Clinical trial NCT03337360: The Impact of a Nutritional Supplement (Impryl®) on Male Fertility
Official title: The Impact of a Nutritional Supplement (Impryl®) on Male Fertility
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: NA
Conditions: Male Subfertility
Keywords: fertility
male subfertility
foodsupplement
oxidative stress
Lead sponsor: Radboud University Medical Center
Sponsor class: OTHER
Collaborators: name: Goodlife Fertility B.V.
First posted: 2017-11-09
Enrollment: 1200
Sex: MALE
Minimum age (years): 18
Maximum age (years): 50
Standard ages: ADULT
Accepts healthy volunteers: yes
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Multicentre, randomised double blind placebo controlled clinical trial/superiority study.
Primary purpose: TREATMENT

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.

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

Primary outcomes:
measure: Ongoing pregnancy rate
timeFrame: 15 months
Secondary outcomes:
measure: Overall pregnancy rate
timeFrame: 15 months
measure: Time to pregnancy 1 - start intervention
timeFrame: 15 months
measure: Time to pregnancy 1 - start fertility treatment
timeFrame: 15 months
measure: Change in semen parameters leading to change in treatment category
timeFrame: 15 months
measure: Number of miscarriages
timeFrame: 15 months
measure: Live birth rate
timeFrame: 15 months
measure: Adverse effects
timeFrame: 15 months
measure: Embryo fertilization rate
timeFrame: 15 months
measure: Embryo-utilization rate
timeFrame: 15 months
measure: Live birth rate
timeFrame: 15 months
Other outcomes:
Locations:
city: Voorburg
country: Netherlands
facility: Fertiliteitscentrum Voorburg
state: Gelderland
city: 's-Hertogenbosch
country: Netherlands
facility: Jeroen Bosch Ziekenhuis
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuizen
city: Arnhem
country: Netherlands
facility: Rijnstate
city: Boxmeer
country: Netherlands
facility: Maasziekenhuis Pantein
city: Breda
country: Netherlands
facility: Amphia ziekenhuis
city: Doetinchem
country: Netherlands
facility: Slingeland Ziekenhuis
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer ziekenhuis
city: Eindhoven
country: Netherlands
facility: Catharina Ziekenhuis Eindhoven
city: Elsendorp
country: Netherlands
facility: Nij Geertgen
city: Emmen
country: Netherlands
facility: Treant ziekenhuis Scheper
city: Gorinchem
country: Netherlands
facility: Nij Linge
city: Leiderdorp
country: Netherlands
facility: Medisch Centrum Kinderwens
city: Nijmegen
country: Netherlands
facility: Radboudumc
city: Roosendaal
country: Netherlands
facility: Bravis Ziekenhuis
city: Rotterdam
country: Netherlands
facility: Franciscus Gasthuis en Vlietland
city: Rotterdam
country: Netherlands
facility: Maasstad ziekenhuis
city: Tilburg
country: Netherlands
facility: Elisabeth-TweeSteden Ziekenhuis
city: Uden
country: Netherlands
facility: Bernhoven Ziekenhuis
city: Veldhoven
country: Netherlands
facility: Máxima Medisch Centrum
city: Wolvega
country: Netherlands
facility: Nij Barrahus
Study officials:
affiliation: Gynecologist, head of department of Obstetrics and Gynaecology
name: Annemiek Nap, Prof.dr.
role: STUDY_DIRECTOR
affiliation: Gynecologist, head of department of Obstetrics and Gynecology
name: Annemiek Nap, Prof MD PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Iwasaki A, Gagnon C. Formation of reactive oxygen species in spermatozoa of infertile patients. Fertil Steril. 1992 Feb;57(2):409-16. doi: 10.1016/s0015-0282(16)54855-9.
citation: Zini A, de Lamirande E, Gagnon C. Reactive oxygen species in semen of infertile patients: levels of superoxide dismutase- and catalase-like activities in seminal plasma and spermatozoa. Int J Androl. 1993 Jun;16(3):183-8. doi: 10.1111/j.1365-2605.1993.tb01177.x.
citation: Shekarriz M, Thomas AJ Jr, Agarwal A. Incidence and level of seminal reactive oxygen species in normal men. Urology. 1995 Jan;45(1):103-7. doi: 10.1016/s0090-4295(95)97088-6.
citation: Agarwal A, Prabakaran S, Allamaneni S. What an andrologist/urologist should know about free radicals and why. Urology. 2006 Jan;67(1):2-8. doi: 10.1016/j.urology.2005.07.012. No abstract available.
citation: Tremellen K. Oxidative stress and male infertility--a clinical perspective. Hum Reprod Update. 2008 May-Jun;14(3):243-58. doi: 10.1093/humupd/dmn004. Epub 2008 Feb 14.
citation: Showell MG, Mackenzie-Proctor R, Brown J, Yazdani A, Stankiewicz MT, Hart RJ. Antioxidants for male subfertility. Cochrane Database Syst Rev. 2014;(12):CD007411. doi: 10.1002/14651858.CD007411.pub3. Epub 2014 Dec 15.
citation: Dattilo M, Cornet D, Amar E, Cohen M, Menezo Y. The importance of the one carbon cycle nutritional support in human male fertility: a preliminary clinical report. Reprod Biol Endocrinol. 2014 Jul 29;12:71. doi: 10.1186/1477-7827-12-71.
citation: Dattilo M, D'Amato G, Caroppo E, Menezo Y. Improvement of gamete quality by stimulating and feeding the endogenous antioxidant system: mechanisms, clinical results, insights on gene-environment interactions and the role of diet. J Assist Reprod Genet. 2016 Dec;33(12):1633-1648. doi: 10.1007/s10815-016-0767-4. Epub 2016 Jul 16.
citation: Smits R, D'Hauwers K, IntHout J, Braat D, Fleischer K. Impact of a nutritional supplement (Impryl) on male fertility: study protocol of a multicentre, randomised, double-blind, placebo-controlled clinical trial (SUppleMent Male fERtility, SUMMER trial). BMJ Open. 2020 Jul 2;10(7):e035069. doi: 10.1136/bmjopen-2019-035069.