Chronic Kidney Disease, End Stage Renal Disease
Conditions
Keywords
Chronic kidney disease, End stage renal disease
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.
Interventions
DRUGMK-0677
The dosage of the drug is 25mg, subjects will take one pill a day for about 30 days.
DRUGPlacebo
Placebo
Sponsors
National Institutes of Health (NIH)
Merck Sharp & Dohme LLC
University of Virginia
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 99 Years
Healthy volunteers
No
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.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in IGF-1 After 30 Days of Intervention Compared to Baseline Level. | Baseline and after 30 days of intervention | Looking for a change in the IGF-1 levels after the subject has been on intervention for 30 days compared to baseline levels. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Leptin After 30 Days of Intervention Compared to Baseline Level. | Baseline and after 30 days of intervention | Looking for a change in the Leptin levels after the subject has been on intervention for 30 days compared to baseline levels. |
| Change in Insulin After 30 Days of Intervention Compared to Baseline Level. | Baseline and after 30 days of intervention | Looking for a change in the Insulin levels after the subject has been on intervention for 30 days compared to baseline levels. |
| Change in Des-Acyl Ghrelin After 30 Days of Intervention Compared to Baseline Level. | Baseline and after 30 days of intervention | Looking for a change in the Des-Acyl Ghrelin levels after the subject has been on intervention for 30 days compared to baseline levels. |
| Change in TNF-alpha After 30 Days of Intervention Compared to Baseline Level. | Baseline and after 30 days of intervention | Looking for a change in the TNF-alpha levels after the subject has been on intervention for 30 days compared to baseline levels. |
| Change in CRPs After 30 Days of Intervention Compared to Baseline Level. | Baseline and after 30 days of intervention | Looking for a change in the CRPs levels after the subject has been on intervention for 30 days compared to baseline levels. |
| Change in Acyl-Ghrelin After 30 Days of Intervention Compared to Baseline Level. | Baseline and after 30 days of intervention. | Looking for a change in the Acyl-Ghrelin levels after the subject has been on intervention for 30 days compared to baseline levels. |
| Changes in the Following Level: IL-6 | After the subject has comleted their last visit | Change in IL-6 after 30 days of intervention. |
| Change in IL-10 After 30 Days of Intervention Compared to Baseline Level. | Baseline and after 30 days of intervention | Looking for a change in the IL-10 levels after the subject has been on intervention for 30 days compared to baseline levels. |
| Change in Esterase After 30 Days of Intervention Compared to Baseline Level. | Baseline and after 30 days of intervention | Looking for a change in the Esterase levels after the subject has been on intervention for 30 days compared to baseline levels. |
| Change in Adiponectin After 30 Days of Intervention Compared to Baseline Level. | Baseline and after 30 days of intervention | Looking for a change in the Adiponectin levels after the subject has been on intervention for 30 days compared to baseline levels. |
| Change in Ghrelin After 30 Days of Intervention Compared to Baseline Level. | Baseline and after 30 days of intervention | Looking for a change in the Ghrelin levels after the subject has been on intervention for 30 days compared to baseline levels. |
| Change in IL-1 After 30 Days of Intervention Compared to Baseline Level. | Baseline and after 30 days of intervention | Looking for a change in the IL-1 levels after the subject has been on intervention for 30 days compared to baseline levels. |
Countries
United States
Participant flow
Recruitment details
We recruited our subjects from 3 clinics at the University of Virginia. Our clinics were located at the Dialysis Units in Charlottesville, VA, Fisherville, VA, and Zion Crossroads, VA. Subjects were recruited into this study between March 2007 and August 2008.
Pre-assignment details
49 Subjects were recruited; 26 Subjects started intervention (4 Subjects started study intervention and then were dropped from the study), 22 Subjects Completed this trial. 1 Subject withdrew their consent prior to study intervention. 22 Subjects did not meet inclusion/exclusion criteria.
