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Evaluation of the Effects of KCNQ1 Mutation on Insulin Tolerance and Obsessive Compulsive Features in Long QT Romano-Ward Syndrome Patients. (PRIME)

Primary Purpose

Romano-Ward Syndrome, Long QT Syndrome, Compulsive Behavior

Status
Unknown status
Phase
Not Applicable
Locations
France
Study Type
Interventional
Intervention
Cognitive assessment of obsessive-compulsive and impulsive behaviours
Genomic analysis
Glucoregulation assessment
Sponsored by
Biotrial
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Romano-Ward Syndrome focused on measuring Romano-Ward Syndrome, Long QT Syndrome, Insulin-related diseases, Compulsive Behavior, ASBQ, CHIRP, OCI-R, UPPS-P, CPT, GWAS, Healthy individuals, KCNQ1 mutations

Eligibility Criteria

18 Years - 48 Years (Adult)All SexesAccepts Healthy Volunteers

Inclusion Criteria:

  • In the investigator's opinion, the subject is generally healthy based on their medical records (subjects with KCNQ1 mutation only), medical history, physical examination, vital signs, body weight, ECG (except long QT if applicable), and based on the results of haematology, clinical chemistry, urinalysis, urine drug screen (UDS) and serology;
  • Subjects with a KCNQ1 mutation: genotyped as having a mutation on the KCNQ1 gene with or without phenotypic manifestation of long QT syndrome;
  • Relatives of subjects with a KCNQ1 mutation: KCNQ1-mutated family relatives (with or without phenotypic expression) of a subject carrying a KCNQ1 mutation (Romano-Ward patients or subjects without phenotypic manifestation of long QT syndrome);
  • Relatives of subjects with a KCNQ1 mutation must live in a different household than the subject with the KCNQ1 mutation;
  • All subjects: negative UDS by dipstick analysis: opiates, methadone, cocaine, amphetamines (including ecstasy), barbiturates, benzodiazepines, and cannabinoids at admission to the assessment visit;
  • All subjects: negative alcohol breath test at admission to the assessment visit.

Exclusion Criteria:

  • All subjects: having taken within 1 year before the assessment visit or currently taking any of the following medications: a. Antidiabetics: metformin, pioglitazone, acarbose, miglitol, sitagliptin, vildagliptin, saxagliptin, exenatide, liraglutide, semaglutide, repaglinide, nateglinide, insulin. b. Medications interfering with the central nervous system (CNS) such as any antipsychotic, antidepressant or regular use of anxiolytic medications > once a week, or any attention deficit/hyperactivity disorder (ADHD) medication (e.g. methylphenidate);
  • Healthy subjects and relatives of subjects with a KCNQ1 mutation not phenotypically affected: any of the following on a de novo ECG: a. Heart rate (HR) < 40 bpm or > 100 bpm; b. PR interval <120 msec; c. Abnormal repolarization; d. QT interval corrected for HR using Fridericia's formula (QTcF) > 450 msec for male subjects or > 470 msec for female subjects.

Sites / Locations

  • L'Institut du Thorax, Nantes HospitalRecruiting
  • Biotrial Clinical Unit

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Sham Comparator

Arm Label

KCNQ1 mutated subjects

Healthy subjects

Arm Description

This arm includes : KCNQ1-mutated subjects with long QT Romano-Ward syndrome KCNQ1-mutated subjects without phenotypic expression of the Romano-Ward syndrome family relatives of a KCNQ1-mutated enrolled subject, carrying the KCNQ1 family mutation

Healthy subjects will be matched to KCNQ1 subjects. The matching factors will be age per decade (18-28 years, > 28-38 years, > 38-48 years), gender and body mass index (BMI: ≤ 24.9 kg/m2; 25-29.9 kg/m2; > 30 kg/m2).

