madman
Super Moderator
Long overdue!
* Clomiphene is a selective oestrogen receptor modulator that could stimulate testosterone secretion from the testes and boost spermatogenesis. Data from small randomised trials and observational studies suggest some benefit of using it to improve semen parameters in affected men. However, evidence of its efficacy and safety for use in this cohort remains heterogenous due to poor study quality
* The findings will be published in medical journals and international conferences. The results will be shared with the NHS repurposing programme to review Clomiphene licence
www.ucl.ac.uk
Abstract
Infertility is a common disease that affects more than 186 million people worldwide. Male factor infertility, defined by abnormal semen and low sperm count, affects up to 50% of couples who are unable to get pregnant. In most cases no clear cause can be identified for the abnormalities in semen quality, which may be associated with a mild reduction in the male hormone (Testosterone). While a common condition, there remains no established medical treatments to improve semen quality, with an over reliance on expensive assisted conception treatments like in-vitro fertilisation (test tube baby). Clomiphene is a drug that regulates male and female body hormones and can help to increase the secretion of testosterone and the production of sperm in the testes. It is currently only licensed in the UK to induce ovulation in women but is frequently prescribed off-license to men with infertility by fertility specialists in other countries. However, its efficacy and safety for use in men remains unclear. Several small clinical studies suggested that Clomiphene can increase sperm production and the chance of natural conception in couples with male factor infertility. However, these studies are of poor quality and could be biased. Clomiphene is a cheap drug and is generally safe in women with minor side effects like upset stomach, dizziness, and some weight gain. A large randomised study comparing Clomiphene to a placebo (no treatment) is needed to evaluate this drug's efficacy and safety as a treatment for men with low sperm count to help them conceive naturally and reduce the need for expensive and invasive assisted conception treatments. We plan to recruit 160 eligible men from five fertility clinics in the NHS and allocate them to Clomiphene for 12 months or placebo (no treatment). The Clomiphene and placebo will be identical in appearance and both the participants and investigators will be blinded to the allocated treatment until the end of the study. Both groups will receive standard care in the NHS to improve sperm production like multivitamins and healthy lifestyle advice. We will primarily report on improvement in sperm count at six months and also assess the mechanism of effect of Clomiphene by reporting on important lab, reproductive, pregnancy, clinical, quality of life, and safety outcomes. We will also conduct interviews with participants and fertility specialists to evaluate the uptake of this drug and improve the study conduct. Our team includes clinical fertility specialists, Andrology urologists, clinical scientists, academics, trialists, methodologists with advanced expertise in producing quality research in reproductive health. We aim to co-produce this research with patient representatives with lived experience of male infertility and we will share the findings with all relevant stakeholder groups and the lay community. We are collaborating with the Fertility Alliance charity and Progress Education Trust to communicate the trial's findings and rally support from the lay community. We will also work with the British Fertility Society to generate guidance based on the study results to directly influence the provision of this treatment to men with infertility in the NHS and work with key decision-makers to quickly incorporate the study findings into clinical practice.
Plain English Summary
Background
Male factor infertility defined by abnormal semen parameters affects >50% of infertile couples. In most cases no clear cause can be identified for (idiopathic), which may be associated with a mild reduction in Testosterone (secondary hypogonadism). While a common health condition, effective medical treatments for men with hypogonadism or idiopathic male infertility remain limited with an over reliance on using expensive and invasive assisted reproductive technology treatments. Clomiphene is a selective oestrogen receptor modulator that could stimulate testosterone secretion from the testes and boost spermatogenesis. Data from small randomised trials and observational studies suggest some benefit of using it to improve semen parameters in affected men. However, evidence of its efficacy and safety for use in this cohort remains heterogenous due to poor study quality.
Research question
What is the efficacy and safety of clomiphene as a treatment for men with secondary hypogonadism or idiopathic male infertility to improve semen parameters and reproductive outcomes compared to placebo.
Aims and objectives
To evaluate the efficacy and safety of clomiphene as a treatment for men with secondary hypogonadism or idiopathic male infertility.
