Primary Ovarian InsufficiencyPOINCT05327283
Investigation of Copy Number Variations and Genetic Variants in POI
An observational study of Primary Ovarian Insufficiency, run by Ospedale Policlinico San Martino at 1 site in Italy.
Trial summary
Primary ovarian insufficiency (POI), also known as premature ovarian failure, is an ovarian defect characterized by the premature (before the age of 40 years) depletion of ovarian follicles. POI affects about 1% of women, reaching 30% in some familial cases. Read more about this study
- Who is it for?
- Ages 15 to 38 years, women only
- Conditions the study is for
- Primary Ovarian Insufficiency
- How many people
- 100 participants
- Where
- 1 siteItaly
- Study dates
- 31 Jan 2012to 31 Dec 2030
- Phase
- Observational
- Are there results?
- Not yet: the study is under way
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 15 to 38 years
- Women only
- Child, Adult
Study population: Idiopathic, sporadic and familial POI cases.
Who may be able to join
- age at diagnosis <38 years;
- a normal 46,XX karyotype (no FRM1 premutation);
- at least one marker of ovarian reserve not age-appropriate:
- baseline FSH levels > cut-off [1] and/or
- age-specific AMH < cut-off [2] and/or
- AFC < 5; and/or
- cancellation of a PMA cycle because of poor response (<3 follicles) to high-dose gonadotrophins (250 U/die) and/or
- retrieval of < 4 oocytes in response to high-dose stimulation protocols (3000 U of gonadotrophins).
Who cannot join
- patients with POI-related conditions, such as ovarian surgery or previous chemo- or radio-therapy; endometriosis or known autoimmune or metabolic diseases.
Trial locations and contacts
1 site in 1 country. Contact the study team or a site near you to ask about taking part.
Paola Scaruffi, PhD contact
Italy1 site, 1 recruiting
- Recruiting
UOS Fisiopatologia della Riuproduzione Umana
Genova
Paola Scaruffi, PhD, paola.scaruffi@hsanmartino.it
Sara Stigliani, PhD
About this study
Official title: Insight Into the Genomics of Idiopathic Premature Ovarian Insufficiency
Primary ovarian insufficiency (POI), also known as premature ovarian failure, is an ovarian defect characterized by the premature (before the age of 40 years) depletion of ovarian follicles. POI affects about 1% of women, reaching 30% in some familial cases.
This heterogeneous disorder is characterized by progressive cessation of the ovarian function with temporary or intermittent amenorrhea associated with elevated serum FSH concentration and low AMH dosage. Low serum AMH dosage is able to detect a diminished ovarian pool occurring before the onset of FSH elevation and the ultimate deficiency leading to amenorrhea.
Read more
POI causes infertility and a poor ovarian response in IVF stimulations, and it has important health consequences for affected patients, including psychological distress, infertility, osteoporosis, autoimmune disorders, ischaemic heart disease.
Although the cause of POI remains unknown in about 80% of the cases, several mechanisms have been proposed to explain ovarian dysfunction. Currently, a wide spectrum of causes has been linked to POI, including genetic, autoimmune, infectious, or iatrogenic ones.
Genetic causes are highly heterogeneous and might explain at least some of the sporadic idiopathic cases, which comprise 50-90% of cases. Ten to fifteen percent of cases are X-linked abnormalities, mainly Turner Syndrome (45,X) or X structural abnormalities such as X deletions, X inversions, isochromosomes or X-autosome translocations. Also fragile X mental retardation 1 (FMR1) gene permutation (defined as having 55 to 200 CGG repeats in the 5' untranslated region of the gene) is another frequent genetic etiology.
Irrespectively, the majority of cases remains idiopathic, and identifying precise causative genes for POI has been challenging.
Read the detailed description
Although in the last decades an increasing number of aberrant genes involved in POI were identified, currently only a minority of affected women can be explained at gene level. Elucidating the biology of the premature declining ovarian function is paramount to develop better testing and treatment strategies for affected women in the future.
Importantly, two clinical features remain unexplained: i) the overall sporadic nature of POI, and ii) observations of patients harboring the identical mutation yet developing POI either early in life (puberty) or later (< 40 years old). Therefore, the investigators postulate that defects affecting more than one gene might explain this variability. Based on investigators' preliminary data and literature reports, it is likely that a synergistic effect of several variant/gene abnormalities may underlie the idiopathic POI phenotype.
The investigators hypothesize that different genome-wide strategies (namely, high resolution array-CGH and WES) may discover genetic variants without the limitation of a single candidate or a panel of candidates, and thus are more promising for explanation of the genetic heterogeneity of POI and elucidating the pathogenic mechanisms.
