Osteoarthritis
Conditions
Brief summary
* To investigate the safety and tolerability of BI 1026706 in male and female healthy subjects and osteoarthritis (OA) patients following oral administration of repeated rising doses * To explore the pharmacokinetics after multiple rising doses of BI 1026706 in male and female healthy subjects and OA patients * The assessment of pharmacodynamics in OA patients
Interventions
DRUGBI 1026706
Multiple Rising Doses (oral solution, tablet)
Multiple Rising Doses (oral solution / tablet, identical to active treatment)
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
ALL
Age
35 Years to 65 Years
Healthy volunteers
Yes
Inclusion criteria
1. Males or females without any clinically relevant medical disorders according to the investigator's assessment, as based on the following: a complete medical history including a physical examination, vital signs (blood pressure, pulse rate), 12-lead electrocardiogram, and clinical laboratory tests 2. For OA patients: Evidence of OA of the knee by radiography or by magnetic resonance tomography (Kellgren-Lawrence grade 1, 2, or 3; excluding grades 0 and 4) of the knee (tibiofemoral joint only) within the last 5 years consistent with the clinical diagnosis of osteoarthritis of the knee according to American College of Rheumatology (ACR) guidelines 3. For OA patients: American Rheumatism Association (ARA) functional class I, II, or III 4. For OA patients: Average pain in the index knee over the previous 48 hours greater than or equal to 4 on the 11-item Likert scale at two time points: 1) at screening (if not on analgesic medication) or after 3 days of wash-out of analgesic medication, and 2) in the evening prior to randomisation 5. For OA patients: Presence of bothersome OA related pain for most days within the last month prior to screening at the investigator's discretion, or pain requiring analgesic treatment on more than 3 days per week during the last month prior to screening. 6. Age 35 to 65 years (inclusive) 7. BMI (Body Mass Index) 18.5 to 33 kg/m2 (inclusive) 8. Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation 9. Females who meet any of the following criteria from at least 30 days before the first study drug administration and until 30 days after trial completion: * using adequate contraception, e.g. any of the following methods plus condom: implants, injectables, combined oral contraceptives, intrauterine device (IUD) * sexually abstinent * have a vasectomised sexual partner (vasectomy at least 1 year prior to enrolment) * surgically sterilised (including hysterectomy) * postmenopausal defined as at least 1 year of spontaneous amenorrhea (in questionable cases a blood sample with simultaneous levels of FSH (Follicle Stimulating Hormon) above 40 U/L and estradiol below 30 ng/L is confirmatory)
Exclusion criteria
1. Any finding in the medical examination (including Blood Pressure, Pulse Rate or electrocardiogram) deviating from normal and judged clinically relevant by the investigator 2. Repeated measurement of systolic blood pressure greater than 140 mm Hg or diastolic blood pressure greater than 90 mm Hg 3. Any laboratory value outside the reference range that the investigator considers to be of clinical relevance 4. Any evidence of a concomitant disease judged clinically relevant by the investigator 5. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders 6. Surgery of the gastrointestinal tract that could interfere with kinetics of the study drug(s) 7. Diseases of the central nervous system (such as epilepsy), other neurological disorders or psychiatric disorders
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Subjects With Drug Related Adverse Events | From first drug administration until 3 days after last drug administration, 15 days | Percentage of subjects with drug related adverse events (AEs) |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time From Dosing to Maximum Measured Concentration (Tmax) | 1 hour (h) 30 minutes (min) before first drug admin and 10min, 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h and 23h 55min after first drug admin. | Time from dosing to maximum measured concentration of the analyte in plasma (Tmax) |
| Area Under the Concentration-time Curve Over the Time Interval From 0 Extrapolated to 24h (AUC0-24) | 1 hour (h) 30 minutes (min) before first drug admin and 10min, 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h and 23h 55min after first drug admin | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to 24 hours (h) (AUC0-24). |
| Area Under the Concentration-time Curve Over the Time Interval From 0 Extrapolated to 12h (AUC0-12) | 1 hour (h) 30 minutes (min) before first drug admin and 10min, 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h and 12h after first drug admin | Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to 12 hours (h) (AUC0-12). |
