Pharmacogenetic Algorithm for Individualized Controlled Ovarian Stimulation

July 14, 2020 updated by: Matheus Roque, Clínica Origen

Pharmacogenetic Algorithm for Individualized Controlled Ovarian Stimulation (iCOS) in Assisted Reproductive Technology Cycles

In this study, the investigators will evaluate genetic variation or polymorphisms between individuals submitted to IVF/ICSI cycles, and how these variations influence response to COS and pregnancy outcomes. Thus, this project has the aim to develop a pharmacogenetic algorithm associating gene polymorphisms, the patient clinical information, and functional and hormonal biomarker to: 1) predict the patient response to gonadotropin; 2) develop individualized gonadotropin regimens; 3) improve the accuracy of determining appropriate dosages of gonadotrophins; 4) improve efficacy and patient compliance to COS; and finally 5) reduce the time-to-pregnancy.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Unknown

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Controlled ovarian stimulation (COS) is crucial for optimizing in vitro fertilization (IVF) / intracytoplasmic sperm injection (ICSI) success. Multiple factors influence the ovarian response to COS, making predictions about oocyte yields not so straightforward. As a result, ovarian response may be poor or suboptimal, or even excessive, all of which has negative consequences to the affected patient. The study of gene polymorphisms regulating the female reproductive function may help to clarify the mechanisms responsible for gonadal function and fertility, and also the inter-individual variability in ovarian response to COS.

The main objective of COS is obtaining an adequate number of good quality oocytes, and also minimize the adverse drug reactions and cycle cancellations due to a high or poor response. The ideal number of oocytes to optimize treatment outcomes has been subject of debate for many years. However, based on recent published data, it seems reasonable to define the optimal number of oocytes to be retrieved after an adequate COS as 10-15 oocytes. To perform an adequate COS, it has been suggested that the antral follicle count (AFC) and anti-müllerian hormone (AMH) are the best biomarkers to predict the ovarian response. Recently, two nomograms have been proposed for the calculation of the follicle stimulating hormone (FSH) starting dose for COS, taking into account different parameters, namely: 1) Age, AFC and day 3 serum FSH; and 2) Age, serum AMH and FSH. Meanwhile, these prediction models are not able to predict an unexpected poor response and also a higher and undesirable ovarian response to FSH monotherapy.

Considering the number of retrieved oocytes, it has been recently purposed a new patient stratification during ART treatments: poor response (1-3 oocytes); sub-optimal response (4-9 oocytes); normal response (10-15 oocytes); high response (>15 oocytes). The reason to create this new category of sub-optimal responder is that they have poorer outcomes during ART treatments when compared to patients that have 10-15 oocytes retrieved. This category of sub-optimal responder has led to the introduction of new concept in reproductive medicine with the objective to stratify low prognosis patients undergoing ART based on the combination of quantitative and qualitative parameters. There is a group of patients that although present normal biomarkers of ovarian reserve, such as AFC and AMH, they have a sub-optimal response to COS. They have 9 retrieved oocytes, showing the inadequacy of using only the traditional ovarian reserve biomarkers to predict the ovarian response. This sub-optimal response should be related to ovarian sensitivity to exogenous gonadotrophins modulated by genetic factors.

Hence, adoption of a pharmacogenetic approach in assisted reproduction seems attractive as it may help understanding the relationship between genetic variants and ovarian response to exogenous gonadotropins. The patient´s genetic profile could be used to select the most appropriate gonadotropin type, predict the optimal dosage for each drug, develop cost-effective treatment plan, maximize the success rates, and finally decrease the time-to-pregnancy.

The study of genetic polymorphisms is undoubtedly a promising field in reproductive medicine. The candidate genes that play a role in the ovarian response to COS are as follows: i) genes that affect follicular function by exerting a hormonal effect - FSH, FSHR, V-LH, AMH, AMHR2, ERα, ERβ, CYP17, CYP19, COMT, MTHFR, GnRH1, KISS1, and KISS1R; ii) genes that affect the rate of initial primordial follicle recruitment in relation to the pool of growing follicles - BMP15, GDF9, and FOXL2; and iii) genes that encode DNA binding proteins and transcription factors, such as LHX8 and NANOS3. Variations in these genes can determine the variability of the follicular pool and explain the variance of the COS response and the results of ART.

In modern reproductive medicine, where the individualization and personalized treatments should be the norm, optimizing and obtaining the best result in each COS would be of great interest to both clinicians and patients alike. Considering the variability of patients´ response to COS, it is clear inadequate to select the type of gonadotropin and its initial dose empirically or based only on clinical and hormonal parameters.