Outcomes

Primary Outcome Measures

Outcome related to glucoregulation : fasted glycemia
Plasma glucose concentration
Outcome related to glucoregulation : fasted insulin levels
Plasma insulin concentration
Outcome related to glucoregulation : glycated haemoglobin (HbA1c)
Blood HbA1c concentration
Outcome related to glucoregulation : glycemia 2hours following an oral glucose challenge
Plasma glucose concentration

Secondary Outcome Measures

Obsessive Compulsive Inventory-Revised (OCI-R) questionnaire total score and subscale scores
Subscales of OCI-R: washing, obsessing, hoarding, ordering, checking, neutralising
Adult Social Behaviour Questionnaire (ASBQ) total score and subscale scores
Subscales of ASBQ : reduced contacts, reduced empathy, reduced interpersonal insight, violations of social conventions, insistence of sameness, sensory stimulation and motor stereotypies.
Urgency, Premeditation, Perseverance, Sensation seeking, and Positive urgency scale (UPPS-P) subscale scores
Subscales of UPPS-P: negative urgency, lack of premeditation, lack of perseverance, sensation-seeking, positive urgency
Childhood Retrospective Perfectionism Questionnaire (CHIRP) total score
Total score
Continuous Performance Task (CPT)
Variables of the CPT : omission errors, commission errors/false alarms, hits, hit rate, hit reaction time, difference between hit rate and false alarms rate (d').

Full Information

First Posted
January 15, 2021
Last Updated
January 15, 2021
Sponsor
Biotrial
Collaborators
European Union, Nantes University Hospital
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1. Study Identification

Unique Protocol Identification Number
NCT04715256
Brief Title
Evaluation of the Effects of KCNQ1 Mutation on Insulin Tolerance and Obsessive Compulsive Features in Long QT Romano-Ward Syndrome Patients.
Acronym
PRIME
Official Title
Interventional Study With Low Risks and Constraints on the Effect of KCNQ1 Mutation (Romano-Ward Syndrome) on Insulin Tolerance and Obsessive Compulsive Features, a Cross-sectional Study With Matched Controls With an Attempt of Linkage to Whole Genome Scanning.
Study Type
Interventional

2. Study Status

Record Verification Date
January 2021
Overall Recruitment Status
Unknown status
Study Start Date
January 8, 2021 (Actual)
Primary Completion Date
December 2021 (Anticipated)
Study Completion Date
December 2021 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Biotrial
Collaborators
European Union, Nantes University Hospital

4. Oversight

Studies a U.S. FDA-regulated Drug Product
No
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
No

5. Study Description

Brief Summary
The objectives of the study are to investigate if KCNQ1 mutation in Romano-Ward long QT patients can be associated with changes in insulin regulation and with psychological features of compulsivity, impulsivity and behavioural rigidity.
Detailed Description
Romano-Ward Syndrome (RWS) is a rare disorder characterized by prolongation of the QT interval, as well as T-wave abnormalities and possibly polymorphic ventricular fibrillation. RWS is inherited in an autosomal dominant fashion. Mutations in the potassium voltage-gated channel subfamily Q Member 1 (KCNQ1), potassium voltage-gated channel subfamily H member 2 (KCNH2), sodium voltage-gated channel alpha subunit 5 (SCN5A), potassium voltage-gated channel subfamily E regulatory subunit 1 (KCNE1), and potassium voltage-gated channel subfamily E regulatory subunit 2 (KCNE2) genes are known to be causative, and these five genes together are responsible for virtually 100% of cases of RWS. Dysregulation of insulin signalling has been implicated in multimorbidity across the lifespan, in particular in type 2 diabetes, metabolic syndrome, obesity and RWS. Numerous studies have shown a relationship between RWS and hyperinsulinemia. More recently, altered insulin signalling has also been implicated in neurodegenerative brain disorders, dementias and Alzheimer's disease. Diseases characterized by dysregulation of insulin signalling (i.e. insulinopathies) present a major health, societal, and economic burden. These insulin signalling-associated diseases are mostly chronic, and with limited or absent curative treatments. At the current time, the recognition and clinical management of insulin comorbidity remains poorly established; brain-based comorbidity is generally neglected, and medical efforts are only devoted to the management of the primary, somatic diagnosis. The present study will be a part of the European Union (EU)-funded PRIME (for Prevention and Remediation of Insulin Multimorbidity in Europe) research program, which primary goal is to identify and specify the molecular mechanisms underlying the insulin multimorbidities through investigation of the diseases that cause the highest burden and costs to patients and society, and to outline new directions for research and clinical care thereof. The primary hypothesis of the PRIME project is that comorbidity observed in these somatic diseases (DM2, metabolic syndrome, obesity, RWS) is a result of dysregulated central and peripheral insulin signalling, downstream of synaptic dysfunction and of learning, memory, and executive functions impairments. This non-competitive EU Horizon2020 project will study the role of KCNQ1, a key molecule in insulin regulation, in the insulinopathies across different levels of organismal organisation. The study will include 50 KCNQ1-mutated subjects (mainly RWS patients but also subjects carrying the KCNQ1 mutation but without phenotypic manifestation of long QT syndrome, and, because of the strong interest of the PRIME project in genetic analyses, family relatives carrying the same KCNQ1 mutation) and 50 matched healthy subjects. By comparing the test population to healthy subjects, the main objective of the trial is to test the hypothesis of an involvement of KCNQ1 in compulsivity, impulsivity and cognitive rigidity. The insulin regulation evaluations will be performed by measuring glucose, insulin and glycated haemoglobin (HbA1c) in subjects. Compulsivity, impulsivity and behavioural rigidity will be assessed using 4 neuropsychological questionnaires (OCI-R, ASBQ, UPPS-P, CHIRP) and one objective test, the CPT. Moreover, DNA extraction will be performed in order to search for associations between mutations, insulin regulation and psychological features in conducting a Genome-Wide Association Study (GWAS) (exploratory objective).

