ESRD
Conditions
Brief summary
By 2030 an estimated 2 million people in the US will need dialysis or transplantation for advanced kidney failure. An even more disturbing statistic is that mortality in End Stage Renal Disease (ESRD) is six times higher than in the general Medicare population with adjustment for age, gender and ethnicity. Protein energy wasting is highly prevalent in these patients and is one of the most important determinants of their poor clinical outcome. Despite its well-recognized occurrence, the etiology and the mechanisms leading to protein energy wasting observed in chronic hemodialysis patients cannot be attributed to any single factor. However, irrespective of the specific etiologic mechanisms, it appears that the common pathway for all the metabolic derangements is related to exaggerated protein degradation relative to protein synthesis (47). Two well-recognized and presumably interrelated metabolic abnormalities, insulin resistance and chronic inflammation, may be the major determinants of protein catabolism in coronary heart disease (CHD) patients. There are no studies examining the effects of anti-inflammatory interventions and/or insulin sensitizers on protein homeostasis in CHD. Due to their established anti-inflammatory and other pleiotropic effects, Interleukin-1 receptor antagonist Anakinra and insulin sensitizer peroxisome proliferator-activated receptors (PPAR) agonist Actos represent two such promising interventions. By modulating inflammatory response and insulin signaling through two pharmacological interventions, the investigators will have the unique opportunity to clarify mechanisms contributing of these two particular metabolic derangements in the development of protein energy wasting observed in chronic hemodialysis patients. The overall goal is to elucidate the mechanisms by which chronic inflammation and insulin resistance influence the development of protein energy wasting in hemodialysis patients. Specific Aim: To test the hypothesis that inhibiting inflammatory response by administration of an Interleukin1receptor antagonist (Anakinra) or increasing insulin sensitivity by administration of a PPAR agonist (Actos) will improve net protein metabolism. Hypothesis: The chronic inflammatory component of protein energy wasting (PEW) observed in hemodialysis patients is, at least in part, mediated by insulin resistance. Interim analysis may be performed (no specific plan at this time).
Interventions
DRUGanakinra
100 mg in syringes; administered subcutaneously 3 times a week for 12 weeks (3 months)
DRUGactos
30 mg capsules; administered orally 1 capsule per day for 12 weeks (3 months)
OTHERplacebo
placebo capsules and injection
Sponsors
VA Office of Research and Development
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
21 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients on CHD undergoing three time a week therapy for more than 6 months; * Age 21 years old; * Acceptable dialysis adequacy (spKt/V \> 1.2); * A patent, well-functioning, arterio-venous dialysis access; * Ability to give informed consent; * Life expectancy greater than 6 months; * BMI \>=20 and \<=45.
Exclusion criteria
* Pregnancy; * Intolerance or allergy to the study medication (including the metabolic clamp studies); * Severe, unstable, active inflammatory disease (active infection, active connective tissue disorder), active cancer or cancer history in the prior 5 years except skin cancer, AIDS-HIV, active or history of liver disease (including hepatitis B virus and hepatitis C virus); * Hospitalization or infection within 1 month prior to the study; * Patients receiving steroids and/or other immunosuppressive agents (Prednisone \> 5 mg/day; excluding inhaled and topical steroids); * Diabetes Mellitus on insulin therapy; * Previous history of tuberculosis (TB) with or without documented adequate therapy; * Patients with recent close exposure to an individual with active TB; * Females using oral contraceptives; * Patients with New York Heart Association (NYHA) Class III or IV heart failure; * Patients with a history of angina, myocardial infarction, transient ischemic attacks, or strokes within the last 6 months.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Change in Leucine Disposal Rate (LDR) | baseline and 3 months | LDR is a sensitive laboratory assessment of amino acid metabolism |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Change in Whole-body Net Protein Balance | baseline and 3 months | Whole-body net protein balance is the difference between protein synthesis (anabolism) and protein breakdown (catabolism) in the whole body |
| Change in Skeletal Muscle Net Protein Balance | baseline and 3 months | Skeletal muscle net protein balance is the difference between protein synthesis (anabolism) and protein breakdown (catabolism) in the skeletal muscles. |
Countries
United States
Participant flow
Recruitment details
This study was conducted at the VA Nashville and the Vanderbilt University Medical Center between October 2014 and March 2017.
Pre-assignment details
There is about a 2-week screening period between enrollment and assignment to a treatment group to access inclusion/exclusion criteria. Although 33 subjects were enrolled, only 24 subjects were assigned to a treatment group (6 subjects were screen failures and 3 subjects withdrew prior to being randomized).
