Dilated Cardiomyopathy
Conditions
Keywords
Single Ascending Dose, Phospholamban
Brief summary
The purpose of the study is to assess the safety, tolerability and the pharmacokinetics (PK) of AZD4063 after single dose administration in participants with phospholamban (PLN) R14del dilated cardiomyopathy.
Detailed description
This is a Phase 1, first in human, unblinded, ascending dose study which will consist of a SAD (single ascending dose) part and an Optional part. The SAD part of the study will assess the single doses of AZD4063 across 4 cohorts. It will consist of: * A Screening period * A Treatment period: The participants will receive a single dose of AZD4063 by subcutaneous (SC) injection * A Follow-up period Optional cohorts may be added based on emerging safety, PK and PD data of the preceding cohorts.
Interventions
DRUGAZD4063
AZD4063 will be administered as solution for injection via subcutaneous route of administration.
Sponsors
AstraZeneca
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 80 Years
Healthy volunteers
No
Inclusion criteria
* Participants must be 18 to 80 years of age inclusive, at the time of Screening * Participants with pre-existing positive screening for R14 del PLN mutation * Participants with screening Left ventricular eject fraction ≤ 45% as assessed by echocardiography * Participants with New York Heart Association (NYHA) function class I-III * Participants on stable medical therapy for at least 6 weeks prior to Screening and during the Screening period, with no significant improvement in heart failure * Participants with implantable cardioverter-defibrillator (ICD) or Cardiac resynchronization therapy device (CRT-D) * Participants with Body mass index (BMI) within the range 18-35 kg/m2 * Females of childbearing potential must not be lactating, and if heterosexually active must agree to use an approved method of highly effective contraception * All women of childbearing potential must have a negative pregnancy test at the Screening Visit.
Exclusion criteria
* Participants with positive hepatitis C antibody, hepatitis B virus surface antigen or hepatitis B virus core antibody * Known to have tested positive for Human immunodeficiency virus (HIV) * Any known genetic mutation associated with hereditary electrical or structural disease * Congenital long QT syndrome * QTcF \< 350 ms * Known Short QT syndrome (SQTS) or family history of SQTS * Catecholaminergic polymorphic ventricular tachycardia (CPVT as calcium ion channelopathy) and recent hospitalization for heart failure or significant ventricular arrhythmia within 3 months * Participants with sustained ventricular arrhythmia requiring treatment and considered clinically not stable by the Investigator * History of subendocardial Late Gadolinium Enhancement (LGE) suggestive of previous myocardial infarction and/or significant coronary artery disease (50% \> stenosis in one major epicardial coronary artery or need for previous percutaneous coronary intervention or coronary artery bypass grafting) * Routinely scheduled outpatient intravenous infusions for heart failure * Uncontrolled hypertension * Significant primary valvular disease * Congenital heart disease * Left ventricular wall thickness of \> 13 mm or with any relative with hypertrophic cardiomyopathy (HCM) * Recent acute presentation of myocarditis * Restrictive or peripartum cardiomyopathy; infiltrative disorders (sarcoidosis) * Alcohol consumption in excess * Any laboratory values with the following deviations: 1. Alanine Transaminase \>2 upper normal limit (ULN) 2. Aspartate Transaminase \>2 ULN 3. Total bilirubin \> 2 x ULN 4. Estimated GFR \< 30 mL/min/1.73 m2 5. Hemoglobin \<10g/dL * Any vital sign values with the following deviations at Screening 1. Systolic blood pressure \> 160 mmHg 2. Diastolic blood pressure \> 100 mmHg 3. Pulse rate \> 100 beats per minute * Toxin exposure, systemic disease known to cause Dilated Cardiomyopathy (DCM) * History of severe allergy/hypersensitivity or ongoing clinically important allergy/hypersensitivity * Any history of cardiotoxic drug exposure with documented cardiomyopathy * Noncardiac condition that limits expected lifespan to less than 1 year * Participation in another clinical study with a study intervention administered in the last 3 months * Participants with a known hypersensitivity to AZD4063 * Participants who have previously received AZD4063 as part of this study * Participants who are part of a gene therapy trial
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of participants with adverse events (AEs) | Cohorts 1 and 2: Day 1 to 80; Cohorts 3 and 4: Day 1 to 210 | The safety and tolerability of AZD4063 following the SC administration of single doses in participants with PLN R14del dilated cardiomyopathy will be evaluated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area under plasma concentration-time curve from 0 to infinity (AUCinf) | Cohorts 1 and 2: Day 1 to 80; Cohorts 3 and 4: Day 1 to 210 | The AUCinf of single ascending doses of AZD4063 following SC administration will be evaluated. |
| Area under the plasma concentration-curve from 0 to the last quantifiable concentration (AUClast) | Cohorts 1 and 2: Day 1 to 80; Cohorts 3 and 4: Day 1 to 210 | The AUClast of single doses of AZD4063 following SC administration will be evaluated. |
| Maximum plasma drug concentration (Cmax) | Cohorts 1 and 2: Day 1 to 80; Cohorts 3 and 4: Day 1 to 210 | The Cmax of single doses of AZD4063 following SC administration will be evaluated. |
| Renal clearance (CLR) | Cohorts 1 and 2: Day 1 to 94; Cohorts 3 and 4: Day 1 to Follow up (Day 224) | The CLR of the single doses of AZD4063 following SC administration will be evaluated. |
| Cumulative amount of analyte excreted (Ae) | Cohorts 1 and 2: Day 1 to 94; Cohorts 3 and 4: Day 1 to Follow up (Day 224) | The Ae of single doses of AZD4063 following SC administration will be evaluated. |
| Fraction of dose excreted unchanged in urine (Fe) | Cohorts 1 and 2: Day 1 to 94; Cohorts 3 and 4: Day 1 to Follow up (Day 224) | The Fe of single doses of AZD4063 following SC administration will be evaluated. |
| Change in endomyocardial biopsy PLN messenger ribonucleic acid (mRNA levels) from baseline to estimated peak knockdown and estimated return-to-baseline | Cohorts 1 and 2: Day 1 to 94; Cohorts 3 and 4: Day 1 to Follow up (Day 224) | The effects of single ascending doses of AZD4063 on knockdown of PLN mRNA will be evaluated. |
Countries
Netherlands
Contacts
CONTACTAstraZeneca Clinical Study Information Center
Outcome results
None listed