Nutrition, Inflammation and Insulin Resistance in End Stage Renal Disease-Aim 2 (INSPIRED)

• ClinicalTrials.gov Identifier: NCT02278562
• Recruitment Status: Completed
• First Posted: October 30, 2014
• Results First Posted: April 2, 2018
• Last Update Posted: April 2, 2018
• Sponsor: VA Office of Research and Development
• Information provided by (Responsible Party): VA Office of Research and Development

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
ESRD	Drug: anakinra; Drug: actos; Other: placebo	Phase 2

Study Design

• Study Type: Interventional (Clinical Trial)
• Actual Enrollment: 33 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Triple (Participant, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Nutrition, Inflammation and Insulin Resistance in End-Stage Renal Disease
• Actual Study Start Date: October 22, 2014
• Actual Primary Completion Date: March 1, 2017
• Actual Study Completion Date: March 1, 2017

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 :

1. Change in Leucine Disposal Rate (LDR) [ Time Frame: baseline and 3 months ]
   LDR is a sensitive laboratory assessment of amino acid metabolism

Secondary Outcome Measures :

1. Change in Whole-body Net Protein Balance [ Time Frame: baseline and 3 months ]
   Whole-body net protein balance is the difference between protein synthesis (anabolism) and protein breakdown (catabolism) in the whole body
2. Change in Skeletal Muscle Net Protein Balance [ Time Frame: 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

• Ages Eligible for Study: 21 Years and older (Adult, Older Adult)
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

United States, Tennessee

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)

Documents provided by VA Office of Research and Development:

Study Protocol and Statistical Analysis Plan  [PDF] December 16, 2015

Informed Consent Form  [PDF] June 2, 2015

More Information

• Responsible Party: VA Office of Research and Development
• ClinicalTrials.gov Identifier: NCT02278562
• Other Study ID Numbers: NEPH-011-11S
• First Posted: October 30, 2014
• Results First Posted: April 2, 2018
• Last Update Posted: April 2, 2018
• Last Verified: March 2018

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided

Additional relevant MeSH terms:

Kidney Failure, Chronic; Insulin Resistance; Inflammation; Pathologic Processes; Hyperinsulinism; Glucose Metabolism Disorders; Metabolic Diseases; Kidney Diseases; Urologic Diseases; Renal Insufficiency, Chronic; Renal Insufficiency; Interleukin 1 Receptor Antagonist Protein; Antirheumatic Agents