Polyamine Treatment in Elderly Patients With Coronary Artery Disease

Obesity Clinical Trial

— PolyCAD  

Official title:

Polyamine Treatment in Elderly Patients With Coronary Artery Disease - a Randomized Controlled Trial

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT06186102
• Other study ID #: M-2023-71-23
• Status: Recruiting
• Phase: Phase 2
• Start date: January 1, 2024
• Est. completion date: January 2027

Study information

• Verified date: October 2023
• Source: University of Aarhus
• Contact: Christian V Thorup, MD
• Phone: 0045 51509421
• Email: christian.thorup[@]clin.au.dk
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The present study is testing spermidine treatment in elderly patients with coronary artery disease. The study is a randomized, double-blind, placebo-controlled, two-armed, parallel-group, single centre, clinical study.

Description:

Life expectancy has increased tremendously over the past century and as populations age, chronic diseases such as cardiovascular disease and diabetes have become more prevalent. Healthy aging is therefore of paramount importance to further promote longevity and quality of life. In humans, a high concentration of whole-blood spermidine is associated with longevity, and individuals with a high dietary spermidine intake have improved cardiovascular health and less obesity. Spermidine is essentially a polyamine found in all plant-derived foods, particularly in whole grains, soybeans, nuts, and fruit. Its favorable effects may act via several mechanisms. In an experimental model of hypertensive heart disease, spermidine reduced cardiac hypertrophy and improved diastolic and mitochondrial function. Spermidine also induces cytoprotective autophagy in skeletal muscle and alters body fat accumulation by metabolically modulating glucose and lipid metabolism. The clinical data on spermidine dietary supplementation are scarce. In elderly subjects with cognitive problems, spermidine supplement was well tolerated and had potential blood-pressure-lowering effects. The reported beneficial effects of spermidine raise the question whether elderly patients with cardiovascular disease can benefit from a dietary supplement of this polyamine. The central hypothesis of the current proposal is that a twelve-month spermidine treatment regimen in elderly patients with cardiovascular disease will yield positive effects on heart and skeletal muscle function, whole body composition and inflammation. The secondary hypotheses are that spermidine reduces blood pressure and has a beneficial impact on cognitive function, daily activity level, quality of life, biomarker risk profile, skeletal muscle cellular metabolism and lastly but not least gut microbiota. The study design is a randomized, double-blind, placebo-controlled trial to investigate the effects of a 24 mg daily oral spermidine dietary supplement vs. matching placebo in elderly patients with cardiovascular disease. A total of 220 patients will be included and randomized 1:1 to either spermidine 24 mg x 1 daily or matching placebo for one year. At baseline and after one year of intervention the patients will undergo study procedures. Changes from baseline to follow-up will be compared between the active and placebo treated patient groups.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 220
• Est. completion date: January 2027
• Est. primary completion date: July 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 65 Years to 90 Years

Eligibility

Inclusion Criteria:

• Age = 65 years
• Chronic ischemic heart disease (previous revascularization or myocardial infarction)
• Left ventricular ejection fraction of > 40%

And at least two of the following risk factors:

• Type 2 diabetes,
• Obesity (BMI = 30 kg/m2),
• Hypertension,
• Previous LVEF < 40%,
• Left atrial volume index = 30 mL/m2
• Left ventricular wall thickness = 1.1 cm.

Exclusion Criteria:

• Unstable coronary syndrome
• Significant and severe cardiac valve disease
• Severe peripheral artery disease
• Permanent atrial fibrillation
• Pacemaker treatment
• Chronic kidney disease with eGFR <45 ml/min/1,73m2
• Severe comorbidity as judged by the investigator (such as severe pulmonary, neurological, or musculoskeletal disease)
• Inability to give informed consent.

Exclusion criteria for MRI:

• Some metallic implants
• Claustrophobia

Exclusion criteria for muscle biopsy:

• Treatment with either two antiplatelet drugs (aspirin and ADP-receptor antagonists)
• Anticoagulants (warfarin, NOACs)

Related Conditions & MeSH terms

• Cardiovascular Diseases
• Cognition Disorder
• Cognition Disorders
• Cognitive Impairment
• Coronary Artery Disease
• Coronary Disease
• Diabetes Mellitus
• Diabetes Mellitus, Type 2
• Diastolic Dysfunction
• Dietary Habits
• Heart Diseases
• Hypertension
• Hypertensive Heart Disease
• Inflammation
• Ischemic Heart Disease
• Metabolic Syndrome
• Myocardial Infarction
• Myocardial Ischemia
• Obesity
• Quality of Life

Intervention

Dietary Supplement:
• Spermidine
Spermidine capsule of 8 mg x 3 capsules daily.

