Polyamine Treatment in Elderly Patients with Coronary Artery Disease

Phase 2

Recruiting

• Conditions: Diastolic Dysfunction; Metabolic Syndrome; Cardiovascular Diseases; Hypertensive Heart Disease; Hypertension; Obesity; Inflammation; Cognition Disorder; Ischemic Heart Disease; Myocardial Infarction
• Interventions: Dietary Supplement: Spermidine; Other: Placebo

• Registration Number: NCT06186102
• Lead Sponsor: University of Aarhus

Brief 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.

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 Timeline

• Study First Submitted: 2023-12-07
• Study First Submitted QC: 2023-12-15
• Study First Posted: 2023-12-29
• Study Start: 2024-01-01
• Status Verified: 2024-11
• Last Update Submitted: 2025-02-06
• Last Update Posted: 2025-02-10
• Primary Completion: 2026-07
• Study Completion: 2027-01

Recruitment & Eligibility

• Status: RECRUITING
• Sex: All
• Target Recruitment: 180

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 & Design

• Study Type: INTERVENTIONAL
• Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Spermidine	Spermidine	Spermidine will be given orally as capsules of cellulose with spermidine (24 mg/day) and rice flour.
Placebo	Placebo	Placebo will be given orally as capsules of cellulose and rice flour (same size and visual appearance as spermidine capsules)

Primary Outcome Measures

Name	Time	Method
Change in left ventricular mass	From randomization (month 0) to 12 months	Measured with Cardiac Magnetic Resonance Imaging (CMR).
Change in appendicular lean mass and ALM index	From randomization (month 0) to 12 months	Appendicular lean mass and ALM index (Appendicular lean mass/height\^2). Measured by a whole-body dual-energy X ray absorptiometry (DXA) scan.
Change in Physical performance, peak oxygen consumption (VO2max)	From randomization (month 0) to 12 months	Measured by cardiopulmonary exercise capacity (CPET) will be performed using a cycle ergometer test. Peak oxygen uptake measured in ml O2/kg/min.
Change in High-sensitivity C-reactive Protein (hs-CRP)	From randomization (month 0) to 12 months	Measured from blood samples.

Secondary Outcome Measures

Name	Time	Method
Muscle strength, Handgrip strength	From randomization (month 0) to 12 months	Hand-held dynamometer for measuring handgrip strength in kilograms.
Skeletal muscle mass	From randomization (month 0) to 12 months	Thigh muscle mass by Magnetic Resonance Imaging (MRI) using Dixon method.
Skeletal muscle tissue cellular composition	From randomization (month 0) to 12 months	Change in muscle tissue cellular composition assessed by cell sorting
Physical performance, 30 seconds sit to stand test	From randomization (month 0) to 12 months	Change in counts of sit to stand.
Estimated visceral adipose tissue	From randomization (month 0) to 12 months	Change in VAT index (kilogram-per-meters-squared index) and in mass (in grams).
Insulin resistance	From randomization (month 0) to 12 months	Changes in insulin resistance assessed by Homeostatic Model Assessment for Insulin Resistance (HOMA-IR).
Polyamine content in muscle biopsy	From randomization (month 0) to 12 months	Measured with liquid chromatography mass spectrometry (LC-MS).
Change in central blood pressure	From randomization (month 0) to 12 months	Measured noninvasive with pulse wave analysis (PWA) using a SphygmoCor system.
Change in myocardial strain	From randomization (month 0) to 12 months	Assessed using Cardiac Magnetic Resonance Imaging (CMR) with intravenous gadolinium-based agent.
HeartQol	From randomization (month 0) to 12 months	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.
White blood cells	From randomization (month 0) to 12 months	Changes in white blood cell differential count.
Days alive and out of hospital	From randomization (month 0) to 12 months	Measured in months.
The Short Physical Performance Battery	From randomization (month 0) to 12 months	Changes in points.
Skeletal muscle cross sectional area (CSA) of fibers	From randomization (month 0) to 12 months	CSA of fibers by cryosection of skeletal muscle biopsy obtained from vastus lateralis muscle.
Skeletal muscle mitochondrial function	From randomization (month 0) to 12 months	Change in muscle mitochondrial function assessed by high-resolution respirometry
Markers of autophagy	From randomization (month 0) to 12 months	Proteomics of skeletal muscle tissue and peripheral blood mononuclear cells (PBMCs).
Change in 24-hour ambulatory blood pressure measurements (24h ABPM)	From randomization (month 0) to 12 months	Measured with the Spacelabs Healthcare 90217A device in an out-of-hospital setting.
Physical performance, 6 minute walk test (6MWT)	From randomization (month 0) to 12 months	Change in walking distance in meters.
Muscle strength, Knee-extension/flexion strength	From randomization (month 0) to 12 months	Change in knee extension and flexion isokinetic strength (assessed by peak torque, Nm) and isometric strength (assessed by peak torque, Nm).
Intramuscular and intermuscular fat content	From randomization (month 0) to 12 months	Calculating thigh adipose tissue mass located between and within muscle fibers by MRI Dixon method.
Free fatty acids	From randomization (month 0) to 12 months	Measured from blood samples.
Change in Aortic pulse wave velocity	From randomization (month 0) to 12 months	Magnetic resonance imaging (MRI) assessment. The unit of measure is m/s.
Change in general cognitive function and memory performance	From randomization (month 0) to 12 months	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.
Cytokines	From randomization (month 0) to 12 months	Changes in cytokines are evaluated through the utilization of multiplex cytokine assays. Measured from plasma blood samples.
Immune cells	From randomization (month 0) to 12 months	Changes in specific immune cell populations are measured using peripheral blood mononuclear cells (PBMCs) isolated from blood samples.
Skeletal muscle tissue fiber composition	From randomization (month 0) to 12 months	Change in ratio between muscle fiber types (type I, IIa and IIb) assessed by immunohistochemistry.
Total lean body mass	From randomization (month 0) to 12 months	Change in lean body mass (in grams) and total lean mass/height\^2.
Total body fat percentage	From randomization (month 0) to 12 months	Changes in body fat percentage.
Change in specific domains of cognitive function	From randomization (month 0) to 12 months	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.
Vascular inflammatory markers	From randomization (month 0) to 12 months	Measured from plasma blood samples with a multiplex assay.
Polyamine content in blood	From randomization (month 0) to 12 months	Plasma samples obtained from blood. Measured with liquid chromatography mass spectrometry (LC-MS).
Change in daily physical activity	From randomization (month 0) to 12 months	Assessed by 14-day activity monitoring with an accelerometer (AX3, Axivity).
Change in cardiac extracellular volume fraction	From randomization (month 0) to 12 months	Assessed using Cardiac Magnetic Resonance Imaging (CMR) with intravenous gadolinium-based agent.
Change in Carotid-femoral pulse wave velocity	From randomization (month 0) to 12 months	Measured non-invasively through applanation tonometry using a SphygmoCor system. The unit of measure is m/s.
Time to first occurrence of Composite cardiovascular endpoint: Cardiovascular death, heart failure hospitalizations, non-fatal myocardial infarction, non-fatal stroke, and coronary revascularization	From randomization (month 0) to 12 months	Measured in months.

Trial Locations

Locations (1)

Aarhus University Hospital; 🇩🇰 Aarhus, Jutland, Denmark