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Romano-Ward Syndrome, Long QT Syndrome, Compulsive Behavior, Healthy Individuals
Keywords
Romano-Ward Syndrome, Long QT Syndrome, Insulin-related diseases, Compulsive Behavior, ASBQ, CHIRP, OCI-R, UPPS-P, CPT, GWAS, Healthy individuals, KCNQ1 mutations

7. Study Design

Primary Purpose
Basic Science
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
100 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
KCNQ1 mutated subjects
Arm Type
Experimental
Arm Description
This arm includes : KCNQ1-mutated subjects with long QT Romano-Ward syndrome KCNQ1-mutated subjects without phenotypic expression of the Romano-Ward syndrome family relatives of a KCNQ1-mutated enrolled subject, carrying the KCNQ1 family mutation
Arm Title
Healthy subjects
Arm Type
Sham Comparator
Arm Description
Healthy subjects will be matched to KCNQ1 subjects. The matching factors will be age per decade (18-28 years, > 28-38 years, > 38-48 years), gender and body mass index (BMI: ≤ 24.9 kg/m2; 25-29.9 kg/m2; > 30 kg/m2).
Intervention Type
Behavioral
Intervention Name(s)
Cognitive assessment of obsessive-compulsive and impulsive behaviours
Intervention Description
The content of the assessment will be the same for all subjects and will consist of a cognitive assessment (attention, impulsivity) and a clinical assessment (impulsive behaviour, autistic traits,obsessive-compulsive behaviour).
Intervention Type
Genetic
Intervention Name(s)
Genomic analysis
Intervention Description
A genome-wide association study (GWAS) will be performed for all subjects to search for associations between KCNQ1 mutations, insulin regulation and psychological features.
Intervention Type
Diagnostic Test
Intervention Name(s)
Glucoregulation assessment
Intervention Description
Fasted glycaemia and insulinaemia, glycated haemoglobin (HbA1c) and glycaemia following an oral glucose challenge test will be measured in all study subjects.
Primary Outcome Measure Information:
Title
Outcome related to glucoregulation : fasted glycemia
Description
Plasma glucose concentration
Time Frame
15 minutes
Title
Outcome related to glucoregulation : fasted insulin levels
Description
Plasma insulin concentration
Time Frame
15 minutes
Title
Outcome related to glucoregulation : glycated haemoglobin (HbA1c)
Description
Blood HbA1c concentration
Time Frame
15 minutes
Title
Outcome related to glucoregulation : glycemia 2hours following an oral glucose challenge
Description
Plasma glucose concentration
Time Frame
2 hours
Secondary Outcome Measure Information:
Title
Obsessive Compulsive Inventory-Revised (OCI-R) questionnaire total score and subscale scores
Description
Subscales of OCI-R: washing, obsessing, hoarding, ordering, checking, neutralising
Time Frame
30 minutes
Title
Adult Social Behaviour Questionnaire (ASBQ) total score and subscale scores
Description
Subscales of ASBQ : reduced contacts, reduced empathy, reduced interpersonal insight, violations of social conventions, insistence of sameness, sensory stimulation and motor stereotypies.
Time Frame
30 minutes
Title
Urgency, Premeditation, Perseverance, Sensation seeking, and Positive urgency scale (UPPS-P) subscale scores
Description
Subscales of UPPS-P: negative urgency, lack of premeditation, lack of perseverance, sensation-seeking, positive urgency
Time Frame
30 minutes
Title
Childhood Retrospective Perfectionism Questionnaire (CHIRP) total score
Description
Total score
Time Frame
30 minutes
Title
Continuous Performance Task (CPT)
Description
Variables of the CPT : omission errors, commission errors/false alarms, hits, hit rate, hit reaction time, difference between hit rate and false alarms rate (d').
Time Frame
1 hour
Other Pre-specified Outcome Measures:
Title
Genomic analyses (GWAS)
Description
DNA methylation status at the KCNQ1 locus and Polygenic Risk Scores (PRS)
Time Frame
15 minutes

