Ensayos clínicos

Inclusion Criteria:

Patients must meet all the following conditions to be eligible for enrollment into the
study:

• Adult males and females, 18 - 65 years of age, inclusive, at screening; or be a male or female child age 12 and up whose weight >=50 kg.
• For children: be up to date on childhood vaccinations, specifically varicella vaccine (chicken pox) and Measles, Mumps & Rubella.
• Children's parent or legal guardian has provided written informed consent/Health Insurance Portability and Accountability Act authorization prior to any study-related procedures.
• Subject and parent/guardian are willing and able to comply with scheduled visits, study drug administration plan, study restrictions, and study procedures.
• For adults: Body mass index (BMI) ≤ 36.0 kg/m2 at screening.
• Confirmed genetic diagnosis of CPVT1 and supporting clinical phenotype, including residual ventricular ectopy (i.e. a complexity score >0) on their last exercise stress test on a stable medical regimen.
• Must have a CYP2C8 extensive or intermediate metabolizer genotype.
• Daily use of medicines and dietary supplements need to be approved by the PI and Sponsor, or a drug/supplement-dependent wash-out prior to inclusion.
• For male subjects:
  • is sterile or agrees to use an appropriate method of contraception;
  • including a condom with spermicide, from study drug administration on the first day of dosing until 5 half-lives plus 90 days (approximately 94 days) after the last dose of study drug administration. No restrictions are required for a vasectomized male subject provided the subject is at least 1-year post-bilateral vasectomy procedure prior to study drug administration on first day of the first dose. A male subject whose vasectomy procedure was performed less than 1 year prior to study drug administration on the first day of dosing must follow the same restrictions as a non-vasectomized male. Appropriate documentation of surgical procedure should be provided.
• For male subjects: agrees to not donate sperm from study drug administration on the first day of dosing until 5 half-lives plus 90 days (approximately 94 days) after the last dose of study drug.
• For female subjects of childbearing potential: uses one of the following highly effective birth control methods (from the first dose until 5 half-lives plus 90 days (approximately 94 days):
  • Prescribed hormonal oral contraceptives, vaginal ring, or transdermal patch;
  • Intrauterine device (IUD);
  • Intrauterine hormone-releasing system (IUS);
  • Depot/implantable hormone (e.g., Depo-Provera®, Implanon);
  • Bilateral tubal occlusion/ligation.
• Sexual abstinence:
  • Refraining from heterosexual intercourse during the entire period of risk associated with the study requirements;
  • If the participant decides to become sexually active during the study, then one of the highly effective birth control methods must be used.
• For female subjects of non childbearing potential; defined by at least 1 of the following criteria:
  • Postmenopausal defined as 12 months of spontaneous amenorrhea and follicle stimulating hormone (FSH) serum level > 40mIU/mL. Appropriated documentation of FSH levels is required;
  • Surgically sterile by hysterectomy and/or bilateral oophorectomy with appropriate documentation of surgical procedure;
  • Has a congenital condition resulting in no uterus.
• Willingness and ability to comply with scheduled visits, drug administration plan, laboratory tests, study restrictions, and study procedures (exercise testing and PK sampling).
• Able to provide written informed consent or assent and understands the study procedures in the informed consent form (ICF) or assent form.

Exclusion Criteria:.

The presence of any of the following conditions will exclude a patient from study
enrollment:

• Patient is mentally or legally incapacitated at the time of the screening visit or during the conduct of the study.
• History or presence of alcoholism or drug abuse within the past 2 years prior to the first dose of study drug.
• History or presence of hypersensitivity or idiosyncratic reaction to the study drug, related compounds, or inactive ingredients.
• Positive urine drug or alcohol results at screening.
• Positive results at screening for human immunodeficiency virus (HIV), hepatitis B surface antigen (HBsAg), or hepatitis C virus (HCV).
• Patients with baseline ALT or AST levels three times above the upper limits of normal (ULN) (isolated elevations of total bilirubin < 2 X ULN with direct bilirubin below the ULN will be included).
• Patients with a history of documented epileptic seizures (not including febrile or Stokes-Adams events, i.e. cardiovascular syncope).
• Subject has a history of cancer (malignancy)
  • Exceptions: Subjects with adequately treated non-melanomatous carcinoma or carcinoma in situ of the cervix may participate in the trial, subjects with other malignancies who have been successfully treated > 10 years prior to the screening where in the judgment of the investigator has revealed no evidence of recurrence from the time of treatment through the time of the screening except those identified at the beginning of the exclusion criterion, or subjects who in the opinion of the investigator are highly unlikely to sustain a recurrence for the duration of the trial.
• Patients with uncontrolled diabetes defined as HbA1c > 7% or diabetic neuropathy.
• Estimated creatinine clearance < 40 mL/minute at screening.
• Patients with a clinically significant abnormality on their resting ECG other than hypertensive related, or heart failure (ejection fraction <30%) or other clinically significant structural heart disease on echocardiogram.
• Patients with a history of myocardial infarction in the last five years, or evidence of congestive heart failure.
• Pregnant and breastfeeding women.
• Unable to refrain from or anticipates the use of:
  • Any non-approved medicines and/or dietary supplements beginning 14 days prior to the first dose of study drug and throughout the study. Thyroid hormone replacement medication may be permitted if subject has been on same stable dose for the last 3 months prior to the first dose of study drug;
  • Any drugs known to be significant inducers or inhibitors of CYP2C8 enzymes for 28 days prior to the first dose of study drug and throughout the study. Any substrates of breast cancer resistance protein (BCRP).
• Is currently taking any drug which raises gastric pH, including proton pump inhibitors or H2 antagonists. Antacids may be used if taken at night.
• Donation of blood or significant blood loss within 56 days prior to the first dose of study drug.
• Plasma donation within 7 days prior to the first dose of study drug.
• Participation in clinical trials for other therapeutic investigational drugs simultaneously or within the 4 weeks prior to the first dose of study drug.
• Ongoing medical condition that is deemed by the Principal Investigator to interfere with the conduct or assessments of the study or safety of the subject.
• Is unable to take orally administered tablets.
• Have known allergy or intolerance to lactose, present in placebo tablets.
• Is an immediate family member of the sponsor or employee of the clinical site or may consent under duress.