Mutation-specific Therapy for the Long QT Syndrome

  • STATUS
    Recruiting
  • End date
    Dec 31, 2023
  • participants needed
    20
  • sponsor
    Istituto Auxologico Italiano
Updated on 1 September 2021
electrocardiogram
hypertension
heart failure
heart disease
holter monitor
myocarditis
beta blockers
fibrillation
electrocardiographic monitoring
atrial flutter

Summary

Novel therapy for the Long QT Syndrome based on the mechanism of action of the disease-causing mutations

Long QT syndrome type 2 (LQT2) accounts for ~ 35% of all LQTS cases and is difficult to manage, as beta-blockers frequently fail to provide full protection. Most LQT2 patients (pts) have a Class 2 mutation, which implies defective "trafficking".

Lumacaftor (LUM) is a drug developed and currently indicated for the treatment of cystic fibrosis (CF) in patients homozygous for the F508del mutation in the CFTR gene. LUM corrects protein folding and trafficking defects of mutant and misfolded CFTR channels, restoring their cell surface expression. The investigators recently demonstrated that LUM can rescue in vitro the LQTS phenotype observed in human induced pluripotent stem cell- derived cardiomyocytes (hiPSC-CMs) from pts with LQT2 Class 2 mutations (PMID: 29020304) and in these same two patients Orkambi administrated for 7 days at the same dosage approved for cystic fibrosis showed to reduce their QTc (PMID: 30753398).

With the present phase II clinical trial (MAST2) the investigators will enroll 20 LQT2 patients (see inclusion and exclusion criteria) and they will test in vivo the efficacy of Orkambi in shortening their QTc. Patients will be admitted to hospital for a maximum of 7 days (minimum in-hospital stay based on evidence of QTc shortening). Orkambi will be administered at the dose approved for cystic fibrosis and during the entire period continuous ECG monitoring through both telemetry and 12-lead 24-hr Holter monitoring will be performed and QTc length and morphology will be analyzed.

Description

The congenital Long QT Syndrome (LQTS) is a life-threatening condition characterized by a prolonged QT interval on the electrocardiogram, and an increased risk of life-threating arrhythmias in otherwise healthy individuals. Typically, the heart is structurally normal and the electric abnormality present in these patients is due to mutations in genes encoding ion channel subunits or proteins modulating ion-channel function. The investigators will specifically study the LQT2 variant which is the second most common form of LQTS (30-35% of all LQTS cases), a rare condition present in approximately 1 in 7.500-8.000 live births characterized by loss-of-function mutations in the KCNH2 gene (hERG) which result in a reduction of the potassium current IKr, pivotal for ventricular repolarization. Four different mutation classes define the molecular mechanisms impairing hERG. Among these, almost 50% are class 2 mutations that determine hERG trafficking defects, with the consequent lack of expression of these essential ion channels on the cardiomyocyte membrane.

According to clinical severity current therapies for LQT2 include -blockers, left cardiac sympathetic denervation and an implantable cardioverter defibrillator (ICD). However, ICD implantation, is not devoid of complications and often, the pain and fear associated with ICD shocks lead to electrical storms with multiple recurrent shocks. Furthermore, there are concerns about the long-term impact of implanting an ICD in young LQTS patients, likely to live another 7 to 8 decades after initial device implantation and who would be subjected to multiple procedures for generator replacement and lead revisions/extractions with frequent complications. There is a clear and unmet need for additional therapeutic strategies and implementation of gene-specific therapy could represent a quite important step for improving the clinical management of these pts.

Lumacaftor (LUM) is a drug developed and currently indicated for the treatment of cystic fibrosis (CF) in patients aged 12 years and older who are homozygous for the F508del mutation in the CFTR gene. By acting as a chaperone, LUM corrects protein folding and trafficking defects of mutant and misfolded CFTR channels, restoring their cell surface expression. In its commercial formulation - brand name Orkambi - it is combined with ivacaftor (IVA), an enhancer of the CFTR protein function. The recommended dose is two tablets (each tablet containing LUM 200 mg/ IVA 125 mg) taken orally every 12 hours for a total daily dose of LUM 800 mg/ IVA 500 mg.

The investigators recently demonstrated that LUM can rescue in vitro the LQTS phenotype observed in human induced pluripotent stem cell- derived cardiomyocytes (hiPSC-CMs) from patients with LQT2 Class 2 mutations (PMID: 29020304) and in these same two patients Orkambi administrated for 7 days at the same dosage approved for cystic fibrosis showed to reduce their QTc (PMID: 30753398).