Objectives
To determine the efficacy of clomiphene in improving semen parameters in this group of men.
-To determine the efficacy of clomiphene in improving clinical, reproductive and pregnancy outcomes in this group of men
-To determine the safety of clomiphene as a treatment for men with secondary hypogonadism or idiopathic male infertility
-To explore the feasibility and acceptability of using Clomiphene as a primary treatment in this group of men
Methods
A multicentre two-arm parallel group double-blind placebo controlled randomised trial with an internal pilot and qualitative process evaluation. Men who meet the eligibility criteria from five NHS fertility clinics will be randomised in a 1:1 ratio to either Clomiphene (25mg/day) or identical placebo for 12 months. Both groups will receive standard lifestyle advice as per national guidelines. We will primarily report on change in sperm concentration at 6 months in addition to other semen parameters, biochemical, reproductive, pregnancy, clinical, and quality of life outcomes. Couples seeking to start any assisted conception treatment during the trial will be enabled without delay. An increase of 5 million/ml in sperm concentration can significantly increase the chances of spontaneous conception in men with oligozoospermia. To detect a 5 million/ml improvement in sperm concentration between groups, assuming a 0.5 correlation coefficient and a SD of 10, we need 160 participants to achieve 90% power, and 5% type-1 error rate and allowing 20% loss to follow-up.
Timelines for delivery
We forecast 48 months to execute the trial including: trial set up (Months 1-9), recruitment and intervention delivery (Months 9-21), follow-up (Months 21-33), site close down and capturing pregnancy outcomes (Months 33-42), and statistical analysis and dissemination (Months 42-48).
Anticipated impact and dissemination
The findings will be published in medical journals and international conferences. The results will be shared with the NHS repurposing programme to review Clomiphene licence. We devised a PPIE strategy, lay communication strategy, and established strong links with relevant charities to promote the voice of lay men with infertility.
* Clomiphene is a selective oestrogen receptor modulator that could stimulate testosterone secretion from the testes and boost spermatogenesis. Data from small randomised trials and observational studies suggest some benefit of using it to improve semen parameters in affected men. However, evidence of its efficacy and safety for use in this cohort remains heterogenous due to poor study quality
* The findings will be published in medical journals and international conferences. The results will be shared with the NHS repurposing programme to review Clomiphene licence
CONCRETE
Effectiveness of ClOmipheNe CitRate for the management of mEn wiTh reduced spErm concentration (CONCRETE): A phase IIb, randomised, double-blind placebo-controlled trial.
Abstract
Infertility is a common disease that affects more than 186 million people worldwide. Male factor infertility, defined by abnormal semen and low sperm count, affects up to 50% of couples who are unable to get pregnant. In most cases no clear cause can be identified for the abnormalities in semen quality, which may be associated with a mild reduction in the male hormone (Testosterone). While a common condition, there remains no established medical treatments to improve semen quality, with an over reliance on expensive assisted conception treatments like in-vitro fertilisation (test tube baby). Clomiphene is a drug that regulates male and female body hormones and can help to increase the secretion of testosterone and the production of sperm in the testes. It is currently only licensed in the UK to induce ovulation in women but is frequently prescribed off-license to men with infertility by fertility specialists in other countries. However, its efficacy and safety for use in men remains unclear. Several small clinical studies suggested that Clomiphene can increase sperm production and the chance of natural conception in couples with male factor infertility. However, these studies are of poor quality and could be biased. Clomiphene is a cheap drug and is generally safe in women with minor side effects like upset stomach, dizziness, and some weight gain. A large randomised study comparing Clomiphene to a placebo (no treatment) is needed to evaluate this drug's efficacy and safety as a treatment for men with low sperm count to help them conceive naturally and reduce the need for expensive and invasive assisted conception treatments. We plan to recruit 160 eligible men from five fertility clinics in the NHS and allocate them to Clomiphene for 12 months or placebo (no treatment). The Clomiphene and placebo will be identical in appearance and both the participants and investigators will be blinded to the allocated treatment until the end of the study. Both groups will receive standard care in the NHS to improve sperm production like multivitamins and healthy lifestyle advice. We will primarily report on improvement in sperm count at six months and also assess the mechanism of effect of Clomiphene by reporting on important lab, reproductive, pregnancy, clinical, quality of life, and safety outcomes. We will also conduct interviews with participants and fertility specialists to evaluate the uptake of this drug and improve the study conduct. Our team includes clinical fertility specialists, Andrology urologists, clinical scientists, academics, trialists, methodologists with advanced expertise in producing quality research in reproductive health. We aim to co-produce this research with patient representatives with lived experience of male infertility and we will share the findings with all relevant stakeholder groups and the lay community. We are collaborating with the Fertility Alliance charity and Progress Education Trust to communicate the trial's findings and rally support from the lay community. We will also work with the British Fertility Society to generate guidance based on the study results to directly influence the provision of this treatment to men with infertility in the NHS and work with key decision-makers to quickly incorporate the study findings into clinical practice.
