Healthy
Conditions
Brief summary
The main objective of this trial is to evaluate the effects of a single therapeutic and a single supra-therapeutic dose of BI 1015550 following oral administration on cardiac safety parameters in healthy male and female volunteers.
Interventions
DRUGBI 1015550
BI 1015550 administered as low (L), and high (H), dose. Oral tablet.
DRUGMoxifloxacin
Moxifloxacin was used as positive control, given as a high dose. Oral tablet.
DRUGPlacebo
Placebo was administered as low (P1), matching the low-dose nerandomilast group, and as high (P2), matching the high-dose neradnomilast group. Oral tablet.
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Masking description
The administration of BI 1015550 and placebo will be blinded while the administration of moxifloxacin will be carried out open label.
Intervention model description
This trial will be performed as a randomized, double-blind, 5-period crossover of BI 1015550 and moxifloxacin. Placebo will be given in two separate periods. There will be 15 treatment sequences based on a Prescott triple Latin square design for 5 treatments and 5 periods.
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male or female subjects according to the assessment of the investigator, as based on a complete medical history including a physical examination, vital signs - blood pressure (BP) and pulse rate (PR), 12-lead electrocardiogram (ECG), and clinical laboratory tests without any clinically significant abnormalities 2. Age of 18 to 50 years (inclusive) 3. Body mass index of 18.5 to 32 kg/m\^2 (inclusive) 4. Signed and dated written informed consent in accordance with International Conference of Harmonization-Good Clinical Practice (ICH-GCP) and local legislation prior to admission to the trial 5. Either male subjects, or female subjects meet the following criteria requiring highly effective contraception from at least 30 days before the first administration of trial medication until 37 days after the last administration of the study drug: * Male participants must use condom plus their partner, if identified as a women of childbearing potential (WOCBP), must use an oral contraceptive or highly effective contraception * Female participants must be using highly effective contraception and in addition their male partner must use a condom if they are using an oral contraceptive
Exclusion criteria
1. Any finding in the medical examination (including BP, Heart rate (HR) or ECG) deviating from normal and assessed as clinically relevant by the investigator 2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or heart rate outside the range of 50 to 90 beats per minute (bpm) 3. Any laboratory value outside the reference range that the investigator considers to be of clinical relevance, in particular, hepatic parameters (alanine transaminase, aspartate transaminase, total bilirubin) or renal parameters (creatinine) exceeding the upper limit of normal 4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator 5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders assessed as clinically relevant by the investigator 6. Cholecystectomy or other surgery of the gastrointestinal tract that could interfere with the pharmacokinetics of the trial medication (except appendectomy or simple hernia repair) 7. Diseases of the central nervous system (including but not limited to any kind of seizures or stroke), and other relevant neurological or psychiatric disorders including but not limited to depression and suicidal behaviour 8. History of clinically relevant orthostatic hypotension, fainting spells, or blackouts Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Maximum Mean Difference Between Each Single Dose of Either a Low Dose or a High Dose of Nerandomilast and Placebo in QTcF Changes From Baseline Between 20 Min to 24 Hours After Drug Administration | MMRM included measurements at these time points [hours:minutes] post-drug: 0:20, 1:00, 1:30, 2:00, 2:30, 3:00, 3:30, 4:00, 4:30, 5:00, 6:00, 8:00, 12:00, and 24:00. MMRM values at 12:00 (low dose) and 4:30 (high dose) are shown in the table below. | QT