Clinical trial NCT02548039: To Study The Influence Of Genomic Factors On Metabolism And Effects Of Clomiphene In Asian Normogonadotrophic Anovulatory Patients.
Official title: To Study The Influence Of Pharmacogenomics Factors On Pharmacokinetics And Pharmacodynamics Of Clomiphene In Asian Normogonadotrophic Anovulatory Patients.
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: Infertility, Female
Keywords: Anovulatory
Clomiphene
Lead sponsor: KK Women's and Children's Hospital
Sponsor class: OTHER_GOV
Collaborators: name: National Cancer Centre, Singapore
First posted: 2015-09-14
Enrollment: 124
Sex: FEMALE
Minimum age (years): 21
Maximum age (years): 43
Standard ages: ADULT
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: NON_PROBABILITY_SAMPLE
Study population: Asian Normogonadotrophic Anovulatory Women

Brief summary: The purpose of this study is to match the genetic component and clinical attributes of anovulatory patients with response to clomiphene treatment.

By improving our understanding on patient-specific clomiphene response will allow optimization of treatment, reduction of side-effects and shorten the time-to-pregnancy.

Detailed description: Anovulation is the commonest cause for infertility, with clomiphene being the standard treatment. Pharmacogenetic causes of variability in the pharmacokinetics and pharmacodynamics of clomiphene is not well characterized in anovulatory Asian women. Although recent findings suggest that the pharmacokinetics and pharmacodynamics of clomiphene may be influenced by several polygenic pathways involving genes regulating its metabolism (CYP3A4, CYP3A5, CYP2B6, CYP2C8, CYP2C19, CYP2D6), thus contributing significantly to the wide variability in dose-response relationships observed in clinical practice. There has not been objective evidence thus far from an unbiased genome-wide perspective. It is likely that polymorphisms at the CYP cluster of genes encoding for their respective cytochrome proteins may not explain all of the variability with regards to clomiphene's dose-response relationship.

The investigators hypothesize that the pharmacokinetics and pharmacodynamics of clomiphene is under strong control by genetic loci and that these genetic variants could also strongly determine the therapeutic outcome in Asian normogonadotrophic anovulatory patients. The contribution by candidate genes mentioned above will also be clarified in a definitive manner by this study.

Eligibility criteria: Inclusion Criteria:

* Women of reproductive age with ovulatory dysfunction desiring pregnancy,
* Willing to discontinue any form of herbal or traditional chinese medicines for at least three weeks before starting Clomiphene
* Ability to provide written and informed consent taken from participating patients, and
* Willingness to cooperate with study instructions

Exclusion Criteria:

* Pregnant at the time of recruitment,
* Ovarian cysts more than 5cm,
* Abnormal menorrhagia at the time of study recruitment,
* Abnormal liver function or active liver disease,
* Presence of neoplastic lesions of any type,
* Primary pituitary or ovarian failure (Type I and III World Health Organisation \[WHO\] Infertility)
* Patients with previous treatment with ovulation inducing agents such as follicle stimulating hormone (FSH) and luteinising hormone releasing hormone-analogues (LHRH-analogues);
* Infertility due to other endocrine abnormalities such as hyperprolactinaemia, hypo/hyperthyroidism, premature ovarian failure, diabetes or male factor
* Allergy to clomiphene.
* Fallopian tubal pathology (hydrosalpinges, previous salpingectomies)
* Patients on any drugs with potential to interact with CYP2D6 such as the selective serotonin receptor uptake inhibitors (ex. Venlafaxine, paroxitene, fluoxetine)

Primary outcomes:
measure: Achievement of successful ovulation
timeFrame: Day 20-23 of menses cycle
Secondary outcomes:
Other outcomes:
Locations:
city: Singapore
country: Singapore
facility: KK Women's and Children's Hospital
Study officials:
affiliation: KK Women's and Children's Hospital
name: Jerry Chan, MB BCh BaO (Hons) MA,FRCOG,PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Ghobadi C, Gregory A, Crewe HK, Rostami-Hodjegan A, Lennard MS. CYP2D6 is primarily responsible for the metabolism of clomiphene. Drug Metab Pharmacokinet. 2008;23(2):101-5. doi: 10.2133/dmpk.23.101.
citation: Rostami-Hodjegan A, Lennard MS, Tucker GT, Ledger WL. Monitoring plasma concentrations to individualize treatment with clomiphene citrate. Fertil Steril. 2004 May;81(5):1187-93. doi: 10.1016/j.fertnstert.2003.07.044.
citation: Murdter TE, Kerb R, Turpeinen M, Schroth W, Ganchev B, Bohmer GM, Igel S, Schaeffeler E, Zanger U, Brauch H, Schwab M. Genetic polymorphism of cytochrome P450 2D6 determines oestrogen receptor activity of the major infertility drug clomiphene via its active metabolites. Hum Mol Genet. 2012 Mar 1;21(5):1145-54. doi: 10.1093/hmg/ddr543. Epub 2011 Nov 22.