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Carnosine for Peripheral Arterial Disease Patients (CAR-PAD)

Primary Purpose

Peripheral Arterial Disease

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Carnosine
Sponsored by
University of Louisville
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Peripheral Arterial Disease

Eligibility Criteria

50 Years - 80 Years (Adult, Older Adult)MaleDoes not accept healthy volunteers

Inclusion Criteria:

  1. Male subjects more than >50 to <80 years of age.
  2. White or African American race.
  3. English Speaking.
  4. ABI 0.4-< 0.60
  5. Willing to comply with protocol requirements.
  6. Able to provide informed consent. -

Exclusion Criteria:

  1. Subjects with HIV, hepatitis, significant liver disease, active infection, anemia, organ transplant, renal disease requiring dialysis, lung disease requiring oxygen, significant congenital heart disease, cancer of any type, and untreated thyroid disease.
  2. Diagnosis of carnosinemia.
  3. Known allergy to L-carnosine or meat.
  4. Presence of a pacemaker.
  5. Obesity from a known genetic defect.
  6. Dementia.
  7. Critical limb ischemia with below or above knee amputations.
  8. Foot ulcers.
  9. Major amputations.
  10. Participating in other clinical trials.
  11. End stage renal disease.
  12. Presence of significant injury within 30 days before enrollment.
  13. Prisoners.
  14. Any metallic implants.
  15. Poorly controlled diabetes (HbA1C >9%) -

Sites / Locations

  • University of LouisvilleRecruiting

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Carnosine intervention for patients with PAD

Arm Description

This is a single arm open labelled safety trial, where we will supplement carnosine for 3 months to subjects with non-claudication and claudication peripheral arterial disease (PAD), and determine if it improves walking ability.

Outcomes

Primary Outcome Measures

Carnosine for Peripheral Arterial Disease patients
Compare the effects of carnosine supplementation on the 6-minute walk test (6MWT) at the baseline and after three months of carnosine supplementation. Measure the total walking distance and compare the walking distance covered by the subjects at the start and completion of carnosine supplementation

Secondary Outcome Measures

Graded treadmill test
Measure the onset of claudication onset time and peak walk time

Full Information

First Posted
April 29, 2022
Last Updated
June 6, 2023
Sponsor
University of Louisville
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1. Study Identification

Unique Protocol Identification Number
NCT05371145
Brief Title
Carnosine for Peripheral Arterial Disease Patients
Acronym
CAR-PAD
Official Title
Carnosine for Peripheral Arterial Disease Patients (Car-PAD)
Study Type
Interventional

2. Study Status

Record Verification Date
June 2023
Overall Recruitment Status
Recruiting
Study Start Date
March 1, 2023 (Actual)
Primary Completion Date
December 30, 2023 (Anticipated)
Study Completion Date
December 30, 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
University of Louisville