| Maximum Measured Concentration (Cmax) | 1 hour (h) 30 minutes (min) before first drug admin and 10min, 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h and 23h 55min after first drug admin | Maximum measured concentration of the analyte in plasma (Cmax) |
| Time From Last Dosing to Maximum Measured Concentration at Steady-state (Tmax,ss) | 5 minutes (min) before drug admin on day 12 and 10min, 20min, 30min, 45min, 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h and 24h after drug admin on day 12 | Time from last dosing to maximum concentration of the analyte in plasma at steady-state (Tmax,ss). |
| Area Under the Concentration-time Curve at Steady-state (AUCτ,ss) | 5 minutes (min) before drug admin on day 12 and 10min, 20min, 30min, 45min, 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h and 24h after drug admin on day 12 | Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ (AUCτ,ss). |
| Maximum Measured Concentration at Steady-state (Cmax,ss) | 5 minutes (min) before drug admin on day 12 and 10min, 20min, 30min, 45min, 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h and 24h after drug admin on day 12 | Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval τ (Cmax,ss). |
Countries
Germany
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Placebo HV Healthy volunteers (HV) received a matching placebo containing quinine sulphate dehydrate, once daily for 12 days. | 9 |
| 50mg BI 1026706 HV Healthy volunteers (HV) received 50mg BI 1026706 once daily on days 1 to 12 in the form of a powder for oral solution. | 9 |
| 100mg BI 1026706 HV Healthy volunteers (HV) received 100mg BI 1026706 once daily on days 1 to 12 in the form of a powder for oral solution. | 9 |
| 300mg BI 1026706 HV Healthy volunteers (HV) received 300mg BI 1026706 once daily on days 1 to 12 in the form of a powder for oral solution. | 9 |
| Placebo OA Patients with osteoarthritis (OA) received a matching placebo containing quinine sulphate dehydrate, once daily for 12 days. | 5 |
| 200mg BI 1026706 OA Patients with osteoarthritis received 200mg BI 1026706 once daily on days 1 to 12 in the form of a powder for oral solution. | 9 |
| 100mg BI 1026706 BID OA Patients with osteoarthritis received oral administration of 100mg BI 1026706 tablets twice daily (BID) on days 2 to 11 and once daily on days 1 and 12. | 8 |
| Total | 58 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 |
|---|---|---|---|---|---|---|---|---|
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 1 | 0 | 0 | 0 |
Baseline characteristics
| Characteristic | 200mg BI 1026706 OA | 100mg BI 1026706 BID OA | Total | Placebo HV | 50mg BI 1026706 HV | 100mg BI 1026706 HV | 300mg BI 1026706 HV | Placebo OA |
|---|---|---|---|---|---|---|---|---|
| Age, Continuous | 49.8 Years STANDARD_DEVIATION 8.4 | 58.1 Years STANDARD_DEVIATION 4.9 | 49.7 Years STANDARD_DEVIATION 9.2 | 48.3 Years STANDARD_DEVIATION 9.6 | 43.6 Years STANDARD_DEVIATION 5.3 | 50.1 Years STANDARD_DEVIATION 11.8 | 48.7 Years STANDARD_DEVIATION 8.8 | 50.2 Years STANDARD_DEVIATION 10.8 |
| Sex: Female, Male Female | 2 Participants | 5 Participants | 28 Participants | 6 Participants | 4 Participants | 4 Participants | 4 Participants | 3 Participants |
| Sex: Female, Male Male | 7 Participants | 3 Participants | 30 Participants | 3 Participants | 5 Participants | 5 Participants | 5 Participants | 2 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 | EG005 affected / at risk | EG006 affected / at risk |
|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 5 / 9 | 3 / 9 | 2 / 9 | 6 / 9 | 3 / 5 | 6 / 9 | 4 / 8 |
| serious Total, serious adverse events | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 9 | 0 / 5 | 0 / 9 | 0 / 8 |
Outcome results
Primary
Percentage of Subjects With Drug Related Adverse Events
Percentage of subjects with drug related adverse events (AEs)
Time frame: From first drug administration until 3 days after last drug administration, 15 days
Population: Treated set (TS)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Placebo HV | Percentage of Subjects With Drug Related Adverse Events | 22.2 Percentage of participants |
| 50mg BI 1026706 HV | Percentage of Subjects With Drug Related Adverse Events | 22.2 Percentage of participants |
| 100mg BI 1026706 HV | Percentage of Subjects With Drug Related Adverse Events | 11.1 Percentage of participants |
| 300mg BI 1026706 HV | Percentage of Subjects With Drug Related Adverse Events | 66.7 Percentage of participants |
| Placebo OA | Percentage of Subjects With Drug Related Adverse Events | 60.0 Percentage of participants |
| 200mg BI 1026706 OA | Percentage of Subjects With Drug Related Adverse Events | 55.6 Percentage of participants |
| 100mg BI 1026706 BID OA | Percentage of Subjects With Drug Related Adverse Events | 37.5 Percentage of participants |
Secondary
Area Under the Concentration-time Curve at Steady-state (AUCτ,ss)
Area under the concentration-time curve of the analyte in plasma at steady-state over a uniform dosing interval τ (AUCτ,ss).