- Conditions
- Primary Ovarian Insufficiency
- Keywords
- Premature ovarian failure, array-CGH, NGS
- Medical subject headings
- Primary Ovarian Insufficiency
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
| Study group | Role | What they receive |
|---|---|---|
| Sporadic POI | Idiopathic, sporadic POI Caucasian cases. The inclusion criteria will be: * age at diagnosis <38 years; * a normal 46,XX karyotype (no FRM1 premutation); * at least one marker of ovarian reserve not age-appropriate: * baseline FSH levels > cut-off [1] and/or * age-specific AMH < cut-off [2] and/or * AFC < 5; and/or * cancellation of a PMA cycle because of poor response (<3 follicles) to high-dose gonadotrophins (250 U/die) and/or * retrieval of < 4 oocytes in response to high-dose stimulation protocols (3000 U of gonadotrophins). | |
| Familial POI | Familial POI cases and not-affected members of pedigrees. |
What is being measured
The primary outcome is the main question the study is designed to answer.
Identification of putative POI-related genes.
Genomic imbalances (<5 Mb in size: copy number variations (CNVs) as micro-deletions and micro-duplications) will be detected in sporadic idiopathic POI patients with the purpose to clarify the role of CNVs in POI pathogenesis and to better unveil both novel candidate genes and pathogenic mechanisms
Measured: Year 1-20
Identification of genetic variants co-segregated with phenotype.
Novel genetic variants not previously anticipated will be found: given the variants co-segregate with phenotype, whole-exome sequencing approach in consanguineous and POI pedigrees will identify the causative gene and variants that cause the phenotype.
Measured: Year 1-20
To combine array-CGH and WES data mining.
The cumulative effect of different genes/variants will be considered in support of the polygenicity of POI and its heterogeneous phenotype (primarily, the sporadic and familial ones).
Measured: Year 1-20
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted14 Apr 2022
- Study start31 Jan 2012
- Primary completion31 Dec 2030 (estimated)
- Study completion31 Dec 2030 (estimated)
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Primary Ovarian InsufficiencyStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Observational
- Observational model
- Cohort
- Time perspective
- Prospective
- Enrolment
- 100 participants (estimated)
Sponsor and investigators
- Lead sponsor
- Ospedale Policlinico San Martino
- Sponsor type
- University, hospital or other
- Responsible party
- Principal investigator, Scaruffi, Ospedale Policlinico San Martino
- Investigators
- Paola Scaruffi, Principal investigator, Ospedale San MartinoPaola Anserini, Study director, Ospedale San Martino
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT05327283
- Sponsor's protocol ID
- POI genome
- Acronym
- POI
- Status last verified
- Apr 2022
- First submitted
- 17 Mar 2022
- Last updated
- 25 Apr 2022
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
- Individual data sharing
- Undecided
Study at a glance
From the registry record, last updated by the sponsor on 25 Apr 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Insight Into the Genomics of Idiopathic Premature Ovarian Insufficiency
- ClinicalTrials.gov ID
- NCT05327283
- Acronym / sponsor ID
- POI / POI genome
- Conditions
- Primary Ovarian Insufficiency
- Keywords
- Premature ovarian failure, array-CGH, NGS
- Study type
- Observational
- Recruitment status
- Recruiting
- Enrolment
- 100 participants (estimated)
- Lead sponsor
- Ospedale Policlinico San MartinoUniversity, hospital or other
- Study start
- 31 Jan 2012
- Primary completion
- 31 Dec 2030 (estimated)
- Study completion
- 31 Dec 2030 (estimated)
- First posted
- 14 Apr 2022 (actual)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
Primary ovarian insufficiency (POI), also known as premature ovarian failure, is an ovarian defect characterized by the premature (before the age of 40 years) depletion of ovarian follicles. POI affects about 1% of women, reaching 30% in some familial cases.
This heterogeneous disorder is characterized by progressive cessation of the ovarian function with temporary or intermittent amenorrhea associated with elevated serum FSH concentration and low AMH dosage. Low serum AMH dosage is able to detect a diminished ovarian pool occurring before the onset of FSH elevation and the ultimate deficiency leading to amenorrhea.
POI causes infertility and a poor ovarian response in IVF stimulations, and it has important health consequences for affected patients, including psychological distress, infertility, osteoporosis, autoimmune disorders, ischaemic heart disease.
Although the cause of POI remains unknown in about 80% of the cases, several mechanisms have been proposed to explain ovarian dysfunction. Currently, a wide spectrum of causes has been linked to POI, including genetic, autoimmune, infectious, or iatrogenic ones.
