Assessment of TetraSOD® Efficacy to Improve Semen Parameters in Men With Idiopathic Infertility

Study Overview
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Brief Summary
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TetraSOD® is a unique marine phytoplankton (Tetraselmis chuii) SOD-rich ingredient that is grown under patent-protected technology exclusively designed by the company Fitoplancton Marino, S.L. (Spain). In a previous pilot trial, the ability of TetraSOD® to improve semen characteristics in idiopathic infertile men after three months of treatment was assessed, revealing significant improvements in almost all of the analyzed parameters. In the present clinical trial, such positive effects will be tested again in a higher number of patients, and additional parameters will be included in order to gain insights into the sperm physiological changes that underpin the improvement in semen quality

Detailed Description
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IInfertility is an increasing global public health problem present in about 15-20% of the population of reproductive age, affecting as many as 186 million people worldwide. A male factor is present in approximately 50% of the infertile couples, a large number of them of unknown or idiopathic origin. Spermatogenesis is a complex biological process that requires a highly regulated genetic and hormonal program in a singular environment created by the interaction with different cell types to orchestrate a successful differentiation process. This process occurs periodically every 72 days during a man's fertile life. It has been demonstrated that semen quality is deteriorating over the time, perhaps as a result of exposition to several environmental factors related with lifestyle: drug use (such us tobacco, alcohol, marijuana, cocaine, opioids and anabolic agents), diet and overweight, disorders of the sleep-wake cycle and working conditions (continuous exposition to heat sources or toxic substances) that could impact both directly and indirectly on the complex process of spermatogenesis. Currently, the impact of oxidative stress, a cellular state product of an imbalance between the generation of highly unstable molecules known as reactive oxygen species (ROS) and the antioxidant cellular capacity in male fertility is being deeply investigated. High levels of oxidative stress in semen have been associated with both lower sperm concentration, sperm motility and acrosome integrity and higher sperm DNA damage and mitochondrial activity. Recent clinical trials have demonstrated the high prevalence of sperm DNA damage by up to 80% of men diagnosed with idiopathic male infertility. This DNA damage produced during spermatogenesis or sperm maturation process could be the result of an increase of reactive oxygen species (ROS) in male reproductive tract, which are related to different known factors (chronic systemic disease, use of some drugs, radiation or pesticides, febrile processes, old age and environmental factors related to lifestyle: smoking, obesity, alcohol) and other unknown so far. Antioxidant supplementation has gained relevance within routine practices in patients with reproductive problems. Different studies have shown the beneficial effect of antioxidant consumption against oxidative damage caused by environmental and pathological components, improving sperm characteristics associated with the seminal analysis. There are scientific evidences about the improvement of male fertility and higher rates of live newborn after antioxidant treatment in subfertile men. TetraSOD® is a unique commercial product comprised of 100% lyophilized biomass of the marine microalgae Tetraselmis chuii strain CCFM03, which is currently marketed for food and nutraceutical applications around the world by the company Fitoplancton Marino, S.L. This microalgae product is characterized by a high content in the antioxidant enzyme superoxide dismutase (SOD), as it is produced using own (patent pending) technology developed by the company. Results of in vitro studies with human cell lines suggest that TetraSOD® stimulates the cellular protective mechanisms against oxidative stress. Moreover, results previously obtained in a pilot study with the highest dose of TetraSOD® (250 mg/day) were promising, since a high statistically significant response was observed in three of the four studied parameters after three months of treatment. Taking into account these results, a new extended double-blind randomized and placebo-controlled clinical study will be performed to confirm the positive effects of dietary supplementation with 250 mg of TetraSOD® during 3 months (corresponding to the time of a complete spermatogenic cycle) in sperm quality. The main objective of our study is to demonstrate the usefulness and safety of TetraSOD® treatment in the improvement of sperm quality including sperm DNA fragmentation. As we previously mentioned, oxidative stress is one of the main causes of sperm DNA damage. Nowadays, a diagnostic test for the study of the sperm DNA fragmentation exists, but it requires a specific sperm sample processing and the results are obtained in delay-time. In our study we are going to also assess the correlation between sperm DNA fragmentation and sORP (static oxidation reduction potential) degree by the use of MiOXSYS. Therefore, the availability of a simple and cheap instantaneous response time diagnostic test seems promising for the reproductive clinics. It allows us to advance in the diagnosis of male fertility potential and in the identification of those patients susceptible to antioxidant treatment in order to improve their reproductive results, increasing the chances of pregnancy both spontaneously or after assisted reproductive treatment

Official Title
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A Double-blind Randomized Placebo-controlled Clinical Study to Verify the Efficacy of TetraSOD® in the Improvement of Semen Quality in Patients With Idiopathic Infertility

Conditions
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Infertility, Male

Intervention / Treatment
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* Dietary Supplement: Marine microalgae Tetraselmis chuii with high Superoxide Dismutase (SOD) activity
* Dietary Supplement: Sham


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age: 18 to 45 Male patients with idiopathic infertility classified with asthenozoospermia, oligozoospermia or oligoasthenozoospermia after seminal assessment. Not achieving pregnancy after at least one year of intercourse with the same partner without protective measures Exclusion Criteria: Azoospermia (absence of spermatozoa) or severe oligozoospermia (< 5 million spermatozoa/ml of ejaculate) Testicular torsion or prostatitis Urinary retention and infections Drug consumption Hormone treatments Recent surgical interventions Diabetes Kidney or liver disease Leukocytosis Antioxidant supplement consumption in the last 3 months BMI >30 Kg/m2 Endocrinopathies, hypo and hyperthyroidism Chromosomal anomalies (XX, XYY, XXY) Treatments with anticoagulants Radiotherapy/Chemotherapy Participation in another clinical study prior to inclusion in this study that could affect the objectives of the current study

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 45 Years

Sexes Eligible for Study
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Male

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control group<br>Group supplemented with a daily dose of placebo | Dietary Supplement: Sham<br>* Participants in the Control group will receive a daily dose of placebo in a capsule during 90 days. After treatment, the group will stop consumption of placebo and a wash-out period of three months will start<br>|
| Experimental: Experimental group<br>Group supplemented with a daily dose of TetraSOD® | Dietary Supplement: Marine microalgae Tetraselmis chuii with high Superoxide Dismutase (SOD) activity<br>* Participants in the Experimental group will receive a daily dose of 250 mg of TetraSOD® in a capsule during 90 days. After treatment, the group will stop consumption of TetraSOD® and a wash-out period of three months will start<br>* Other names: TetraSOD®;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Sperm motility | Sperm motility will be assessed according to the method described in the WHO laboratory manual for the examination and processing of human semen, 5th ed. Geneva: World Health Organization (2010) | 90 days | 
| Sperm concentration | Sperm concentration will be determined according to the method described in the WHO laboratory manual for the examination and processing of human semen, 5th ed. Geneva: World Health Organization (2010) | 90 days | 
| Sperm oxidative stress | Oxidative stress status will be evaluated by measuring: i) intracellular Reactive Oxygen Species (ROS; includes superoxide anion, hydroxyl radical, hydrogen peroxide), and ii) sperm DNA oxidation via quantification of 8-hydroxydeoxyguanosine (8-OHdG). Flow cytometry will be employed in both cases. | 90 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| DNA integrity | DNA integrity/fragmentation will be evaluated using the COMET assay | 90 days | 
| Adverse effects | Any kind of adverse event attributable to TetraSOD® will be recorded during the duration of the trial | 90 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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TetraSOD®, Infertility