4. Oversight

Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Product Manufactured in and Exported from the U.S.
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
Oral supplementation of L-carnosine will increase muscle carnosine, stabilize HIF1-alpha promote angiogenesis, and thus improve the functioning of lower extremities in PAD patients.
Detailed Description
Peripheral arterial disease (PAD) is caused by atherosclerotic occlusion of the lower extremities that reduces blood flow and leads to intermittent claudication and critical limb ischemia. PAD is diagnosed by calculating the ratio of blood pressure at the ankle to that of the arm (the ankle-brachial index [ABI]). An ABI of <0.90 is indicative of atherosclerosis in the leg. Recent data from developed and developing countries have estimated that >200 million people worldwide and approximately 12 million people in United States have PAD3. Both symptomatic and asymptomatic PAD patients have an increased risk of mortality, morbidity, and a lower quality of life. With the increasing incidence of type 2 diabetes (T2D) and a rising aging population, the number of PAD patients is likely to increase. Because PAD is an under-recognized disease, currently few medications are available to improve the functional performance of these patients. Although surgical revascularization is an available treatment, grafts can fail and the stenosis can reoccur in these patients. To adequately compensate the loss of tissue due to occlusion, the current emphasis is to increase the therapeutic angiogenesis and arteriogenesis in the ischemic limb that could improve the walking ability and the quality of life in PAD patients. In a recent pre-clinical study it was shown that supplementation of carnosine(β-alanine-histidine) (500 mg/day) in heart failure patients for 6 months improves their performance on the 6-minute walking test (6MWT) compared with placebo-treated patients. Carnosine is a histidyl dipeptide present in high concentration in the skeletal muscle, brain, and heart. It is a food constituent that is present in red meat, chicken, and turkey. This dipeptide is synthesized by the ATP grasp enzyme carnosine synthetase and hydrolyzed to β-alanine and histidine by the serum and kidney carnosinase. Carnosine has the abilities to quench reactive aldehydes, bind metals, and buffer intracellular pH7. Numerous studies have shown that the supplementation of beta-alanine or carnosine increases the levels of carnosine in the skeletal muscle and improves the exercise performance in humans. Our preliminary studies with the mice model of hind limb ischemia (HLI) showed that both the pretreatment and supplementation of carnosine after femoral artery ligation increased blood flow in the ischemic limb compared with the non-treated mice. Mechanistic studies showed that the metal quenching ability of carnosine increased the expression of angiogenic factor VEGF and endothelial progenitor cells mobilization in the carnosine treated HLI mice. Similarly, the stabilization of HIF-1α, the master regulator of angiogenesis and angiogenic factor VEGF, was increased in the hypoxic C2C12 cells (murine myoblasts). Based on these pre-clinical studies, in this study PAD subjects will be recruited and supplemented with carnosine (2 g/day) for 3 months to examine if its supplementation improves walking performance compared with the baseline. Further, we will examine whether the supplementation of carnosine increases the capacity of pain-free treadmill walking time, extrusion of oxidative stress markers and mobilizes the endothelial progenitor cells in the blood.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Peripheral Arterial Disease

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Model Description
In a single arm open labelled safety trial, we will supplement carnosine for 3 months to subjects with non-claudication and claudication peripheral arterial disease (PAD), and determine if it improves walking ability. In our pilot study, we will enroll 20 male subjects measure the distance covered on the 6-minute walk test and the pain free walking capacity on the treadmill before, at baseline, and three months after carnosine supplementation.
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Carnosine intervention for patients with PAD
Arm Type
Experimental
Arm Description
This is a single arm open labelled safety trial, where we will supplement carnosine for 3 months to subjects with non-claudication and claudication peripheral arterial disease (PAD), and determine if it improves walking ability.
Intervention Type
Biological
Intervention Name(s)
Carnosine
Intervention Description
Determine whether carnosine supplementation (2 g/day) for 3 months in peripheral arterial disease patients improves 6MWT ability.
Primary Outcome Measure Information:
Title
Carnosine for Peripheral Arterial Disease patients
Description
Compare the effects of carnosine supplementation on the 6-minute walk test (6MWT) at the baseline and after three months of carnosine supplementation. Measure the total walking distance and compare the walking distance covered by the subjects at the start and completion of carnosine supplementation
Time Frame
One year
Secondary Outcome Measure Information:
Title
Graded treadmill test
Description
Measure the onset of claudication onset time and peak walk time
Time Frame
one year

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
50 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male subjects more than >50 to <80 years of age. White or African American race. English Speaking. ABI 0.4-< 0.60 Willing to comply with protocol requirements. Able to provide informed consent. - Exclusion Criteria: Subjects with HIV, hepatitis, significant liver disease, active infection, anemia, organ transplant, renal disease requiring dialysis, lung disease requiring oxygen, significant congenital heart disease, cancer of any type, and untreated thyroid disease. Diagnosis of carnosinemia. Known allergy to L-carnosine or meat. Presence of a pacemaker. Obesity from a known genetic defect. Dementia. Critical limb ischemia with below or above knee amputations. Foot ulcers. Major amputations. Participating in other clinical trials. End stage renal disease. Presence of significant injury within 30 days before enrollment. Prisoners. Any metallic implants. Poorly controlled diabetes (HbA1C >9%) -
Facility Information:
Facility Name
University of Louisville
City
Louisville
State/Province
Kentucky
ZIP/Postal Code
40202
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Shahid P Baba, Ph.D
Phone
502-852-4274
Email
spbaba01@louisville.edu
First Name & Middle Initial & Last Name & Degree
Amit J Dwivedi
Phone
5026450749
Email
amit.dwivedi@louisville.edu

