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Trial registered on ANZCTR


Registration number
ACTRN12623000329662
Ethics application status
Approved
Date submitted
16/03/2023
Date registered
29/03/2023
Date last updated
1/09/2024
Date data sharing statement initially provided
29/03/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Clomiphene in male infertility (CIMI) trial: A double-blind randomised placebo-controlled trial of clomiphene in normogonadotrophic idiopathic male infertility
Scientific title
Impact of clomiphene on semen parameters in normogonadotrophic idiopathic male infertility: a double-blind randomised placebo-controlled trial
Secondary ID [1] 309108 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Male infertility 329189 0
Condition category
Condition code
Reproductive Health and Childbirth 326154 326154 0 0
Fertility including in vitro fertilisation

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Prospective double-blind randomised control trial comparing clomiphene versus placebo in men with unexplained infertility and normal levels of serum gonadotrophins.

Eligible men will be randomised to one of two study groups in a 1:1 ratio (clomiphene or placebo). Both groups will receive menevit, which is a commercially available men's fertility multivitamin.

Intervention group
- Clomiphene 25 mg once daily, oral tablet, duration 6 months (180 days)
- Menevit 1 tablet daily, oral tablet, duration 6 months (180 days)

Adherence will be assessed by research team by inspecting a medication diary kept by participants.
Intervention code [1] 325555 0
Treatment: Drugs
Comparator / control treatment
Control group
- Placebo 1 tablet daily, oral glucose capsule (lactose free, gluten free and halal), duration 6 months (180 days)
- Menevit 1 tablet daily, oral tablet, duration 6 months (180 days)

Both participants and researchers will be blinded to randomisation. The intervention (clomiphene) and placebo will both be encapsulated and look identical.
Control group
Placebo

Outcomes
Primary outcome [1] 334029 0
Total sperm count, measured on a standard semen analysis.
Timepoint [1] 334029 0
4 weeks after commencement of intervention
12 weeks after commencement of intervention
24 weeks after commencement of intervention (primary timepoint)
Secondary outcome [1] 419125 0
Sperm concentration, measured on standard semen analysis
Timepoint [1] 419125 0
4 weeks after commencement of intervention
12 weeks after commencement of intervention
24 weeks after commencement of intervention
Secondary outcome [2] 419127 0
Total motile sperm count, measured by standard semen analysis
Timepoint [2] 419127 0
4 weeks after commencement of intervention
12 weeks after commencement of intervention
24 weeks after commencement of intervention
Secondary outcome [3] 419128 0
Progressive sperm motility, measured by standard semen analysis
Timepoint [3] 419128 0
4 weeks after commencement of intervention
12 weeks after commencement of intervention
24 weeks after commencement of intervention
Secondary outcome [4] 419129 0
Normal sperm morphology, measured by standard semen analysis
Timepoint [4] 419129 0
4 weeks after commencement of intervention
12 weeks after commencement of intervention
24 weeks after commencement of intervention
Secondary outcome [5] 419130 0
Serum FSH, measured by blood test
Timepoint [5] 419130 0
4 weeks after commencement of intervention
12 weeks after commencement of intervention
24 weeks after commencement of intervention
Secondary outcome [6] 419131 0
Serum LH, measured on a blood test
Timepoint [6] 419131 0
4 weeks after commencement of intervention
12 weeks after commencement of intervention
24 weeks after commencement of intervention
Secondary outcome [7] 419132 0
Serum total testosterone, measured on a blood test
Timepoint [7] 419132 0
4 weeks after commencement of intervention
12 weeks after commencement of intervention
24 weeks after commencement of intervention
Secondary outcome [8] 419133 0
Pregnancies, reported by participants via an online study-specific survey
Timepoint [8] 419133 0
4 weeks after commencement of intervention
12 weeks after commencement of intervention
24 weeks after commencement of intervention
36 weeks after commencement of intervention
Secondary outcome [9] 419134 0
Live births, as reported by participants via telephone report
Timepoint [9] 419134 0
24 weeks after commencement of intervention
36 weeks after commencement of intervention

Eligibility
Key inclusion criteria
1) Men of heterosexual couples with at least 12 months of infertility
2) Aged 18-50 years at enrolment
3) Able to provide informed consent in English
4) Have at least two semen analysis in the preceding 6 months showing oligozoospermia (<10 million/ml or total count <26 million)
Minimum age
18 Years
Maximum age
50 Years
Sex
Males
Can healthy volunteers participate?
No
Key exclusion criteria
Azoospermia
BMI >= 35 kg/m2
Serum FSH >8.4 IU/L
Morning serum total testosterone <8 nmol/L
Serum oestradiol >160 pmol/L
Any genetic or endocrine disorder known to cause infertility (e.g. Prader-Willi, hyperprolactinaemia, Yq deletion, hypogonadotrophic hypogonadism).
Any medications within the prior 6 months known to disrupt the hypothalamic-pituitary gonadal axis, e.g. testosterone, aromatase inhibitors, opioids.
History of testicular cancer or surgery, untreated cryptorchidism, previous chemotherapy, or pelvic irradiation, large or clinically significant varicocele, prior vasectomy.
Current genitourinary tract infection or seminal white cell count >1 mill/ml
Sperm antibodies >50% bound (excluding tail-tip only)
Retrograde ejaculation
Systemic severe chronic disease (e.g. severe kidney or liver disease)
Current smoker
Alcohol abuse >20 standard drinks per week