Time frame: 5 minutes (min) before drug admin on day 12 and 10min, 20min, 30min, 45min, 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h and 24h after drug admin on day 12
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo HV | Area Under the Concentration-time Curve at Steady-state (AUCτ,ss) | 1610 nmol*h/L | Geometric Coefficient of Variation 51.4 |
| 50mg BI 1026706 HV | Area Under the Concentration-time Curve at Steady-state (AUCτ,ss) | 4080 nmol*h/L | Geometric Coefficient of Variation 24.5 |
| 100mg BI 1026706 HV | Area Under the Concentration-time Curve at Steady-state (AUCτ,ss) | 8550 nmol*h/L | Geometric Coefficient of Variation 44.5 |
| 300mg BI 1026706 HV | Area Under the Concentration-time Curve at Steady-state (AUCτ,ss) | 7200 nmol*h/L | Geometric Coefficient of Variation 38.9 |
| Placebo OA | Area Under the Concentration-time Curve at Steady-state (AUCτ,ss) | 3280 nmol*h/L | Geometric Coefficient of Variation 61.3 |
Comparison: Investigation of dose proportionality - dose groups 50mg to 300mg90% CI: [0.7744, 1.1122]ANCOVA
Comparison: Investigation of dose proportionality - dose groups 50mg to 200mg90% CI: [0.8583, 1.3037]ANCOVA
Secondary
Area Under the Concentration-time Curve Over the Time Interval From 0 Extrapolated to 12h (AUC0-12)
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to 12 hours (h) (AUC0-12).
Time frame: 1 hour (h) 30 minutes (min) before first drug admin and 10min, 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h and 12h after first drug admin
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo HV | Area Under the Concentration-time Curve Over the Time Interval From 0 Extrapolated to 12h (AUC0-12) | 1050 nmol*h/L | Geometric Coefficient of Variation 41.3 |
| 50mg BI 1026706 HV | Area Under the Concentration-time Curve Over the Time Interval From 0 Extrapolated to 12h (AUC0-12) | 2370 nmol*h/L | Geometric Coefficient of Variation 27.8 |
| 100mg BI 1026706 HV | Area Under the Concentration-time Curve Over the Time Interval From 0 Extrapolated to 12h (AUC0-12) | 5080 nmol*h/L | Geometric Coefficient of Variation 63.6 |
| 300mg BI 1026706 HV | Area Under the Concentration-time Curve Over the Time Interval From 0 Extrapolated to 12h (AUC0-12) | 4720 nmol*h/L | Geometric Coefficient of Variation 45.1 |
| Placebo OA | Area Under the Concentration-time Curve Over the Time Interval From 0 Extrapolated to 12h (AUC0-12) | 2290 nmol*h/L | Geometric Coefficient of Variation 54.2 |
Secondary
Area Under the Concentration-time Curve Over the Time Interval From 0 Extrapolated to 24h (AUC0-24)
Area under the concentration-time curve of the analyte in plasma over the time interval from 0 extrapolated to 24 hours (h) (AUC0-24).
Time frame: 1 hour (h) 30 minutes (min) before first drug admin and 10min, 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h and 23h 55min after first drug admin
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo HV | Area Under the Concentration-time Curve Over the Time Interval From 0 Extrapolated to 24h (AUC0-24) | 1230 nmol*h/L | Geometric Coefficient of Variation 44.9 |
| 50mg BI 1026706 HV | Area Under the Concentration-time Curve Over the Time Interval From 0 Extrapolated to 24h (AUC0-24) | 2790 nmol*h/L | Geometric Coefficient of Variation 26.7 |
| 100mg BI 1026706 HV | Area Under the Concentration-time Curve Over the Time Interval From 0 Extrapolated to 24h (AUC0-24) | 6410 nmol*h/L | Geometric Coefficient of Variation 66.2 |
| 300mg BI 1026706 HV | Area Under the Concentration-time Curve Over the Time Interval From 0 Extrapolated to 24h (AUC0-24) | 5530 nmol*h/L | Geometric Coefficient of Variation 44.9 |
| Placebo OA | Area Under the Concentration-time Curve Over the Time Interval From 0 Extrapolated to 24h (AUC0-24) | 2790 nmol*h/L | Geometric Coefficient of Variation 58.5 |
Comparison: Investigation of dose proportionality - dose groups 50mg to 300mg90% CI: [0.7654, 1.1367]ANCOVA
Comparison: Investigation of dose proportionality - dose groups 50mg to 200mg90% CI: [0.8655, 1.3013]ANCOVA
Secondary
Maximum Measured Concentration at Steady-state (Cmax,ss)
Maximum measured concentration of the analyte in plasma at steady-state over a uniform dosing interval τ (Cmax,ss).