Genetic causes are highly heterogeneous and might explain at least some of the sporadic idiopathic cases, which comprise 50-90% of cases. Ten to fifteen percent of cases are X-linked abnormalities, mainly Turner Syndrome (45,X) or X structural abnormalities such as X deletions, X inversions, isochromosomes or X-autosome translocations. Also fragile X mental retardation 1 (FMR1) gene permutation (defined as having 55 to 200 CGG repeats in the 5' untranslated region of the gene) is another frequent genetic etiology.
Irrespectively, the majority of cases remains idiopathic, and identifying precise causative genes for POI has been challenging.
Detailed description
Although in the last decades an increasing number of aberrant genes involved in POI were identified, currently only a minority of affected women can be explained at gene level. Elucidating the biology of the premature declining ovarian function is paramount to develop better testing and treatment strategies for affected women in the future.
Importantly, two clinical features remain unexplained: i) the overall sporadic nature of POI, and ii) observations of patients harboring the identical mutation yet developing POI either early in life (puberty) or later (< 40 years old). Therefore, the investigators postulate that defects affecting more than one gene might explain this variability. Based on investigators' preliminary data and literature reports, it is likely that a synergistic effect of several variant/gene abnormalities may underlie the idiopathic POI phenotype.
The investigators hypothesize that different genome-wide strategies (namely, high resolution array-CGH and WES) may discover genetic variants without the limitation of a single candidate or a panel of candidates, and thus are more promising for explanation of the genetic heterogeneity of POI and elucidating the pathogenic mechanisms.
Study design
- Observational model
- Cohort
- Time perspective
- Prospective
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Sporadic POI | – | –Idiopathic, sporadic POI Caucasian cases. The inclusion criteria will be: * age at diagnosis <38 years; * a normal 46,XX karyotype (no FRM1 premutation); * at least one marker of ovarian reserve not age-appropriate: * baseline FSH levels > cut-off [1] and/or * age-specific AMH < cut-off [2] and/or * AFC < 5; and/or * cancellation of a PMA cycle because of poor response (<3 follicles) to high-dose gonadotrophins (250 U/die) and/or * retrieval of < 4 oocytes in response to high-dose stimulation protocols (3000 U of gonadotrophins). |
| Familial POI | – | –Familial POI cases and not-affected members of pedigrees. |
Who may qualify
- Ages
- 15 to 38 years
- Sex
- Female only
- Age groups
- Child, Adult
- Study population
- Idiopathic, sporadic and familial POI cases.
Key inclusion criteria (8 listed)
- age at diagnosis <38 years;
- a normal 46,XX karyotype (no FRM1 premutation);
- at least one marker of ovarian reserve not age-appropriate:
- cancellation of a PMA cycle because of poor response (<3 follicles) to high-dose gonadotrophins (250 U/die) and/or
- retrieval of < 4 oocytes in response to high-dose stimulation protocols (3000 U of gonadotrophins).
Key exclusion criteria (1 listed)
- patients with POI-related conditions, such as ovarian surgery or previous chemo- or radio-therapy; endometriosis or known autoimmune or metabolic diseases.
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Primary outcome
Identification of putative POI-related genes.
Time frame: Year 1-20
Genomic imbalances (<5 Mb in size: copy number variations (CNVs) as micro-deletions and micro-duplications) will be detected in sporadic idiopathic POI patients with the purpose to clarify the role of CNVs in POI pathogenesis and to better unveil both novel candidate genes and pathogenic mechanisms
Identification of genetic variants co-segregated with phenotype.
Time frame: Year 1-20
Novel genetic variants not previously anticipated will be found: given the variants co-segregate with phenotype, whole-exome sequencing approach in consanguineous and POI pedigrees will identify the causative gene and variants that cause the phenotype.
To combine array-CGH and WES data mining.
Time frame: Year 1-20
The cumulative effect of different genes/variants will be considered in support of the polygenicity of POI and its heterogeneous phenotype (primarily, the sporadic and familial ones).
Results and safety
This study is still under way. Results are not available in the source record yet.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 25 Apr 2022.
- Individual participant dataSharing planned: Undecided
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part.
Paola Scaruffi, PhD contact
Paola Scaruffi principal investigator
Ospedale San Martino
Paola Anserini study director
Ospedale San Martino
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
An observational study of Primary Ovarian Insufficiency, run by Ospedale Policlinico San Martino at 1 site in Italy.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 8 inclusion and 1 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: looking for participants now, as of the sponsor's last update on 25 Apr 2022. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in Italy. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
This study is still under way. Results are not available in the source record yet.
How can a doctor refer a patient or contact the research team?
Contact Paola Scaruffi, PhD (paola.scaruffi@hsanmartino.it), or a site near the patient. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Identification of putative POI-related genes. (time frame: Year 1-20). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 25 Apr 2022.