Idiopathic Pulmonary Fibrosis
Conditions
Brief summary
The primary objective is to investigate safety and tolerability of BI 1015550 in patients with IPF. The secondary objectives are to evaluate the pharmacokinetics (PK) of BI 1015550 in patients with IPF.
Interventions
DRUGBI 1015550
3 tablets of 6 milligram (mg) of BI 101550 (total: 18 mg) were administrated as an oral dose together with about 240 milliliter (mL) of water twice daily (bid).
DRUGPlacebo
3 tablets of Placebo, matching in size and weight to BI 1015550 6 milligram (mg) tablet, were administrated as an oral dose together with about 240 milliliter (mL) of water twice daily.
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
40 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Signed and dated written informed consent prior to admission to the study in accordance with ICH Harmonised Tripartite Guideline for Good Clinical Practice (ICH-GCP) and local legislation * Male or female patients aged ≥40 years at visit 1. * A clinical diagnosis of IPF based on ATS/ERS/JRS/ALAT 2011 guideline within the previous 5 years as confirmed by the investigator based on chest high-resolution computed tomography (HRCT) scan taken within 12 months of visit 1 and confirmed by central review prior to visit 2. * Forced Vital Capacity (FVC) ≥50% of predicted normal at visit 1 * Diffusion capacity of the lung for carbon monoxide (DLCO) (corrected for haemoglobin \[Hb\] \[Visit 1\]): \> 30% of predicted normal at visit 1
Exclusion criteria
* Patients with a significant disease or condition other than IPF which in the opinion of the investigator, may put the patient at risk because of participation, interfere with study procedures, or cause concern regarding the patient's ability to participate in the study. * Any laboratory value outside the reference range that the investigator considers to be of clinical relevance * Surgery of the GI tract that could interfere with PK of the trial medication (except appendectomy) * 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 mood disorders. * Evidence of active infection (chronic or acute) based on clinical exam or laboratory findings. * History of allergy or hypersensitivity to the trial medication or its excipients * Use of drugs within 30 days prior to administration of trial medication that are known to influence the results of the trial including time between start of the Q-wave and the end of the T-wave in an electrocardiogram (QT) / QT interval corrected for heart rate using the method of Fridericia (QTcF) or Bazett (QTcB) (QTc) * A marked baseline prolongation of QT/QTc interval (such as QTc intervals that are repeatedly greater than 450 ms in males or repeatedly greater than 470 ms in females) or any other relevant ECG finding at screening * A history of additional risk factors for Torsades de Pointes (such as heart failure, hypokalemia, or family history of Long QT Syndrome) * Participation in another trial where an investigational drug has been administered within 30 days or less than 5 half-lives (whichever is greater) of the respective drug prior to planned administration of trial medication, or current participation in another trial involving administration of investigational drug. * Inability to refrain from smoking on trial days * Alcohol abuse (consumption of more than 20 g per day) * Active drug abuse * Blood donation of more than 100 mL within 30 days prior to administration of trial medication or intended donation during the trial * Inability to comply with dietary regimen required for the trial * Patient 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 * Male patients who do not agree to minimize the risk of female partners becoming pregnant from first dosing day until two months after the study completion. Acceptable methods of contraception comprises barrier contraception and a medically accepted contraceptive method for the female partner (intra-uterine device with spermicide, hormonal contraceptive used for at least two months prior), true sexual abstinence (when this is in line with the preferred and usual lifestyle of the patient), or surgically sterilized, including vasectomy. * Females who are not surgically sterilised or who are not postmenopausal, defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous levels of Follicle-stimulating hormone (FSH) above 40 U/L and estradiol below 30 ng/L is confirmatory). * Relevant airways obstruction (i.e. pre-bronchodilator FEV1/FVC \<0.7) at visit 1 * Patients who have previously been treated with nintedanib or pirfenidone within 30 days of visit 1. * Positive fecal occult blood (no retest allowed), * Positive testing for hematuria if confirmed by microscopic urine analysis (retest allowed) * Any lifetime history of suicidal behavior (i.e. actual attempt, interrupted attempt, aborted attempt, or preparatory acts or behavior) * Any suicidal ideation of type 2 to 5 on the C-SSRS in the past 12 months (i.e. active suicidal thought without method, intent or plan; active suicidal thought with method, but without intent or plan; active suicidal thought with method and intent but without specific plan; or active suicidal thought with method, intent and plan).