Polyamine Treatment in Elderly Patients With Coronary Artery Disease (PolyCAD)

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

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.

Study Overview

• Status: Active, not recruiting
• Conditions: Myocardial Infarction; Cardiovascular Diseases; Quality of Life; Inflammation; Hypertension; Obesity; Diabetes Mellitus, Type 2; Cognitive Impairment; Metabolic Syndrome; Ischemic Heart Disease; Dietary Habits; Diastolic Dysfunction; Cognition Disorder; Hypertensive Heart Disease
• Intervention / Treatment: Dietary supplement: Spermidine; Other: Placebo

Detailed 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 200 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.

• Study Type: Interventional
• Enrollment (Estimated): 180
• Phase: Phase 2

Contacts and Locations

Study Locations

• Denmark
  • Jutland
    • Aarhus, Jutland, Denmark, 8200
      • Aarhus University Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Older Adult
• Accepts Healthy Volunteers: No

Description

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)

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo; Placebo will be given orally as capsules of cellulose and rice flour (same size and visual appearance as spermidine capsules)	Other: Placebo; Placebo capsule. 3 capsules daily.
Active Comparator: Spermidine; Spermidine will be given orally as capsules of cellulose with spermidine (24 mg/day) and rice flour.	Dietary supplement: Spermidine; Spermidine capsule of 8 mg x 3 capsules daily.; Other Names: Polyamine

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change in left ventricular mass	Measured with Cardiac Magnetic Resonance Imaging (CMR).	From randomization (month 0) to 12 months
Change in High-sensitivity C-reactive Protein (hs-CRP)	Measured from blood samples.	From randomization (month 0) to 12 months
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
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Free fatty acids	Measured from blood samples.	From randomization (month 0) to 12 months
Polyamine content in muscle biopsy	Measured with liquid chromatography mass spectrometry (LC-MS).	From randomization (month 0) to 12 months
Polyamine content in blood	Plasma samples obtained from blood. Measured with liquid chromatography mass spectrometry (LC-MS).	From randomization (month 0) to 12 months
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
Change in daily physical activity	Assessed by 14-day activity monitoring with an accelerometer (AX3, Axivity).	From randomization (month 0) to 12 months
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
Change in myocardial strain	Assessed using Cardiac Magnetic Resonance Imaging (CMR) with intravenous gadolinium-based agent.	From randomization (month 0) to 12 months
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
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
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
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
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
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
White blood cells	Changes in white blood cell differential count.	From randomization (month 0) to 12 months
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
Vascular inflammatory markers	Measured from plasma blood samples with a multiplex assay.	From randomization (month 0) to 12 months
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
Days alive and out of hospital	Measured in months.	From randomization (month 0) to 12 months
Muscle strength, Handgrip strength	Hand-held dynamometer for measuring handgrip strength in kilograms.	From randomization (month 0) to 12 months
Physical performance, 6 minute walk test (6MWT)	Change in walking distance in meters.	From randomization (month 0) to 12 months
Physical performance, 30 seconds sit to stand test	Change in counts of sit to stand.	From randomization (month 0) to 12 months
The Short Physical Performance Battery	Changes in points.	From randomization (month 0) to 12 months
Skeletal muscle mass	Thigh muscle mass by Magnetic Resonance Imaging (MRI) using Dixon method.	From randomization (month 0) to 12 months
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
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
Skeletal muscle tissue cellular composition	Change in muscle tissue cellular composition assessed by cell sorting	From randomization (month 0) to 12 months
Skeletal muscle mitochondrial function	Change in muscle mitochondrial function assessed by high-resolution respirometry	From randomization (month 0) to 12 months
Total lean body mass	Change in lean body mass (in grams) and total lean mass/height^2.	From randomization (month 0) to 12 months
Total body fat percentage	Changes in body fat percentage.	From randomization (month 0) to 12 months
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
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
Insulin resistance	Changes in insulin resistance assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR).	From randomization (month 0) to 12 months
Markers of autophagy	Proteomics of skeletal muscle tissue and peripheral blood mononuclear cells (PBMCs).	From randomization (month 0) to 12 months
Change in central blood pressure	Measured noninvasive with pulse wave analysis (PWA) using a SphygmoCor system.	From randomization (month 0) to 12 months
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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
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
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
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
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
Whole body metabolism	Changes in circulating metabolic markers	From randomization (month 0) to 12 months
Muscle metabolism	Changes in metabolic signature of muscle tissue assessed by liquid chromatography-high-resolution mass spectrometry	From randomization (month 0) to 12 months
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
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

Collaborators and Investigators

• Sponsor: University of Aarhus
• Collaborators: Danish Cardiovascular Academy (DCA); Danish Diabetes Academy; Sygesikringen Danmark; Steno Diabetes Center Aarhus (SDCA), Aarhus University Hospital; Eva and Henry Frænkels Mindefond; DoNotAge.org
• Investigators: Principal Investigator: Henrik Wiggers, DMSC PHD MD, Dept. of Cardiology, Aarhus University Hospital

Publications and helpful links

General Publications

• Thorup CV, Jeppesen CNA, Jensen TH, Tinggaard AB, Hvas CL, Rud CL, Skou MK, Mortensen JK, Reggiori F, Dengjel J, Wang J, Farup J, Jessen N, Kim WY, Wiggers H. POLYamine treatment in elderly patients with Coronary Artery Disease (POLYCAD): study protocol for a Danish randomised, double-blind, placebo-controlled trial of spermidine treatment versus placebo. Trials. 2025 Oct 30;26(1):452. doi: 10.1186/s13063-025-09176-z.

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2024
• Primary Completion (Estimated): July 1, 2026
• Study Completion (Estimated): January 1, 2027

Study Registration Dates

• First Submitted: December 7, 2023
• First Submitted That Met QC Criteria: December 15, 2023
• First Posted (Actual): December 29, 2023

Study Record Updates

• Last Update Posted (Actual): November 18, 2025
• Last Update Submitted That Met QC Criteria: November 14, 2025
• Last Verified: November 1, 2024

More Information

Terms related to this study

• Keywords: Treatment; Cardiovascular disease; Inflammation; Obesity; Insulin resistance; Coronary artery disease; Hypertension; Dietary supplement; Quality of life; Prevention; Memory; Cognitive function; Diabetes Mellitus, Type 2; Heart disease; Lifestyle; Autophagy; Ischemic heart disease; Spermidine; Polyamine
• Additional Relevant MeSH Terms: Endocrine System Diseases; Vascular Diseases; Mental Disorders; Pathologic Processes; Nutrition Disorders; Metabolic Diseases; Overnutrition; Body Weight; Neurocognitive Disorders; Glucose Metabolism Disorders; Diabetes Mellitus; Infarction; Necrosis; Hyperinsulinism; Overweight; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Ischemia; Pathological Conditions, Signs and Symptoms; Behavior; Nutritional and Metabolic Diseases; Signs and Symptoms; Behavior, Animal; Obesity; Hypertension; Cognitive Dysfunction; Diabetes Mellitus, Type 2; Cardiovascular Diseases; Metabolic Syndrome; Inflammation; Heart Diseases; Coronary Artery Disease; Insulin Resistance; Myocardial Ischemia; Myocardial Infarction; Cognition Disorders; Feeding Behavior; Organic Chemicals; Amines; Biogenic Amines; Putrescine; Biogenic Polyamines; Spermidine; Polyamines
• Other Study ID Numbers: M-2023-71-23

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