Phospholamban R14del CardiomyopathyDECIPHER-PLNNCT04978987
Identification of Disease Specific Pathways and Modifiers in Phospholamban R14del Cardiomyopathy
An observational study of Phospholamban R14del Cardiomyopathy and Heart Failure, run by University Medical Center Groningen at 1 site in Netherlands.
Trial summary
Background A specific mutation in phospholamban (the PLN R14del mutation), has its origin in the northern parts of the Netherlands (Figure) and causes a severe lethal dilated and/or an arrhythmogenic cardiomyopathy. A large proportion of the population of Groningen (1:1000) carries this mutation. Read more about this study
- Who is it for?
- Ages 18 years and olderHealthy volunteers can take part
- Conditions the study is for
- Phospholamban R14del Cardiomyopathy, Heart Failure, Cardiomyopathy, Familial
- How many people
- 103 participants
- Where
- 1 siteNetherlands
- Study dates
- 1 Nov 2020to 1 May 2023
- 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 years and older
- All sexes
- Healthy volunteers accepted
- Adult, Older adult
Study population: The population consists of patients with PLN R14del, end-stage ACM or DCM, and non-R14del family members of the PLN r14del patients. For this study, we will include 90 PLN R14del carriers, subdivided in 30 end-stage R14del patients, 30 early abnormal and 30 unaffected family members with the PLN R14del mutation and 10 ACM, 10 DCM and 10 PLN R14del cardiomyopathy patients undergoing LVAD or HTx surgery. Finally, we will recruit a total of 5 PLN R14del cardiomyopathy patients and 5 unaffected (non-R14del) family members for the skeletal muscle biopsy collection alone.
Who may be able to join
- A minimum age of 18.
- Of adequate communication.
- Informed consent is obtained.
- Genetically confirmed r14del mutation in PLN, family member or other DCM/ACM
Who cannot join
- Known allergy for local anaesthetics.
- Other subgroup specific exclusion criteria.
Trial locations and contacts
1 site in 1 country.
About this study
Background
A specific mutation in phospholamban (the PLN R14del mutation), has its origin in the northern parts of the Netherlands (Figure) and causes a severe lethal dilated and/or an arrhythmogenic cardiomyopathy. A large proportion of the population of Groningen (1:1000) carries this mutation. Until now, there is no specific treatment available for patients with PLN cardiomyopathy. Patients are treated like any other type of heart failure patients, although PLN cardiomyopathy has a different etiology from "usual" heart failure. Treatment is therefore insufficient; malignant ventricular arrhythmias and end-stage heart failure at a young age are very prevalent. To develop treatment options, the investigators aim to study the following knowledge gaps:
Read more
- Pathophysiology. The clinical phenotype of PLN R14del cardiomyopathy bears characteristics of both arrhythmogenic and dilated cardiomyopathy (ACM and DCM). Using an "omics" approach of plasma, cardiac and skeletal muscle of patients and controls, the investigators aim to reveal distinct pathways affected by the mutant PLN, unique to the PLN R14del cardiomyopathy. This will be related to clinical data and mutant PLN expression levels in both cardiac and skeletal muscle biopsies. Using this extensive profiling, the investigators aim to identify disease mechanisms and provide the context for future risk stratification and disease progression monitoring.
- Penetrance. Subjects with a heterozygous PLN R14del mutation show a wide variety in phenotype. Within the same family, patients can present either with over heart failure in their 20's or completely asymptomatic until at least their 70's. So far, no modifiers have been identified. The investigators will study cardiomyocytes derived from induced pluripotent stem cells from patients who are severely affected versus family members who are unaffected but carry the mutation.
- Treatment response. The investigators have identified potential treatments, and confirmed their efficacy in in vivo models of PLN cardiomyopathy. To establish their efficacy in a human setting, the investigators will generate 3D cardiac tissues of cardiomyocytes gathered from induced pluripotent stem cells of patients affected in varying degrees and subject these tissues to the treatment.
Methods:
For the above purposes, the investigators will collect and analyze the following data/materials:
- Serum and plasma of 90 PLN R14del carriers: 30 unaffected, 30 early affected and 30 end stage.
- Skin biopsy of 20 PLN R14del carriers: 10 unaffected, 10 end stage.
- Cardiac muscle biopsy (obtained during left ventricular assist device [LVAD]/ heart transplant [HTx] surgery) of 30 patients: 10 R14del, 10 arrhythmogenic cardiomyopathy, 10 dilating cardiomyopathy.
- Skeletal muscle biopsy of 10 patients: 5 R14del, 5 non R14del family members
- Medical subject headings
- Heart Failure, Cardiomyopathies
What is being measured
The primary outcome is the main question the study is designed to answer.
The level of proteins in circulating blood and cardiac- and skeletal muscle tissue
An in-dept analyses of an extensive set of proteins assessed using large scale proteomic techniques to assess differences in individual protein levels and the total proteome of the circulating blood, cardiac tissue and skeletal muscle tissue of patients clinically differentially affected by the PLN R14del mutant protein.
Measured: At baseline visit
The level of metabolites in circulating blood and cardiac- and skeletal muscle tissue
An in-dept analyses of an extensive set of metabolites assessed using large scale metabolomic techniques to assess differences in individual metabolite levels and the total metabolome of the circulating blood, cardiac tissue and skeletal muscle tissue of patients clinically differentially affected by the PLN R14del mutant protein
Measured: At baseline visit
The level of mRNA in circulating blood and cardiac- and skeletal muscle tissue
An in-dept analyses of an extensive set of mRNA transcripts assessed using large scale transcriptomic techniques to assess differences in individual mRNA levels and the total transcriptome of the circulating blood, cardiac tissue and skeletal muscle tissue of patients clinically differentially affected by the PLN R14del mutant protein
Measured: At baseline visit
The level of DNA methylation in cardiac muscle tissue
An in-dept analyses of differences in individual DNA methylation levels and patterns of cardiac tissue of patients clinically differentially affected by the PLN R14del mutant protein
Measured: At baseline visit
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted27 Jul 2021
- Study start1 Nov 2020
- Primary completion1 May 2023
- Study completion1 May 2023
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for Phospholamban R14del CardiomyopathyStudies of the same condition, open and under way.
- More trials run by University Medical Center GroningenThe 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
- Other
- Time perspective
- Cross-sectional
- Enrolment
- 103 participants (actual)
Sponsor and investigators
- Lead sponsor
- University Medical Center Groningen
- Sponsor type
- University, hospital or other
- Collaborators
- AstraZeneca
- Responsible party
- Sponsor
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT04978987
- Sponsor's protocol ID
- 202000350 / 202000351
- Acronym
- DECIPHER-PLN
- Status last verified
- Aug 2023
- First submitted
- 18 Jan 2021
- Last updated
- 25 Aug 2023
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- No
- FDA-regulated device
- No
Study at a glance
From the registry record, last updated by the sponsor on 25 Aug 2023. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- Identification of Disease Specific Pathways and Modifiers in Phospholamban R14del Cardiomyopathy
- ClinicalTrials.gov ID
- NCT04978987
- Acronym / sponsor ID
- DECIPHER-PLN / 202000350 / 202000351
- Study type
- Observational
- Recruitment status
- Completed
- Enrolment
- 103 participants (actual)
- Lead sponsor
- University Medical Center GroningenUniversity, hospital or other
- Collaborators
- AstraZeneca
- Study start
- 1 Nov 2020 (actual)
- Primary completion
- 1 May 2023 (actual)
- Study completion
- 1 May 2023 (actual)
- First posted
- 27 Jul 2021 (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.
Background
A specific mutation in phospholamban (the PLN R14del mutation), has its origin in the northern parts of the Netherlands (Figure) and causes a severe lethal dilated and/or an arrhythmogenic cardiomyopathy. A large proportion of the population of Groningen (1:1000) carries this mutation. Until now, there is no specific treatment available for patients with PLN cardiomyopathy. Patients are treated like any other type of heart failure patients, although PLN cardiomyopathy has a different etiology from "usual" heart failure. Treatment is therefore insufficient; malignant ventricular arrhythmias and end-stage heart failure at a young age are very prevalent. To develop treatment options, the investigators aim to study the following knowledge gaps:
- Pathophysiology. The clinical phenotype of PLN R14del cardiomyopathy bears characteristics of both arrhythmogenic and dilated cardiomyopathy (ACM and DCM). Using an "omics" approach of plasma, cardiac and skeletal muscle of patients and controls, the investigators aim to reveal distinct pathways affected by the mutant PLN, unique to the PLN R14del cardiomyopathy. This will be related to clinical data and mutant PLN expression levels in both cardiac and skeletal muscle biopsies. Using this extensive profiling, the investigators aim to identify disease mechanisms and provide the context for future risk stratification and disease progression monitoring.