Participants by arm
| Arm | Count |
|---|---|
| Anakinra 100 mg of Anakinra in syringes administered subcutaneously 3 times a week for 3 months and lactose (placebo) in capsules administered orally 1 capsule per day for 3 months
anakinra: 100 mg in syringes; administered subcutaneously 3 times a week for 12 weeks (3 months) | 9 |
| Actos Normal saline (placebo) in syringes administered subcutaneously 3 times a week for 3 months and 30 mg of Actos in capsules administered orally 1 capsule per day for 3 months
actos: 30 mg capsules; administered orally 1 capsule per day for 12 weeks (3 months) | 7 |
| Placebo 1 and 2 Normal saline (placebo) in syringes administered subcutaneously 3 times a week for 3 months and lactose (placebo) in capsules administered orally 1 capsule per day for 3 months
placebo: placebo capsules and injection | 8 |
| Total | 24 |
Baseline characteristics
| Characteristic | Anakinra | Total | Placebo 1 and 2 | Actos |
|---|---|---|---|---|
| Age, Continuous | 45 years STANDARD_DEVIATION 17 | 49 years STANDARD_DEVIATION 15 | 56 years STANDARD_DEVIATION 12 | 46 years STANDARD_DEVIATION 15 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 1 Participants | 1 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 9 Participants | 23 Participants | 7 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 6 Participants | 19 Participants | 7 Participants | 6 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 3 Participants | 5 Participants | 1 Participants | 1 Participants |
| Region of Enrollment United States | 9 Participants | 24 Participants | 8 Participants | 7 Participants |
| Sex: Female, Male Female | 4 Participants | 7 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 5 Participants | 17 Participants | 6 Participants | 6 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 9 | 0 / 7 | 0 / 8 |
| other Total, other adverse events | 5 / 9 | 1 / 7 | 2 / 8 |
| serious Total, serious adverse events | 0 / 9 | 0 / 7 | 0 / 8 |
Outcome results
Primary
Change in Leucine Disposal Rate (LDR)
LDR is a sensitive laboratory assessment of amino acid metabolism
Time frame: baseline and 3 months
Population: The number of participants for analysis was based on those subjects who completed the 3-month study. The analysis was per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anakinra | Change in Leucine Disposal Rate (LDR) | -0.011 mg/kg/min |
| Actos | Change in Leucine Disposal Rate (LDR) | 0.005 mg/kg/min |
| Placebo 1 and 2 | Change in Leucine Disposal Rate (LDR) | 0.001 mg/kg/min |
Comparison: Prior data indicate that LDR is normally distributed with standard deviation ranging from 0.16 to 0.23 in hemodialysis and control patients, respectively. If the true difference in the experimental and control means is 0.21, we will be able to reject the null hypothesis that the population means of the experimental and control groups are equal with probability (power) 0.933. The Type I error probability associated with this test of this null hypothesis is 0.05.p-value: 0.37Wilcoxon Rank-Sum
Comparison: Prior data indicate that LDR is normally distributed with standard deviation ranging from 0.16 to 0.23 in hemodialysis and control patients, respectively. If the true difference in the experimental and control means is 0.21, we will be able to reject the null hypothesis that the population means of the experimental and control groups are equal with probability (power) 0.933.p-value: 0.955Wilcoxon Rank-Sum
Secondary
Change in Skeletal Muscle Net Protein Balance
Skeletal muscle net protein balance is the difference between protein synthesis (anabolism) and protein breakdown (catabolism) in the skeletal muscles.
Time frame: baseline and 3 months
Population: The number of participants for analysis was based on those subjects who completed the 3-month study. The analysis was per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anakinra | Change in Skeletal Muscle Net Protein Balance | -5.1 μg/100 ml/min |
| Actos | Change in Skeletal Muscle Net Protein Balance | 11.8 μg/100 ml/min |
| Placebo 1 and 2 | Change in Skeletal Muscle Net Protein Balance | 134.1 μg/100 ml/min |
Secondary
Change in Whole-body Net Protein Balance
Whole-body net protein balance is the difference between protein synthesis (anabolism) and protein breakdown (catabolism) in the whole body
Time frame: baseline and 3 months
Population: The number of participants for analysis was based on those subjects who completed the 3-month study. The analysis was per protocol.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Anakinra | Change in Whole-body Net Protein Balance | -0.184 mg/kg/min |
| Actos | Change in Whole-body Net Protein Balance | -0.215 mg/kg/min |
| Placebo 1 and 2 | Change in Whole-body Net Protein Balance | 0.018 mg/kg/min |