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

NCT02278562 | Completed Phase 2 Results DMC

• 1 other identifier: NEPH-011-11S
• Study Type: interventional
• Target: 33
• Locations: 1 country
• Sites: 1

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).

Conditions

ESRD

Outcome Measures

Primary Outcomes (1)

• Change in Leucine Disposal Rate (LDR)

  LDR is a sensitive laboratory assessment of amino acid metabolism

  baseline and 3 months

Secondary Outcomes (2)

• Change in Whole-body Net Protein Balance

  baseline and 3 months

• Change in Skeletal Muscle Net Protein Balance

  baseline and 3 months

Study Arms (3)

anakinra

ACTIVE COMPARATOR

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

actos

ACTIVE COMPARATOR

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

placebo 1 and 2

PLACEBO COMPARATOR

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

Interventions

anakinra DRUG

100 mg in syringes; administered subcutaneously 3 times a week for 12 weeks (3 months)

anakinra

actos DRUG

30 mg capsules; administered orally 1 capsule per day for 12 weeks (3 months)

actos

placebo OTHER

placebo capsules and injection

placebo 1 and 2

Eligibility Criteria

• Age: 21 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• VA Office of Research and Development: lead

Study Sites (1)

Tennessee Valley Healthcare System Nashville Campus, Nashville, TN

Nashville, Tennessee, 37212-2637, United States

Location

Related Publications (1)

• 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.

  PMID: 38178557 RESULT

MeSH Terms

Conditions

Kidney Failure, Chronic

Interventions

Interleukin 1 Receptor Antagonist Protein; Pioglitazone

Condition Hierarchy (Ancestors)

Renal Insufficiency, Chronic; Renal Insufficiency; Kidney Diseases; Urologic Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Male Urogenital Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Cytokines; Intercellular Signaling Peptides and Proteins; Peptides; Amino Acids, Peptides, and Proteins; Proteins; Biological Factors; Thiazolidinediones; Thiazoles; Sulfur Compounds; Organic Chemicals; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds

Results Point of Contact

• Title: Alp Ikizler MD
• Organization: VA TN Valley Healthcare System

alp.ikizler@vanderbilt.edu

615-322-5000

Study Officials

• Talat A Ikizler, MD

  Tennessee Valley Healthcare System Nashville Campus, Nashville, TN

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restrictive Agreement: No

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: TRIPLE
• Who Masked: PARTICIPANT, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: FED
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 28, 2014
• First Posted: October 30, 2014
• Study Start: October 22, 2014
• Primary Completion: March 1, 2017
• Study Completion: March 1, 2017
• Last Updated: February 6, 2025
• Results First Posted: April 2, 2018

Record last verified: 2025-01

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)