Pain, Postoperative
Conditions
Brief summary
To investigate the effectiveness of BI 1026706 powder for reconstitution of an oral solution compared to placebo and the relative effectiveness compared to Celecoxib.
Interventions
DRUGPlacebo to BI 1026706 solution
Placebo to BI 1026706 solution
DRUGBI 1026706
BI 1026706
DRUGPlacebo to BI 1026706 tablet
Placebo to BI 1026706 tablet
DRUGCelecoxib
Celecoxib capsule
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE
Eligibility
Sex/Gender
MALE
Age
18 Years to 55 Years
Healthy volunteers
No
Inclusion criteria
1. Healthy males according to the investigator's assessment, as based on the following criteria: a complete medical history including a physical examination, vital signs (Blood Pressure,Pulse Rate), 12-lead electrocardiogram, and clinical laboratory tests 2. Age 18 to 55 years (incl.) 3. Body Mass Index 18.5 to 29.9 kg/m2 (incl.) 4. Patients scheduled for removal of one mandibular third molar with partial or complete bony impaction. If medically indicated, the ipsilateral third molar in the upper jaw could also be removed; 5. Surgery will be conducted under local anaesthesia using 12% lidocaine (with epinephrine). Intravenous sedations and general anaesthetics are not permitted. 6. Reliable, cooperative, and of adequate intelligence to record the requested information on the analgesic questionnaire form 7. Examined by the attending oral surgeon or physician and medically cleared to participate in the study 8. Scheduled to undergo a qualifying surgical procedure 9. Signed and dated written informed consent prior to admission to the study in accordance with GCP and local legislation
Exclusion criteria
1. Any finding in the medical examination (including Blod 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. Acute local infection at the time of surgery that could confound the post-surgical evaluation 6. Gastrointestinal, hepatic, renal, respiratory, cardiovascular, metabolic, immunological or hormonal disorders 7. Surgery of the gastrointestinal tract that could interfere with kinetics of the study drug(s)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| SPID0-8h | up to 8 hours post drug administration | Time-weighted sum of pain intensity difference (PID) from 0 to 8 hours post drug administration (SPID0-8h). SPID0-8h: possible range (-400; 800). The greater SPID0-8 the greater the reduction of pain intensity over the first 8 hours post drug administration. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| TOTPAR0-8h | up to 8 hours post drug administration | Time-weighted total pain relief (PAR) from 0 to 8 hours (TOTPAR0-8h). (TOTPAR0-8h)TOTPAR0-8h: possible range (0;32). The greater TOTPAR0-8h the more pain relief was experienced over the first 8 hours post drug administration. |
| SPID0-2h | up to 2 hours post drug administration | Time-weighted sum of PID from 0 to 2 hours (SPID0-2h). SPID0-2h: possible range (-100; 200). The greater SPID0-2 the greater the reduction of pain intensity over the first 2 hours post drug administration. |
| Time to Meaningful Pain Relief | up to 10 hours post drug administration | Time to meaningful pain relief was captured by a stopwatch started by the trial staff immediately after administration of study medication and stopped by the subject as soon as a meaningful pain relief was felt by the subject. If a subject did not have any meaningful pain relief up to 10 h, the time was censored at 10 h. Kaplan-Meier estimates over time for each treatment and time to event endpoint 'Time to meaningful pain relief' were presented descriptively. |
| Time to First Dose of Rescue Medication | up to 10 hours post drug administration | The time to first dose of rescue medication was defined by the difference in time of the study drug intake and the time of first rescue medication use within the first 10 h after study drug administration. Kaplan-Meier estimates over time for each treatment and time to event endpoint 'Time to first dose of rescue medication' were presented descriptively. Subjects without intake of rescue medication within the first 10 hours after study drug administration were censored at 10 hours. |
| Percentage of Patients With Drug-related Adverse Events | From first drug administration until 3 days after last drug administration, upto 4 days | Percentage of patients with drug-related adverse events |
Countries
Italy
Participant flow
Pre-assignment details
This was a randomised, placebo and active comparator-controlled, partially double-blinded, single-dose, parallel-group, single-centre trial in male patients in double dummy design investigating 4 different treatments.