interval corrected for heart rate (using the method of Fridericia, QTcF) changes from baseline, measured between 20 minutes and 24 hours after drug administration, were analyzed using a linear Mixed Model for Repeated Measures (MMRM). Pairwise comparison was used to compare the QTcF changes for each dose of nerandomilast (e.g., low dose, high dose) with the placebo at every time point. Mean treatment differences in the QTcF changes from baseline at each time point were estimated by the differences in the corresponding least-squares means. Two-sided 90% confidence intervals based on the t-distribution were computed for each time point. The MMRM was adjusted for the discrete fixed effects treatment, period, time, the continuous fixed effects period- and participant-baseline, the fixed effect-by-time terms, participant as random effect and time within period as a repeated effect per participant. The covariance structure for the repeated effect time was unstructured. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Maximum Mean Difference Between Moxifloxacin and Placebo in QTcF Changes From Baseline Between 20 Min to 24 Hours After Drug Administration. | MMRM included measurements at these time points [hours:minutes] post-drug: 0:20, 1:00, 1:30, 2:00, 2:30, 3:00, 3:30, 4:00, 4:30, 5:00, 6:00, 8:00, 12:00, and 24:00. MMRM values at 3:30 (high dose moxifloxacin) are shown in the table below. | QT interval corrected for heart rate (using the method of Fridericia, QTcF) changes from baseline, measured between 20 minutes and 24 hours after drug administration, were analyzed using a linear Mixed Model for Repeated Measures (MMRM). Pairwise comparison was used to compare the QTcF changes for moxifloxacin with the placebo at every time point. Mean treatment differences in the QTcF changes from baseline at each time point were estimated by the differences in the corresponding least-squares means. Two-sided 90% confidence intervals based on the t-distribution were computed for each time point. The MMRM was adjusted for the discrete fixed effects treatment, period, time, the continuous fixed effects period- and participant-baseline, the fixed effect-by-time terms, participant as random effect and time within period as a repeated effect per participant. The covariance structure for the repeated effect time was unstructured. |
Countries
United Kingdom
Participant flow
Recruitment details
This randomized, placebo-controlled, double-blind (moxifloxacin: open-label), crossover study had 5 treatment periods separated by ≥7-day washouts. Treatments included a low dose nerandomilast \[L\], a high dose nerandomilast \[H\], a high dose moxifloxacin (positive control) \[M\]), and placebo \[P1, P2\]. The study assessed nerandomilast's effect on cardiac safety (QT/QTc interval) in healthy female and male participants across 15 sequences, each with 3 participants.
Pre-assignment details
A total of 46 participants who met all inclusion and no exclusion criteria were enrolled in the study, and all completed the planned observation period per protocol. Participants could withdraw from the trial at any time. Two participants were partially excluded from the analysis: one due to a protocol deviation and the other due to the use of rescue medication.
Participants by arm
| Arm | Count |
|---|---|
| All Participants In this study, all participants received five treatments, administered in 15 different sequences. Each treatment was given orally with 240 mL of water following an overnight fast of at least 10 hours. A washout period of at least 7 days separated each treatment.
The treatments were as follows:
H (High-dose nerandomilast): Participants received film-coated tablets containing a high dose of nerandomilast.
L (Low-dose nerandomilast): Participants received film-coated tablets containing a low dose of nerandomilast.
M (High-dose moxifloxacin - Positive Control): Participants received film-coated tablets containing a high dose of moxifloxacin, which served as a positive control.
P1 (Placebo 1): Participants received placebo tablets designed to match the low-dose nerandomilast group.
