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Clinical Trial Details — Status: Recruiting

Administrative data

NCT number NCT06186102
Other study ID # M-2023-71-23
Secondary ID
Status Recruiting
Phase Phase 2
First received
Last updated
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
Health authority
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 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.


Recruitment information / eligibility

Status Recruiting
Enrollment 180
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)

Study Design


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
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