BI 409306 Cardiac Safety Trial in Healthy Volunteers

A Randomized, Double-blind, Double Dummy, Placebo-controlled, Three-way Crossover Study to Assess Cardiac Effects After Single Oral Doses of BI409306 Under Resting and Exercise Conditions in Healthy Male Volunteers

This trial will be conducted to further evaluate, in a controlled setting, potential cardiac effects of an anticipated therapeutic and supra-therapeutic dose of BI 409306 under resting and exercise conditions. Since the drug is being developed in part for a disease with an expectedly high number of elderly (AD), the characterization of cardiac safety of BI 409306 is considered to be important for the development of this compound.

This trial will be conducted to further evaluate, in a controlled setting, potential cardiac effects of an anticipated therapeutic and supra-therapeutic dose of BI 409306 under resting and exercise conditions.

Since the drug is being developed in part for a disease with an expectedly high number of elderly (AD), the characterization of cardiac safety of BI 409306 is considered to be important for the development of this compound.

Study Overview

• Status: Completed
• Conditions: Healthy
• Intervention / Treatment: Drug: Placebo; Drug: BI 409306; Drug: BI 409306

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 1

Contacts and Locations

Study Locations

• Germany
  • Biberach, Germany
    • 1289.28.1 Boehringer Ingelheim Investigational Site

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 45 years (Adult)
• Accepts Healthy Volunteers: Yes

Description

Inclusion criteria:

- Healthy males according to the following criteria: Based upon a complete medical history, including the physical examination, vital signs (BP, PR), 12-lead ECG, and clinical laboratory tests.

• Age of 18 to 45 years (incl.)
• BMI of 18.5 to 29.9 kg/m2 (incl.)
• Waist-to-height ratio less than 0.5
• Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation
• Ready and able to use highly effective methods of birth control that result in a low failure rate of less than 1% per year when used consistently and correctly. A list of contraception methods meeting these criteria is provided in the subject information.

Exclusion criteria:

• Any finding in the medical examination (including BP, PR or ECG) is deviating from normal and judged as clinically relevant by the investigator

• Repeated measurement of

  • Systolic blood pressure less than 90 mm Hg or more than140 mmHg
  • Diastolic blood pressure less than 50 mm Hg or more than 90 mmHg
  • Pulse rate less than 45 bpm or more than 90 bpm
• Any laboratory value outside the reference range that the investigator considers to be of clinical relevance
• Any evidence of a concomitant disease judged as clinically relevant by the investigator
• Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders
• Cholecystectomy and/or surgery of the gastrointestinal tract that could interfere with the PK of the trial medication (except appendectomy and simple hernia repair)
• Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders
• History of relevant orthostatic hypotension, fainting spells, or blackouts
• Chronic or relevant acute infections
• History of relevant allergy or hypersensitivity (including allergy to the trial medication or its excipients)
• Intake of drugs with a long half-life (more than 24 h) within 30 days or less than 10 half-lives of the respective drug prior to administration of trial medication
• Within 10 days prior to administration of trial medication, use of drugs that might reasonably influence the results of the trial or that might prolong the QT/QTc interval
• Participation in another trial where an investigational drug has been administered within 60 days prior to planned administration of trial medication
• Smoker (unless the subject quit smoking for at least 30 days prior to screening)
• Alcohol abuse (consumption of more than 30 g per day)
• Drug abuse or positive drug screening
• Blood donation of more than 100 mL within 30 days prior to administration of trial medication or intended donation during the trial
• Intention to perform excessive physical activities within one week prior to administration of trial medication or during the trial
• Inability to comply with dietary regimen of trial site
• A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are repeatedly greater than 450 ms) or any other relevant ECG finding at screening
• A history of additional risk factors for Torsades de Pointes (such as heart failure, hypokalaemia, or family history of Long QT Syndrome)
• Subject is assessed as unsuitable for inclusion by the investigator, for instance, because considered not able to understand and comply with study requirements, or has a condition that would not allow safe participation in the study
• Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active suicidal thought, active suicidal thought with method, active suicidal thought with intent but without specific plan, or active suicidal thought with plan and intent)
• Any lifetime history of suicidal behaviour (i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behaviour).

