The Impact of a Nutritional Supplement (Impryl®) on Male Fertility

Study Overview
=================
Brief Summary
-----------------
Infertility is a worldwide problem and about 10%-15% of all couples will be affected by the inability to have children. In approximately 50% of infertile couples a male factor is involved. Male infertility is of multifactorial origin. In the past decade, the role of oxidative stress on sperm has been researched thoroughly and found to be the problem in 30% to 80% of male infertility cases. Impryl® is a nutritional supplement mainly consisting of vitamin B, which works on the metabolic system by activating the one carbon cycle and recycling of homocysteine without the use of any direct strong antioxidants. In this study the investigators want to determine the effectiveness of nutritional supplement Impryl® in men of infertile couples on ongoing pregnancy rate, with or without assisted reproduction technology (ART).

Detailed Description
-----------------
Rationale: Infertility is a worldwide problem and about 10%-15% of all couples will be affected by the inability to have children. In approximately 50% of infertile couples a male factor is involved. In the past decade, the role of oxidative stress on sperm has been researched thoroughly and found to be the problem in 30% to 80% of male infertility cases. Impryl® is a nutritional supplement which works on the metabolic system and regulation of oxidative stress by activating the 1-Carbon cycle and therefore recycling of homocysteine. Objective: To determine the effectiveness of nutritional supplement Impryl® in men of infertile couples on ongoing pregnancy rate, with or without assisted reproduction technology (ART). Study design: Multicentre, randomised double blind placebo controlled clinical trial/superiority study. Study population: All participants in this study are male adults, age 18-50 years, part of a couple that is diagnosed with infertility, regardless the outcome of semen analysis. The couple will either start or is already started with fertility treatment, i.e. expectative management (EM, duration 6 months), intra-uterine insemination (IUI) with or without ovarian stimulation (mild ovarian hyperstimulation (MOH) or ovulation induction (OI)), either in vitro fertilization (IVF) or intracytoplasmic sperm injection (ICSI) treatment. Intervention: Impryl® or placebo, with identical appearance one tablet each day for a total duration of maximal 6 months. Patients can start directly with study medication and fertility treatment (or to conceive spontaneously). Main study parameters/endpoints: The primary outcome is the number of ongoing pregnancies confirmed by ultrasound at ≥ 10-12 weeks. Secondary outcomes are change in semen parameters between baseline and 3 months intervention in IUI/IVF/ICSI group, based on (pre-wash) total motile sperm count (TMSC), leading to a change in treatment category Furthermore the occurrence of pregnancy, time to pregnancy, embryo fertilization rate in IVF/ICSI, embryo-utilization rate in IVF/ICSI, number of miscarriages and live birth rate are documented within the study period. The occurrence of adverse events will be reported.

Official Title
-----------------
The Impact of a Nutritional Supplement (Impryl®) on Male Fertility

Conditions
-----------------
Male Subfertility

Intervention / Treatment
-----------------
* Dietary Supplement: Impryl
* Other: Placebo


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Couples with failure to conceive for at least 12 months and starting with EM or Couples starting with 1st/ 2nd/3rd cycle of IUI (with/without ovarian stimulation) or Couples starting with 1st/ 2nd/3rd cycle of IVF/ICSI Furthermore: Male with age 18-50 years Female partner with age 18-43 years Willing and able to give informed consent Exclusion Criteria: Planned or performed diagnostic testicular biopsy (TESE) or percutaneous epididymal sperm aspiration (PESA) Use of donor-, cryopreserved- or electro-ejaculated semen Ovulation induction (OI) without IUI IVF for an absolute tubal factor Embryo-transfers after cryopreservation Embryo-transfer after pre-implantation genetic diagnosis Known genetic abnormalities related to infertility Known urological abnormality such as a varicocele or bilateral cryptorchism Use of other vitamin supplements

Ages Eligible for Study
-----------------
Minimum Age: 18 Years
Maximum Age: 50 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
Accepts Healthy Volunteers

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Multicentre, randomised double blind placebo controlled clinical trial/superiority study.
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Impryl<br>One tablet daily for 6 months | Dietary Supplement: Impryl<br>* Food supplement with betaine, cystine, zinc, niacin, folic acid (5MTHF-glucosamine), Vitamin B12 (cobalamin), Vitamin B6, Vitamin B2 (riboflavin)<br>|
| Placebo Comparator: Placebo<br>One tablet daily for 6 months | Other: Placebo<br>* Inactive ingredients, placebo<br>|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Ongoing pregnancy rate | Ongoing pregnancy ≥10-12 weeks of gestation | 15 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall pregnancy rate | All pregnancies confirmed with a positive pregnancy (HCG) test | 15 months | 
| Time to pregnancy 1 - start intervention | The time between start of intervention and reaching ongoing pregnancy | 15 months | 
| Time to pregnancy 1 - start fertility treatment | The time between start of fertility treatment and reaching ongoing pregnancy | 15 months | 
| Change in semen parameters leading to change in treatment category | Between baseline and 3 months intervention, based on pre-wash total motile sperm count (TMSC) from the subpopulation from Radboudumc and sites that deliver a pre-wash TMSC before IUI/IVF/ICSI | 15 months | 
| Number of miscarriages | Defined as a non-vital intra-uterine pregnancy before 16 weeks of gestation | 15 months | 
| Live birth rate | Live birth rate defined as beyond 24 weeks of gestation, the birth of a living child. | 15 months | 
| Adverse effects | Gastro-intestinal problems such as reflux, obstipation, diarrhea, nausea or vomiting, furthermore loss of appetite, headache, dizziness, pruritus or skin rash. | 15 months | 
| Embryo fertilization rate | Relative improvement. Fertilization rate is the percentage of oocytes with >=2 PN after insemination (IVF) of injection (ICSI). | 15 months | 
| Embryo-utilization rate | Relative improvement of the embryo-utilization rate (EUR), defined as the number of high quality embryos obtained, embryo's used at transfer plus the number of embryos frozen, divided by the number of zygotes obtained in a cycle | 15 months | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
fertility, male subfertility, foodsupplement, oxidative stress