Clinical trial NCT00395291: Growth Hormone Secretagogue MK-0677 Effect on IGF-1 Levels in ESRD Patients
Official title: Growth Hormone Secretagogue MK-0677 Effect on IGF-1 Levels in ESRD Patients
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Chronic Kidney Disease
End Stage Renal Disease
Keywords: Chronic kidney disease
End stage renal disease
Lead sponsor: University of Virginia
Sponsor class: OTHER
Collaborators: name: National Institutes of Health (NIH)
name: Merck Sharp & Dohme LLC
First posted: 2006-11-02
Enrollment: 49
Sex: ALL
Minimum age (years): 18
Maximum age (years): 99
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

Brief summary: The objective of this study is to determine MK-0677 increases IGF-1 in patients with end stage renal disease (ESRD) on hemodialysis.

Detailed description: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Change in IGF-1 After 30 Days of Intervention Compared to Baseline Level.
timeFrame: Baseline and after 30 days of intervention
Secondary outcomes:
measure: Change in Acyl-Ghrelin After 30 Days of Intervention Compared to Baseline Level.
timeFrame: Baseline and after 30 days of intervention.
measure: Change in Leptin After 30 Days of Intervention Compared to Baseline Level.
timeFrame: Baseline and after 30 days of intervention
measure: Change in Insulin After 30 Days of Intervention Compared to Baseline Level.
timeFrame: Baseline and after 30 days of intervention
measure: Change in Des-Acyl Ghrelin After 30 Days of Intervention Compared to Baseline Level.
timeFrame: Baseline and after 30 days of intervention
measure: Change in TNF-alpha After 30 Days of Intervention Compared to Baseline Level.
timeFrame: Baseline and after 30 days of intervention
measure: Change in CRPs After 30 Days of Intervention Compared to Baseline Level.
timeFrame: Baseline and after 30 days of intervention
measure: Change in IL-1 After 30 Days of Intervention Compared to Baseline Level.
timeFrame: Baseline and after 30 days of intervention
measure: Changes in the Following Level: IL-6
timeFrame: After the subject has comleted their last visit
measure: Change in IL-10 After 30 Days of Intervention Compared to Baseline Level.
timeFrame: Baseline and after 30 days of intervention
measure: Change in Esterase After 30 Days of Intervention Compared to Baseline Level.
timeFrame: Baseline and after 30 days of intervention
measure: Change in Adiponectin After 30 Days of Intervention Compared to Baseline Level.
timeFrame: Baseline and after 30 days of intervention
measure: Change in Ghrelin After 30 Days of Intervention Compared to Baseline Level.
timeFrame: Baseline and after 30 days of intervention
Other outcomes:
Locations:
city: Charlottesville
country: United States
facility: University of Virginia
state: Virginia
Study officials:
affiliation: University of Virginia
name: Warren K Bolton, MD
role: PRINCIPAL_INVESTIGATOR
References: