The Persistence of Autoantibody Neutralisation by BC 007 in Patients With Chronic HFrEF and Autoantibodies Against the Beta1-Adrenergic Receptor

Heart Failure Clinical Trial

Official title:

A Two Arm Randomised, Open-label Study to Investigate the Persistence of Autoantibody Neutralisation, the Safety, and Pharmacokinetics of BC 007 in Patients With Chronic Heart Failure With Reduced Ejection Fraction (HFrEF) and Autoantibodies Directed Against the beta1 Adrenergic Receptor

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04192214
• Other study ID #: SBC007C201
• Status: Completed
• Phase: Phase 2
• Start date: March 29, 2019
• Est. completion date: December 6, 2022

Study information

• Verified date: March 2023
• Source: Berlin Cures GmbH
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Chronic heart failure (CHF) is one of the major causes of death in Western societies. Evidence has accumulated that functionally active autoantibodies directed against the beta1 adrenergic receptor (β1 AAb) are of pathophysiological relevance for the development and progression of cardiomyopathy and associated CHF. BC 007 is under development for targeted neutralisation of autoantibodies directed against G protein coupled receptors, including β1 AAb. This is an open label, three-centre, randomised phase 2a study in participants with chronic HFrEF. The study will evaluate whether BC 007 causes a persistent neutralisation of the β1 AAb demonstrated by a negative β1 AAb status up to 12 months. Participants will be randomised in a 2:1 ratio to the treatment arm (BC 007) or the control arm (untreated). Treatment is repeated once up to month 11 if the participant's β1 AAb were not neutralised after 1st dosing on day 1 or reoccur.

Description:

Primary objective is:

• To compare the efficacy of an intravenous (i.v.) infusion of BC 007 with an untreated control arm in removal of β1 AAb at month 12 in participants with chronic heart failure with reduced ejection fraction (HFrEF)

Secondary objectives are:

• To evaluate the time to recurrence of β1 AAb after a single i.v. infusion of BC 007

• To evaluate the response rate and time to recurrence of β1 AAb after a repeated single i.v. infusion of BC 007 after the first recurrence of β1 AAb

• To evaluate the safety and tolerability of BC 007 after a single and a repeated single i.v. infusion

• To determine the pharmacokinetic (PK) plasma and urine profiles of BC 007

• To investigate the PK plasma profiles of BC 007 metabolites

• To investigate the β aminoisobutyric acid (β-AIBA) plasma and urine, and uric acid serum and urine concentration as a marker for BC 007 degradation

• To investigate the spontaneous conversion of β1 AAb status from positive to negative in untreated participants (control arm)

Exploratory objective is:

• To evaluate the change of the left ventricular ejection fraction (LVEF) after a single and a repeated single i.v. infusion

Recruitment information / eligibility

• Status: Completed
• Enrollment: 30
• Est. completion date: December 6, 2022
• Est. primary completion date: December 6, 2022
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 90 Years

Eligibility

Inclusion Criteria:

• Male or female participant =18 years of age, at the time of signing the informed consent.

• Participant has CHF class II III, according to the NYHA classification.

• Participant has a chronic HFrEF with a left ventricular ejection fraction (LVEF) =40 % during screening (as assessed by in-hospital echocardiography).

• Participant screened positive for ß1 AAb by a validated functional assay.

Exclusion Criteria:

• Participant has a sustained systolic blood pressure =160 mmHg prior to randomisation.

• Participant has a sustained bradycardia with resting heart rate <45 beats per minute (bpm) or tachycardia with resting heart rate >100 bpm prior to randomisation.

• Participant has an untreated primary valvular disease, considered clinically significant by the Investigator.

• Participant has any condition or therapy, which would make the participant unsuitable for the study, or life expectancy less than 12 months (e.g., active malignancy).

Related Conditions & MeSH terms

• Autoantibodies
• Cardiomyopathies
• Cardiomyopathy, Dilated
• Heart Failure

Intervention

Drug:
• BC 007
1350 mg of BC 007

Locations

Country	Name	City	State
Serbia	Bežanijska Kosa Clinical and Hospital Centre	Belgrad
Serbia	Institut za kardiovaskularne bolesti Dedinje	Belgrade
Serbia	Zvezdara Clinical and Hospital Centre	Belgrade

Sponsors (1)

Lead Sponsor	Collaborator
Berlin Cures GmbH

Country where clinical trial is conducted

Serbia, 

References & Publications (3)

Haberland A, Holtzhauer M, Schlichtiger A, Bartel S, Schimke I, Muller J, Dandel M, Luppa PB, Wallukat G. Aptamer BC 007 - A broad spectrum neutralizer of pathogenic autoantibodies against G-protein-coupled receptors. Eur J Pharmacol. 2016 Oct 15;789:37-45. doi: 10.1016/j.ejphar.2016.06.061. Epub 2016 Jul 1. — View Citation