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
48 Years
Accepts Healthy Volunteers
Accepts Healthy Volunteers
Eligibility Criteria
Inclusion Criteria: In the investigator's opinion, the subject is generally healthy based on their medical records (subjects with KCNQ1 mutation only), medical history, physical examination, vital signs, body weight, ECG (except long QT if applicable), and based on the results of haematology, clinical chemistry, urinalysis, urine drug screen (UDS) and serology; Subjects with a KCNQ1 mutation: genotyped as having a mutation on the KCNQ1 gene with or without phenotypic manifestation of long QT syndrome; Relatives of subjects with a KCNQ1 mutation: KCNQ1-mutated family relatives (with or without phenotypic expression) of a subject carrying a KCNQ1 mutation (Romano-Ward patients or subjects without phenotypic manifestation of long QT syndrome); Relatives of subjects with a KCNQ1 mutation must live in a different household than the subject with the KCNQ1 mutation; All subjects: negative UDS by dipstick analysis: opiates, methadone, cocaine, amphetamines (including ecstasy), barbiturates, benzodiazepines, and cannabinoids at admission to the assessment visit; All subjects: negative alcohol breath test at admission to the assessment visit. Exclusion Criteria: All subjects: having taken within 1 year before the assessment visit or currently taking any of the following medications: a. Antidiabetics: metformin, pioglitazone, acarbose, miglitol, sitagliptin, vildagliptin, saxagliptin, exenatide, liraglutide, semaglutide, repaglinide, nateglinide, insulin. b. Medications interfering with the central nervous system (CNS) such as any antipsychotic, antidepressant or regular use of anxiolytic medications > once a week, or any attention deficit/hyperactivity disorder (ADHD) medication (e.g. methylphenidate); Healthy subjects and relatives of subjects with a KCNQ1 mutation not phenotypically affected: any of the following on a de novo ECG: a. Heart rate (HR) < 40 bpm or > 100 bpm; b. PR interval <120 msec; c. Abnormal repolarization; d. QT interval corrected for HR using Fridericia's formula (QTcF) > 450 msec for male subjects or > 470 msec for female subjects.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Valerie Bertaina-Anglade, PhD
Phone
+33 (0)2 99 59 91 91
Email
Valerie.Bertaina-Anglade@biotrial.com
First Name & Middle Initial & Last Name or Official Title & Degree
Philippe Danjou, MD
Phone
+33 (0)9 75 51 88 82
Email
Philippe.Danjou@biotrial.com
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Sophie Hays, MD
Organizational Affiliation
Biotrial
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Probst Vincent, MD
Organizational Affiliation
Nantes University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
L'Institut du Thorax, Nantes Hospital
City
Nantes
ZIP/Postal Code
44000
Country
France
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Vincent Probst, MD
Phone
+33 (0)6 15 40 84 13
Email
vincent.probst@univ-nantes.fr
Facility Name
Biotrial Clinical Unit
City
Rennes
ZIP/Postal Code
35000
Country
France
Individual Site Status
Not yet recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Sophie Hays, MD
Phone
+33 (0)2 99 59 91 91
Email
Sophie.Hays@biotrial.com

12. IPD Sharing Statement

Plan to Share IPD
Yes
IPD Sharing Plan Description
All anonymized individual participant data will be shared within the PRIME consortium collaborators in accordance with the PRIME Consortium Agreement
IPD Sharing Time Frame
Individual participant data will be available starting in january 2023 and until december 2025
Citations:
PubMed Identifier
24357532
Citation
Torekov SS, Iepsen E, Christiansen M, Linneberg A, Pedersen O, Holst JJ, Kanters JK, Hansen T. KCNQ1 long QT syndrome patients have hyperinsulinemia and symptomatic hypoglycemia. Diabetes. 2014 Apr;63(4):1315-25. doi: 10.2337/db13-1454. Epub 2013 Dec 18.
Results Reference
background
PubMed Identifier
26854754
Citation
van de Vondervoort I, Poelmans G, Aschrafi A, Pauls DL, Buitelaar JK, Glennon JC, Franke B. An integrated molecular landscape implicates the regulation of dendritic spine formation through insulin-related signalling in obsessive-compulsive disorder. J Psychiatry Neurosci. 2016 Jun;41(4):280-5. doi: 10.1503/jpn.140327.
Results Reference
background
PubMed Identifier
31515486
Citation
van de Vondervoort IIGM, Amiri H, Bruchhage MMK, Oomen CA, Rustogi N, Cooper JD, van Asten JJA, Heerschap A, Bahn S, Williams SCR, Buitelaar JK, Poelmans G, Glennon JC. Converging evidence points towards a role of insulin signaling in regulating compulsive behavior. Transl Psychiatry. 2019 Sep 12;9(1):225. doi: 10.1038/s41398-019-0559-6.
Results Reference
background
PubMed Identifier
18444228
Citation
Southgate L, Tchanturia K, Collier D, Treasure J. The development of the childhood retrospective perfectionism questionnaire (CHIRP) in an eating disorder sample. Eur Eat Disord Rev. 2008 Nov;16(6):451-62. doi: 10.1002/erv.870.
Results Reference
background
PubMed Identifier
12501574
Citation
Foa EB, Huppert JD, Leiberg S, Langner R, Kichic R, Hajcak G, Salkovskis PM. The Obsessive-Compulsive Inventory: development and validation of a short version. Psychol Assess. 2002 Dec;14(4):485-96.
Results Reference
background
Citation
Lynam, D.R., Smith, G.T., Whiteside, S.P., Cyders, M.A. (2006). The UPPS-P: Assessing five personality pathways to impulsive behavior (Technical Report). West Lafayette: Purdue University.
Results Reference
background
Citation
Zermatten, A., Van der Linden, M., Jermann, F., Ceschi, G. Validation of a French version of the Obsessive-Compulsive Inventory-Revised in a non-clinical sample. (2006). Revue Européenne de Psychologie Appliquée. 56:151-155
Results Reference
background
Citation
Van der Linden, M., d'Acremont, M., Zermatten, A., Jermann, F., Laroi, F., Willems, S., Juillerat, A., Bechara, A. (2006). A French Adaptation of the UPPS Impulsive Behavior Scale: Confirmatory factor analysis in a sample of undergraduate students. Eur J Psychol Assess. 22:38-42.
Results Reference
background
PubMed Identifier
28083030
Citation
Fatima SS, Chaudhry B, Khan TA, Farooq S. KCNQ1 rs2237895 polymorphism is associated with Gestational Diabetes in Pakistani Women. Pak J Med Sci. 2016 Nov-Dec;32(6):1380-1385. doi: 10.12669/pjms.326.11052.
Results Reference
result
Links:
URL
https://prime-study.eu/
Description
Official website of the PRIME project
URL
https://www.biotrial.com/
Description
Biotrial's website

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Evaluation of the Effects of KCNQ1 Mutation on Insulin Tolerance and Obsessive Compulsive Features in Long QT Romano-Ward Syndrome Patients.

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