INSPIRED: Nutrition, Inflammation and Insulin Resistance in End Stage Renal Disease-Aim 2
Study Details
Study Description
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).
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Active Comparator: 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 |
Drug: anakinra
100 mg in syringes; administered subcutaneously 3 times a week for 12 weeks (3 months)
|
| Active Comparator: 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 |
Drug: actos
30 mg capsules; administered orally 1 capsule per day for 12 weeks (3 months)
|
| Placebo Comparator: 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 |
Other: placebo
placebo capsules and injection
|
Outcome Measures
Primary Outcome Measures
- Change in Leucine Disposal Rate (LDR) [baseline and 3 months]
LDR is a sensitive laboratory assessment of amino acid metabolism
Secondary Outcome Measures
- 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.
Eligibility Criteria
Criteria
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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Tennessee Valley Healthcare System Nashville Campus, Nashville, TN | Nashville | Tennessee | United States | 37212-2637 |
Sponsors and Collaborators
- VA Office of Research and Development
Investigators
- Principal Investigator: Talat A Ikizler, MD, Tennessee Valley Healthcare System Nashville Campus, Nashville, TN
Study Documents (Full-Text)
More Information
Publications
None provided.- NEPH-011-11S
Study Results
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 Detail | 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). |
| Arm/Group Title | Anakinra | Actos | Placebo 1 and 2 |
|---|---|---|---|
| Arm/Group Description | 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) | 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) | 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 |
| Period Title: Overall Study | |||
| STARTED | 9 | 7 | 8 |
| COMPLETED | 9 | 7 | 8 |
| NOT COMPLETED | 0 | 0 | 0 |
Baseline Characteristics
| Arm/Group Title | Anakinra | Actos | Placebo 1 and 2 | Total |
|---|---|---|---|---|
| Arm/Group Description | 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) | 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) | 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 | Total of all reporting groups |
| Overall Participants | 9 | 7 | 8 | 24 |
| Age (years) [Mean (Standard Deviation) ] | ||||
| Mean (Standard Deviation) [years] |
45
(17)
|
46
(15)
|
56
(12)
|
49
(15)
|
| Sex: Female, Male (Count of Participants) | ||||
| Female |
4
44.4%
|
1
14.3%
|
2
25%
|
7
29.2%
|
| Male |
5
55.6%
|
6
85.7%
|
6
75%
|
17
70.8%
|
| Ethnicity (NIH/OMB) (Count of Participants) | ||||
| Hispanic or Latino |
0
0%
|
0
0%
|
1
12.5%
|
1
4.2%
|
| Not Hispanic or Latino |
9
100%
|
7
100%
|
7
87.5%
|
23
95.8%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Race (NIH/OMB) (Count of Participants) | ||||
| American Indian or Alaska Native |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Asian |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Native Hawaiian or Other Pacific Islander |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Black or African American |
6
66.7%
|
6
85.7%
|
7
87.5%
|
19
79.2%
|
| White |
3
33.3%
|
1
14.3%
|
1
12.5%
|
5
20.8%
|
| More than one race |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Unknown or Not Reported |
0
0%
|
0
0%
|
0
0%
|
0
0%
|
| Region of Enrollment (Count of Participants) | ||||
| United States |
9
100%
|
7
100%
|
8
100%
|
24
100%
|
Outcome Measures
| Title | Change in Leucine Disposal Rate (LDR) |
|---|---|
| Description | LDR is a sensitive laboratory assessment of amino acid metabolism |
| Time Frame | baseline and 3 months |
Outcome Measure Data
| Analysis Population Description |
|---|
| The number of participants for analysis was based on those subjects who completed the 3-month study. The analysis was per protocol. |
| Arm/Group Title | Anakinra | Actos | Placebo 1 and 2 |
|---|---|---|---|
| Arm/Group Description | 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) | 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) | 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 |
| Measure Participants | 9 | 7 | 8 |