P2 (Placebo 2): Participants received placebo tablets designed to match the high-dose nerandomilast group. | 46 |
| Total | 46 |
Baseline characteristics
| Characteristic | All Participants |
|---|---|
| Age, Continuous | 36.9 Years STANDARD_DEVIATION 8.8 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 3 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 43 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 1 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants |
| Race (NIH/OMB) White | 44 Participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 25 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk |
|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 45 | 0 / 46 | 0 / 45 | 0 / 45 | 0 / 45 |
| other Total, other adverse events | 0 / 45 | 4 / 46 | 4 / 45 | 3 / 45 | 3 / 45 |
| serious Total, serious adverse events | 0 / 45 | 0 / 46 | 0 / 45 | 0 / 45 | 0 / 45 |
Outcome results
Primary
The Maximum Mean Difference Between Each Single Dose of Either a Low Dose or a High Dose of Nerandomilast and Placebo in QTcF Changes From Baseline Between 20 Min to 24 Hours After Drug Administration
QT interval corrected for heart rate (using the method of Fridericia, QTcF) changes from baseline, measured between 20 minutes and 24 hours after drug administration, were analyzed using a linear Mixed Model for Repeated Measures (MMRM). Pairwise comparison was used to compare the QTcF changes for each dose of nerandomilast (e.g., low dose, high dose) with the placebo at every time point. Mean treatment differences in the QTcF changes from baseline at each time point were estimated by the differences in the corresponding least-squares means. Two-sided 90% confidence intervals based on the t-distribution were computed for each time point. The MMRM was adjusted for the discrete fixed effects treatment, period, time, the continuous fixed effects period- and participant-baseline, the fixed effect-by-time terms, participant as random effect and time within period as a repeated effect per participant. The covariance structure for the repeated effect time was unstructured.
Time frame: MMRM included measurements at these time points [hours:minutes] post-drug: 0:20, 1:00, 1:30, 2:00, 2:30, 3:00, 3:30, 4:00, 4:30, 5:00, 6:00, 8:00, 12:00, and 24:00. MMRM values at 12:00 (low dose) and 4:30 (high dose) are shown in the table below.
Population: Electrocardiogram set (ECGS): This participant set includes all participants in the treated set who have at least one on-treatment value for at least one electrocardiogram (ECG) endpoint, which is not excluded due to ECG relevant important protocol deviations (iPDs). Such iPDs may be e.g., the use of pro-arrhythmic medications. Only participants with available ECG data were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Low-dose nerandomilast | The Maximum Mean Difference Between Each Single Dose of Either a Low Dose or a High Dose of Nerandomilast and Placebo in QTcF Changes From Baseline Between 20 Min to 24 Hours After Drug Administration | 3.0 Milliseconds |
| High-dose nerandomilast | The Maximum Mean Difference Between Each Single Dose of Either a Low Dose or a High Dose of Nerandomilast and Placebo in QTcF Changes From Baseline Between 20 Min to 24 Hours After Drug Administration | 3.2 Milliseconds |
Secondary
The Maximum Mean Difference Between Moxifloxacin and Placebo in QTcF Changes From Baseline Between 20 Min to 24 Hours After Drug Administration.
QT interval corrected for heart rate (using the method of Fridericia, QTcF) changes from baseline, measured between 20 minutes and 24 hours after drug administration, were analyzed using a linear Mixed Model for Repeated Measures (MMRM). Pairwise comparison was used to compare the QTcF changes for moxifloxacin with the placebo at every time point. Mean treatment differences in the QTcF changes from baseline at each time point were estimated by the differences in the corresponding least-squares means. Two-sided 90% confidence intervals based on the t-distribution were computed for each time point. The MMRM was adjusted for the discrete fixed effects treatment, period, time, the continuous fixed effects period- and participant-baseline, the fixed effect-by-time terms, participant as random effect and time within period as a repeated effect per participant. The covariance structure for the repeated effect time was unstructured.
Time frame: MMRM included measurements at these time points [hours:minutes] post-drug: 0:20, 1:00, 1:30, 2:00, 2:30, 3:00, 3:30, 4:00, 4:30, 5:00, 6:00, 8:00, 12:00, and 24:00. MMRM values at 3:30 (high dose moxifloxacin) are shown in the table below.
Population: Electrocardiogram set (ECGS): This participant set includes all participants in the treated set who have at least one on-treatment value for at least one electrocardiogram (ECG) endpoint, which is not excluded due to ECG relevant important protocol deviations (iPDs). Such iPDs may be e.g., the use of pro-arrhythmic medications. Only participants with available ECG data were included.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| Low-dose nerandomilast | The Maximum Mean Difference Between Moxifloxacin and Placebo in QTcF Changes From Baseline Between 20 Min to 24 Hours After Drug Administration. | 14.2 Milliseconds |