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Supplementation for Male Subfertility (FertEnhancer)

Primary Purpose

Male Infertility

Status
Not yet recruiting
Phase
Phase 2
Locations
Canada
Study Type
Interventional
Intervention
Active multi-ingredient supplement (Fertility Enhancer, FE)
Inactive placebo (Placebo; PLA)
Sponsored by
Hamilton Health Sciences Corporation
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Male Infertility focused on measuring Sub-fertility, Infertility, Antioxidants, Supplements, Creatine, Arginine, Vitamins, Aging, Oxidative stress, Inflammation, DNA, Mitochondria, Fragmentation, ATP

Eligibility Criteria

25 Years - 50 Years (Adult)MaleAccepts Healthy Volunteers

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

Sites / Locations

  • Mark Tarnopololsky

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Active multi-ingredient supplement (Fertility Enhancer; FE)

Inactive placebo (Placebo; PLA)

Arm Description

Volunteers will be randomized in a double-blinded fashion into the experimental treatment group, which entails daily supplementation of an active multi-ingredient supplement designed to enhance fertility (Fertility Enhancer; FE) for 3 months.

Volunteers will be randomized in a double-blinded fashion into a placebo group, which entails daily supplementation of a calorie-matched, inactive placebo (Placebo; PLA) identical in flavor to the active supplement for 3 months.

Outcomes

Primary Outcome Measures

Percent change in sperm count/concentration from baseline to 3 months
Sperm count/concentration (millions spermatozoa/mL semen)
Percent change in sperm motility from baseline to 3 months
Proportion motile sperm (%)
Percent change in sperm morphology from baseline to 3 months
Proportion normal sperm morphology (%)
Percent change in sperm vitality from baseline to 3 months
Proportion viable sperm (vitality) (%)

Secondary Outcome Measures

Percent change in sperm DNA fragmentation index from baseline to 3 months
Sperm DNA fragmentation index by flow cytometry (%)
Percent change in sperm DNA 8-hydroxydeoxyguanosine from baseline to 3 months
Sperm DNA 8-hydroxydeoxyguanosine by ELISA (ng/mL)
Percent change in sperm protein carbonyls from baseline to 3 months
Sperm protein carbonyls immunoblot (optical density)
Percent change in sperm lipid peroxidation (4-hydroxynonenal) from baseline to 3 months
Sperm 4-hydroxynonenal immunoblot (optical density)
Percent change in sperm antioxidant marker superoxide dismutase 1 from baseline to 3 months
Sperm superoxide dismutase 1 expression immunoblot (optical density)
Percent change in sperm antioxidant marker superoxide dismutase 2 from baseline to 3 months
Sperm superoxide dismutase 2 expression immunoblot (optical density)
Percent change in sperm apoptotic marker cleaved caspase 3 from baseline to 3 months
Sperm cleaved caspase 3 expression immunoblot (optical density)
Percent change in sperm apoptotic marker total caspase 3 from baseline to 3 months
Sperm total caspase 3 expression immunoblot (optical density)
Percent change in sperm mitochondrial OXPHOS from baseline to 3 months
Sperm mitochondrial OXPHOS expression immunoblot (optical density)
Percent change in sperm cell cycle arrest marker p16 from baseline to 3 months
Sperm p16 messenger RNA levels by rtPCR (fold control/placebo)
Percent change in sperm cell cycle arrest marker p21 from baseline to 3 months
Sperm p21 messenger RNA levels by rtPCR (fold control/placebo)
Percent change in sperm inflammatory marker interleukin 1 from baseline to 3 months
Sperm interleukin 1 messenger RNA levels by rtPCR (fold control/placebo)
Percent change in sperm inflammatory marker TNF-alpha from baseline to 3 months
Sperm TNF-alpha messenger RNA levels by rtPCR (fold control/placebo)
Percent change in sperm inflammatory marker interleukin-6 from baseline to 3 months
Sperm interleukin-6 messenger RNA levels by rtPCR (fold control/placebo)
Percent change in sperm inflammatory marker interleukin-8 from baseline to 3 months
Sperm interleukin-8 messenger RNA levels by rtPCR (fold control/placebo)
Percent change in sperm inflammatory marker interleukin-18 from baseline to 3 months
Sperm interleukin-18 messenger RNA levels by rtPCR (fold control/placebo)
Percent change in sperm inflammasome marker caspase 1 from baseline to 3 months
Sperm caspase 1 messenger RNA levels by rtPCR (fold control/placebo)
Percent change in sperm ATP levels from baseline to 3 months
Sperm ATP levels by ELISA (pM/100 mg protein)
Percent change in sperm phosphocreatine levels from baseline to 3 months
Sperm phosphocreatine levels by ELISA (ng/100 mg protein)