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Drug-related Adverse Events (AEs) On-treatment | From first dose until last dose of treatment period (duration depends on the time a patient entered the trial) + 7 days of REP or until patient's trial termination date, whichever occurred earlier, up to 35 or 91 days. | The analysis of AEs was based on the concept of treatment-emergent AEs (TEAEs). All AEs which occurred through the treatment phase and throughout the residual effect period (REP) were considered as on treatment. Treatment period was 4 weeks for patients entered after approval of a global protocol amendment at 12 Feb 2019 or 12 weeks for those entered before approval. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve (AUCτ,1) of the BI 1015550 in Plasma Over a Uniform Dosing Interval τ After Administration of the First Dose on Day 1 | On Day 1, within 2 hours before morning dose and at 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours after morning dose. | Area under the concentration-time curve (AUCτ,1) of the BI 1015550 in plasma over a uniform dosing interval τ after administration of the first dose on Day 1. |
| Maximum Measured Concentration (Cmax) of the BI 1015550 in Plasma on Day 1 | On Day 1, within 2 hours before morning dose and at 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours after morning dose. | Maximum measured concentration (Cmax) of the BI 1015550 in plasma on Day 1. |
| Area Under the Concentration-time Curve (AUCτ,ss) of the BI 1015550 in Plasma at Steady State Over a Uniform Dosing Interval τ on Day 14 | On Day 14, within 2 hours before morning dose and at 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours after morning dose. | Area under the concentration-time curve (AUCτ,ss) of the BI 1015550 in plasma at steady state over a uniform dosing interval τ on Day 14. |
| Maximum Measured Concentration (Cmax,ss) of the BI 1015550 in Plasma at Steady State Over a Uniform Dosing Interval τ on Day 14 | On Day 14, within 2 hours before morning dose and at 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours after morning dose. | Maximum measured concentration (Cmax,ss) of the BI 1015550 in plasma at steady state over a uniform dosing interval τ on Day 14. |
Countries
Denmark, Finland, Germany, Italy, Netherlands, Spain, United Kingdom
Participant flow
Recruitment details
This randomized, double-blind, placebo-controlled, multiple rising dose trial was to test safety and tolerability of BI 1015550 in patients with idiopathic pulmonary fibrosis under dosage of 18mg and 24mg twice daily (bid). Dose escalation was stopped after the 18 mg bid dose group as predefined stopping criteria was met.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they strictly met all inclusion and none of the exclusion criteria. Subjects were not to be allocated to a treatment group if any of the entry criteria were violated. Participant flow was based on treatment period.
Participants by arm
| Arm | Count |
|---|---|
| Placebo 3 tablets of Placebo, matching in size and weight to BI 1015550 6 milligram (mg) tablet, were administrated as an oral dose together with about 240 milliliter (mL) of water twice daily. Treatment period was 4 weeks for patients entered after approval of a global protocol amendment 3 at 12 Feb 2019 or 12 weeks for those entered before approval. | 5 |
| 18 mg BI 1015550 3 tablets of 6 milligram (mg) of BI 101550 (total: 18 mg) were administrated as an oral dose together with about 240 milliliter (mL) of water twice daily (bid). Treatment period was 4 weeks for patients entered after approval of a global protocol amendment 3 at 12 Feb 2019 or 12 weeks for those entered before approval. | 10 |
| Total | 15 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 0 | 1 |
| Overall Study | Inconvenience to frequent study visits | 0 | 1 |
Baseline characteristics
| Characteristic | 18 mg BI 1015550 | Total | Placebo |
|---|---|---|---|
| Age, Continuous | 69.5 Years STANDARD_DEVIATION 10.1 | 69.7 Years STANDARD_DEVIATION 8.3 | 70.2 Years STANDARD_DEVIATION 3.3 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 10 Participants | 15 Participants | 5 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 10 Participants | 15 Participants | 5 Participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 1 Participants |
| Sex: Female, Male Male | 9 Participants | 13 Participants | 4 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 5 | 0 / 10 |
| other Total, other adverse events | 5 / 5 | 10 / 10 |
| serious Total, serious adverse events | 0 / 5 | 1 / 10 |
Outcome results
Primary
Percentage of Participants With Drug-related Adverse Events (AEs) On-treatment
The analysis of AEs was based on the concept of treatment-emergent AEs (TEAEs). All AEs which occurred through the treatment phase and throughout the residual effect period (REP) were considered as on treatment. Treatment period was 4 weeks for patients entered after approval of a global protocol amendment at 12 Feb 2019 or 12 weeks for those entered before approval.