Wallukat G, Muller J, Haberland A, Berg S, Schulz A, Freyse EJ, Vetter R, Salzsieder E, Kreutz R, Schimke I. Aptamer BC007 for neutralization of pathogenic autoantibodies directed against G-protein coupled receptors: A vision of future treatment of patients with cardiomyopathies and positivity for those autoantibodies. Atherosclerosis. 2016 Jan;244:44-7. doi: 10.1016/j.atherosclerosis.2015.11.001. Epub 2015 Nov 10. — View Citation

Wenzel K, Schulze-Rothe S, Haberland A, Muller J, Wallukat G, Davideit H. Performance and in-house validation of a bioassay for the determination of beta1-autoantibodies found in patients with cardiomyopathy. Heliyon. 2017 Jul 31;3(7):e00362. doi: 10.1016/j.heliyon.2017.e00362. eCollection 2017 Jul. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Echocardiographic parameter LVEF compared to untreated participants (control arm) from baseline to month 12		12 month
Primary	Proportion of ß1 AAb negative participants at month 12		12 month
Secondary	Persistence of response defined as the time from initial ß1 AAb neutralisation to ß1 AAb recurrence.		12 month
Secondary	Response rate defined as the percentage of ß1 AAb negative participants after a second treatment and persistence of response defined as the time from subsequent ß1 AAb neutralisation to ß1 AAb recurrence		12 month
Secondary	Comparative conversion rate of ß1 AAb from positive to negative status measured by a cardiomyocyte beat rate assay in untreated participants (control arm)		12 month
Secondary	Number of Participants with abnormal laboratory values and/or adverse events that are related to treatment		12 month
Secondary	Area under the plasma concentration time curve (AUC) from time zero to the last quantifiable concentration (AUC0-t) derived from BC 007 and BC 007 metabolite (N-1, N-2 and N-3) plasma concentrations		6 hour post start of infusion
Secondary	Area under the plasma concentration time curve (AUC) from time zero extrapolated to infinity (AUC0-inf) derived from BC 007 and BC 007 metabolite (N-1, N-2 and N-3) plasma concentrations		6 hour post start of infusion
Secondary	Maximum observed plasma concentration (Cmax) derived from BC 007 and BC 007 metabolite (N-1, N-2 and N-3) plasma concentrations		6 hour post start of infusion
Secondary	Apparent terminal half-life (t1/2) derived from BC 007 and BC 007 metabolite (N-1, N-2 and N-3) plasma concentrations		6 hour post start of infusion
Secondary	Nominal time of Cmax (tmax) derived from BC 007 and BC 007 metabolite (N-1, N-2 and N-3) plasma concentrations		6 hour post start of infusion
Secondary	Plasma clearance (CL) derived from BC 007 and BC 007 metabolite (N-1, N-2 and N-3) plasma concentrations		6 hour post start of infusion
Secondary	Volume of distribution during terminal phase (Vz) derived from BC 007 and BC 007 metabolite (N-1, N-2 and N-3) plasma concentrations		6 hour post start of infusion
Secondary	Terminal elimination rate constant (?z) derived from BC 007 and BC 007 metabolite (N-1, N-2 and N-3) plasma concentrations		6 hour post start of infusion
Secondary	Cumulative amount of unchanged drug excreted into urine (Ae)		6 hour post start of infusion
Secondary	Fraction of intravenous administered drug that is excreted unchanged in urine (fe)		6 hour post start of infusion
Secondary	Renal clearance (CLR) of BC 007		6 hour post start of infusion
Secondary	Area under the plasma concentration time curve (AUC) from time zero to the last quantifiable concentration (AUC0-t) derived from ß-aminoisobutyric acid and uric acid plasma concentrations		6 hour post start of infusion
Secondary	Area under the plasma concentration time curve (AUC) from time zero to the concentration after 4 hours (AUC0-4h) derived from ß-aminoisobutyric acid and uric acid plasma concentrations		4 hour post start of infusion
Secondary	Area under the plasma concentration time curve (AUC) from time zero to the concentration after 6 hours (AUC0-6h) derived from ß-aminoisobutyric acid and uric acid plasma concentrations		6 hour post start of infusion
Secondary	Area under the plasma concentration time curve (AUC) from time zero extrapolated to infinity (AUC0-inf) derived from ß-aminoisobutyric acid and uric acid plasma concentrations		6 hour post start of infusion
Secondary	Maximum observed plasma concentration (Cmax) derived from ß-aminoisobutyric acid and uric acid plasma concentrations		6 hour post start of infusion
Secondary	Nominal time of Cmax (tmax) derived from ß-aminoisobutyric acid and uric acid plasma concentrations		6 hour post start of infusion
Secondary	Cumulative amount of ß-aminoisobutyric acid and uric acid excreted into urine (Ae)		6 hour post start of infusion
Secondary	Renal clearance (CLR) of ß-aminoisobutyric acid and uric acid		6 hour post start of infusion