- Penetrance. Subjects with a heterozygous PLN R14del mutation show a wide variety in phenotype. Within the same family, patients can present either with over heart failure in their 20's or completely asymptomatic until at least their 70's. So far, no modifiers have been identified. The investigators will study cardiomyocytes derived from induced pluripotent stem cells from patients who are severely affected versus family members who are unaffected but carry the mutation.
- Treatment response. The investigators have identified potential treatments, and confirmed their efficacy in in vivo models of PLN cardiomyopathy. To establish their efficacy in a human setting, the investigators will generate 3D cardiac tissues of cardiomyocytes gathered from induced pluripotent stem cells of patients affected in varying degrees and subject these tissues to the treatment.
Methods:
For the above purposes, the investigators will collect and analyze the following data/materials:
- Serum and plasma of 90 PLN R14del carriers: 30 unaffected, 30 early affected and 30 end stage.
- Skin biopsy of 20 PLN R14del carriers: 10 unaffected, 10 end stage.
- Cardiac muscle biopsy (obtained during left ventricular assist device [LVAD]/ heart transplant [HTx] surgery) of 30 patients: 10 R14del, 10 arrhythmogenic cardiomyopathy, 10 dilating cardiomyopathy.
- Skeletal muscle biopsy of 10 patients: 5 R14del, 5 non R14del family members
Study design
- Observational model
- Other
- Time perspective
- Cross-sectional
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Accepted
- Age groups
- Adult, Older adult
- Study population
- The population consists of patients with PLN R14del, end-stage ACM or DCM, and non-R14del family members of the PLN r14del patients. For this study, we will include 90 PLN R14del carriers, subdivided in 30 end-stage R14del patients, 30 early abnormal and 30 unaffected family members with the PLN R14del mutation and 10 ACM, 10 DCM and 10 PLN R14del cardiomyopathy patients undergoing LVAD or HTx surgery. Finally, we will recruit a total of 5 PLN R14del cardiomyopathy patients and 5 unaffected (non-R14del) family members for the skeletal muscle biopsy collection alone.
Key inclusion criteria (4 listed)
- A minimum age of 18.
- Of adequate communication.
- Informed consent is obtained.
- Genetically confirmed r14del mutation in PLN, family member or other DCM/ACM
Key exclusion criteria (2 listed)
- Known allergy for local anaesthetics.
- Other subgroup specific exclusion criteria.
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
The level of proteins in circulating blood and cardiac- and skeletal muscle tissue
Time frame: At baseline visit
An in-dept analyses of an extensive set of proteins assessed using large scale proteomic techniques to assess differences in individual protein levels and the total proteome of the circulating blood, cardiac tissue and skeletal muscle tissue of patients clinically differentially affected by the PLN R14del mutant protein.
The level of metabolites in circulating blood and cardiac- and skeletal muscle tissue
Time frame: At baseline visit
An in-dept analyses of an extensive set of metabolites assessed using large scale metabolomic techniques to assess differences in individual metabolite levels and the total metabolome of the circulating blood, cardiac tissue and skeletal muscle tissue of patients clinically differentially affected by the PLN R14del mutant protein
The level of mRNA in circulating blood and cardiac- and skeletal muscle tissue
Time frame: At baseline visit
An in-dept analyses of an extensive set of mRNA transcripts assessed using large scale transcriptomic techniques to assess differences in individual mRNA levels and the total transcriptome of the circulating blood, cardiac tissue and skeletal muscle tissue of patients clinically differentially affected by the PLN R14del mutant protein
The level of DNA methylation in cardiac muscle tissue
Time frame: At baseline visit
An in-dept analyses of differences in individual DNA methylation levels and patterns of cardiac tissue of patients clinically differentially affected by the PLN R14del mutant protein
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 25 Aug 2023.
Related trials for Phospholamban R14del Cardiomyopathy
RecruitingPhase 1
A Study of AZD4063 in PLN R14del Dilated Cardiomyopathy
Dilated Cardiomyopathy
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.
The record lists no contact. Use the official record to reach the sponsor.
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 Phospholamban R14del Cardiomyopathy and Heart Failure, run by University Medical Center Groningen at 1 site in Netherlands.
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 4 inclusion and 2 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 25 Aug 2023. 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 Netherlands. 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?
The level of proteins in circulating blood and cardiac- and skeletal muscle tissue (time frame: At baseline visit). The study lists 4 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 Aug 2023.