Effects of Carnosine In Patients With Peripheral Arterial Disease Patients

Official title

Effects of Carnosine In Patients With Peripheral Arterial Disease Patients; Randomized Intervention Trial (CIPHER)

Overview

The purpose of this study is to determine whether carnosine (a food ingredient found in chicken and red meat) supplementation (2 g) for 6 months in participants with non-claudication and claudication peripheral arterial disease (PAD) improves walking ability. Previous studies with heart failure patients have shown that carnosine supplementation increases walking capacity in these patients.

Detailed description

The objective of this double-blinded longitudinal study is to determine whether carnosine supplementation (2 g) for 6 months in participants with non-claudication and claudication peripheral arterial disease (PAD) improves walking ability. In this pilot study we will enroll 144 participants that will be divided into placebo (n=72) and carnosine groups (n=72). We will measure the distance covered on the 6-minute walk test (6-MWT) and the pain free walking capacity on the treadmill before and after the placebo or carnosine supplementation. We will measure ankle branchial index (ABI) and blood flow by magnetic resonance imaging (MRI) before and after the carnosine and placebo supplementation. In addition, we will measure carnosine by 1HMRS (Proton magnetic resonance spectroscopy), perform, global metabolomics and proteomics in the skeletal muscle, a comprehensive lipid and metabolic profile of blood, uptake of carnosine in red blood cells (RBCs), and measure carnosine aldehyde conjugates in the urine before and after 6 months of carnosine and placebo supplementation. Following completion of the study, we will follow the participants for another 3 months and examine the durability of carnosine supplementation.

Interventions

• Drug Carnosine
  Food ingredient (supplement)

Primary outcome measures

• Measure distance covered on six-minute walk test (6MWT) [Time frame: Baseline, 3 months, 6 months, 9 months]

Secondary outcome measures (12)

• Measure Ankle-Brachial Index (ABI) [Time frame: Baseline, 3 months, 6 months, 9 months]
• Treadmill Testing [Time frame: Baseline, 3 months, 6 months]
• Skin Integrity [Time frame: Baseline, 3 months, 6 months]
• Musculoskeletal Assessment [Time frame: Baseline, 3 months, 6 months]
• Neuromuscular Assessment [Time frame: Baseline, 3 months, 6 months]
• Balance Assessment [Time frame: Baseline, 3 months, 6 months]
• Quality of life Questionnaire [Time frame: Baseline, 3 months, 6 months, 9 months]
• Assessment of PAD Severity [Time frame: Baseline, 3 months, 6 months, 9 months]
• Depressive Symptoms Questionnaire [Time frame: Baseline, 3 months, 6 months, 9 months]
• 24-hour Dietary Recall [Time frame: Baseline, 3 months, 6 months, 9 months]
• Daily Walking Ability [Time frame: -7-Baseline, Day 90-97, Day 180-187, Day 270-277]
• Blood Collection and Analysis [Time frame: Baseline, 3 months, 6 months, 9 months]

Eligibility criteria

Inclusion criteria

• Participants between 40-80 years of age.
• White or African American race.
• Literate in English.
• ABI >0.4-<0.90, obtained within 6 weeks from enrollment.
• Willing and able to comply with protocol requirements.
• Participant is able to provide informed consent.

Exclusion criteria

• As per physician's discretion, participants with HIV, hepatitis, significant liver disease, anemia, renal disease requiring dialysis, lung disease requiring home oxygen therapy, and active cancer may be excluded.
• Critical limb ischemia with below or above the knee amputations or any form of foot ulceration over the symptomatic leg.
• Presence of significant injury within 30 days, or vascular intervention on the symptomatic leg within 6 months before enrollment, as per physician's discretion.
• Participants with a baseline 6MWT of less than 152.0 meters (498ft) or greater than 487.7 meters (1600ft).
• Known allergy to L-carnosine.
• Participants with rare autosomal recessive metabolic disorder carnosinemia or carnosinase deficiency.
• Currently participating in other clinical trials.
• Participation in any carnosine supplementation clinical trial anytime in the past.
• Participants already taking carnosine.
• Participants unable to provide urine sample (anuric).
• Pregnant participants.
• Participants using dual antiplatelet therapies will not be included for biopsy.
• Participants with internal metallic objects in body will not be eligible for MRI or 1HMRS.

