Long QT SyndromeFetal LQTSNCT02876380
Prospective Identification of Long QT Syndrome in Fetal Life
An observational study of Long QT Syndrome, run by University of Colorado, Denver at 1 site in United States.
Trial summary
The postnatal diagnosis of Long QT Syndrome (LQTS) is suggested by a prolonged QT interval on 12 lead electrocardiogram (ECG), strengthened by a positive family history and/or characteristic arrhythmias and confirmed by genetic testing. Read more about this study
- Who is it for?
- Ages 18 to 45 years
- Conditions the study is for
- Long QT Syndrome
- How many people
- 25 participants
- Where
- 1 siteUnited States
- Study dates
- Nov 2014to 8 Jul 2019
- Phase
- Observational
- Are there results?
- None posted in the registry
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 18 to 45 years
- All sexes
- No healthy volunteers
- Adult
Study population: Up to 500 total subjects will be enrolled globally. Up to 303 subjects will be enrolled locally. This number includes mothers, fetuses, and fathers who have long QT syndrome.
Who may be able to join
- 18-45 years of age
- Pregnant women with a previously identified mutation in a known LQTS gene or pregnant women whose partner (and the father of the baby) has a previously identified mutation in a known LQTS gene will be invited to participate. If the pregnant partner of a man with a LQTS gene is enrolled, then the man/father of child will be enrolled as well.
- Women at 7-30 weeks of gestation
- 18-45 years of age
- Women with a previous pregnancy and a known LQTS gene or where the father of the baby had a known LQTS gene
- Women with a mutation in a known LQTS gene, or
- Women whose partner/father of the baby has a mutation in a known LQTS gene (The father of the child will be enrolled if mother of child is enrolled)
Who cannot join
- Phenotype positive but genotype negative pregnant woman or father of the fetus,
- Fetuses with congenital or chromosomal anomaly identified before or after birth
- Pregnant women who present beyond 30 weeks of pregnancy.
- Phenotype positive but genotype negative pregnant woman or father of the fetus,
- Fetuses with congenital or chromosomal anomaly identified before or after birth
- Fetal heart rate data unavailable prior to 30 weeks of pregnancy
Trial locations and contacts
1 site in 1 country.
United States1 site
Children's Hospital Colorado
Aurora, Colorado, 80045
About this study
The postnatal diagnosis of Long QT Syndrome (LQTS) is suggested by a prolonged QT interval on 12 lead electrocardiogram (ECG), strengthened by a positive family history and/or characteristic arrhythmias and confirmed by genetic testing. However, for several reasons such LQTS testing cannot be performed successfully before birth. First, fetal ECG is not possible and direct measure of the fetal QT interval by magnetocardiography is limited to fewer than 10 sites world-wide. Second, while genetic testing can be performed in utero, there is risk to the pregnancy and the fetus. Third, although some fetuses present with arrhythmias easily recognized as LQTS (torsade des pointes (TdP) and/or 2° atrioventricular (AV) block, this is uncommon, occurring in <25% of fetal LQTS cases. Rather, the most common presentation of fetal LQTS is sinus bradycardia, a subtle rhythm disturbance that often is unappreciated to be abnormal. Consequently, the majority of LQTS cases are unsuspected and undiagnosed during fetal life, with dire consequences. For example, maternal medications commonly used during pregnancy can prolong the fetal QT interval and may provoke lethal fetal ventricular arrhythmias. But the most significant consequence is the missed opportunity for primary prevention of life threatening ventricular arrhythmias after birth because the infant is not suspected to have LQTS before birth. The over-arching goal of the study is to overcome the barriers to prenatal detection of LQTS. The investigators plan to do so by developing an algorithm using fetal heart rate (FHR) which will discriminate fetuses with or without LQTS.
Immediate Goal: The investigators propose a multicenter pre-birth observational cohort study to develop a Fetal Heart Rate (FHR)/Gestational Age (GA) algorithm from a cohort of fetuses recruited from 13 national and international centers where one parent is known by prior genetic testing to have a mutation in one of the common LQTS genes: potassium voltage-gated channel subfamily Q member 1 (KCNQ1), potassium voltage-gated channel subfamily H member 2 (KCNH2), or sodium voltage-gated channel alpha subunit 5 (SCN5A). The investigators have chosen this population because 1) These mutations are the most common genetic causes of LQTS, and 2) Offspring will have high risk of LQTS as inheritance of these LQTS gene mutations is autosomal dominant. Thus, progeny of parents with a known mutation are at high (50%) risk of having the same parental LQTS mutation. The algorithm will be developed using FHR measured serially throughout pregnancy. All offspring will undergo postnatal genetic testing for the parental mutation as the gold standard for diagnosing the presence or absence of LQTS.
Read the detailed description
Ascertainment of LQTS, an inherited arrhythmia disorder in a group of conditions known as the channelopathies, is challenging before birth. Recently, in a retrospective study it was reported that a gestational age dependent bradycardia allows a much higher recognition of genotype positive LQTS than the standard obstetrical gestational age independent definition of bradycardia (Mitchell 2012).
However, the fetal heart rate in pregnancies with maternal or paternal LQTS diagnosed prior to the pregnancy has not been evaluated prospectively from the first trimester to birth. Nor is it known if the fetal heart rate /gestational age profile might be mutation specific. In addition, the use of fetal heart rate to successfully distinguish between LQTS and normal fetuses of pregnancies in which a parent has a known mutation has not been tested.
The investigators believe that fetuses with an LQTS mutation born to families in which the mother or father has an LQTS mutation will have slower heart compared to fetuses, shown after birth not to have the family mutation. If the investigators hypothesis is correct, these findings could be applied to the general population of pregnant women to prospectively identify fetuses with LQTS and without a known family history. Since a fetal proband has been led to the identification of unsuspecting family members, prospectively identifying affected fetuses would increase ascertainment of life-threatening mutations in all ages (Cuneo 2013).
- Conditions
- Long QT Syndrome
- Medical subject headings
- Long QT Syndrome
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 |
|---|---|---|
| Prospective cohort | These are women who are currently pregnant and who have a LQTS mutation. This also includes women whose partner/father of the baby has a LQTS mutation. If the father of the child has the LQTS mutation, the father will also be enrolled. | |
| Retrospective cohort | In this cohort the investigators will collect information about previous pregnancies affected by the LQTS mutation. Parents may enroll in both retrospective and prospective cohorts |
What is being measured
The primary outcome is the main question the study is designed to answer.
Effectiveness of an Fetal Heart Rate/Gestational Age, FHR/GA, Algorithm
The investigators hypothesize that from this fetal cohort, they can construct a FHR/GA algorithm that will discriminate fetuses who inherit the parental LQTS mutation from those who do not, with an area under the ROC ≥0.75.
Measured: 5 years
Differences in the Receiver Operating Characteristic (ROC) of FHR/GA vs gold standard of genetic testing
The area under the ROC of the FHR/GA algorithm compared to a gold standard of genetic testing will remain ≥0.75 across mutation types and offspring sex. Based on power calculations using preliminary studies, the investigators estimate they can test this hypothesis by study of 200 fetal subjects.
Measured: 5 years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted23 Aug 2016 (estimated)
- Study startNov 2014
- Primary completion8 Jul 2019
- Study completion8 Jul 2019
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Long QT SyndromeStudies of the same condition, open and under way.
- More trials run by University of Colorado, DenverThe sponsor's other registered studies.
- 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
- Other
- Enrolment
- 25 participants (actual)
Sponsor and investigators
- Lead sponsor
- University of Colorado, Denver
- Sponsor type
- University, hospital or other
- Collaborators
- Children's Hospital Colorado, University of Pavia, University of Utah, Mayo Clinic, University of Helsinki, University of Amsterdam, University of Oslo, University Hospital, Umeå, Deutsches Herzzentrum Muenchen, Vanderbilt University, University of Bonn, University of Tsukuba, Eastern Virginia Medical School
- Responsible party
- Sponsor
- Investigators
- Bettina F Cuneo, MD, Principal investigator, University of Colorado, Denver
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02876380
- Sponsor's protocol ID
- 13-3129
- Acronym
- Fetal LQTS
- Status last verified
- Feb 2022
- First submitted
- 8 Aug 2016
- Last updated
- 21 Feb 2022
- Results posted
- No
- Data monitoring committee
- No
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 21 Feb 2022. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Prospective Identification of Long QT Syndrome in Fetal Life
- ClinicalTrials.gov ID
- NCT02876380
- Acronym / sponsor ID
- Fetal LQTS / 13-3129
- Conditions
- Long QT Syndrome
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 25 participants (actual)
- Lead sponsor
- University of Colorado, DenverUniversity, hospital or other
- Collaborators
- Children's Hospital Colorado, University of Pavia, University of Utah, Mayo Clinic, University of Helsinki, University of Amsterdam, University of Oslo, University Hospital, Umeå, Deutsches Herzzentrum Muenchen, Vanderbilt University, University of Bonn, University of Tsukuba, Eastern Virginia Medical School
- Study start
- Nov 2014 (actual)
- Primary completion
- 8 Jul 2019 (actual)
- Study completion
- 8 Jul 2019 (actual)
- First posted
- 23 Aug 2016 (estimated)
- 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.
The postnatal diagnosis of Long QT Syndrome (LQTS) is suggested by a prolonged QT interval on 12 lead electrocardiogram (ECG), strengthened by a positive family history and/or characteristic arrhythmias and confirmed by genetic testing. However, for several reasons such LQTS testing cannot be performed successfully before birth. First, fetal ECG is not possible and direct measure of the fetal QT interval by magnetocardiography is limited to fewer than 10 sites world-wide. Second, while genetic testing can be performed in utero, there is risk to the pregnancy and the fetus. Third, although some fetuses present with arrhythmias easily recognized as LQTS (torsade des pointes (TdP) and/or 2° atrioventricular (AV) block, this is uncommon, occurring in <25% of fetal LQTS cases. Rather, the most common presentation of fetal LQTS is sinus bradycardia, a subtle rhythm disturbance that often is unappreciated to be abnormal. Consequently, the majority of LQTS cases are unsuspected and undiagnosed during fetal life, with dire consequences. For example, maternal medications commonly used during pregnancy can prolong the fetal QT interval and may provoke lethal fetal ventricular arrhythmias. But the most significant consequence is the missed opportunity for primary prevention of life threatening ventricular arrhythmias after birth because the infant is not suspected to have LQTS before birth. The over-arching goal of the study is to overcome the barriers to prenatal detection of LQTS. The investigators plan to do so by developing an algorithm using fetal heart rate (FHR) which will discriminate fetuses with or without LQTS.
Immediate Goal: The investigators propose a multicenter pre-birth observational cohort study to develop a Fetal Heart Rate (FHR)/Gestational Age (GA) algorithm from a cohort of fetuses recruited from 13 national and international centers where one parent is known by prior genetic testing to have a mutation in one of the common LQTS genes: potassium voltage-gated channel subfamily Q member 1 (KCNQ1), potassium voltage-gated channel subfamily H member 2 (KCNH2), or sodium voltage-gated channel alpha subunit 5 (SCN5A). The investigators have chosen this population because 1) These mutations are the most common genetic causes of LQTS, and 2) Offspring will have high risk of LQTS as inheritance of these LQTS gene mutations is autosomal dominant. Thus, progeny of parents with a known mutation are at high (50%) risk of having the same parental LQTS mutation. The algorithm will be developed using FHR measured serially throughout pregnancy. All offspring will undergo postnatal genetic testing for the parental mutation as the gold standard for diagnosing the presence or absence of LQTS.
