Effectiveness of Growth Hormone Releasing Hormone in Reducing Abdominal Fat 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.

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