Full Information

First Posted
October 16, 2023
Last Updated
October 23, 2023
Sponsor
Hamilton Health Sciences Corporation
Collaborators
One Fertility
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1. Study Identification

Unique Protocol Identification Number
NCT06091969
Brief Title
Supplementation for Male Subfertility
Acronym
FertEnhancer
Official Title
Nutraceutical Supplementation for Male Subfertility
Study Type
Interventional

2. Study Status

Record Verification Date
October 2023
Overall Recruitment Status
Not yet recruiting
Study Start Date
February 2, 2024 (Anticipated)
Primary Completion Date
February 2, 2025 (Anticipated)
Study Completion Date
February 2, 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Hamilton Health Sciences Corporation
Collaborators
One Fertility

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes

5. Study Description

Brief 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.
Detailed 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 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: Other outcomes of interest include body morphology (bodyweight and waist/height), body composition by dual X-ray absorptiometry (lean mass, fat mass, lean mass/fat mass) 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 World Health Organization (WHO) semen quality parameters (count, motility, morphology, and 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Male Infertility
Keywords
Sub-fertility, Infertility, Antioxidants, Supplements, Creatine, Arginine, Vitamins, Aging, Oxidative stress, Inflammation, DNA, Mitochondria, Fragmentation, ATP

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 2
Interventional Study Model
Parallel Assignment
Model Description
This is a 3-month placebo-controlled, double-blinded, randomized clinical trial comparing an active supplement designed to enhance sperm function (Fertility Enhancer) to an inactive placebo (PLACEBO) in subfertile males.
Masking
ParticipantCare ProviderInvestigator
Masking Description
Volunteers will be given an identifier number and then randomized into placebo or active groups by an independent third party meaning that all participants, care providers and investigators will be blinded to the treatment allocations until the end of the study.
Allocation
Randomized
Enrollment
64 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Active multi-ingredient supplement (Fertility Enhancer; FE)
Arm Type
Experimental
Arm Description
Volunteers will be randomized in a double-blinded fashion into the experimental treatment group, which entails daily supplementation of an active multi-ingredient supplement designed to enhance fertility (Fertility Enhancer; FE) for 3 months.
Arm Title
Inactive placebo (Placebo; PLA)
Arm Type
Placebo Comparator
Arm Description
Volunteers will be randomized in a double-blinded fashion into a placebo group, which entails daily supplementation of a calorie-matched, inactive placebo (Placebo; PLA) identical in flavor to the active supplement for 3 months.
Intervention Type
Dietary Supplement
Intervention Name(s)
Active multi-ingredient supplement (Fertility Enhancer, FE)
Intervention Description
Consuming a multi-ingredient supplement targeting multiple cell pathways daily for 3 months.
Intervention Type
Dietary Supplement
Intervention Name(s)
Inactive placebo (Placebo; PLA)
Intervention Description
Consuming an inactive placebo that is calorie-matched to the active supplement daily for 3 months.
Primary Outcome Measure Information:
Title
Percent change in sperm count/concentration from baseline to 3 months
Description
Sperm count/concentration (millions spermatozoa/mL semen)
Time Frame
Baseline to 3 months
Title
Percent change in sperm motility from baseline to 3 months
Description
Proportion motile sperm (%)
Time Frame
Baseline to 3 months
Title
Percent change in sperm morphology from baseline to 3 months
Description
Proportion normal sperm morphology (%)
Time Frame
Baseline to 3 months
Title
Percent change in sperm vitality from baseline to 3 months
Description
Proportion viable sperm (vitality) (%)
Time Frame
Baseline to 3 months
Secondary Outcome Measure Information:
Title
Percent change in sperm DNA fragmentation index from baseline to 3 months
Description
Sperm DNA fragmentation index by flow cytometry (%)
Time Frame
Baseline to 3 months
Title
Percent change in sperm DNA 8-hydroxydeoxyguanosine from baseline to 3 months
Description
Sperm DNA 8-hydroxydeoxyguanosine by ELISA (ng/mL)
Time Frame
Baseline to 3 months
Title
Percent change in sperm protein carbonyls from baseline to 3 months
Description
Sperm protein carbonyls immunoblot (optical density)
Time Frame
Baseline to 3 months
Title
Percent change in sperm lipid peroxidation (4-hydroxynonenal) from baseline to 3 months
Description
Sperm 4-hydroxynonenal immunoblot (optical density)
Time Frame
Baseline to 3 months
Title
Percent change in sperm antioxidant marker superoxide dismutase 1 from baseline to 3 months
Description
Sperm superoxide dismutase 1 expression immunoblot (optical density)
Time Frame
Baseline to 3 months
Title
Percent change in sperm antioxidant marker superoxide dismutase 2 from baseline to 3 months
Description
