Mutation-specific Therapy for the Long QT Syndrome

NCT04581408 | Completed Phase 2

• 1 other identifier: 26A804
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 1

Brief 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.

Conditions

Long QT Syndrome

Keywords

Long QT syndrome; Sudden cardiac death; Channelopathy; Gene-specific therapy; Life-threatening arrhythmias

Outcome Measures

Primary Outcomes (1)

• QT interval

  Change in QT interval after drug treatment

  3 to 7 days after start of treatment

Study Arms (1)

Orkambi

EXPERIMENTAL

Generic name: Lumacaftor/Ivacaftor Dosage form: tablet Dosage: each tablet contains 200 mg of Lumacaftor and 125 mg of Ivacaftor Frequency: two tablets twice a day.

Drug: Lumacaftor / Ivacaftor, Orkambi® Oral Tablet

Interventions

Lumacaftor / Ivacaftor, Orkambi® Oral Tablet DRUG

Total daily dose: 800 mg of Lumacaftor and 500 mg of Ivacaftor. Duration of treatment: according to the clinical conditions of the patient and based on the response to the drugs: up to a maximum of 7 days

Also known as: Orkambi

Orkambi

Eligibility Criteria

• Age: 18 Years - 65 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Informed consent: it is requested that the partipants understand the nature of the study and can give their voluntary conset after being fully informed, after having received satisfying replies to their questions regarding the study, and all the authorizations according to local requirements. The informed consent form was previously approved by the local Ethics Committee and will have to be dated and signed before enrollment in the study.
• Age and gender: participants of both the male and female sex aged between 18 and 65 years will be included
• Mutations: the study will enrol patients with LQT2, i.e., with pathogenic mutations on the KCNH2 gene, that present such functional characterization that classifies them as class II mutations, namely mutations that cause a trafficking defect. This characterization includes, but is not limited to, patch clamp data in single cells, immunofluorescence data, positive reactions to drugs that correct the trafficking defect in vitro.
• Consent of the patient to not participate in any other clinical study during the entire period of participation in the present study
• Women with child-bearing potential (pre-menopausal women, less than two years after start of menopause and women who are not surgically sterile) must use a highly effective contraceptive method from 30 days before enrollment in the study until 28 days after the last administration of study drug. It is specified that the sole use of hormonal contraception, both oral, injectable, transdermic and implantable cannot be considered an effective contraceptive method. Orkambi (Lumacaftor/ivacaftor) may reduce the exposure to the hormonal contraceptives and possibly cause their ineffectiveness. Male patients with a female partner with child-bearing potential must use 2 forms of contraception (one of which should be a double-barrier method) from enrolment in the study until 28 days after the last administration of study drug. Highly effective contraceptive methods are: i) abstinence, ii) surgical sterilization (=6 months postsurgery), iii) intrauterine device or intrauterine system, iv) oral contraceptives combined with a barrier method, v) double-barrier method (e.g., male condom or diaphragm with vaginal spermicides).

You may not qualify if:

• 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).

Sponsors & Collaborators

• Istituto Auxologico Italiano: lead

Study Sites (1)

Istituto Auxologico Italiano, Ospedale San Luca

Milan, 20149, Italy

Location

MeSH Terms

Conditions

Long QT Syndrome; Death, Sudden, Cardiac; Channelopathies

Interventions

lumacaftor; ivacaftor; lumacaftor, ivacaftor drug combination

Condition Hierarchy (Ancestors)

Arrhythmias, Cardiac; Heart Diseases; Cardiovascular Diseases; Cardiac Conduction System Disease; Heart Defects, Congenital; Cardiovascular Abnormalities; Congenital Abnormalities; Congenital, Hereditary, and Neonatal Diseases and Abnormalities; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Heart Arrest; Death, Sudden; Death

Study Officials

• Lia Crotti, MD

  Istituto Auxologico Italiano

  PRINCIPAL INVESTIGATOR

• Peter J Schwartz, MD

  Istituto Auxologico Italiano

  STUDY DIRECTOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Open label, single arm, before vs after treatment

Study Record Dates

• First Submitted: September 27, 2020
• First Posted: October 9, 2020
• Study Start: June 15, 2021
• Primary Completion: April 15, 2025
• Study Completion: April 15, 2025
• Last Updated: April 25, 2025

Record last verified: 2025-04

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)