Plain English Summary
Background
Male factor infertility defined by abnormal semen parameters affects >50% of infertile couples. In most cases no clear cause can be identified for (idiopathic), which may be associated with a mild reduction in Testosterone (secondary hypogonadism). While a common health condition, effective medical treatments for men with hypogonadism or idiopathic male infertility remain limited with an over reliance on using expensive and invasive assisted reproductive technology treatments. Clomiphene is a selective oestrogen receptor modulator that could stimulate testosterone secretion from the testes and boost spermatogenesis. Data from small randomised trials and observational studies suggest some benefit of using it to improve semen parameters in affected men. However, evidence of its efficacy and safety for use in this cohort remains heterogenous due to poor study quality.
Research question
What is the efficacy and safety of clomiphene as a treatment for men with secondary hypogonadism or idiopathic male infertility to improve semen parameters and reproductive outcomes compared to placebo.
Aims and objectives
To evaluate the efficacy and safety of clomiphene as a treatment for men with secondary hypogonadism or idiopathic male infertility.
Objectives
To determine the efficacy of clomiphene in improving semen parameters in this group of men.
-To determine the efficacy of clomiphene in improving clinical, reproductive and pregnancy outcomes in this group of men
-To determine the safety of clomiphene as a treatment for men with secondary hypogonadism or idiopathic male infertility
-To explore the feasibility and acceptability of using Clomiphene as a primary treatment in this group of men
Methods
A multicentre two-arm parallel group double-blind placebo controlled randomised trial with an internal pilot and qualitative process evaluation. Men who meet the eligibility criteria from five NHS fertility clinics will be randomised in a 1:1 ratio to either Clomiphene (25mg/day) or identical placebo for 12 months. Both groups will receive standard lifestyle advice as per national guidelines. We will primarily report on change in sperm concentration at 6 months in addition to other semen parameters, biochemical, reproductive, pregnancy, clinical, and quality of life outcomes. Couples seeking to start any assisted conception treatment during the trial will be enabled without delay. An increase of 5 million/ml in sperm concentration can significantly increase the chances of spontaneous conception in men with oligozoospermia. To detect a 5 million/ml improvement in sperm concentration between groups, assuming a 0.5 correlation coefficient and a SD of 10, we need 160 participants to achieve 90% power, and 5% type-1 error rate and allowing 20% loss to follow-up.
Timelines for delivery
We forecast 48 months to execute the trial including: trial set up (Months 1-9), recruitment and intervention delivery (Months 9-21), follow-up (Months 21-33), site close down and capturing pregnancy outcomes (Months 33-42), and statistical analysis and dissemination (Months 42-48).
Anticipated impact and dissemination
The findings will be published in medical journals and international conferences. The results will be shared with the NHS repurposing programme to review Clomiphene licence. We devised a PPIE strategy, lay communication strategy, and established strong links with relevant charities to promote the voice of lay men with infertility.