Sperm superoxide dismutase 2 expression immunoblot (optical density)
Time Frame
Baseline to 3 months
Title
Percent change in sperm apoptotic marker cleaved caspase 3 from baseline to 3 months
Description
Sperm cleaved caspase 3 expression immunoblot (optical density)
Time Frame
Baseline to 3 months
Title
Percent change in sperm apoptotic marker total caspase 3 from baseline to 3 months
Description
Sperm total caspase 3 expression immunoblot (optical density)
Time Frame
Baseline to 3 months
Title
Percent change in sperm mitochondrial OXPHOS from baseline to 3 months
Description
Sperm mitochondrial OXPHOS expression immunoblot (optical density)
Time Frame
Baseline to 3 months
Title
Percent change in sperm cell cycle arrest marker p16 from baseline to 3 months
Description
Sperm p16 messenger RNA levels by rtPCR (fold control/placebo)
Time Frame
Baseline to 3 months
Title
Percent change in sperm cell cycle arrest marker p21 from baseline to 3 months
Description
Sperm p21 messenger RNA levels by rtPCR (fold control/placebo)
Time Frame
Baseline to 3 months
Title
Percent change in sperm inflammatory marker interleukin 1 from baseline to 3 months
Description
Sperm interleukin 1 messenger RNA levels by rtPCR (fold control/placebo)
Time Frame
Baseline to 3 months
Title
Percent change in sperm inflammatory marker TNF-alpha from baseline to 3 months
Description
Sperm TNF-alpha messenger RNA levels by rtPCR (fold control/placebo)
Time Frame
Baseline to 3 months
Title
Percent change in sperm inflammatory marker interleukin-6 from baseline to 3 months
Description
Sperm interleukin-6 messenger RNA levels by rtPCR (fold control/placebo)
Time Frame
Baseline to 3 months
Title
Percent change in sperm inflammatory marker interleukin-8 from baseline to 3 months
Description
Sperm interleukin-8 messenger RNA levels by rtPCR (fold control/placebo)
Time Frame
Baseline to 3 months
Title
Percent change in sperm inflammatory marker interleukin-18 from baseline to 3 months
Description
Sperm interleukin-18 messenger RNA levels by rtPCR (fold control/placebo)
Time Frame
Baseline to 3 months
Title
Percent change in sperm inflammasome marker caspase 1 from baseline to 3 months
Description
Sperm caspase 1 messenger RNA levels by rtPCR (fold control/placebo)
Time Frame
Baseline to 3 months
Title
Percent change in sperm ATP levels from baseline to 3 months
Description
Sperm ATP levels by ELISA (pM/100 mg protein)
Time Frame
Baseline to 3 months
Title
Percent change in sperm phosphocreatine levels from baseline to 3 months
Description
Sperm phosphocreatine levels by ELISA (ng/100 mg protein)
Time Frame
Baseline to 3 months
Other Pre-specified Outcome Measures:
Title
Percent change in bodyweight from baseline to 3 months
Description
Bodyweight by standard scale (kg)
Time Frame
Baseline to 3 months
Title
Percent change in total fat mass from baseline to 3 months
Description
Total fat mass by dual X-ray absorptiometry scan (kg)
Time Frame
Baseline to 3 months
Title
Percent change in lean mass from baseline to 3 months
Description
Lean mass by dual X-ray absorptiometry scan (kg)
Time Frame
Baseline to 3 months
Title
Percent change in lean mass/fat mass ratio from baseline to 3 months
Description
Lean mass/fat mass ration by dual X-ray absorptiometry scan (body composition index)
Time Frame
Baseline to 3 months
Title
Percent change in liver enzyme ALT from baseline to 3 months
Description
Serum alanine aminotransferase levels (IU/L)
Time Frame
Baseline to 3 months
Title
Percent change in liver enzyme AST from baseline to 3 months
Description
Serum aspartate aminotransferase levels (IU/L)
Time Frame
Baseline to 3 months
Title
Percent change in liver enzyme creatinine from baseline to 3 months
Description
Serum creatinine levels (mg/dL)
Time Frame
Baseline to 3 months
Title
Percent change in malondialdehyde levels from baseline to 3 months
Description
Plasma malondialdehyde levels (uM)
Time Frame
Baseline to 3 months
Title
Percent change in Oxygen Radical Absorbance Levels (ORAC) from baseline to 3 months
Description
Plasma Oxygen Radical Absorbance Levels (ORAC units)
Time Frame
Baseline to 3 months
Title
Percent change in Trolox Equivalent Antioxidant Capacity (TEAC) from baseline to 3 months
Description
Serum Trolox Equivalent Antioxidant Capacity (mM)
Time Frame
Baseline to 3 months
Title
Percent change in inflammatory cytokine interleukin-1 from baseline to 3 months
Description
Serum interleukin 1 levels (pg/mL)
Time Frame
Baseline to 3 months
Title
Percent change in inflammatory cytokine interleukin-6 from baseline to 3 months
Description
Serum interleukin-6 levels (pg/mL)
Time Frame
Baseline to 3 months
Title
Percent change in inflammatory cytokine TNF-alpha from baseline to 3 months
Description
Serum TNF-alpha levels (pg/mL)
Time Frame
Baseline to 3 months
Title
Percent change in inflammatory marker c-reactive protein from baseline to 3 months
Description
Serum c-reactive protein levels (mg/dL)
Time Frame
Baseline to 3 months
Title
Percent change in ATP levels from baseline to 3 months
Description
Plasma ATP levels (mmol/L)
Time Frame
Baseline to 3 months
Title
Percent change in phosphocreatine levels from baseline to 3 months
Description
Plasma phosphocreatine levels (mmol/L)
Time Frame
Baseline to 3 months

