Growth Hormone Secretagogue MK-0677 Effect on IGF-1 Levels in ESRD Patients
Growth Hormone Secretagogue MK-0677 Effect on IGF-1 Levels in ESRD Patients
The objective of this study is to determine MK-0677 increases IGF-1 in patients with end
 stage renal disease (ESRD) on hemodialysis.
With development and progression of chronic kidney disease (CKD) to end stage renal disease
 (ESRD), malnutrition becomes an increasingly severe problem. This is thought to occur from
 two mechanisms: decreased appetite secondary to uremia and development of a catabolic
 inflammatory milieu. Patients experience decreased muscle mass and functional activity
 associated with increased morbidity and mortality. Many therapies to improve poor nutritional
 state have been used with little success. Growth hormone (GH) and insulin like growth hormone
 (IGF-1) improve muscle mass, quality of life, nutritional parameters, immune and physical
 functions but must be given parenterally and are limited by expense and patient compliance.
 Recently, the endogenous GH receptor secretagogue (GHRS) ghrelin has been shown to raise
 endogenous GH and improve food intake but must be given parenterally and is not available.
 The experimental drug MK-0677, a synthetic GHRS, ghrelin mimetic, which is given orally, has
 recently been shown to increase IGF-1 and muscle mass in the elderly. Its effects in CKD and
 ESRD are unknown. We will study the effects of MK-0677 on renal patients. Specifically, we
 hope to show that the drug increases IGF-1 in renal patients, and has similar effects to
 exogenous GH and IGF-1. Subjects will be ESRD hemodialysis patients. This protocol is an
 investigator-initiated, randomized, double-blind crossover, placebo-controlled pilot study.
 The study's primary outcome is IGF-1 levels for subjects. Secondary outcomes will be levels
 of cytokines, esterase, leptin, insulin, ghrelin, TNF-alpha, CRPs, IL-1, IL-6, IL-10, and
 adiponectin.
Inclusion Criteria:

 - GFR by the MDRD estimate < 30ml/minute/1.73m2 or on hemodialysis

 Exclusion Criteria:

 -  Body mass index greater than 35 kg/m2, or morbid obesity

 -  Uncontrolled hypothyroidism, defined as an elevated serum thyroid stimulating hormone
 (THS) and a free serum thyroxine (T4) less than the lower limit of normal, when tested
 at baseline (Patients requiring thyroid replacement during the study may continue.)

 -  Uncontrolled hyperthyroidism, defined as a TSH less than the lower limit of normal and
 an elevated free T4, when tested at baseline

 -  Hemoglobin <10 Gm/dl

 -  Elevated serum transaminases (>2.0 times the upper limit of normal at baseline)

 -  Diabetes with one of more of the following:

 1. Poorly controlled diabetes as defined by a HbA1C > 7.0% at baseline)

 2. Proliferative diabetic retinopathy [To participate in this study, diabetic
 patients will need to have had a dilated ophthalmology exam within 12 months of
 enrollment. Individuals who already have extensive background retinopathy will
 need to have a dilated ophthalmology exam within the 3 months of enrollment.
 Patients with pre-proliferative or proliferative retinopathy will be excluded].

 3. Unwilling or unable to check blood glucose at home at least daily.

 -  Currently receiving a systemic corticosteroid dose of >10 mg prednisone (or
 equivalent), or patient has received, for a duration > 30 days in the previous 6
 months (i.e., prior to signing the informed consent form), a systemic corticosteroid
 dose of > 10 mg prednisone (or equivalent). (The previous use, or current use, of a
 topical or inhaled corticosteroid is allowed.)

 -  Currently taking or previously on an anabolic steroid or growth hormone at any dose,
 or for any duration, during the 12 months prior to study entry.

 -  Significant end-organ disease, other than kidney disease, which, in the opinion of the
 investigator may pose an added risk to the patient, confound the study results, or
 impair the patient's ability to complete the trial.

 -  Any of the following disorders within 6 months prior to baseline:

 1. Acute coronary syndrome (e.g., myocardial infarction or unstable angina)

 2. Coronary artery intervention (e.g., coronary bypass graft [CABG], percutaneous
 transluminal coronary angioplasty [PTCA]).

 3. Stroke or transient ischemic neurological disorder (e.g. transient ischemic
 attack [TIA])

 -  New or worsening signs or symptoms of coronary heart disease within the 3 months prior
 to baseline.

 -  NYHA (New York Heart Association)Class III or IV congestive heart failure (definitions
 shown in Appendix A)

 -  Uncontrolled hypertension when checked at screening visit: as evidenced by > 160
 systolic and/or 100 diastolic (measured in dominant or non-dialysis access arm, after
 at least 5 minutes, sitting)

 -  Cancer, or diagnosis of malignancy within the last 5 years, except for adequately
 treated basal cell or squamous cell skin cancer, or adequately treated in situ
 cervical cancer.

 -  Active carpal tunnel syndrome

 -  Patient is, in the opinion of the investigator, mentally or legally incapacitated such
 that informed consent cannot be obtained or such that adherence to the study
 procedures and dosing regimens is questionable.

 -  Patient is, at study entry, a regular user (including "recreational use") of illicit
 drugs or had a recent history (within the last 5 years) of drug or alcohol abuse.

 -  Patient plans to relocate or change to a different dialysis center during the study,
 rendering follow-up per protocol, impractical.

 -  Patient is participating in, or has participated in, another study with an
 investigational drug within 30 days prior to signing the informed consent form.

 -  Women who are pregnant or lactating

 -  HIV positive (medical history review and patient report)

 -  Patient is on potent CYP3A4 Inhibitor or Inducer Drugs within one week of starting
 study drug.