Time frame: From first dose until last dose of treatment period (duration depends on the time a patient entered the trial) + 7 days of REP or until patient's trial termination date, whichever occurred earlier, up to 35 or 91 days.
Population: Treated set (TS): This patient set included all patients who received at least one dose of study drug. It was used for the analysis of safety, demographic data, and baseline characteristics.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| 18 mg BI 1015550 | Percentage of Participants With Drug-related Adverse Events (AEs) On-treatment | 90.0 Percentage of participants |
| Placebo | Percentage of Participants With Drug-related Adverse Events (AEs) On-treatment | 60.0 Percentage of participants |
Secondary
Area Under the Concentration-time Curve (AUCτ,1) of the BI 1015550 in Plasma Over a Uniform Dosing Interval τ After Administration of the First Dose on Day 1
Area under the concentration-time curve (AUCτ,1) of the BI 1015550 in plasma over a uniform dosing interval τ after administration of the first dose on Day 1.
Time frame: On Day 1, within 2 hours before morning dose and at 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours after morning dose.
Population: Pharmacokinetic parameter set (PKS): This patient set included all patients in the TS who provided at least one pharmacokinetic (PK) parameter that was not excluded because of protocol deviations relevant to the analysis of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 18 mg BI 1015550 | Area Under the Concentration-time Curve (AUCτ,1) of the BI 1015550 in Plasma Over a Uniform Dosing Interval τ After Administration of the First Dose on Day 1 | 1990 nanomol (nmol) * hours (h) / Litre (L) | Geometric Coefficient of Variation 18.2 |
Secondary
Area Under the Concentration-time Curve (AUCτ,ss) of the BI 1015550 in Plasma at Steady State Over a Uniform Dosing Interval τ on Day 14
Area under the concentration-time curve (AUCτ,ss) of the BI 1015550 in plasma at steady state over a uniform dosing interval τ on Day 14.
Time frame: On Day 14, within 2 hours before morning dose and at 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours after morning dose.
Population: Pharmacokinetic parameter set (PKS): This patient set included all patients in the TS who provided at least one pharmacokinetic (PK) parameter that was not excluded because of protocol deviations relevant to the analysis of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 18 mg BI 1015550 | Area Under the Concentration-time Curve (AUCτ,ss) of the BI 1015550 in Plasma at Steady State Over a Uniform Dosing Interval τ on Day 14 | 3720 nanomol (nmol) * hours (h) / Litre (L) | Geometric Coefficient of Variation 49.5 |
Secondary
Maximum Measured Concentration (Cmax) of the BI 1015550 in Plasma on Day 1
Maximum measured concentration (Cmax) of the BI 1015550 in plasma on Day 1.
Time frame: On Day 1, within 2 hours before morning dose and at 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours after morning dose.
Population: Pharmacokinetic parameter set (PKS): This patient set included all patients in the TS who provided at least one pharmacokinetic (PK) parameter that was not excluded because of protocol deviations relevant to the analysis of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 18 mg BI 1015550 | Maximum Measured Concentration (Cmax) of the BI 1015550 in Plasma on Day 1 | 277 nanomol (nmol) / Litre (L) | Geometric Coefficient of Variation 23.1 |
Secondary
Maximum Measured Concentration (Cmax,ss) of the BI 1015550 in Plasma at Steady State Over a Uniform Dosing Interval τ on Day 14
Maximum measured concentration (Cmax,ss) of the BI 1015550 in plasma at steady state over a uniform dosing interval τ on Day 14.
Time frame: On Day 14, within 2 hours before morning dose and at 0.5, 1, 1.5, 2, 4, 6, 8, 12 hours after morning dose.
Population: Pharmacokinetic parameter set (PKS): This patient set included all patients in the TS who provided at least one pharmacokinetic (PK) parameter that was not excluded because of protocol deviations relevant to the analysis of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| 18 mg BI 1015550 | Maximum Measured Concentration (Cmax,ss) of the BI 1015550 in Plasma at Steady State Over a Uniform Dosing Interval τ on Day 14 | 460 nanomol (nmol) / Litre (L) | Geometric Coefficient of Variation 41.7 |