10. Eligibility

Sex
Male
Minimum Age & Unit of Time
25 Years
Maximum Age & Unit of Time
50 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
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
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Mark A Tarnopolsky, PhD
Phone
9055212100
Ext
76593
Email
tarnopol@mcmaster.ca
First Name & Middle Initial & Last Name or Official Title & Degree
Mats Nilsson
Phone
9055212100
Ext
76680
Email
mats.nilsson@exerkine.com
Facility Information:
Facility Name
Mark Tarnopololsky
City
Hamilton
State/Province
Ontario
ZIP/Postal Code
L8N 3Z5
Country
Canada
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Mark A Tarnopolsky, PhD
Phone
905-525-2100
Ext
76593
Email
tarnopol@mcmaster.ca
First Name & Middle Initial & Last Name & Degree
Mats I Nilsson, PhD
Phone
905-525-2100
Ext
76680
Email
mats.nilsson@exerkine.com

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
The study protocol, informed consent form and statistical analysis plan may be made available from February 2025 onward. This may occur along with the release of the deidentified results for publishing requirements and/or upon request by qualified researchers.
IPD Sharing Time Frame
The study protocol, informed consent form and statistical analysis plan may be made available from February 2025 onward. This may occur along with the release of the deidentified results for publishing requirements and/or upon request by qualified researchers.
IPD Sharing Access Criteria
Access to trial data can be requested by qualified researchers engaging in independent scientific research studies.

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Supplementation for Male Subfertility

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