In addition, the following trial-specific exclusion criteria apply:

• CYP2C19 PM (no treatment allocation)
• History of macular degeneration
• Beard or unwillingness to shave for the trial (to facilitate appropriate measurements during CPX which requires wearing a face mask)
• Physical disability that precludes safe and adequate CPX investigation
• Known latex allergy

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Crossover Assignment
• Masking: Double

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Placebo Comparator: Placebo under resting/exercise conditions; Participants received matching Placebo oral dose with 240 mL of water after a standardized light breakfast on Day 1 and Day 3 under resting/exercise conditions.	Drug: Placebo; single dose, oral administration
Experimental: BI 409306 50 mg under resting/exercise conditions; Participants received BI 409306 50 mg oral dose with 240 mL of water after a standardized light breakfast on Day 1 and Day 3 under resting/exercise conditions.	Drug: BI 409306; low dose, single dose, oral administration; Drug: BI 409306; high dose, single dose, oral administration
Experimental: BI 409306 200 mg under resting/exercise conditions; Participants received BI 409306 200 mg oral dose with 240 mL of water after a standardized light breakfast on Day 1 and Day 3 under resting/exercise conditions.	Drug: BI 409306; low dose, single dose, oral administration; Drug: BI 409306; high dose, single dose, oral administration

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Slope of the Placebo-corrected Change From Baseline of Heart Rate at Rest and Plasma Concentration Between 0 to 10 Hours	Slope of the placebo-corrected change from baseline in resting heart rate (ΔΔHR) vs. plasma concentration of BI 409306, as assessed from 0 to 10 hours (h) after intake of trial medication. The predicted mean value (90% CI) of ΔΔHR at geometric Mean of Cmax of the corresponding dose group is presented in the measured values table. Primary analysis excluded measurement with missing values. Patients with available data were included.	Baseline and up to 10 hours
Maximum Difference to Placebo of the Change From Baseline in Heart Rate at Rest Between 0 to 4 Hours, Per 50 mg Dose Group	For 50 mg dose, the maximal difference in the change from baseline in resting HR for BI 409306 treatment compared with placebo treatment, as assessed from 0 to 4 hours after intake of trial medication (change from baseline in heart rate at rest between 0-4 hours at the time when maximum difference to placebo of the change from baseline was reached). The note "Not Calculated" represents that the endpoint was not planned to be analyzed for the particular arm and category as only pairwise comparisons were built, no difference to placebo is build. Maximum difference reached at 1 hour. Predicted mean changes from baseline (90% Cis) are shown in the measured value table.	Baseline and up to 4 hours
Maximum Difference to Placebo of the Change From Baseline in Heart Rate at Rest Between 0 to 4 Hours, Per 200 mg Dose Group	For 200 mg dose, the maximal difference in the change from baseline in resting HR for BI 409306 treatment compared with placebo treatment, as assessed from 0 to 4 hours after intake of trial medication (change from baseline in heart rate at rest between 0-4 hours at the time when maximum difference to placebo of the change from baseline was reached). The note "Not Calculated" represents that the endpoint was not planned to be analyzed for the particular arm and category as only pairwise comparisons were built, no difference to placebo is build. Maximum difference reached at 1 hour. Predicted mean changes from baseline (90% Cis) are shown in the measured value table.	Baseline and up to 4 hours

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Slope of Placebo-corrected Change From Baseline of Time Between Start of the Q Wave and End of the T Wave in an ECG Corrected for Heart Rate Using the Fridericia Correction Formula (QTcF) at Rest and Plasma Concentration Between 0 to 10 Hours	Slope of placebo-corrected change from baseline in resting Fridericia correction formula QTcF vs. plasma concentration of BI 409306, as assessed from 0 to 10 h after intake of trial medication. The predicted mean value (90% CI) of ΔΔQTcF at geometric Mean of Cmax of the corresponding dose group is presented in the measured values table. Patients with available data were included.	Baseline and up to 10 hours
Maximum Difference to Placebo of the Change From Baseline of QTcF at Rest to Placebo Between 0 to 4 Hours, Per 50 mg Dose Group	For 50 mg dose, the maximal difference in the change from baseline in resting Fridericia correction formula QTcF for BI 409306 treatment compared with placebo treatment, as assessed from 0 to 4 hours after intake of trial medication (change from baseline in resting QTcF at rest between 0-4 hours at the time when maximum difference to placebo of the change from baseline was reached). The note "Not Calculated" represents that the endpoint was not planned to be analyzed for the particular arm and category as only pairwise comparisons were built, no difference to placebo is build. Maximum difference reached at 20 minutes. The predicted mean changes from baseline (90% Cis) are shown in the measured value table.	Baseline and up to 4 hours
Maximum Difference to Placebo of the Change From Baseline of QTcF at Rest to Placebo Between 0 to 4 Hours, Per 200 mg Dose Group	For 200 mg dose, the maximal difference in the change from baseline in resting Fridericia correction formula QTcF for BI 409306 treatment compared with placebo treatment, as assessed from 0 to 4 hours after intake of trial medication (change from baseline in resting QTcF at rest between 0-4 hours at the time when maximum difference to placebo of the change from baseline was reached). The note "Not Calculated" represents that the endpoint was not planned to be analyzed for the particular arm and category as only pairwise comparisons were built, no difference to placebo is build. Maximum difference reached at 20 minutes. The predicted mean changes from baseline (90% Cis) are shown in the measured value table.	Baseline and up to 4 hours
Slope of the Placebo-corrected Maximum Heart Rate During Exercise vs. Plasma Concentration of BI 409306	Slope of the placebo-corrected maximum heart rate during exercise vs. plasma concentration of BI 409306. Patients with available data were included. Exercise testing was completed before gMean Cmax was reached for BI 409306 200 mg arm. The predicted mean value (90% CI) at geometric Mean of Cmax of the corresponding dose group is presented in the measured values table.	20 minutes and 2 hours 20 minutes after drug intake
Slope of the Placebo Corrected Change From Maximum Heart Rate 1 and 5 Minutes After End of Exercise and Plasma Concentration	Slope of the placebo-corrected difference between maximum heart rate (HR) during exercise and recovery HR at 1 and 5 minutes (min) after the end of exercise vs. plasma concentration of BI 409306. The note "Not Calculated" represents that the plasma concentrations 1 min after the end of exercise did not reach gMean Cmax for the perticular arm. Patients with available data were included. The predicted mean value (90% CI) at geometric Mean of Cmax of the corresponding dose group is presented in the measured values table.	20 minutes and 2 hours 20 minutes after drug intake

Collaborators and Investigators

• Sponsor: Boehringer Ingelheim
• Investigators: Study Chair: Boehringer Ingelheim, Boehringer Ingelheim

Publications and helpful links

Helpful Links

• Related Info

Study record dates

Study Major Dates

• Study Start (Actual): May 4, 2015
• Primary Completion (Actual): August 12, 2015
• Study Completion (Actual): August 13, 2015

Study Registration Dates

• First Submitted: May 6, 2015
• First Submitted That Met QC Criteria: May 6, 2015
• First Posted (Estimated): May 8, 2015

Study Record Updates

• Last Update Posted (Actual): October 26, 2024
• Last Update Submitted That Met QC Criteria: October 16, 2024
• Last Verified: October 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Phosphodiesterase Inhibitors; BI 409306
• Other Study ID Numbers: 1289.28; 2014-005132-34 (EudraCT Number: EudraCT)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

IPD Plan Description

Clinical studies sponsored by Boehringer Ingelheim, phases I to IV, interventional and non-interventional, are in scope for sharing of the raw clinical study data and clinical study documents. Exceptions might apply, e.g. studies in products where Boehringer Ingelheim is not the license holder; studies regarding pharmaceutical formulations and associated analytical methods, and studies pertinent to pharmacokinetics using human biomaterials; studies conducted in a single center or targeting rare diseases (in case of low number of patients and therefore limitations with anonymization).

For more details refer to: https://www.mystudywindow.com/msw/datatransparency