| Median (Inter-Quartile Range) [mg/kg/min] |
-0.011
|
0.005
|
0.001
|
Statistical Analysis 1
| Statistical Analysis Overview | Comparison Group Selection | Anakinra, Placebo 1 and 2 |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.37 |
| Comments | 0.05 is the a priori threshold for statistical significance | |
| Method | Wilcoxon Rank-Sum | |
| Comments | ||
Statistical Analysis 2
| Statistical Analysis Overview | Comparison Group Selection | Actos, Placebo 1 and 2 |
|---|---|---|
| Comments | 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. | |
| Type of Statistical Test | Superiority | |
| Comments | ||
| Statistical Test of Hypothesis | p-Value | 0.955 |
| Comments | 0.05 is the a priori threshold for statistical significance | |
| Method | Wilcoxon Rank-Sum | |
| Comments | ||
| Title | Change in Whole-body Net Protein Balance |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The number of participants for analysis was based on those subjects who completed the 3-month study. The analysis was per protocol. |
| Arm/Group Title | Anakinra | Actos | Placebo 1 and 2 |
|---|---|---|---|
| Arm/Group Description | 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) | 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) | 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 |
| Measure Participants | 9 | 7 | 8 |
| Median (Inter-Quartile Range) [mg/kg/min] |
-0.184
|
-0.215
|
0.018
|
| Title | Change in Skeletal Muscle Net Protein Balance |
|---|---|
| Description | 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 |
Outcome Measure Data
| Analysis Population Description |
|---|
| The number of participants for analysis was based on those subjects who completed the 3-month study. The analysis was per protocol. |
| Arm/Group Title | Anakinra | Actos | Placebo 1 and 2 |
|---|---|---|---|
| Arm/Group Description | 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) | 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) | 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 |
| Measure Participants | 9 | 7 | 8 |
| Median (Inter-Quartile Range) [μg/100 ml/min] |
-5.1
|
11.8
|
134.1
|
Adverse Events
| Time Frame | 3 months | |||||
|---|---|---|---|---|---|---|
| Adverse Event Reporting Description | ||||||
| Arm/Group Title | Anakinra | Actos | Placebo 1 and 2 | |||
| Arm/Group Description | 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) | 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) | 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 | |||
All Cause Mortality |
||||||
| Anakinra | Actos | Placebo 1 and 2 | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/9 (0%) | 0/7 (0%) | 0/8 (0%) | |||
Serious Adverse Events |
||||||
| Anakinra | Actos | Placebo 1 and 2 | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 0/9 (0%) | 0/7 (0%) | 0/8 (0%) | |||
Other (Not Including Serious) Adverse Events |
||||||
| Anakinra | Actos | Placebo 1 and 2 | ||||
| Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | Affected / at Risk (%) | # Events | |
| Total | 5/9 (55.6%) | 1/7 (14.3%) | 2/8 (25%) | |||
| Cardiac disorders | ||||||
| arrhythmia | 0/9 (0%) | 0 | 1/7 (14.3%) | 1 | 0/8 (0%) | 0 |
| Gastrointestinal disorders | ||||||
| diarrhea | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 1/8 (12.5%) | 1 |
| General disorders | ||||||
| syncope | 2/9 (22.2%) | 2 | 0/7 (0%) | 0 | 0/8 (0%) | 0 |
| allergic reaction | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/8 (0%) | 0 |
| Nervous system disorders | ||||||
| right side weakness | 0/9 (0%) | 0 | 1/7 (14.3%) | 1 | 0/8 (0%) | 0 |
| seizure | 0/9 (0%) | 0 | 0/7 (0%) | 0 | 1/8 (12.5%) | 1 |
| Renal and urinary disorders | ||||||
| fluid overload | 1/9 (11.1%) | 1 | 0/7 (0%) | 0 | 0/8 (0%) | 0 |
| access related | 0/9 (0%) | 0 | 1/7 (14.3%) | 1 | 0/8 (0%) | 0 |
| Skin and subcutaneous tissue disorders | ||||||
| injection site reaction | 2/9 (22.2%) | 2 | 0/7 (0%) | 0 | 0/8 (0%) | 0 |
Limitations/Caveats
More Information
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Results Point of Contact
| Name/Title | Alp Ikizler MD |
|---|---|
| Organization | VA TN Valley Healthcare System |
| Phone | 615-322-5000 |
| alp.ikizler@vanderbilt.edu |
- NEPH-011-11S