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

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).

Study Overview

• Status: Active, not recruiting
• Conditions: Male Subfertility
• Intervention / Treatment: Dietary supplement: Impryl; Other: Placebo

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.

• Study Type: Interventional
• Enrollment (Actual): 1200
• Phase: Not Applicable

Contacts and Locations

Study Locations

• Netherlands
  • 's-Hertogenbosch, Netherlands, 5200ME
    • Jeroen Bosch ziekenhuis
  • Apeldoorn, Netherlands, 7334DZ
    • Gelre Ziekenhuizen
  • Arnhem, Netherlands, 6815AD
    • Rijnstate
  • Boxmeer, Netherlands, 5835DV
    • Maasziekenhuis Pantein
  • Breda, Netherlands, 4818CK
    • Amphia Ziekenhuis
  • Doetinchem, Netherlands, 7002BL
    • Slingeland Ziekenhuis
  • Dordrecht, Netherlands, 3318AT
    • Albert Schweitzer Ziekenhuis
  • Eindhoven, Netherlands, 5623EJ
    • Catharina Ziekenhuis Eindhoven
  • Elsendorp, Netherlands, 5424SM
    • Nij Geertgen
  • Emmen, Netherlands, 7824AA
    • Treant ziekenhuis Scheper
  • Gorinchem, Netherlands, 4207HG
    • Nij Linge
  • Leiderdorp, Netherlands
    • Medisch Centrum Kinderwens
  • Nijmegen, Netherlands, 6500HB
    • Radboudumc
  • Roosendaal, Netherlands, 4708AE
    • Bravis Ziekenhuis
  • Rotterdam, Netherlands, 3079DZ
    • Maasstad Ziekenhuis
  • Rotterdam, Netherlands, 3045PM
    • Franciscus Gasthuis en Vlietland
  • Tilburg, Netherlands, 5022GC
    • Elisabeth-TweeSteden Ziekenhuis
  • Uden, Netherlands, 5400AS
    • Bernhoven Ziekenhuis
  • Veldhoven, Netherlands, 5504DB
    • Máxima Medisch Centrum
  • Wolvega, Netherlands
    • Nij Barrahus
  • Gelderland
    • Voorburg, Gelderland, Netherlands
      • Fertiliteitscentrum Voorburg

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 50 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Triple

Number of Arms

2

Arms and Interventions

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

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
Live birth rate	All live births	15 months

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Collaborators: Goodlife Fertility B.V.
• Investigators: Study Director: Annemiek Nap, Prof.dr., Gynecologist, head of department of Obstetrics and Gynaecology; Principal Investigator: Annemiek Nap, Prof MD PhD, Gynecologist, head of department of Obstetrics and Gynecology

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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.
• 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. Erratum In: J Assist Reprod Genet. 2017 Jan;34(1):155.
• 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.

Helpful Links

• Website Impryl

Study record dates

Study Major Dates

• Study Start (Actual): April 23, 2018
• Primary Completion (Estimated): January 30, 2025
• Study Completion (Estimated): April 30, 2026

Study Registration Dates

• First Submitted: November 6, 2017
• First Submitted That Met QC Criteria: November 6, 2017
• First Posted (Actual): November 9, 2017

Study Record Updates

• Last Update Posted (Estimated): March 6, 2024
• Last Update Submitted That Met QC Criteria: March 4, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: oxidative stress; fertility; male subfertility; foodsupplement
• Additional Relevant MeSH Terms: Urogenital Diseases; Male Urogenital Diseases; Genital Diseases, Male; Genital Diseases; Infertility; Infertility, Male
• Other Study ID Numbers: NL61414.091.17; NTR6551 (Registry Identifier: Nederlands Trial Register)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No