 2/3 multicenter, double-blind, randomized, parallel-group, placebo-controlled, dose-finding trial of Serostim® vs. placebo in 228 patients with Human Immunodeficiency Virus-Associated Adipose Tissue Redistribution Syndrome (HARS).

The primary study objective is to determine whether Serostim® treatment reduces adipose tissue maldistribution more effectively than placebo. The primary co-endpoints are derived from measures of visceral adipose tissue assessed by Computerized Tomography (CT) and the ratio of trunk:limb fat assessed by Dual-Energy X-Ray Absorptiometry (DXA) scans. Anthropometric Measures, Physical Exams, Quality of Life assessments, Serial Photographs, and various laboratory measures will be used to address secondary objectives. These secondary objectives relate to the impact of Serostim® on physician and patient assessments of change in body shape, health-related quality of life, attitudes toward medication compliance, metabolic markers, fat redistribution, and safety.

On Day 1, eligible patients will be randomized in a 1:1:1 ratio to receive daily Serostim®, Serostim® and placebo given on alternate days, or daily placebo. Serostim® doses will be based on body weight, with a maximum dose of 4 mg.

Therapy will continue for 12 weeks. Treatment will then be altered (Figure1) and the new treatment continued through Week 24. Interim Study Visits are required at Weeks 2 and 4 (Treatment Period I) and at Weeks 14 and 16 (Treatment Period II). Patients will be offered a maintenance protocol at Week 24.

• Human Immunodeficiency Virus-Associated Adipose Redistribution Syndrome (HARS)
• HIV Infections

Inclusion Criteria:

• In order to enroll, a patient must:
• Have an HIV infection documented either by viral load as measured by polymerase chain reaction (PCR) amplification(22); or by the presence of HIV antibodies with confirmation by one of the following:
• Western blot
• Immunofluorescence assay
• Branched DNA (bDNA) signal amplification
• The presence of p24 antigen These tests may have been performed at any time in the past, but the results must be available for review by the Serono monitor prior to randomization.
• Have evidence of excess abdominal adipose deposition when measured by the methodology described in Appendix H. Using the following cut points:
• Men: Waist circumference >88.2 cm AND waist:hip ratio ³0.95
• Women: Waist circumference >75.3 cm AND waist:hip ratio ³0.9 (23)
• Be taking antiretroviral medication(s) which is(are) approved or is(are) available under a Treatment IND. The regimen must have remained stable for the 30 days prior to study entry. Patients must also have agreed not to discontinue or to change their regimen for the duration of the study except as judged medically necessary.
• Have parameter values less than the following limits:
• AST, ALT, and amylase £ 3 times the upper limit of normal (Screening)
• Fasting triglycerides £ 1,000 mg/dL (Screening)
• Fasting glucose <110 mg/dL (Screening)
• Two hour (120 minute) glucose <140 mg/dL (following an oral glucose load at Screening)
• Weigh ³ 36 kg (79.3 lb)
• Be between 18 and 60 years of age unless local law dictates different limits
• Be able and willing to comply with the protocol for the duration of the study
• Have given written informed consent
• If female, be post-menopausal or surgically sterilized (i.e., have undergone tubal ligation or hysterectomy), or is
• Using a contraceptive method such as a hormonal contraceptive, intra uterine device, diaphragm with spermicide, or condom with spermicide, for the duration of the study
• Not pregnant or breast feeding

Exclusion Criteria:

• A patient was ineligible to participate in the study if she/he:
• Had an active AIDS-defining OI as defined by the Center for Disease Control; or have had an untreated or suspected serious systemic infection, or persistent fever ³ 101°F (38.3°C) during the 30 days prior to study entry
• Had any active malignancy, except for localized cutaneous Karposi's sarcoma (fewer than 10 lesions, none of which are larger than 2 cm, and not on active therapy)
• Had a CNS mass or active CNS process associated with neurological findings
• Had unstable or untreated hypertension, defined as ³ 140/90 mm Hg at the time of the Screening Visit, and/or has initiated or changed antihypertensive therapy in the 30 days prior to Day 1
• Had an acute critical illness treated in an intensive care unit, e.g., due to complications following open heart or abdominal surgery, multiple accidental trauma, or acute respiratory failure
• Had any condition, which interferes with informed consent or protocol compliance including, but not limited to, active substance abuse and/or dementia
• Was unable to comply with the Concomitant Therapy restrictions
• Had ever been diagnosed with any of the following conditions:
• Pancreatitis
• Carpal tunnel syndrome (unless resolved by surgical release)
• Diabetes mellitus
• Angina pectoris
• Coronary artery disease
• Any disorder associated with moderate to severe edema (e.g., cirrhosis, nephrotic syndrome, congestive heart failure, lymphedema)
• Allergy or hypersensitivity to growth hormone