Criteria are shown verbatim from the registry (in English). Final eligibility is always assessed by the study center.

Healthy volunteers: No

Study design

Allocation

Randomized

Model

Parallel assignment

Masking

Triple blind

Primary purpose

Treatment

Study locations

United States · 3 centers

• University of Louisville School of Medicine, Department of Medicine, Division of Environme — Louisville
• University Surgical Associates, 401 E. Chestnut St, Suite 710 — Louisville
• UofL Physicians - Vascular Surgery Associates, 201 Abraham Flexner Way, Suite 1004 — Louisville

Publications

• de Courten B, Jakubova M, de Courten MP, Kukurova IJ, Vallova S, Krumpolec P, Valkovic L, Kurdiova T, Garzon D, Barbaresi S, Teede HJ, Derave W, Krssak M, Aldini G, Ukropec J, Ukropcova B. Effects of carnosine supplementation on glucose metabolism: Pilot clinical trial. Obesity (Silver Spring). 2016 May;24(5):1027-34. doi: 10.1002/oby.21434. Epub 2016 Apr 4. PMID 27040154
• Vincent KA, Shyu KG, Luo Y, Magner M, Tio RA, Jiang C, Goldberg MA, Akita GY, Gregory RJ, Isner JM. Angiogenesis is induced in a rabbit model of hindlimb ischemia by naked DNA encoding an HIF-1alpha/VP16 hybrid transcription factor. Circulation. 2000 Oct 31;102(18):2255-61. doi: 10.1161/01.cir.102.18.2255. PMID 11056102
• Hiatt WR, Hoag S, Hamman RF. Effect of diagnostic criteria on the prevalence of peripheral arterial disease. The San Luis Valley Diabetes Study. Circulation. 1995 Mar 1;91(5):1472-9. doi: 10.1161/01.cir.91.5.1472. PMID 7867189
• Waeckel L, Mallat Z, Potteaux S, Combadiere C, Clergue M, Duriez M, Bao L, Gerard C, Rollins BJ, Tedgui A, Levy BI, Silvestre JS. Impairment in postischemic neovascularization in mice lacking the CXC chemokine receptor 3. Circ Res. 2005 Mar 18;96(5):576-82. doi: 10.1161/01.RES.0000159389.55544.20. Epub 2005 Feb 17. PMID 15718500
• Gerhardt H, Golding M, Fruttiger M, Ruhrberg C, Lundkvist A, Abramsson A, Jeltsch M, Mitchell C, Alitalo K, Shima D, Betsholtz C. VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia. J Cell Biol. 2003 Jun 23;161(6):1163-77. doi: 10.1083/jcb.200302047. Epub 2003 Jun 16. PMID 12810700
• Creager MA, Olin JW, Belch JJ, Moneta GL, Henry TD, Rajagopalan S, Annex BH, Hiatt WR. Effect of hypoxia-inducible factor-1alpha gene therapy on walking performance in patients with intermittent claudication. Circulation. 2011 Oct 18;124(16):1765-73. doi: 10.1161/CIRCULATIONAHA.110.009407. Epub 2011 Sep 26. PMID 21947297
• Wang GL, Semenza GL. Desferrioxamine induces erythropoietin gene expression and hypoxia-inducible factor 1 DNA-binding activity: implications for models of hypoxia signal transduction. Blood. 1993 Dec 15;82(12):3610-5. PMID 8260699
• Silvestre JS, Mallat Z, Tedgui A, Levy BI. Post-ischaemic neovascularization and inflammation. Cardiovasc Res. 2008 May 1;78(2):242-9. doi: 10.1093/cvr/cvn027. Epub 2008 Feb 5. PMID 18252762

Identifiers

NCT: NCT06480760 · 24.0309 · R01HL163419

Primary sources (government registries)

• ClinicalTrials.gov (US NIH)

View this study on ClinicalTrials.gov ↗