Clinical trial NCT05642507: Phase Ib/IIa Trial With AC01 in Patients With HFrEF
Official title: Randomized, Double-blind, Multiple Ascending Dose, Placebo-controlled, Safety, Tolerability, Efficacy, Pharmacokinetic (PK) and Pharmacodynamic (PD) Phase Ib/IIa Clinical Trial With AC01 in Patients With HFrEF
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
PHASE2
Conditions: Heart Failure With Reduced Ejection Fraction
Lead sponsor: AnaCardio AB
Sponsor class: INDUSTRY
First posted: 2022-12-08
Enrollment: 80
Sex: ALL
Minimum age (years): 18
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Sequential, escalating, multiple doses
Primary purpose: TREATMENT

Brief summary: This is a randomized, double-blind, placebo-controlled two-part study with a multiple escalating dose phase followed by a cohort expansion phase to assess safety, tolerability, pharmacokinetics and pharmacodynamics of AC01 in patients with heart failure with reduced ejection fraction (HFrEF).

Detailed description: During the dose escalation phase, patients will be given AC01 orally twice daily for seven days. In the cohort expansion phase, patients will be given AC01 orally twice daily for 28 days at dose levels selected on the basis of results of the dose escalation phase.

Eligibility criteria: Key Inclusion Criteria:

* Male and female out-patients of any ethnicity, between 18-80 years (inclusive), with stable HFrEF.
* Chronic HF for at least 6 months duration defined by history with current NYHA class II-III severity.
* LVEF ≤40% by TTE more than 6 months before screening and again at screening (screening measurement confirmed by echocardiography core lab).
* Sinus rhythm with mean resting heart rate 55-90 bpm.
* Cardiac Index 0.5-2.4 measured by Innocor at screening and Day -1. Screening measurement confirmed by core lab.
* Transvenous ICD for primary prevention in place and active (as long as it is not subcutaneous).
* Optimal guideline-based medical therapy for HFrEF as judged by the Investigator, at stable doses for ≥2 weeks with no intention to change dosing during trial duration.

Key Exclusion Criteria:

* Any cardiac rhythm that does or could interfere with ECG or TTE interpretation, including but not limited to permanent or persistent atrial fibrillation or flutter or paroxysmal atrial fibrillation or flutter with an episode in the last 3 months, frequent premature ventricular contractions, or atrial or ventricular pacing
* Ongoing or planned mechanical circulatory support, treatment with any IV vasoactive drugs (vasodilators, inotropes, or vasopressors) or diuretics, and/or dialysis or hemofiltration or ultrafiltration.
* Probable alternative explanations for symptoms or signs (e.g., but not limited to, known primary cardiomyopathy \[hypertrophic, constrictive, restrictive, infiltrative, congenital\]). Primary uncorrected hemodynamically significant valve disease, right-sided HF not due to left-sided HF.
* History of aborted cardiac arrest and/or ICD for secondary prevention.
* Hospitalized for HF or received IV diuretics, vasodilators, or inotropes for HF ≤30 days.
* Clinical diagnosis of acute coronary syndrome or stroke ≤30 days.
* PCI or percutaneous valve intervention ≤30 days or planned.
* Angina pectoris ≤30 days.
* Any cardiovascular procedure planned during study duration.
* Hospitalized or unplanned visit to the emergency department for any reason in last 30 days; patient is eligible 30 days from discharge from hospital.
* Use of any drugs or substances known to be strong inducers of CYP3A4 enzyme within 28 days prior to the dosing day and/or planned to be used during the overall study period.
* eGFR by CKD-EPI \<30 mL/min/1.73 m2 at screening or at Day -1.
* Serum or plasma potassium \<3.5 or \>5.2 mEq/L at screening or at Day -1. Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) \>3 times upper limit of normal (ULN) or total bilirubin \>2 times ULN at screening or at Day -1. Or known cirrhosis or severe liver or pancreatic disease, or Gilbert's syndrome.
* Any condition that in the opinion of the Investigator may interfere with adherence to the protocol.
* Systolic blood pressure \<90 mmHg or \>140 mmHg at screening or at Day-1.
* Any of the following ECG findings: atrial or ventricular pacing, QTcF \>450 ms, AV block I with PQ \> 240 ms, AV block II or III at screening and at Day -1. In the case of non-paced QRS prolongation \>120 ms, or if CRT is determined to be required and is actively pacing the ventricles, the QTcF is allowed to be up to but not greater than 470 ms.

Primary outcomes:
measure: Safety and tolerability: Adverse Events (AEs)
timeFrame: Up to 12 days during dose escalation phase and up to 35 days during cohort expansion phase.
measure: Safety and tolerability: Vital signs.
timeFrame: Up to 12 days during dose escalation phase and up to 35 days during cohort expansion phase.
measure: Safety and tolerability: Vital signs.
timeFrame: Up to 12 days during dose escalation phase and up to 35 days during cohort expansion phase.
measure: Safety and tolerability: Electrocardiogram (ECG).
timeFrame: Up to 12 days during dose escalation phase and up to 35 days during cohort expansion phase.
measure: Safety and tolerability: Clinical laboratory evaluations.
timeFrame: Up to 12 days during dose escalation phase and up to 35 days during cohort expansion phase.
Secondary outcomes:
measure: Pharmacokinetics of AC01 and its major metabolite: Cmax.
timeFrame: Up to Day 8 during dose escalation phase and up to Day 32 during cohort expansion phase.
measure: Pharmacokinetics of AC01 and its major metabolite: AUC
timeFrame: Up to Day 8 during dose escalation phase and up to Day 32 during cohort expansion phase.
measure: Pharmacodynamics: Cardiac Function.
timeFrame: Up to 12 days during dose escalation phase and up to 35 days during cohort expansion phase.
measure: Pharmacodynamics: Cardiac Function.
timeFrame: Up to 12 days during dose escalation phase and up to 35 days during cohort expansion phase.
measure: Pharmacodynamics: Cardiac Function.
timeFrame: Up to 12 days during dose escalation phase and up to 35 days during cohort expansion phase.
measure: Pharmacodynamics: Mechanistic markers.
timeFrame: Up to 12 days during dose escalation phase and up to 35 days during cohort expansion phase.
Other outcomes:
Locations:
city: Brescia
country: Italy
facility: Spedali Civilia di Brescia
city: Trieste
country: Italy
facility: Azienda Sanitaria Universitaria Integrata
city: Amsterdam
country: Netherlands
facility: Amsterdam University Medical Centre
city: Groningen
country: Netherlands
facility: University Medical Centre Groningen/ICON
city: Maastricht
country: Netherlands
facility: Maastricht Heart and Vascular Center
city: Rotterdam
country: Netherlands
facility: Erasmus Medical Centre
city: Gothenburg
country: Sweden
facility: Sahlgrenska University Hospital
city: Lund
country: Sweden
facility: Skånes Universitetssjukhus Lund
city: Stockholm
country: Sweden
facility: Karolinska University Hospital
city: Dundee
country: United Kingdom
facility: Ninewells Hospital and Medical School
city: Glasgow
country: United Kingdom
facility: University of Glasgow, Institute of Cardiovascular & Medical Sciences
city: Glasgow
country: United Kingdom
facility: Golden Jubilee National Hospital
city: London
country: United Kingdom
facility: King's College Hospital
Study officials:
affiliation: AnaCardio AB
name: Lars Lund, MD PhD
role: STUDY_CHAIR
References: