As shown in Figure 1, for the initial 12 weeks of treatment, eligible patients were randomized in a 3:1 ratio to receive induction therapy, 4 mg of r-hGH dosed daily (group A, DD) or PL (group B, PL). At week 12, subjects in group A were rerandomized in a 1:1 ratio to receive maintenance therapy, 2 mg of r-hGH on AD or PL on AD, from weeks 12 through 36. Subjects from group A, on r-hGH induction and r-hGH maintenance, are referred to as the DD-AD-AD group; those from group A on induction therapy with r-hGH followed by PL maintenance are the DD-PL-PL group. Subjects in group B, who received PL from baseline to week 24 and then received 4 mg/d of r-hGH for weeks 24 through 36, are the PL-PL-DD group.
Figure 1. (click image to zoom)
The prespecified primary efficacy parameter was the absolute change from baseline to week 12 in area of VAT on a cross-sectional computed tomography (CT) scan at L4-L5. Secondary efficacy endpoints included changes in other body composition parameters, serum lipids, body image, and quality-of-life variables (results for body image and quality of life are reported separately).
Safety data included glucose and insulin parameters, viral load, CD4 cell counts, adverse events (AEs), insulin-like growth factor (IGF)-I and its main binding protein (IGF-BP3), hemoglobin A1c (HbA1c; an indicator of adequacy of glucose control over a 3-month period), and standard hematologic and clinical chemistry parameters.
The primary prespecified criterion of efficacy for maintenance therapy at week 36 was maintenance failure rate, defined as the proportion of subjects originally given 4 mg/d of r-hGH 4 for weeks 1 through 12 who succeeded in losing VAT during baseline to week 12 but then regained more than 50% of their VAT loss by week 36 (see statistical analysis). Failure rates were also compared between those assigned to PL or 2 mg of r-hGH on AD for weeks 12 through 36. Mean changes from baseline to week 36 in VAT, other body composition parameters, lipid profile, and safety parameters were also examined.
Randomization was stratified by gender and implemented by a central system operated by an independent vendor (Clinphone, Nottingham, United Kingdom), assigning patients to treatment using a blinded computer-generated randomization list. The trial was conducted according to the Declaration of Helsinki principles and Good Clinical Practice. Independent institutional review boards approved the protocol at each site. Written informed consent was obtained from each patient before screening.Study Subjects
Eligibility criteria were the same as for the previous trial. Patients were between 18 and 60 years old, had documented HIV infection, had been on stable antiretroviral therapy (ARVT) for ≥30 days, and agreed to continue on ARVT while on study. They also had fasting glucose <110 mg/dL, 2-hour postload glucose on oral glucose tolerance testing (OGTT) results <140 mg/dL, and evidence of excess abdominal adipose tissue as determined by waist/hip ratio (WHR) ≥0.95 and waist circumference (WC) >88.2 cm for men and WHR ≥0.90 and WC >75.3 cm for women. The WHR criteria are similar to those identified as indicative of abdominal adiposity in the literature on obesity and are known to be associated with increased cardiovascular risk.[15,16]
Patients were excluded if they had active systemic infection, unstable or untreated hypertension (≥140/90 mm Hg), acute illness treated in an intensive care unit, a history of pancreatitis, carpal tunnel syndrome (unless resolved by surgical release), diabetes mellitus, malignancy (except for limited cutaneous Kaposi sarcoma or excised basal cell or squamous cell skin carcinoma), angina pectoris, coronary artery disease, or any disorder associated with moderate to severe edema. Patients must not have been receiving insulin or insulin-sensitizing agents, systemic glucocorticoids, or weight reduction agents for 3 months before screening or therapy for HIV-associated wasting (eg, anabolic steroids other than testosterone replacement, appetite stimulants, r-hGH) for 12 months before screening. Lipid-lowering agents were permitted if they were started at least 8 weeks before study entry.Treatment and Assessment
The 4-mg induction dose of r-hGH (Serostim; EMD Serono, Rockland, MA) and its PL were given as 1.0-mL single subcutaneous injections each evening. The 2-mg AD maintenance dose of r-hGH and its PL were given as single 0.5-mL subcutaneous injections every other evening. Active and PL study drug were labeled and packaged identically, and doses were sequentially numbered. Patients were taught to self-inject according to the prescribed sequence. The protocol for dose adjustments for weight and toxicity was the same as used previously.
Study visits were scheduled at screening; baseline; and weeks 2, 4, 12, 16, 24, 26, 28, and 36. CT and dual x-ray absorptiometry (DXA) scans to assess fat distribution were obtained at baseline, week 12, and week 36. OGTT and lipid profiles were obtained after a minimum 12-hour fast. These and serum IGF-I, IGF-BP3, HIV-1 RNA, and testosterone levels and CD4 T-cell count were obtained at baseline, week 12, week 24, and week 36. HbA1c levels were assessed at baseline and weeks 4, 12, and 36 by affinity chromatography. At each visit, standard hematologic and biochemistry panels, physical examinations, and reporting of AEs using the Medical Dictionary for Regulatory Activities (MedDRA), version 8.0 (MSSO, Reston, VA) were conducted. Laboratory testing was performed centrally (Esoterix Laboratories, Calabasas Hills, CA).Statistical Analysis
Data were analyzed in the modified intention-to-treat (ITT) population, which included subjects who received at least 1 dose of study drug and who had follow-up data. There were separate analysis plans for the initial 12-week induction treatment period and the 24-week maintenance period. The week 12 analysis was the primary analysis. The primary efficacy parameter, change from baseline to week 12 in absolute area of VAT, was analyzed using a nonparametric ANCOVA model with effects for treatment and gender, with baseline VAT as a covariate. The major efficacy endpoint for the maintenance phase of the study was the percentage of patients regaining >50% of the VAT they had lost during induction (weeks 1-12). Maintenance therapy was considered efficacious if, during maintenance (weeks 12-36), no more than half of the subjects who had lost VAT regained >50% of the amount they lost. Mean changes in VAT, other body composition parameters, and lipid parameters were examined in the ITT sample from baseline to week 36 and from weeks 12 to 36 as well. The trial was not powered statistically to test differences in changes in study endpoints between maintenance groups, however.
Between-group differences in continuous secondary efficacy parameters were analyzed using raw data with an ANOVA model, including effects for treatment, gender, and treatment-by-gender interaction, when parametric model assumptions were met or, using ranked data, when parametric assumptions were not met. Within-group differences were analyzed using the Wilcoxon signed rank test. Safety results were summarized for the population of patients who received at least 1 dose of study drug and had follow-up data (n = 325 for induction, n = 258 for maintenance). Between-group differences in categoric variables were analyzed using the Fisher exact test. Printer- Friendly Email This
J Acquir Immune Defic Syndr. 2007;45(3):286-297. ©2007 Lippincott Williams & Wilkins
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