Participants by arm
| Arm | Count |
|---|---|
| Entire Study Population Includes groups randomized to placebo first and MK-0677 first. | 26 |
| Total | 26 |
Baseline characteristics
| Characteristic | Entire Study Population |
|---|---|
| Age, Categorical <=18 years | 0 Participants |
| Age, Categorical >=65 years | 8 Participants |
| Age, Categorical Between 18 and 65 years | 18 Participants |
| Age, Continuous | 57.3 years STANDARD_DEVIATION 14.4 |
| Gender Female | 8 Participants |
| Gender Male | 18 Participants |
| Region of Enrollment United States | 26 participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 5 / 26 | 0 / 26 |
| serious Total, serious adverse events | 4 / 26 | 3 / 26 |
Outcome results
Primary
Change in IGF-1 After 30 Days of Intervention Compared to Baseline Level.
Looking for a change in the IGF-1 levels after the subject has been on intervention for 30 days compared to baseline levels.
Time frame: Baseline and after 30 days of intervention
Population: 22 Subjects completed both interventions and lab results were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-0677 | Change in IGF-1 After 30 Days of Intervention Compared to Baseline Level. | 92.7 ng/ml | Standard Deviation 62.3 |
| Placebo | Change in IGF-1 After 30 Days of Intervention Compared to Baseline Level. | 6.7 ng/ml | Standard Deviation 40.2 |
Comparison: Null hypothesis: the intra-subject pre-intervention to post-intervention change in IGF-1 is the same for both the MK-0677 and placebo interventions.~Power calculation: We assumed that the IGF-I data will be lognormally distributed and thus the parameter of interest will be the IGF-1 geometric mean. If n=22 individuals complete the study and the intervention effect is 48% greater for one intervention than the other we will have at least 0.80 power to reject the null hypothesis.p-value: <0.001ANCOVA
Secondary
Change in Acyl-Ghrelin After 30 Days of Intervention Compared to Baseline Level.
Looking for a change in the Acyl-Ghrelin levels after the subject has been on intervention for 30 days compared to baseline levels.
Time frame: Baseline and after 30 days of intervention.
Population: 22 subjects completed both interventions.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-0677 | Change in Acyl-Ghrelin After 30 Days of Intervention Compared to Baseline Level. | -23.4 pg/ml | Standard Deviation 68.9 |
| Placebo | Change in Acyl-Ghrelin After 30 Days of Intervention Compared to Baseline Level. | 3.5 pg/ml | Standard Deviation 150.3 |
Comparison: Null hypothesis: the intra-subject pre-intervention to post-intervention change in Acyl-Ghrelin is the same for both the MK-0677 and placebo interventions.~Because Acyl-Ghrelin is considered as a secondary outcome, no power analysis was conducted.p-value: 0.169ANCOVA
Secondary
Change in Adiponectin After 30 Days of Intervention Compared to Baseline Level.
Looking for a change in the Adiponectin levels after the subject has been on intervention for 30 days compared to baseline levels.
Time frame: Baseline and after 30 days of intervention
Population: 22 subjects had samples available for the MK-0677 intervention, and 21 samples were available for the placebo intervention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-0677 | Change in Adiponectin After 30 Days of Intervention Compared to Baseline Level. | 1242.0 ng/ml | Standard Deviation 7858.1 |
| Placebo | Change in Adiponectin After 30 Days of Intervention Compared to Baseline Level. | 735.1 ng/ml | Standard Deviation 4485 |
Comparison: Null hypothesis: the intra-subject pre-intervention to post-intervention change in adiponectin is the same for both the MK-0677 and placebo interventions.~Because Acyl-Ghrelin is considered as a secondary outcome, no power analysis was conducted.p-value: 0.545ANCOVA
Secondary
Change in CRPs After 30 Days of Intervention Compared to Baseline Level.
Looking for a change in the CRPs levels after the subject has been on intervention for 30 days compared to baseline levels.
Time frame: Baseline and after 30 days of intervention
Population: 22 Subjects completed both interventions.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-0677 | Change in CRPs After 30 Days of Intervention Compared to Baseline Level. | 2.6 mg/ml | Standard Deviation 13.4 |
| Placebo | Change in CRPs After 30 Days of Intervention Compared to Baseline Level. | 6.0 mg/ml | Standard Deviation 32.7 |
Comparison: Null hypothesis: the intra-subject pre-intervention to post-intervention change in CRPs is the same for both the MK-0677 and placebo interventions.~Because CRPs is considered as a secondary outcome, no power analysis was conducted.p-value: 0.929ANCOVA
Secondary
Change in Des-Acyl Ghrelin After 30 Days of Intervention Compared to Baseline Level.
Looking for a change in the Des-Acyl Ghrelin levels after the subject has been on intervention for 30 days compared to baseline levels.
Time frame: Baseline and after 30 days of intervention
Population: 22 Subjects completed both interventions.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-0677 | Change in Des-Acyl Ghrelin After 30 Days of Intervention Compared to Baseline Level. | 30.2 pg/ml | Standard Deviation 201.5 |
| Placebo | Change in Des-Acyl Ghrelin After 30 Days of Intervention Compared to Baseline Level. | -44.05 pg/ml | Standard Deviation 157.4 |
p-value: 0.782ANCOVA
Secondary
Change in Esterase After 30 Days of Intervention Compared to Baseline Level.
Looking for a change in the Esterase levels after the subject has been on intervention for 30 days compared to baseline levels.
Time frame: Baseline and after 30 days of intervention
Population: 22 subjects completed both interventions and results were available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-0677 | Change in Esterase After 30 Days of Intervention Compared to Baseline Level. | -1.6 units/ml | Standard Deviation 10.3 |
| Placebo | Change in Esterase After 30 Days of Intervention Compared to Baseline Level. | -1.3 units/ml | Standard Deviation 12.6 |
Comparison: Null hypothesis: the intra-subject pre-intervention to post-intervention change in esterase is the same for both the MK-0677 and placebo interventions.~Because Acyl-Ghrelin is considered as a secondary outcome, no power analysis was conducted.p-value: 0.875ANCOVA
Secondary
Change in Ghrelin After 30 Days of Intervention Compared to Baseline Level.
Looking for a change in the Ghrelin levels after the subject has been on intervention for 30 days compared to baseline levels.
Time frame: Baseline and after 30 days of intervention
Population: 22 subjects completed both interventions and lab results were available for all 22.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-0677 | Change in Ghrelin After 30 Days of Intervention Compared to Baseline Level. | 6.9 pg/ml | Standard Deviation 162.5 |
| Placebo | Change in Ghrelin After 30 Days of Intervention Compared to Baseline Level. | -40.5 pg/ml | Standard Deviation 192.5 |
Comparison: Null hypothesis: the intra-subject pre-intervention to post-intervention change in Total-Ghrelin is the same for both the MK-0677 and placebo interventions.~Because Acyl-Ghrelin is considered as a secondary outcome, no power analysis was conducted.p-value: 0.9ANCOVA
Secondary
Change in IL-10 After 30 Days of Intervention Compared to Baseline Level.
Looking for a change in the IL-10 levels after the subject has been on intervention for 30 days compared to baseline levels.
Time frame: Baseline and after 30 days of intervention
Population: 22 subjects had samples available for the MK-0677 intervention, and 21 samples were available for the placebo intervention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-0677 | Change in IL-10 After 30 Days of Intervention Compared to Baseline Level. | -0.1 pg/ml | Standard Deviation 1.9 |
| Placebo | Change in IL-10 After 30 Days of Intervention Compared to Baseline Level. | 0.7 pg/ml | Standard Deviation 1.7 |
Comparison: Null hypothesis: the intra-subject pre-intervention to post-intervention change in IL-10 is the same for both the MK-0677 and placebo interventions.~Because IL-10 is considered as a secondary outcome, no power analysis was conducted.p-value: 0.277ANCOVA
Secondary
Change in IL-1 After 30 Days of Intervention Compared to Baseline Level.
Looking for a change in the IL-1 levels after the subject has been on intervention for 30 days compared to baseline levels.
Time frame: Baseline and after 30 days of intervention
Population: 22 subjects had samples available for the MK-0677 intervention, and 21 samples were available for the placebo intervention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-0677 | Change in IL-1 After 30 Days of Intervention Compared to Baseline Level. | 0.0 pg/ml | Standard Deviation 0.2 |
| Placebo | Change in IL-1 After 30 Days of Intervention Compared to Baseline Level. | -0.0 pg/ml | Standard Deviation 0.3 |
Comparison: Null hypothesis: the intra-subject pre-intervention to post-intervention change in IL-1 is the same for both the MK-0677 and placebo interventions.~Because IL-1 is considered as a secondary outcome, no power analysis was conductedp-value: 0.905ANCOVA
Secondary
Change in Insulin After 30 Days of Intervention Compared to Baseline Level.
Looking for a change in the Insulin levels after the subject has been on intervention for 30 days compared to baseline levels.
Time frame: Baseline and after 30 days of intervention
Population: 22 subjects completed both interventions.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-0677 | Change in Insulin After 30 Days of Intervention Compared to Baseline Level. | 3.77 uIU/ml | Standard Deviation 10.5 |
| Placebo | Change in Insulin After 30 Days of Intervention Compared to Baseline Level. | -.2 uIU/ml | Standard Deviation 12.5 |
Comparison: Null hypothesis: the intra-subject pre-intervention to post-intervention change in serum-insulin is the same for both the MK-0677 and placebo interventions.~Because serum-insulin is considered a secondary outcome, no power analysis was conducted.p-value: 0.075ANCOVA
Secondary
Change in Leptin After 30 Days of Intervention Compared to Baseline Level.
Looking for a change in the Leptin levels after the subject has been on intervention for 30 days compared to baseline levels.
Time frame: Baseline and after 30 days of intervention
Population: 22 subjects completed both interventions.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-0677 | Change in Leptin After 30 Days of Intervention Compared to Baseline Level. | 24.4 ng/ml | Standard Deviation 50.2 |
| Placebo | Change in Leptin After 30 Days of Intervention Compared to Baseline Level. | -6.9 ng/ml | Standard Deviation 30.4 |
Comparison: Null hypothesis: the intra-subject pre-intervention to post-intervention change in leptin is the same for both the MK-0677 and placebo interventions.~Because Leptin is considered a secondary outcome, no power analysis was conducted.p-value: 0.063ANCOVA
Secondary
Change in TNF-alpha After 30 Days of Intervention Compared to Baseline Level.
Looking for a change in the TNF-alpha levels after the subject has been on intervention for 30 days compared to baseline levels.
Time frame: Baseline and after 30 days of intervention
Population: 22 subjects had samples available for the MK-0677 intervention, and 21 samples were available for the placebo intervention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-0677 | Change in TNF-alpha After 30 Days of Intervention Compared to Baseline Level. | 1.2 pg/ml | Standard Deviation 5.9 |
| Placebo | Change in TNF-alpha After 30 Days of Intervention Compared to Baseline Level. | -0.7 pg/ml | Standard Deviation 14.6 |
Comparison: Null hypothesis: the intra-subject pre-intervention to post-intervention change in TNF-a is the same for both the MK-0677 and placebo interventions.~Because Acyl-Ghrelin is considered as a secondary outcome, no power analysis was conducted.p-value: 0.385ANCOVA
Secondary
Changes in the Following Level: IL-6
Change in IL-6 after 30 days of intervention.
Time frame: After the subject has comleted their last visit
Population: 22 subjects had samples available for the MK-0677 intervention, and 21 samples were available for the placebo intervention.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| MK-0677 | Changes in the Following Level: IL-6 | 3.1 pg/mL | Standard Deviation 5.2 |
| Placebo | Changes in the Following Level: IL-6 | 0.8 pg/mL | Standard Deviation 6.9 |
p-value: 0.233ANCOVA