Replacement GH Therapy After Bariatric Surgery in Patients With Very Severe Obesity
Condition: Obesity; GHD
MeSH terms: Obesity; Obesity, Morbid
Study type: Interventional
Phase: Phase 3

Summary: 
      Obesity and obesity-related diseases have reached epidemic proportions in Western countries
      (1-3). Laparoscopic-adjustable silicone gastric banding (LASGB) is a purely restrictive
      operation that determine effective weight loss without inducing malabsorption (4-6). However,
      also after LASGB body weight loss is almost invariably associated with Free Fat Mass (FFM)
      loss, and the relevance of the FFM contribution to total energy expenditure is well-known
      (7-8). Different endocrine axes are reported to affect FFM. We previously reported that low
      levels of DHEA-S, an adrenal steroid with controversial anti-adipogenic and anti-atherogenic
      effects, are increased after the massive and sustainable weight loss induced by LASGB in
      severely obese premenopausal women and correlated with the higher post-operative FFM (9-10).
      It is also well known that GH/IGF-I axis exerts relevant effects on FFM and that reduced GH
      levels might increase Fat Mass (FM) and reduce FFM (11,12). Morbidly obese patients have a
      reduced GH secretion, generally reversible after weight loss (13-14). In a recent study
      currently in press, we reported that a persistent deficiency in the GH/IGF-I axis in very
      obese females is associated to lower decrease in FM after LASGB. Low IGF-I plasma levels have
      also been reported to be independent prognostic factors of liver steatosis and non-alcoholic
      steatohepatitis in morbidly obese patients (15) and ultrasound- measured hepatic left lobe
      volume might represent a reliable tool for the evaluation of liver involvement in obesity
      (16). GH deficiency (GHD) in adult patients is associated with an increase in FM and a
      parallel decrease in FFM (17). The severity of GDH is correlated to cardiovascular risk, body
      composition abnormalities and bone loss, and decreased left ventricular ejection fraction
      (18-20). GH therapy has been demonstrated to be effective in normalizing body composition,
      with beneficial effects up to a 2-years follow-up period (21-24). GH therapy has also been
      reported to be effective in sparing FFM during weight loss in obese patients and metabolic
      syndrome (25,26). However, these studies have some limitations due to the duration of the
      treatment and the lack of a preliminary evaluation of the GH/IGF-I axis secretory status in
      obese patients before the GH therapy. At present there are no data on the evaluation of the
      GH/IGF-I status before and after bariatric surgery and the effectiveness of recombinant GH
      treatment in very severe obese patients.
    

Detailed description: 
      The objectives of the study are:

        1. To evaluate the GH/GF-I status is correlation with body composition in very severe obese
           patients. IGF-I levels were classified as deficient when the standard deviation score
           from the mean was <-2 for age and gender.

        2. To evaluate the efficacy of a medical treatment with recombinant GH replacement therapy
           in very severe obese patients after LASGB on the Fat mass (%), free fat mass (%),
           percent decrease of fat mass. In line with GHD diagnosis, obese patients with persistent
           GHD after bariatric surgery will be randomized to be treated with or without recombinant
           GH therapy with replacement doses, in addition to the controlled trial of dietary
           management, as routinely performed after LASGB.

      Study protocol The study protocol includes two different arms: a correlation observational
      longitudinal open study (Phase I), and a treatment study (Phase II).

      PHASE I: In the correlation study a clinical, biochemical and instrumental evaluation will be
      performed in 20-30 patients with very severe obesity (grade III) with GHD followed-up in a
      multi-disciplinary approach at the Unit of Endocrinology of the Departments of Molecular and
      Clinical Endocrinology and Oncology and at the Physiology Nutrition Unit of the Department of
      Neuroscience and the Department of Surgery of "S. Giovanni Bosco" Hospital of Naples,
      according to the current criteria of the National Institute of Health (27). The clinical
      examination will focus on the GH/IGF-I status effects on body composition changes before and
      after LASGB. The clinical examination will determine anthropometric indexes (weight, height,
      BMI, waist circumference). The biochemical evaluation will include the measurement of lipid
      profile, fasting plasma glucose and insulin, liver test function, FT3, FT4, GHRH + Arginine
      test to detect GHD, plasma IGF-I levels. The instrumental evaluation will include DEXA Total
      Body and bioimpedance analysis to determine body composition, and liver ultrasounds.

      PHASE II: In the medical treatment protocol very severe obese patients with persistent GHD
      after LASGB will be inclosed. Starting from 15-day, GHD patients were re-evaluated by GHRH +
      Arginine test. After evaluation, the patients with persistent GHD will be randomized to be
      treated with Recombinant GH replacement therapy (Group A: Recombinant GH replacement therapy
      at the initial dose 0.15-0.30 mg/die; dose adjustment will be made according to IGF-I levels;
      Group B: no GH treatment). In both subgroups, the diet will arranged to fit an energy intake
      of 5.7 MJ/day (55% carbohydrate, 25% fat, 20% protein, 30 g fiber) and a moderate-intensity
      activity (brisk walking for 30-45 min/day) will be encouraged.

      The evaluation of medical treatment efficacy will be based on the analysis of changes in
      anthropometric indexes, IGF-I levels, liver function test, body composition assessed by DEXA
      Total Body and bioimpedance analysis, liver ultrasounds. At 3 and 6 months, the patients of
      both subgroups A and B will be clinically re-evaluated, plasma samples for metabolic, liver
      function tests, and endocrine profile will be obtained, body composition and liver
      ultrasounds will be determined. At the end of the 6-months period of treatment and
      observation, the GH response to a subsequent GHRH + Arginine will be re-tested to confirm or
      to exclude GHD. All the patients with persistent GHD will continue recombinant GH therapy.
    

Intervention name(s): Recombinant GH Saizen (Merck-Serono)
Intervention type(s): Drug
Intervention description(s): Treatment will start at the initial dose 0.15-0.30 mg/day; dose adjustment will be performed according to IGF-I levels. The duration of medical treatment is 6 months.
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Very Severe Obesity; Body Composition; GH deficiency; IGF-I; LASGB; GH therapy