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Allocation concealed from clinician involved in assessing eligibility. Allocation will involve contacting the holder of the allocation schedule who is "off-site".
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Simple randomisation using a randomisation table created by computer software, i.e. computerised sequence generation.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
Phase
Phase 3
Type of endpoint/s
Efficacy
Statistical methods / analysis
Baseline characteristics will be compared for the intervention and placebo groups including age of male participant, age of female partner, infertility duration, BMI, smoking status, alcohol intake, ethnicity, semen parameters, serum gonadotrophins, testosterone, oestradiol and testicular volumes. Continuous variables will be summarised using means and standard deviations (SD). Non-Gaussian data will be presented as medians and interquartile ranges (IQR). Categorical exposures and outcomes will be summarised using frequency distributions. The normal distribution of each variable will be evaluated with the Shapiro–Wilk test.

Primary and secondary outcomes will be reported before and after completion of the intervention period. Intra- and inter-group differences will be investigated using two-sample t-tests (or Mann-Whitney U tests for non-Gaussian data) for continuous data and chi-square tests for categorical data. Differences in the percentage of responders (defined as participants whose total sperm count per ejaculate doubled after 6 months of intervention compared to before intervention) between the two study groups will be evaluated by chi-square tests. Baseline characteristics such as age, FSH and testicular volumes will be compared between responders and non-responders using chi-square tests.

To investigate the role of age, FSH levels, total sperm count and testicular volume at enrolment, these variables will be included in a multivariate regression analysis with a stepwise procedure performed for post-treatment values of total sperm count for each group.

It is estimated that 16 patients are required in each arm (total 32) to detect with 80% power a difference in total sperm count of 15 million between the two groups. The analysis was based on a mean pre-treatment total sperm count of 20 million.

Study data will be managed using REDCap electronic database with data analysed using Stata, version 17.1 (StataCorp LLC). A p-value <0.05 will be accepted as statistically significant.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
1/09/2024
Actual
Date of last participant enrolment
Anticipated
1/09/2026
Actual
Date of last data collection
Anticipated
1/06/2027
Actual
Sample size
Target
32
Accrual to date
0
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 24297 0
The Royal Women's Hospital - Parkville
Recruitment hospital [2] 24298 0
Monash IVF - Clayton - Clayton
Recruitment postcode(s) [1] 39841 0
3052 - Parkville
Recruitment postcode(s) [2] 39842 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 313311 0
Charities/Societies/Foundations
Name [1] 313311 0
Endocrine Society of Australia
Country [1] 313311 0
Australia
Funding source category [2] 313404 0
Other Collaborative groups
Name [2] 313404 0
Hudson Institute of Medical Research
Country [2] 313404 0
Australia
Primary sponsor type
Other Collaborative groups
Name
Hudson Institute of Medical Research
Address
27-31 Wright St, Clayton VIC 3168
Country
Australia
Secondary sponsor category [1] 315053 0
None
Name [1] 315053 0
Address [1] 315053 0
Country [1] 315053 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312535 0
Monash Health HREC
Ethics committee address [1] 312535 0
Ethics committee country [1] 312535 0
Australia
Date submitted for ethics approval [1] 312535 0
Approval date [1] 312535 0
11/09/2023
Ethics approval number [1] 312535 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 125010 0
Dr Sarah Catford
Address 125010 0
Hudson Institute of Medical Research
27-31 Wright St, Clayton, VIC 3168
Country 125010 0
Australia
Phone 125010 0
+61 3 85722700
Fax 125010 0
Email 125010 0
sarah.catford@thewomens.org.au
Contact person for public queries
Name 125011 0
Sarah Catford
Address 125011 0
Hudson Institute of Medical Research
27-31 Wright St, Clayton, VIC 3168
Country 125011 0
Australia
Phone 125011 0
+61 3 85722700
Fax 125011 0
Email 125011 0
sarah.catford@thewomens.org.au
Contact person for scientific queries
Name 125012 0
Sarah Catford
Address 125012 0
Hudson Institute of Medical Research
27-31 Wright St, Clayton, VIC 3168
Country 125012 0
Australia
Phone 125012 0
+61 3 85722700
Fax 125012 0
Email 125012 0
sarah.catford@thewomens.org.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
Individual participant data underlying published results only, after de-identification, upon reasonable request.
When will data be available (start and end dates)?
Data will be available 1 year after publication of results and ending 5 years following main results publication.
Available to whom?
Only researchers who provide a methodologically sound proposal and at the discretion of the primary investigator.
Available for what types of analyses?
For the purpose of achieving the aims in the approved proposal.
How or where can data be obtained?
Access subject to approvals by primary investigator who can be contacted by email at Sarah.catford@thewomens.org.au


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
No additional documents have been identified.