Supplementation for Male Subfertility

Male Infertility Clinical Trial

— FertEnhancer  

Official title:

Nutraceutical Supplementation for Male Subfertility

Clinical Trial Details — Status: Not yet recruiting

Administrative data

• NCT number: NCT06091969
• Other study ID #: 16502
• Status: Not yet recruiting
• Phase: Phase 2
• Start date: February 2, 2024
• Est. completion date: February 2, 2025

Study information

• Verified date: November 2023
• Source: McMaster University
• Contact: Mark A Tarnopolsky, PhD
• Phone: 9055212100
• Email: tarnopol[@]mcmaster.ca
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Old age, physical inactivity, environmental factors and genetics may contribute negatively to fertility in both males and females. In males, specifically, certain supplements, such as single antioxidants and trace minerals, have previously been shown to improve sperm function marginally. One hypothesis is that sperm function can be improved even further by combining several different types of supplements (e.g., amino acids, energy carriers, vitamins, antioxidants, and trace minerals) to target several age-related cell pathways, for example, oxidative stress, mitochondrial dysfunction, inflammation and cell energetics. This 3-month placebo-controlled, randomized clinical trial, aims to test the effects of a novel multi-ingredient supplement (Fertility Enhancer) that targets several age-related cell pathways on sperm function in subfertile males.

Description:

BACKGROUND: Infertility is characterized by the failure to become pregnant after one year of regular intercourse without the use of contraceptives and impacts 10-15% of couples worldwide. Both male and female partners contribute to a couple's reproductive health, with approximately one third of infertility cases caused by male factors, one third by female factors, and the remaining by either a combination of both or unknown causes. The prevalence of infertility is a growing concern in Canada, as is seen in an increased use of assisted reproductive technology (ART), which may be both invasive and expensive. Cost-effective, safe, and accessible alternatives to ART are therefore needed. The most common cause of subfertility is 'biological aging', characterized by the hallmarks of aging, such as mitochondrial dysfunction, oxidative damage and inflammation. PURPOSE: The aim of this placebo-controlled, double-blind randomized clinical trial is to test the effects of a multi-ingredient supplement (Fertility Enhancer) designed to target several age-related pathways on World Health Organization (WHO) semen quality parameters in subfertile males (sperm count, motility, morphology and vitality). SAMPLE-SIZE ESTIMATE AND DESIGN: Sperm count/concentration is strongly correlated to all World Health Organization semen quality parameters. With significance set at 0.05 (Z = 1.96) and power to 0.8 (Z = 0.84), a sample-size of 17-32 per group is sufficient to detect an increase of 10 x 10^6 spermatozoa/mL with a standard deviation of 15 to 20 x 10^6 spermatozoa/mL. Thus, sixty-four (n = 64) males between 25 and 50 years of age with confirmed subfertility will be randomized into age-matched Placebo (PLA, n = 32) vs Fertility Enhancer (FE, n = 32) groups and undergo daily supplementation for 3 months. SUPPLEMENTS: The FE supplement contains energy carriers (creatine), conditionally essential amino acids (arginine), Omega 3 fatty acids (DHA and EPA), vitamins (B9, B12, E, and D3), antioxidants (CoQ10 and alpha lipoic acid), trace minerals (selenium, iron, zinc, and copper), and plant extracts (beet root, green tea, and green coffee bean). The isocaloric and inactive placebo contains safflower oil, microcrystalline cellulose and sugar and is identical in flavor to FE. CO-PRIMARY OUTCOMES: All outcomes will be measured at baseline and post intervention for assessing % pre-to-post changes. Co-primary outcomes are body composition by dual x-ray absorptiometry, including lean mass to fat mass ratio (body composition index; BCI) and total fat mass, and the WHO semen quality parameters; specifically, % improvements in sperm count, motility, morphology, and vitality. SECONDARY OUTCOMES: Secondary outcomes are % improvements in sperm DNA fragmentation (flow cytometry-assessed) and markers of oxidative damage (protein carbonyls, lipid peroxidation, 8-hydroxydeoxyguanosine)), inflammation (interleukin-1, tumor necrosis factor-alpha, interleukin-6), apoptosis (total and cleaved caspase 3), cell cycle arrest (p16 and p21), mitochondrial biogenesis (complexes I-V), antioxidant status (superoxide dismutases 1 and 2), and energy state (ATP and phosphocreatine). OTHER: Additional outcomes are body morphology (bodyweight, waist/height ratio, and body mass index), other body composition outcomes (lean mass and appendicular skeletal muscle mass index), and blood markers of oxidative damage (malondialdehyde), inflammation (c-reactive protein, interleukin-1, tumor necrosis factor-alpha, interleukin-6), antioxidant status (ORAC, TEAC), liver enzymes (alanine aminotransferase, aspartate aminotransferase, and creatinine) and energy state (ATP & phosphocreatine levels). HYPOTHESIS: The main hypothesis of the current trial is that co-primary body composition outcomes and the World Health Organization (WHO) semen quality parameters (count, motility, morphology, and/or vitality) will be significantly improved following FE supplementation and superior to PLA. STATISTICS: A standard omnibus one-way repeated measures ANOVA F-test followed by Duncan post hoc analyses will be used for all parametric data analyses. Non-parametric equivalents will be used for non-normally distributed data with significance set at p = 0.05. Delta pre-post changes (% improvements) for all outcomes within and between groups are biologically relevant and planned a priori comparisons.