In this study, the investigators will evaluate genetic variation or polymorphisms between individuals submitted to IVF/ICSI cycles, and how these variations influence response to COS and pregnancy outcomes. Thus, this project has the aim to develop a pharmacogenetic algorithm associating gene polymorphisms, the patient clinical information, and functional and hormonal biomarker to: 1) predict the patient response to gonadotropin; 2) develop individualized gonadotropin regimens; 3) improve the accuracy of determining appropriate dosages of gonadotrophins; 4) improve efficacy and patient compliance to COS; and finally 5) reduce the time-to-pregnancy.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Anticipated)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
1350

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Not Applicable

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Contact

Study Contact

The name and contact information for the person who can answer enrollment questions for a clinical study. Each location where the study is being conducted may also have a specific contact, who may be better able to answer those questions.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 38 years (ADULT)

Accepts Healthy Volunteers

No

Genders Eligible for Study

Female

Description

Inclusion Criteria:

  • Females aged ≤38 years
  • AMH 1.2 ng/mL and AFC 5
  • Normal TSH and prolactin levels
  • The presence of both ovaries without morphological abnormalities
  • Ovulatory cycles with a mean duration between 25-35 days
  • BMI ≤30
  • No evidence of endocrine diseases such as hyperprolactinemia, thyroid dysfunction, or PCOS

Exclusion Criteria:

  • Females aged >38 years
  • PCOS patients
  • Moderate/severe endometriosis (grade III and IV)
  • Previous ovarian surgery
  • Previous radio/chemotherapy
  • Severe male factor infertility (severe oligozoospermia and nonobstructive azoospermia).

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: OTHER
  • Allocation: NON_RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
ACTIVE_COMPARATOR: Group 1
recombinant FSH starting dose: 100 IU to develop a pharmacogenetic test
Diagnostic test: Pharmacogenetic test
To develop a pharmacogenetic prediction test
ACTIVE_COMPARATOR: Group 2
recombinant FSH starting dose: 125 IU to develop a pharmacogenetic test
Diagnostic test: Pharmacogenetic test
To develop a pharmacogenetic prediction test
ACTIVE_COMPARATOR: Group 3
recombinant FSH starting dose: 150 IU to develop a pharmacogenetic test
Diagnostic test: Pharmacogenetic test
To develop a pharmacogenetic prediction test
ACTIVE_COMPARATOR: Group 4
recombinant FSH starting dose: 175 IU to develop a pharmacogenetic test
Diagnostic test: Pharmacogenetic test
To develop a pharmacogenetic prediction test
ACTIVE_COMPARATOR: Group 5
recombinant FSH starting dose: 200 IU to develop a pharmacogenetic test
Diagnostic test: Pharmacogenetic test
To develop a pharmacogenetic prediction test
ACTIVE_COMPARATOR: Group 6
recombinant FSH starting dose: 225 IU to develop a pharmacogenetic test
Diagnostic test: Pharmacogenetic test
To develop a pharmacogenetic prediction test

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Measure Description
Time Frame
Number of retrieved oocytes
Time Frame: It will be assessed on the 22th month after the first patient recruitment
The number of retrieved oocytes during an IVF treatment
It will be assessed on the 22th month after the first patient recruitment

Secondary Outcome Measures

Secondary Outcome Measures

In a clinical study's protocol, a planned outcome measure that is not as important as the primary outcome measure for evaluating the effect of an intervention but is still of interest. Most clinical studies have more than one secondary outcome measure.
Outcome Measure
Measure Description
Time Frame
Number of mature oocytes
Time Frame: It will be assessed on the 22th month after the first patient recruitment
The number of mature during an IVF treatment
It will be assessed on the 22th month after the first patient recruitment
Embryo quality - morphological classification
Time Frame: It will be assessed on the 22th month after the first patient recruitment
Assessment of morphological embryo quality in each group of patients
It will be assessed on the 22th month after the first patient recruitment
Ovarian Hyperstimulation Syndrome
Time Frame: It will be assessed on the 22th month after the first patient recruitment
The incidence of OHSS in each group of patients
It will be assessed on the 22th month after the first patient recruitment
Pregnancy Rate
Time Frame: It will be assessed on the 22th month after the first patient recruitment
The ratio between the number of positive pregnancy blood test and the number of patients submitted to and IVF cycle
It will be assessed on the 22th month after the first patient recruitment
Clinical Pregnancy Rate
Time Frame: It will be assessed on the 22th month after the first patient recruitment
The ratio between the number of patients with at least one gestational sac identified in an ultrasound scan and the number of patients submitted to and IVF cycle
It will be assessed on the 22th month after the first patient recruitment
Miscarriage Rate
Time Frame: It will be assessed on the 22th month after the first patient recruitment
The ratio between ongoing pregnancy and clinical pregnancy
It will be assessed on the 22th month after the first patient recruitment
Ongoing Pregnancy Rate
Time Frame: It will be assessed on the 22th month after the first patient recruitment
The ratio between the number of ongoing pregnancies in 12th week and the number of patients submitted to and IVF cycle
It will be assessed on the 22th month after the first patient recruitment
Live Birth Rate
Time Frame: It will be assessed on the 22th month after the first patient recruitment
The ratio between the number of live birth and the number of patients that started the treatment
It will be assessed on the 22th month after the first patient recruitment

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
Clínica Origen

Collaborators

Collaborators

An organization other than the sponsor that provides support for a clinical study. This support may include activities related to funding, design, implementation, data analysis, or reporting.
ANDROFERT - Clinica de Andrologia e Reproducao Humana
Faculdade de Medicina do ABC

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Matheus Roque, MD, ORIGEN - Center for Reproductive Medicine

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ANTICIPATED)

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
November 1, 2020

Primary Completion (ANTICIPATED)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
November 30, 2021

Study Completion (ANTICIPATED)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
November 30, 2022

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 4, 2017

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
May 10, 2017

First Posted (ACTUAL)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
May 11, 2017

Study Record Updates

Last Update Posted (ACTUAL)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 16, 2020

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 14, 2020

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2020

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • 64167716.9.1001.0082

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

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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