With the present phase II clinical trial (MAST2) 20 LQT2 patients will be enrolled (see inclusion and exclusion criteria). Patients will be admitted to hospital for a maximum of 7 days (minimum in-hospital stay based on evidence of QTc shortening) while beta-blocker therapy will continue at the current dose. Orkambi will be administered at the dose approved for cystic fibrosis [Orkambi (Lumacaftor 200 mg/Ivacaftor 125 mg) 2 tablets twice a day for a total daily dose of 800 mg of Lumacaftor and 500 mg of Ivacaftor] and blood exams will be performed at day 1, 3, 5 and 7. During the entire period continuous ECG monitoring through both telemetry and 12-lead 24-hr Holter monitoring will be performed and QTc length and morphology will be analysed. Independently of the result the patient will be discharged without Orkambi as a chronic therapy. Therefore, the drug will be administered orally for a maximum of 7 days.

In case of side effects a reduction of the dose will be considered and according to the specific problem the possibility of an interruption will be evaluated. Furthermore, as an additional "stopping rule" the patient can freely decide to withdraw from the study in any moment even during the Hospitalization phase.

Compliance will be strictly monitored as the drug will be assumed in Hospital in front of the nurse twice a day for the maximum of 7 days. Placebo will not be used.

Details
Condition Long QT Syndrome, Arrhythmia, Congenital Heart Defect, Congenital Heart Disease, Heart Defect, Dysrhythmia
Treatment Lumacaftor / Ivacaftor, Orkambi® Oral Tablet
Clinical Study IdentifierNCT04581408
SponsorIstituto Auxologico Italiano
Last Modified on1 September 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Hypersensitivity to the active substance (to one or both active substances) or to one of the excipients
Pregnancy (established before enrollment by positive urine pregnancy test in potentially fertile women) or breastfeeding
Participation in a clinical study in which an experimental drugs has been administered less than 30 days or less than 5 half-lives before the present study drug
Any clinical condition that in the opinion of the investigator causes the patients not to be suitable for the study and/or that may involve an unreasonable/significant risk for the participants, thereby changing the interpretation of that data and affecting the continuation of the study
Other important cardiac diseases and in particular: cardiomyopathies and myocarditis, pericardial diseases, other associated channelopathies, ischemic heart disease, heart failure, pulmonary heart disease, severe valuvulopathies, rhythm alterations such as atrial fibrillation or atrial flutter, complete right or left bundle branch block, advanced atrio-ventricular blocks, uncontrolled arterial hypertension on beta-blocker therapy
Significant extracardiac diseases and in particular
renal failure. In accordance with the SmPC, patients with severe (estimated GFR <30 mL/min/1.73 m2) and moderate (estimated GFR 30-60 mL/min/1.73 m2) renal impairment at screening are excluded
impairment of liver function. In accordance with the SmPC, patients with severe (Child-Pugh Class C) and moderate (Child-Pugh Classe B) liver function impairment are excluded
important diseases of the respiratory system and in particular: any pulmonitis, obstructive bronchopulmonary disease with FEV1 <80%, asthmatic bronchitis, infiltrative lung disease, lung emboly, pulmonary hypertension, idiopathic pulmonary fibrosis, pneumothorax, neoplasms of lungs and pleura
important neurological diseases and in particular: epilepsy, cerebral hemorrhage, stroke, multiple sclerosis, cerebral tumours, cerebral or spinal traumas, Parkinson's disease, cognitive deterioration and Alzheimer's disease
Chronic use of therapies other than beta-blocker treatment and intake of any potassium/magnesium supplement that the patient may use chronically or intermittently (oral contraceptives are allowed, but must be interrupted during the study)
Clear my responses

How to participate?

Step 1 Connect with a study center
What happens next?
  • You can expect the study team to contact you via email or phone in the next few days.
  • Sign up as volunteer to help accelerate the development of new treatments and to get notified about similar trials.

You are contacting

Investigator Avatar

Primary Contact

site

0/250

Additional screening procedures may be conducted by the study team before you can be confirmed eligible to participate.

Learn more

If you are confirmed eligible after full screening, you will be required to understand and sign the informed consent if you decide to enroll in the study. Once enrolled you may be asked to make scheduled visits over a period of time.

Learn more

Complete your scheduled study participation activities and then you are done. You may receive summary of study results if provided by the sponsor.

Learn more

Similar trials to consider

Loading...

Browse trials for

Not finding what you're looking for?

Every year hundreds of thousands of volunteers step forward to participate in research. Sign up as a volunteer and receive email notifications when clinical trials are posted in the medical category of interest to you.

Sign up as volunteer

user name

Added by • 

 • 

Private

Reply by • Private
Loading...

Lorem ipsum dolor sit amet consectetur, adipisicing elit. Ipsa vel nobis alias. Quae eveniet velit voluptate quo doloribus maxime et dicta in sequi, corporis quod. Ea, dolor eius? Dolore, vel!

  The passcode will expire in None.
Loading...

No annotations made yet

Add a private note
  • abc Select a piece of text from the left.
  • Add notes visible only to you.
  • Send it to people through a passcode protected link.
Add a private note