To Study The Influence Of Genomic Factors On Metabolism And Effects Of Clomiphene In Asian Normogonadotrophic Anovulatory Patients.

To Study The Influence Of Pharmacogenomics Factors On Pharmacokinetics And Pharmacodynamics Of Clomiphene In Asian Normogonadotrophic Anovulatory Patients.

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.

Study Overview

• Status: Completed
• Conditions: Infertility, Female

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.

• Study Type: Observational
• Enrollment (Actual): 124

Contacts and Locations

Study Locations

• Singapore
  • Singapore, Singapore, 229899
    • KK Women's and Children's Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 43 years (Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: Female

• Sampling Method: Non-Probability Sample

Study Population

Asian Normogonadotrophic Anovulatory Women

Description

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)

Study Plan

How is the study designed?

Design Details

• Observational Models: Cohort
• Time Perspectives: Prospective

Number of groups / cohorts

1

Cohorts and Interventions

Group / Cohort
Asian Normogonadotrophic Anovulatory Women; Asian women with normal gonadotropin levels but do not ovulate.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Achievement of successful ovulation	Successful ovulation is defined as a mid-luteal phase serum progesterone level of >20 nmol/L.	Day 20-23 of menses cycle

Collaborators and Investigators

• Sponsor: KK Women's and Children's Hospital
• Collaborators: National Cancer Centre, Singapore
• Investigators: Principal Investigator: Jerry Chan, MB BCh BaO (Hons) MA,FRCOG,PhD, KK Women's and Children's Hospital

Publications and helpful links

General Publications

• 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.
• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: January 1, 2015
• Primary Completion (Actual): March 1, 2017
• Study Completion (Actual): May 1, 2018

Study Registration Dates

• First Submitted: September 8, 2015
• First Submitted That Met QC Criteria: September 10, 2015
• First Posted (Estimate): September 14, 2015

Study Record Updates

• Last Update Posted (Actual): August 7, 2018
• Last Update Submitted That Met QC Criteria: August 5, 2018
• Last Verified: June 1, 2018

More Information

Terms related to this study

• Keywords: Anovulatory; Clomiphene
• Additional Relevant MeSH Terms: Endocrine System Diseases; Ovarian Diseases; Adnexal Diseases; Gonadal Disorders; Infertility; Infertility, Female; Anovulation
• Other Study ID Numbers: 2014/RM/001

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Undecided

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No