Detailed description
Ascertainment of LQTS, an inherited arrhythmia disorder in a group of conditions known as the channelopathies, is challenging before birth. Recently, in a retrospective study it was reported that a gestational age dependent bradycardia allows a much higher recognition of genotype positive LQTS than the standard obstetrical gestational age independent definition of bradycardia (Mitchell 2012).
However, the fetal heart rate in pregnancies with maternal or paternal LQTS diagnosed prior to the pregnancy has not been evaluated prospectively from the first trimester to birth. Nor is it known if the fetal heart rate /gestational age profile might be mutation specific. In addition, the use of fetal heart rate to successfully distinguish between LQTS and normal fetuses of pregnancies in which a parent has a known mutation has not been tested.
The investigators believe that fetuses with an LQTS mutation born to families in which the mother or father has an LQTS mutation will have slower heart compared to fetuses, shown after birth not to have the family mutation. If the investigators hypothesis is correct, these findings could be applied to the general population of pregnant women to prospectively identify fetuses with LQTS and without a known family history. Since a fetal proband has been led to the identification of unsuspecting family members, prospectively identifying affected fetuses would increase ascertainment of life-threatening mutations in all ages (Cuneo 2013).
Study design
- Observational model
- Cohort
- Time perspective
- Other
- Number of arms
- 2
| Arm | Type | Receives |
|---|---|---|
| Prospective cohort | – | –These are women who are currently pregnant and who have a LQTS mutation. This also includes women whose partner/father of the baby has a LQTS mutation. If the father of the child has the LQTS mutation, the father will also be enrolled. |
| Retrospective cohort | – | –In this cohort the investigators will collect information about previous pregnancies affected by the LQTS mutation. Parents may enroll in both retrospective and prospective cohorts |
Who may qualify
- Ages
- 18 to 45 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult
- Study population
- Up to 500 total subjects will be enrolled globally. Up to 303 subjects will be enrolled locally. This number includes mothers, fetuses, and fathers who have long QT syndrome.
Key inclusion criteria (7 listed)
- 18-45 years of age
- Pregnant women with a previously identified mutation in a known LQTS gene or pregnant women whose partner (and the father of the baby) has a previously identified mutation in a known LQTS gene will be invited to participate. If the pregnant partner of a man with a LQTS gene is enrolled, then the man/father of child will be enrolled as well.
- Women at 7-30 weeks of gestation
- 18-45 years of age
- Women with a previous pregnancy and a known LQTS gene or where the father of the baby had a known LQTS gene
Key exclusion criteria (6 listed)
- Phenotype positive but genotype negative pregnant woman or father of the fetus,
- Fetuses with congenital or chromosomal anomaly identified before or after birth
- Pregnant women who present beyond 30 weeks of pregnancy.
- Phenotype positive but genotype negative pregnant woman or father of the fetus,
- Fetuses with congenital or chromosomal anomaly identified before or after birth
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
Effectiveness of an Fetal Heart Rate/Gestational Age, FHR/GA, Algorithm
Time frame: 5 years
The investigators hypothesize that from this fetal cohort, they can construct a FHR/GA algorithm that will discriminate fetuses who inherit the parental LQTS mutation from those who do not, with an area under the ROC ≥0.75.
Differences in the Receiver Operating Characteristic (ROC) of FHR/GA vs gold standard of genetic testing
Time frame: 5 years
The area under the ROC of the FHR/GA algorithm compared to a gold standard of genetic testing will remain ≥0.75 across mutation types and offspring sex. Based on power calculations using preliminary studies, the investigators estimate they can test this hypothesis by study of 200 fetal subjects.
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Feb 2022.
- Individual participant dataSharing planned: No
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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. This study is not recruiting at the moment.
Bettina F Cuneo, MD principal investigator
University of Colorado, Denver
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 Long QT Syndrome, run by University of Colorado, Denver at 1 site in United States.
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 7 inclusion and 6 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: finished, as of the sponsor's last update on 21 Feb 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 United States. 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?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Effectiveness of an Fetal Heart Rate/Gestational Age, FHR/GA, Algorithm (time frame: 5 years). The study lists 2 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 21 Feb 2022.