Participants by arm
| Arm | Count |
|---|---|
| BI 50 mg PfOS This trial has double dummy design, thus subjects were orally administered single dose of 50 mg of Boehringer Ingelheim (BI) 1026706 powder for oral solution (PfOS) with 200 mL of water plus matching placebo to BI 1026706 PfOS (to have 80 mL volume in total) and a placebo film-coated tablet. | 20 |
| BI 200 mg PfOS This trial has double dummy design, thus subjects were orally administered single dose of 200 mg of BI 1026706 powder for oral solution (PfOS) with 200 mL of water and a placebo film-coated tablet. | 20 |
| Placebo This trial has double dummy design, thus subjects were orally administered single dose of matching placebo to BI 1026706 powder for oral solution with 200 mL of water and placebo film coated tablet. | 20 |
| Celecoxib 200 mg This trial has double dummy design, thus subjects were orally administered single dose of Celecoxib hard capsule of 200 mg with 200 mL of water plus matching placebo to BI 1026706 PfOS. | 20 |
| Total | 80 |
Baseline characteristics
| Characteristic | BI 50 mg PfOS | BI 200 mg PfOS | Placebo | Celecoxib 200 mg | Total |
|---|---|---|---|---|---|
| Age, Continuous | 27.0 Years STANDARD_DEVIATION 8.7 | 24.2 Years STANDARD_DEVIATION 6 | 26.9 Years STANDARD_DEVIATION 5.7 | 26.5 Years STANDARD_DEVIATION 7.8 | 26.1 Years STANDARD_DEVIATION 7.1 |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 20 Participants | 20 Participants | 20 Participants | 20 Participants | 80 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — | — / — |
| other Total, other adverse events | 0 / 20 | 0 / 20 | 0 / 20 | 0 / 20 |
| serious Total, serious adverse events | 0 / 20 | 0 / 20 | 0 / 20 | 0 / 20 |
Outcome results
Primary
SPID0-8h
Time-weighted sum of pain intensity difference (PID) from 0 to 8 hours post drug administration (SPID0-8h). SPID0-8h: possible range (-400; 800). The greater SPID0-8 the greater the reduction of pain intensity over the first 8 hours post drug administration.
Time frame: up to 8 hours post drug administration
Population: The pharmacodynamic set (PD set) included all subjects of the Treated set (TS) who provided at least 1 primary or secondary PD endpoint value that was not flagged for exclusion.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 50 mg PfOS | SPID0-8h | -50.14 units on scale |
| BI 200 mg PfOS | SPID0-8h | -24.06 units on scale |
| Placebo | SPID0-8h | -77.54 units on scale |
| Celecoxib 200 mg | SPID0-8h | 124.47 units on scale |
Comparison: ANCOVA model was used with 'treatment' as fixed effect, 'patient baseline pain intensity (BPI)' as continuous covariate and the residual error term.95% CI: [-76.3, 131.1]
Comparison: ANCOVA model was used with 'treatment' as fixed effect, 'patient baseline pain intensity (BPI)' as continuous covariate and the residual error term.95% CI: [-50.2, 157.1]
Comparison: ANCOVA model was used with 'treatment' as fixed effect, 'patient baseline pain intensity (BPI)' as continuous covariate and the residual error term.95% CI: [-278.3, -70.9]
Comparison: ANCOVA model was used with 'treatment' as fixed effect, 'patient baseline pain intensity (BPI)' as continuous covariate and the residual error term.95% CI: [-252.4, -44.7]
Secondary
Percentage of Patients With Drug-related Adverse Events
Percentage of patients with drug-related adverse events
Time frame: From first drug administration until 3 days after last drug administration, upto 4 days
Population: Treated Set
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| BI 50 mg PfOS | Percentage of Patients With Drug-related Adverse Events | 0.0 Percentage of participants |
| BI 200 mg PfOS | Percentage of Patients With Drug-related Adverse Events | 0.0 Percentage of participants |
| Placebo | Percentage of Patients With Drug-related Adverse Events | 0.0 Percentage of participants |
| Celecoxib 200 mg | Percentage of Patients With Drug-related Adverse Events | 0.0 Percentage of participants |
Secondary
SPID0-2h
Time-weighted sum of PID from 0 to 2 hours (SPID0-2h). SPID0-2h: possible range (-100; 200). The greater SPID0-2 the greater the reduction of pain intensity over the first 2 hours post drug administration.
