Effectiveness of Growth Hormone Releasing Hormone in Reducing Abdominal Fat in People Who Are Obese

• Change in Carotid Intima-media Thickness [ Time Frame: Measured at baseline and Months 6 and 12 ] [ Designated as safety issue: No ]
  Carotid intima media thickness imaging of the common carotid artery was conducted using a high-resolution 7.5-MHz phased-array transducer (SONOS 2000/2500. The change of the carotid intima media thickness measurement between baseline and 12 months is reported.
• Change in Lipid Profile (Total Cholesterol, High-density Lipoproteins [HDL] Cholesterol, Low-density Lipoproteins [LDL] Cholesterol, Triglycerides) [ Time Frame: Measured at baseline and Months 6 and 12 ] [ Designated as safety issue: No ]
  Lipid Profile (total cholesterol, high-density lipoproteins [HDL] cholesterol, low-density lipoproteins [LDL] cholesterol, triglycerides)was determined after an overnight fast. The change in lipid profile between baseline and 12 months is reported.
• Change in Glucose Tolerance as Measured by Oral Glucose Tolerance Test [ Time Frame: Measured at baseline and Months 6 and 12 ] [ Designated as safety issue: Yes ]
  Glucose tolerance was determined after an overnight fast using standard 75 gram oral glucose tolerance test (OGTT) with glucose measured at timepoints 0, 30, 60, 90 and 120. Change in glucose tolerance (fasting and 2 hour OGTT) between baseline and twelve months is reported.
• Change in Growth Hormone Pulse Characteristics as Assessed by Overnight Frequent Sampling of Growth Hormone [ Time Frame: Measured at baseline and Month 12 ] [ Designated as safety issue: No ]
  Analysis ongoing, no data available currently.
• Mitochondrial Function by 31P-MRS [ Time Frame: Measured at Baseline and Months 6 and 12 ] [ Designated as safety issue: No ]
  Analysis ongoing, no data available currently.

• Change in Growth Hormone pulse characteristics as assessed by overnight frequent sampling of Growth Hormone [ Time Frame: Baseline, 12 months ] [ Designated as safety issue: No ]
• Change in carotid intima-media thickness [ Time Frame: Baseline, 6 months, 12 months ] [ Designated as safety issue: No ]
• Change in lipid profile - total cholesterol, HDL cholesterol, LDL cholesterol, triglycerides [ Time Frame: Baseline, 6 months, 12 months ] [ Designated as safety issue: No ]
• Change in glucose tolerance as measured by oral glucose tolerance test [ Time Frame: Baseline, 6 months, 12 months ] [ Designated as safety issue: Yes ]

Obesity, a condition that occurs when a person has too much body fat, affects about 31% of people in the United States. It is associated with increased risk of diabetes, high blood pressure, high cholesterol, and cardiovascular disease. Abdominal obesity, in particular, is also associated with low levels of growth hormone, a hormone that affects rate of growth and the way the body uses energy. Growth hormone releasing hormone (GHRH) is a substance that makes the body naturally increase its own growth hormone levels. Administering GHRH to people who are obese may help return their growth hormone levels to normal and, in turn, may lead to reduced abdominal fat and improved cardiovascular function. This study will evaluate the effectiveness of synthetic GHRH in decreasing the amount of abdominal fat and improving cardiovascular function in people who are obese.

Obesity, defined as having a high amount of excess body fat, is one of the most wide-spread health problems of today. A variety of factors can lead to obesity. These factors include physical inactivity, family history and genetics, metabolism, and hormone imbalance. The excess body fat in obesity increases a person's risk of a number of life-threatening diseases, including heart disease, gall stones, type 2 diabetes, and certain types of cancer. People with abdominal obesity, where fat is stored predominantly around a person's midsection, are particularly prone to weight-related diseases. Studies have shown that administration of growth hormone to obese people reduces abdominal fat, but can be associated with adverse side effects. GHRH is a natural hypothalamic peptide that stimulates growth hormone release. GHRH may be able to normalize growth hormone levels, reduce abdominal fat, and lessen risk for cardiovascular disease in people who are obese, without the associated side effects of growth hormone administration. However, further study is needed on GHRH. This study will evaluate the safety and effectiveness of synthetic GHRH in decreasing the amount of abdominal fat and improving cardiovascular function in people who are obese.