Other:
• Placebo
Placebo capsule. 3 capsules daily.

Locations

Country	Name	City	State
Denmark	Aarhus University Hospital	Aarhus	Jutland

Sponsors (7)

Lead Sponsor	Collaborator
University of Aarhus	Danish Cardiovascular Academy (DCA), Danish Diabetes Academy, DoNotAge.org, Eva and Henry Frænkels Mindefond, Steno Diabetes Center Aarhus (SDCA), Aarhus University Hospital, Sygesikringen Danmark

Country where clinical trial is conducted

Denmark, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Changes in gut microbiota	16S RNA analysis will be used for characterization of the bacterial composition.; Full sequencing will be used for characterisation of the collective composition of bacteria, viruses, bacteriophages, fungi, and parasites.	From randomization (month 0) to 12 months
Other	Changes in fecal metabolites	Mass spectrometric metabolome analyses will be used for assessing fecal metabolites before and after intervention.	From randomization (month 0) to 12 months
Other	Skeletal muscle quality assesment	An explorative analysis of skeletal muscle quality including MRI with Dixon method, fiber CSA and type composition, tissue vascularity, morphology and architecture of skeletal muscle biopsy taken from vastus lateralis.	From randomization (month 0) to 12 months
Other	Explorative analysis of adipose tissue	Measurement of enzymes involved in lipid storage. FACS to examine the cellular composition of the adipose tissue sample and to allow downstream PCR analysis of DNA/RNA or western blot analysis of proteins from specific cell populations or from non-sorted biopsy material.	From randomization (month 0) to 12 months
Other	Explorative analysis of skeletal muscle tissue	FACS to examine the cellular composition and to allow downstream PCR analysis of DNA/RNA or western blot analysis of proteins from specific cell populations or from non-sorted biopsy material. RNA sequencing, and protein content will be assessed as metabolomics and proteomics by mass-spectrometry.	From randomization (month 0) to 12 months
Other	Whole body metabolism	Changes in circulating metabolic markers	From randomization (month 0) to 12 months
Other	Muscle metabolism	Changes in metabolic signature of muscle tissue assessed by liquid chromatography-high-resolution mass spectrometry	From randomization (month 0) to 12 months
Other	Skeletal muscle satellite cell (MuSC) proliferation assays	Proliferation and differentiation analysis in cell numbers and cell viability of MuSC	From randomization (month 0) to 12 months
Primary	Change in left ventricular mass	Measured with Cardiac Magnetic Resonance Imaging (CMR).	From randomization (month 0) to 12 months
Primary	Change in appendicular lean mass and ALM index	Appendicular lean mass and ALM index (Appendicular lean mass/height^2). Measured by a whole-body dual-energy X ray absorptiometry (DXA) scan.	From randomization (month 0) to 12 months
Primary	Change in High-sensitivity C-reactive Protein (hs-CRP)	Measured from blood samples.	From randomization (month 0) to 12 months
Primary	Change in Physical performance, peak oxygen consumption (VO2max)	Measured by cardiopulmonary exercise capacity (CPET) will be performed using a cycle ergometer test. Peak oxygen uptake measured in ml O2/kg/min.	From randomization (month 0) to 12 months
Secondary	Muscle strength, Handgrip strength	Hand-held dynamometer for measuring handgrip strength in kilograms.	From randomization (month 0) to 12 months
Secondary	Muscle strength, Knee-extension/flexion strength	Change in knee extension and flexion isokinetic strength (assessed by peak torque, Nm) and isometric strength (assessed by peak torque, Nm).	From randomization (month 0) to 12 months
Secondary	Physical performance, 6 minute walk test (6MWT)	Change in walking distance in meters.	From randomization (month 0) to 12 months
Secondary	Physical performance, 30 seconds sit to stand test	Change in counts of sit to stand.	From randomization (month 0) to 12 months
Secondary	The Short Physical Performance Battery	Changes in points.	From randomization (month 0) to 12 months
Secondary	Skeletal muscle mass	Thigh muscle mass by Magnetic Resonance Imaging (MRI) using Dixon method.	From randomization (month 0) to 12 months
Secondary	Skeletal muscle cross sectional area (CSA) of fibers	CSA of fibers by cryosection of skeletal muscle biopsy obtained from vastus lateralis muscle.	From randomization (month 0) to 12 months
Secondary	Skeletal muscle tissue fiber composition	Change in ratio between muscle fiber types (type I, IIa and IIb) assessed by immunohistochemistry.	From randomization (month 0) to 12 months
Secondary	Skeletal muscle tissue cellular composition	Change in muscle tissue cellular composition assessed by cell sorting	From randomization (month 0) to 12 months