12. IPD Sharing Statement

Plan to Share IPD
No
Citations:
PubMed Identifier
23670612
Citation
Annex BH. Therapeutic angiogenesis for critical limb ischaemia. Nat Rev Cardiol. 2013 Jul;10(7):387-96. doi: 10.1038/nrcardio.2013.70. Epub 2013 May 14.
Results Reference
result
PubMed Identifier
7867189
Citation
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.
Results Reference
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PubMed Identifier
25908725
Citation
Criqui MH, Aboyans V. Epidemiology of peripheral artery disease. Circ Res. 2015 Apr 24;116(9):1509-26. doi: 10.1161/CIRCRESAHA.116.303849. Erratum In: Circ Res. 2015 Jun 19;117(1):e12.
Results Reference
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PubMed Identifier
25287762
Citation
Lombardi C, Carubelli V, Lazzarini V, Vizzardi E, Bordonali T, Ciccarese C, Castrini AI, Dei Cas A, Nodari S, Metra M. Effects of oral administration of orodispersible levo-carnosine on quality of life and exercise performance in patients with chronic heart failure. Nutrition. 2015 Jan;31(1):72-8. doi: 10.1016/j.nut.2014.04.021. Epub 2014 May 10.
Results Reference
result
PubMed Identifier
20097752
Citation
Drozak J, Veiga-da-Cunha M, Vertommen D, Stroobant V, Van Schaftingen E. Molecular identification of carnosine synthase as ATP-grasp domain-containing protein 1 (ATPGD1). J Biol Chem. 2010 Mar 26;285(13):9346-9356. doi: 10.1074/jbc.M109.095505. Epub 2010 Jan 22.
Results Reference
result
PubMed Identifier
12473676
Citation
Teufel M, Saudek V, Ledig JP, Bernhardt A, Boularand S, Carreau A, Cairns NJ, Carter C, Cowley DJ, Duverger D, Ganzhorn AJ, Guenet C, Heintzelmann B, Laucher V, Sauvage C, Smirnova T. Sequence identification and characterization of human carnosinase and a closely related non-specific dipeptidase. J Biol Chem. 2003 Feb 21;278(8):6521-31. doi: 10.1074/jbc.M209764200. Epub 2002 Dec 6.
Results Reference
result
PubMed Identifier
22020113
Citation
Hipkiss AR. Energy metabolism, proteotoxic stress and age-related dysfunction - protection by carnosine. Mol Aspects Med. 2011 Aug;32(4-6):267-78. doi: 10.1016/j.mam.2011.10.004. Epub 2011 Oct 15.
Results Reference
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PubMed Identifier
23899755
Citation
Harris RC, Stellingwerff T. Effect of beta-alanine supplementation on high-intensity exercise performance. Nestle Nutr Inst Workshop Ser. 2013;76:61-71. doi: 10.1159/000350258. Epub 2013 Jul 25.
Results Reference
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PubMed Identifier
22852051
Citation
Caruso J, Charles J, Unruh K, Giebel R, Learmonth L, Potter W. Ergogenic effects of beta-alanine and carnosine: proposed future research to quantify their efficacy. Nutrients. 2012 Jul;4(7):585-601. doi: 10.3390/nu4070585. Epub 2012 Jun 26.
Results Reference
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PubMed Identifier
21160056
Citation
Roger VL, Go AS, Lloyd-Jones DM, Adams RJ, Berry JD, Brown TM, Carnethon MR, Dai S, de Simone G, Ford ES, Fox CS, Fullerton HJ, Gillespie C, Greenlund KJ, Hailpern SM, Heit JA, Ho PM, Howard VJ, Kissela BM, Kittner SJ, Lackland DT, Lichtman JH, Lisabeth LD, Makuc DM, Marcus GM, Marelli A, Matchar DB, McDermott MM, Meigs JB, Moy CS, Mozaffarian D, Mussolino ME, Nichol G, Paynter NP, Rosamond WD, Sorlie PD, Stafford RS, Turan TN, Turner MB, Wong ND, Wylie-Rosett J; American Heart Association Statistics Committee and Stroke Statistics Subcommittee. Heart disease and stroke statistics--2011 update: a report from the American Heart Association. Circulation. 2011 Feb 1;123(4):e18-e209. doi: 10.1161/CIR.0b013e3182009701. Epub 2010 Dec 15. Erratum In: Circulation. 2011 Feb 15;123(6):e240. Circulation. 2011 Oct 18;124(16):e426.
Results Reference
result

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Carnosine for Peripheral Arterial Disease Patients

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