Participation is this study will last 1 year from screening and will include 9 study visits. During Visit 1, participants will undergo screening tests that will include a medical history, a physical exam, body measurements, a blood draw, a urine test, a GHRH+Arginine stimulation test, an electrocardiogram (ECG), and a test for the presence of blood in stool. Eligible participants will return within the next 3 weeks for an inpatient clinic stay for Visit 2. Participants will be asked to keep a food record of all food consumed during the 4 days before the second visit. Visit 2 will include a physical exam, a medical and smoking history, a review of current medications, body measurements, an overnight blood draw, a body metabolism evaluation, an oral glucose tolerance test, and two questionnaires. Also during Visit 2, participants will be assigned randomly to treatment with active GHRH or placebo. Participants will then be taught how to give themselves injections of the study drug, which will be taken daily for 12 months. Participants will also receive a 1-month supply of study drug and will be supplied with refills in subsequent study visits. Upon starting treatment, participants will undergo more testing, including a whole body DEXA scan, abdominal computed tomography (CT) scan, carotid ultrasound, and ECG.

Visit 3 will occur at Week 2 of treatment and will include a review of study medications, questions about any side effects experienced, vital sign measurements, a blood draw, an ECG, and, if female, a urine test. Visits 4, 5, and 7 will be identical to Visit 3 and will occur at Months 1, 3, and 9 respectively. Visit 6 will occur at Month 6 and will be identical to Visit 2 but without the overnight blood draw. Visit 8 will occur at Month 12 and will be identical to Visit 2, except no further study drug will be dispensed. At Month 13, participants will complete the final study visit, which will include repeat tests from Visit 1.

• Abdominal Obesity
• Growth Hormone Deficiency

• Drug: Growth hormone releasing hormone (GHRH) 1-44
  2-mg sub-cutaneous injections once daily for 12 months
  Other Name: TH9507
• Drug: Placebo
  2-mg sub-cutaneous injections once daily for 12 months

• Experimental: 1
  Participants will receive treatment with growth hormone releasing hormone 1-44 (TH9507).
  Intervention: Drug: Growth hormone releasing hormone (GHRH) 1-44
• Placebo Comparator: 2
  Participants will receive treatment with placebo medication.
  Intervention: Drug: Placebo

Inclusion Criteria:

• Body mass index (BMI) greater than or equal to 30 kg/m2
• Waist circumference greater than or equal to 102 cm in men and greater than or equal to 88 cm in women
• Relative growth hormone (GH) deficiency, defined as a peak GH value of less than or equal to 8 ng/mL on Arginine-GHRH stimulation test
• Hemoglobin level greater than 12.0 g/dL
• Serum glutamic oxaloacetic transaminase and serum glutamic pyruvic transaminase less than 2.5 times the upper limit of normal
• Creatinine level less than 1.5 mg/dL
• Follicle stimulating hormone less than 20 IU/L in women
• Negative mammogram within 1 year of study entry for women older than 40 years of age

Exclusion Criteria:

• Obesity due to a known secondary cause (e.g., Cushing's syndrome, hypothyroidism) or a history of gastric bypass procedure
• Known hypersensitivity to GHRH 1-44 (TH9507)
• Known history of diabetes, fasting blood sugar less than 125 mg/dL, or antidiabetic drug use
• Using any weight lowering drugs
• Using estrogen, hormone replacement therapy, oral contraceptives, testosterone, glucocorticoids, anabolic steroids, GHRH, GH, or insulin-like growth factor-1 (IGF-1) within 3 months of study entry
• Changes in lipid lowering or antihypertensive regimen within 3 months of study entry
• Long-term illness, including anemia, chronic kidney disease, and liver disease
• History of cancer (except patients with surgically cured basal cell or squamous cell skin cancers) or history of abnormalities on age appropriate malignancy screen, including mammography, colonoscopy, and prostate exam (or prostate specific antigen greater than 5 ng/mL)
• History of hypopituitarism, pituitary surgery, pituitary/brain radiation, traumatic brain injury, or any other condition known to affect the growth hormone axis
• History of any recent cardiovascular event, including heart attack, stroke, transient ischemic attack, unstable angina pectoris, or oxygen-dependent severe pulmonary disease, within 3 months of study entry
• Clinical depression or other psychiatric illness that will not allow completion of the study as per investigator's judgement
• History of or current eating disorder
• History of recent alcohol or substance abuse (less than 1 year before study entry)
• Positive pregnancy test or breastfeeding females and positive fecal occult blood test
• Women of childbearing potential not currently using nonhormonal birth control methods, including barrier methods (e.g., IUD, condoms, diaphragms) or abstinence
• Currently enrolled in another investigational device or drug trial(s) or has received other investigational agent(s) within 28 days of study entry
• Any condition that would make this clinical trial detrimental to the patient, as judged by the patient's physician
• History of noncompliance with other therapies
• Any condition in which compliance with the study protocol is unlikely