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

Nutrition, Inflammation and Insulin Resistance in End-Stage Renal Disease

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).

Study Overview

• Status: Completed
• Conditions: ESRD
• Intervention / Treatment: Drug: anakinra; Drug: actos; Other: placebo

• Study Type: Interventional
• Enrollment (Actual): 33
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Tennessee
    • Nashville, Tennessee, United States, 37212-2637
      • Tennessee Valley Healthcare System Nashville Campus, Nashville, TN

Participation Criteria

Eligibility Criteria

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

Description

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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

3

Arms and Interventions

Participant Group / 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

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in Leucine Disposal Rate (LDR)	LDR is a sensitive laboratory assessment of amino acid metabolism	baseline and 3 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	baseline and 3 months
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.	baseline and 3 months

Collaborators and Investigators

• Sponsor: VA Office of Research and Development
• Investigators: Principal Investigator: Talat A Ikizler, MD, Tennessee Valley Healthcare System Nashville Campus, Nashville, TN

Publications and helpful links

General Publications

• Ertuglu LA, Deger SM, Alsouqi A, Hung A, Gamboa J, Mambungu C, Sha F, Siew E, Abumrad NN, Ikizler TA. A randomized controlled pilot trial of anakinra and pioglitazone for protein metabolism in patients on maintenance haemodialysis. J Cachexia Sarcopenia Muscle. 2024 Feb;15(1):401-411. doi: 10.1002/jcsm.13395. Epub 2024 Jan 4.

Study record dates

Study Major Dates

• Study Start (Actual): October 22, 2014
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): March 1, 2017

Study Registration Dates

• First Submitted: October 28, 2014
• First Submitted That Met QC Criteria: October 28, 2014
• First Posted (Estimated): October 30, 2014

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 23, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Urogenital Diseases; Pathologic Processes; Male Urogenital Diseases; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Chronic Disease; Disease Attributes; Metabolic Diseases; Glucose Metabolism Disorders; Renal Insufficiency; Hyperinsulinism; Renal Insufficiency, Chronic; Inflammation; Insulin Resistance; Kidney Failure, Chronic; Antirheumatic Agents; Interleukin 1 Receptor Antagonist Protein
• Other Study ID Numbers: NEPH-011-11S

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No