Time frame: 5 minutes (min) before drug admin on day 12 and 10min, 20min, 30min, 45min, 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h and 24h after drug admin on day 12
Population: PKS
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo HV | Maximum Measured Concentration at Steady-state (Cmax,ss) | 485 nmol/L | Geometric Coefficient of Variation 37.4 |
| 50mg BI 1026706 HV | Maximum Measured Concentration at Steady-state (Cmax,ss) | 1190 nmol/L | Geometric Coefficient of Variation 26.1 |
| 100mg BI 1026706 HV | Maximum Measured Concentration at Steady-state (Cmax,ss) | 1800 nmol/L | Geometric Coefficient of Variation 43.3 |
| 300mg BI 1026706 HV | Maximum Measured Concentration at Steady-state (Cmax,ss) | 2040 nmol/L | Geometric Coefficient of Variation 27 |
| Placebo OA | Maximum Measured Concentration at Steady-state (Cmax,ss) | 723 nmol/L | Geometric Coefficient of Variation 65.1 |
Comparison: Investigation of dose proportionality - dose groups 50mg to 300mg90% CI: [0.6235, 0.9428]ANCOVA
Comparison: Investigation of dose proportionality - dose groups 50mg to 200mg90% CI: [0.8593, 1.2137]ANCOVA
Secondary
Maximum Measured Concentration (Cmax)
Maximum measured concentration of the analyte in plasma (Cmax)
Time frame: 1 hour (h) 30 minutes (min) before first drug admin and 10min, 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h and 23h 55min after first drug admin
Population: Pharmacokinetic set (PKS) which included all patients and healthy subjects in the TS who provided at least 1 PK endpoint value without relevant protocol deviations with respect to the evaluation of PK endpoints.
| Arm | Measure | Value (GEOMETRIC_MEAN) | Dispersion |
|---|---|---|---|
| Placebo HV | Maximum Measured Concentration (Cmax) | 423 nmol/L | Geometric Coefficient of Variation 31.2 |
| 50mg BI 1026706 HV | Maximum Measured Concentration (Cmax) | 1010 nmol/L | Geometric Coefficient of Variation 25.3 |
| 100mg BI 1026706 HV | Maximum Measured Concentration (Cmax) | 1600 nmol/L | Geometric Coefficient of Variation 54.3 |
| 300mg BI 1026706 HV | Maximum Measured Concentration (Cmax) | 1730 nmol/L | Geometric Coefficient of Variation 36.1 |
| Placebo OA | Maximum Measured Concentration (Cmax) | 578 nmol/L | Geometric Coefficient of Variation 53.6 |
Comparison: Investigation of dose proportionality - dose groups 50mg to 300mg90% CI: [0.6193, 0.9537]ANCOVA
Comparison: Investigation of dose proportionality - dose groups 50mg to 200mg90% CI: [0.8378, 1.1964]ANCOVA
Secondary
Time From Dosing to Maximum Measured Concentration (Tmax)
Time from dosing to maximum measured concentration of the analyte in plasma (Tmax)
Time frame: 1 hour (h) 30 minutes (min) before first drug admin and 10min, 20min, 30min, 45min, 1h, 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h and 23h 55min after first drug admin.
Population: PKS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo HV | Time From Dosing to Maximum Measured Concentration (Tmax) | 0.52 hours |
| 50mg BI 1026706 HV | Time From Dosing to Maximum Measured Concentration (Tmax) | 0.52 hours |
| 100mg BI 1026706 HV | Time From Dosing to Maximum Measured Concentration (Tmax) | 0.69 hours |
| 300mg BI 1026706 HV | Time From Dosing to Maximum Measured Concentration (Tmax) | 0.75 hours |
| Placebo OA | Time From Dosing to Maximum Measured Concentration (Tmax) | 1.53 hours |
Secondary
Time From Last Dosing to Maximum Measured Concentration at Steady-state (Tmax,ss)
Time from last dosing to maximum concentration of the analyte in plasma at steady-state (Tmax,ss).
Time frame: 5 minutes (min) before drug admin on day 12 and 10min, 20min, 30min, 45min, 1 hour (h), 1h 30min, 2h, 2h 30min, 3h, 4h, 6h, 8h, 10h, 12h, 14h and 24h after drug admin on day 12
Population: PKS
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Placebo HV | Time From Last Dosing to Maximum Measured Concentration at Steady-state (Tmax,ss) | 0.53 hours |
| 50mg BI 1026706 HV | Time From Last Dosing to Maximum Measured Concentration at Steady-state (Tmax,ss) | 0.52 hours |
| 100mg BI 1026706 HV | Time From Last Dosing to Maximum Measured Concentration at Steady-state (Tmax,ss) | 0.58 hours |
| 300mg BI 1026706 HV | Time From Last Dosing to Maximum Measured Concentration at Steady-state (Tmax,ss) | 0.58 hours |
| Placebo OA | Time From Last Dosing to Maximum Measured Concentration at Steady-state (Tmax,ss) | 1.13 hours |