Secondary	Skeletal muscle mitochondrial function	Change in muscle mitochondrial function assessed by high-resolution respirometry	From randomization (month 0) to 12 months
Secondary	Total lean body mass	Change in lean body mass (in grams) and total lean mass/height^2.	From randomization (month 0) to 12 months
Secondary	Total body fat percentage	Changes in body fat percentage.	From randomization (month 0) to 12 months
Secondary	Estimated visceral adipose tissue	Change in VAT index (kilogram-per-meters-squared index) and in mass (in grams).	From randomization (month 0) to 12 months
Secondary	Intramuscular and intermuscular fat content	Calculating thigh adipose tissue mass located between and within muscle fibers by MRI Dixon method.	From randomization (month 0) to 12 months
Secondary	Free fatty acids	Measured from blood samples.	From randomization (month 0) to 12 months
Secondary	Insulin resistance	Changes in insulin resistance assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR).	From randomization (month 0) to 12 months
Secondary	Markers of autophagy	Proteomics of skeletal muscle tissue and peripheral blood mononuclear cells (PBMCs).	From randomization (month 0) to 12 months
Secondary	Polyamine content in muscle biopsy	Measured with liquid chromatography mass spectrometry (LC-MS).	From randomization (month 0) to 12 months
Secondary	Polyamine content in blood	Plasma samples obtained from blood. Measured with liquid chromatography mass spectrometry (LC-MS).	From randomization (month 0) to 12 months
Secondary	Change in 24-hour ambulatory blood pressure measurements (24h ABPM)	Measured with the Spacelabs Healthcare 90217A device in an out-of-hospital setting.	From randomization (month 0) to 12 months
Secondary	Change in central blood pressure	Measured noninvasive with pulse wave analysis (PWA) using a SphygmoCor system.	From randomization (month 0) to 12 months
Secondary	Change in daily physical activity	Assessed by 14-day activity monitoring with an accelerometer (AX3, Axivity).	From randomization (month 0) to 12 months
Secondary	Change in cardiac extracellular volume fraction	Assessed using Cardiac Magnetic Resonance Imaging (CMR) with intravenous gadolinium-based agent.	From randomization (month 0) to 12 months
Secondary	Change in myocardial strain	Assessed using Cardiac Magnetic Resonance Imaging (CMR) with intravenous gadolinium-based agent.	From randomization (month 0) to 12 months
Secondary	Change in Carotid-femoral pulse wave velocity	Measured non-invasively through applanation tonometry using a SphygmoCor system. The unit of measure is m/s.	From randomization (month 0) to 12 months
Secondary	Change in Aortic pulse wave velocity	Magnetic resonance imaging (MRI) assessment. The unit of measure is m/s.	From randomization (month 0) to 12 months
Secondary	Change in general cognitive function and memory performance	Evaluated using the Montreal Cognitive Assessment (MoCA). It will be administered in a clinical setting using a tablet. MoCA score ranges from 0-30 and a score of 26 or higher is considered normal.	From randomization (month 0) to 12 months
Secondary	Change in specific domains of cognitive function	Evaluated using Cambridge Cognition (CANTAB) digital assessment software in a clinical setting using a tablet. The cognitive tests are MOT, RTI, SWM, DMS and PAL. These tests will objectively measure psychomotor speed, executive function and memory.	From randomization (month 0) to 12 months
Secondary	HeartQol	HeartQol measures health-related quality of life (HRQL) and is a disease-specific health status instrument for ischemic heart disease. It consists of 14 items and provides two subscales; a 10-item physical subscale and a 4-item emotional subscale, which are scored on a four-point Likert scale (0 to 3). Higher scores indicate a better HRQL. Measured as global, physical and emotional score.	From randomization (month 0) to 12 months
Secondary	Cytokines	Changes in cytokines are evaluated through the utilization of multiplex cytokine assays. Measured from plasma blood samples.	From randomization (month 0) to 12 months
Secondary	White blood cells	Changes in white blood cell differential count.	From randomization (month 0) to 12 months
Secondary	Immune cells	Changes in specific immune cell populations are measured using peripheral blood mononuclear cells (PBMCs) isolated from blood samples.	From randomization (month 0) to 12 months
Secondary	Vascular inflammatory markers	Measured from plasma blood samples with a multiplex assay.	From randomization (month 0) to 12 months
Secondary	Time to first occurrence of Composite cardiovascular endpoint: Cardiovascular death, heart failure hospitalizations, non-fatal myocardial infarction, non-fatal stroke, and coronary revascularization	Measured in months.	From randomization (month 0) to 12 months
Secondary	Days alive and out of hospital	Measured in months.	From randomization (month 0) to 12 months