Recruitment information / eligibility

• Status: Not yet recruiting
• Enrollment: 64
• Est. completion date: February 2, 2025
• Est. primary completion date: February 2, 2025
• Accepts healthy volunteers: Accepts Healthy Volunteers
• Gender: Male
• Age group: 25 Years to 50 Years

Eligibility

Inclusion Criteria:

• Males between the ages of 25-50 years diagnosed with subfertility through Ontario Networks of Experts in Fertility (ONE Fertility, Burlington, ON).
• For diagnosis of male subfertility, the 2010 and 2021 World Health Organization criteria will be used for sperm count, motility, morphology and vitality.

Exclusion Criteria:

• Smoking,
• history and drug alcohol abuse,
• BMI > 30 kg/m2,
• genital disease (cryptorchidism, current genital inflammation, or varicocele),
• genital trauma or surgery to the male reproductive system,
• known Y chromosome microdeletions or karyotype abnormalities (if known prior),
• hepatobiliary disease,
• significant renal insufficiency,
• occupational exposures to reproductive toxins,
• endocrine abnormality,
• recent or current sexually transmitted infection,
• use of cytotoxic drugs,
• use of immunosuppressants,
• use of anticonvulsants,
• use of androgens or antiandrogens,
• history of central nervous system injury,
• neurological or psychiatric disease to potentially compromise study data collection,
• treatment of erectile dysfunction with any drugs during the past 4 weeks,
• history of cancer chemotherapy,
• current supplementation with ingredients being tested unless 1-month washout period

Related Conditions & MeSH terms

• Infertility
• Infertility, Male
• Male Infertility

Intervention

Dietary Supplement:
• Active multi-ingredient supplement (Fertility Enhancer, FE)
Consuming a multi-ingredient supplement targeting multiple cell pathways daily for 3 months.
• Inactive placebo (Placebo; PLA)
Consuming an inactive placebo that is calorie-matched to the active supplement daily for 3 months.

Locations

Country	Name	City	State
Canada	Mark Tarnopololsky	Hamilton	Ontario

Sponsors (2)