Time frame: up to 2 hours post drug administration
Population: PD set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 50 mg PfOS | SPID0-2h | -8.08 units on scale |
| BI 200 mg PfOS | SPID0-2h | 6.57 units on scale |
| Placebo | SPID0-2h | -14.01 units on scale |
| Celecoxib 200 mg | SPID0-2h | 5.20 units on scale |
Comparison: ANCOVA model was used with 'treatment' as fixed effect, 'patient baseline pain intensity (BPI)' as continuous covariate and the residual error term.95% CI: [-16, 27.8]
Comparison: ANCOVA model was used with 'treatment' as fixed effect, 'patient baseline pain intensity (BPI)' as continuous covariate and the residual error term.95% CI: [-1.3, 42.5]
Comparison: ANCOVA model was used with 'treatment' as fixed effect, 'patient baseline pain intensity (BPI)' as continuous covariate and the residual error term.95% CI: [-35.2, 8.6]
Comparison: ANCOVA model was used with 'treatment' as fixed effect, 'patient baseline pain intensity (BPI)' as continuous covariate and the residual error term.95% CI: [-20.6, 23.3]
Secondary
Time to First Dose of Rescue Medication
The time to first dose of rescue medication was defined by the difference in time of the study drug intake and the time of first rescue medication use within the first 10 h after study drug administration. Kaplan-Meier estimates over time for each treatment and time to event endpoint 'Time to first dose of rescue medication' were presented descriptively. Subjects without intake of rescue medication within the first 10 hours after study drug administration were censored at 10 hours.
Time frame: up to 10 hours post drug administration
Population: PD set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 50 mg PfOS | Time to First Dose of Rescue Medication | 1.57 hours |
| BI 200 mg PfOS | Time to First Dose of Rescue Medication | 1.53 hours |
| Placebo | Time to First Dose of Rescue Medication | 1.52 hours |
| Celecoxib 200 mg | Time to First Dose of Rescue Medication | NA hours |
Comparison: Log rank test used to evaluate the difference between each active treatment and placebo.p-value: 0.415Log Rank
Comparison: Log rank test used to evaluate the difference between each active treatment and placebo.p-value: 0.3093Log Rank
Comparison: Log rank test used to evaluate the difference between each active treatment and placebo.p-value: 0.0074Log Rank
Secondary
Time to Meaningful Pain Relief
Time to meaningful pain relief was captured by a stopwatch started by the trial staff immediately after administration of study medication and stopped by the subject as soon as a meaningful pain relief was felt by the subject. If a subject did not have any meaningful pain relief up to 10 h, the time was censored at 10 h. Kaplan-Meier estimates over time for each treatment and time to event endpoint 'Time to meaningful pain relief' were presented descriptively.
Time frame: up to 10 hours post drug administration
Population: PD set
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| BI 50 mg PfOS | Time to Meaningful Pain Relief | 5.00 hours |
| BI 200 mg PfOS | Time to Meaningful Pain Relief | 2.67 hours |
| Placebo | Time to Meaningful Pain Relief | NA hours |
| Celecoxib 200 mg | Time to Meaningful Pain Relief | 1.93 hours |
Comparison: Log rank test used to evaluate the difference between each active treatment and placebo.p-value: 0.2503Log Rank
Comparison: Log rank test used to evaluate the difference between each active treatment and placebo.p-value: 0.1851Log Rank
Comparison: Log rank test used to evaluate the difference between each active treatment and placebo.p-value: 0.0167Log Rank
Secondary
TOTPAR0-8h
Time-weighted total pain relief (PAR) from 0 to 8 hours (TOTPAR0-8h). (TOTPAR0-8h)TOTPAR0-8h: possible range (0;32). The greater TOTPAR0-8h the more pain relief was experienced over the first 8 hours post drug administration.
Time frame: up to 8 hours post drug administration
Population: PD Set
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| BI 50 mg PfOS | TOTPAR0-8h | 3.85 units on scale |
| BI 200 mg PfOS | TOTPAR0-8h | 3.14 units on scale |
| Placebo | TOTPAR0-8h | 2.16 units on scale |
| Celecoxib 200 mg | TOTPAR0-8h | 10.12 units on scale |
Comparison: ANCOVA model was used with 'treatment' as fixed effect, 'patient baseline pain intensity (BPI)' as continuous covariate and the residual error term.95% CI: [-2.3, 5.7]
Comparison: ANCOVA model was used with 'treatment' as fixed effect, 'patient baseline pain intensity (BPI)' as continuous covariate and the residual error term.95% CI: [-3, 5]
Comparison: ANCOVA model was used with 'treatment' as fixed effect, 'patient baseline pain intensity (BPI)' as continuous covariate and the residual error term.95% CI: [-10.3, -2.2]
Comparison: ANCOVA model was used with 'treatment' as fixed effect, 'patient baseline pain intensity (BPI)' as continuous covariate and the residual error term.95% CI: [-11, -2.9]