Lead Sponsor	Collaborator
Hamilton Health Sciences Corporation	One Fertility

Country where clinical trial is conducted

Canada, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Percent change in bodyweight from baseline to 3 months	Bodyweight by standard scale (kg; %)	Baseline to 3 months
Other	Percent change in body mass index from baseline to 3 months	Body mass index (BMI) (bodyweight/height squared; kg/m2; %)	Baseline to 3 months
Other	Percent change in lean mass from baseline to 3 months	Lean mass by dual X-ray absorptiometry scan (kg; %)	Baseline to 3 months
Other	Percent change in appendicular skeletal muscle mass from baseline to 3 months	Appendicular skeletal muscle mass by dual X-ray absorptiometry scan (kg; %)	Baseline to 3 months
Other	Percent change in appendicular skeletal muscle mass index from baseline to 3 months	Appendicular skeletal muscle mass index by dual X-ray absorptiometry scan (kg/height squared; %)	Baseline to 3 months
Other	Percent change in liver enzyme ALT from baseline to 3 months	Serum alanine aminotransferase levels (IU/L; %)	Baseline to 3 months
Other	Percent change in liver enzyme AST from baseline to 3 months	Serum aspartate aminotransferase levels (IU/L; %)	Baseline to 3 months
Other	Percent change in liver enzyme creatinine from baseline to 3 months	Serum creatinine levels (mg/dL; %)	Baseline to 3 months
Other	Percent change in malondialdehyde levels from baseline to 3 months	Plasma malondialdehyde levels (uM; %)	Baseline to 3 months
Other	Percent change in Oxygen Radical Absorbance Levels (ORAC) from baseline to 3 months	Plasma Oxygen Radical Absorbance Levels (ORAC units; %)	Baseline to 3 months
Other	Percent change in Trolox Equivalent Antioxidant Capacity (TEAC) from baseline to 3 months	Serum Trolox Equivalent Antioxidant Capacity (mM; %)	Baseline to 3 months
Other	Percent change in inflammatory cytokine interleukin-1 from baseline to 3 months	Serum interleukin 1 levels (pg/mL; %)	Baseline to 3 months
Other	Percent change in inflammatory cytokine interleukin-6 from baseline to 3 months	Serum interleukin-6 levels (pg/mL; %)	Baseline to 3 months
Other	Percent change in inflammatory cytokine TNF-alpha from baseline to 3 months	Serum TNF-alpha levels (pg/mL)	Baseline to 3 months
Other	Percent change in inflammatory marker c-reactive protein from baseline to 3 months	Serum c-reactive protein levels (mg/dL; %)	Baseline to 3 months
Other	Percent change in ATP levels from baseline to 3 months	Plasma ATP levels (mmol/L; %)	Baseline to 3 months
Other	Percent change in phosphocreatine levels from baseline to 3 months	Plasma phosphocreatine levels (mmol/L; %)	Baseline to 3 months
Primary	Percent change in body composition index from baseline to 3 months	Lean mass/fat mass ratio by dual X-ray absorptiometry scan (body composition index; % change)	Baseline to 3 months
Primary	Percent change in total fat mass from baseline to 3 months	Total fat mass by dual X-ray absorptiometry scan (kg; % change)	Baseline to 3 months
Primary	Percent change in sperm count/concentration from baseline to 3 months	Sperm count/concentration (millions spermatozoa/mL semen)	Baseline to 3 months
Primary	Percent change in sperm motility from baseline to 3 months	Proportion motile sperm (%)	Baseline to 3 months
Primary	Percent change in sperm morphology from baseline to 3 months	Proportion normal sperm morphology (%)	Baseline to 3 months
Primary	Percent change in sperm vitality from baseline to 3 months	Proportion viable sperm (vitality) (%)	Baseline to 3 months
Secondary	Percent change in sperm DNA fragmentation index from baseline to 3 months	Sperm DNA fragmentation index by flow cytometry (%)	Baseline to 3 months
Secondary	Percent change in sperm DNA 8-hydroxydeoxyguanosine from baseline to 3 months	Sperm DNA 8-hydroxydeoxyguanosine by ELISA (ng/mL; %)	Baseline to 3 months
Secondary	Percent change in sperm protein carbonyls from baseline to 3 months	Sperm protein carbonyls immunoblot (optical density; %)	Baseline to 3 months
Secondary	Percent change in sperm lipid peroxidation (4-hydroxynonenal) from baseline to 3 months	Sperm 4-hydroxynonenal immunoblot (optical density; %)	Baseline to 3 months
Secondary	Percent change in sperm antioxidant marker superoxide dismutase 1 from baseline to 3 months	Sperm superoxide dismutase 1 expression immunoblot (optical density; %)	Baseline to 3 months
Secondary	Percent change in sperm antioxidant marker superoxide dismutase 2 from baseline to 3 months	Sperm superoxide dismutase 2 expression immunoblot (optical density; %)	Baseline to 3 months
Secondary	Percent change in sperm apoptotic marker cleaved caspase 3 from baseline to 3 months	Sperm cleaved caspase 3 expression immunoblot (optical density; %)	Baseline to 3 months
Secondary	Percent change in sperm apoptotic marker total caspase 3 from baseline to 3 months	Sperm total caspase 3 expression immunoblot (optical density; %)	Baseline to 3 months
Secondary	Percent change in sperm mitochondrial OXPHOS from baseline to 3 months	Sperm mitochondrial OXPHOS expression immunoblot (optical density; %)	Baseline to 3 months
Secondary	Percent change in sperm cell cycle arrest marker p16 from baseline to 3 months	Sperm p16 messenger RNA levels by rtPCR (fold control/placebo; %)	Baseline to 3 months
Secondary	Percent change in sperm cell cycle arrest marker p21 from baseline to 3 months	Sperm p21 messenger RNA levels by rtPCR (fold control/placebo; %)	Baseline to 3 months
Secondary	Percent change in sperm inflammatory marker interleukin 1 from baseline to 3 months	Sperm interleukin 1 messenger RNA levels by rtPCR (fold control/placebo; %)	Baseline to 3 months
Secondary	Percent change in sperm inflammatory marker TNF-alpha from baseline to 3 months	Sperm TNF-alpha messenger RNA levels by rtPCR (fold control/placebo; %)	Baseline to 3 months
Secondary	Percent change in sperm inflammatory marker interleukin-6 from baseline to 3 months	Sperm interleukin-6 messenger RNA levels by rtPCR (fold control/placebo; %)	Baseline to 3 months
Secondary	Percent change in sperm inflammatory marker interleukin-8 from baseline to 3 months	Sperm interleukin-8 messenger RNA levels by rtPCR (fold control/placebo; %)	Baseline to 3 months
Secondary	Percent change in sperm inflammatory marker interleukin-18 from baseline to 3 months	Sperm interleukin-18 messenger RNA levels by rtPCR (fold control/placebo; %)	Baseline to 3 months
Secondary	Percent change in sperm inflammasome marker caspase 1 from baseline to 3 months	Sperm caspase 1 messenger RNA levels by rtPCR (fold control/placebo; %)	Baseline to 3 months
Secondary	Percent change in sperm ATP levels from baseline to 3 months	Sperm ATP levels by ELISA (pM/100 mg protein; %)	Baseline to 3 months
Secondary	Percent change in sperm phosphocreatine levels from baseline to 3 months	Sperm phosphocreatine levels by ELISA (ng/100 mg protein; %)	Baseline to 3 months