Pain Management
Conditions
Brief summary
The study evaluates the effectiveness and safety of IV tramadol compared to placebo managing postoperative pain following a bunionectomy
Detailed description
(Non-clinical summary) Tramadol is a centrally-acting synthetic analgesic of the aminocyclohexanol group with opioidlike effects. Tramadol is extensively metabolized following administration, which results in a number of enantiomeric metabolites that display different opioid-receptor binding properties, and monoaminergic reuptake inhibition.
Interventions
DRUGTramadol
IV; 25 mg or 50 mg, given at Hours 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44
OTHERPlacebo
IV; Placebo, given at Hours 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44
Sponsors
Avenue Therapeutics, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
TRIPLE (Subject, Caregiver, Investigator)
Eligibility
Sex/Gender
ALL
Age
18 Years to 75 Years
Healthy volunteers
No
Inclusion criteria
Key Inclusion Criteria: * The patient is male or female 18-75 years of age undergoing unilateral first metatarsal bunionectomy surgery * Willing to give consent and able to understand the study procedures * Female patients must be of non-childbearing potential or be practicing a highly effective contraception * The patient must be willing to be housed in a healthcare facility and able to receive parenteral analgesia for at least 72 hours after surgery. * The patient meets definition of American Society of Anesthesiologists (ASA) Physical Class 1, or 2.
Exclusion criteria
* Patient is not expected to receive a continuous infusion nerve block as described in the Post-Op anesthetic procedures protocol * Patient is undergoing bilateral or revision bunionectomy surgery * The patient has allergy or hypersensitivity (or is intolerant) to opioids or tramadol The patient has known physical dependence on opioids * The patient has taken other prior/concurrent chronic medications that have not been at a stable dose for at least 2 weeks prior to screening * The patient is taking herbal or dietary supplements or medications that are moderate or strong inhibitors of CYP2D6 or CYP3A4 or inducers of CYP3A4 * The patient has taken monoamine oxidase (MAO) inhibitors, trazodone, or cyclobenzaprine within 14 days prior to surgery * The patient cannot be withdrawn from medications (at least 7 days prior to surgery) that may lower the seizure threshold (e.g. anti-psychotic agents, MAOI inhibitors) or which increase serotonergic tone (e.g. selective serotonin reuptake inhibitors (SSRIs), serotonin norepinephrine reuptake inhibitors (SNRIs), tricyclic antidepressants, triptans). * The patient has a history of epilepsy, or is known to be susceptible to seizures * The patient has a history of Long QT Syndrome or a relative with this condition * The patient has expressed suicidal ideation or is considered to be at risk of suicide. * The patient is morbidly obese (body mass index \[BMI\] ≥ 40 kg/m2) or has documented sleep apnea requiring pharmacological or device intervention. * Clinically significant abnormalities in the judgement of the Investigator * The patient was administered an investigational product within 30 days prior to Screening. * The patient has previously participated in a clinical study with AVE-901.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Sum of Pain Intensity Differences (SPID) Through 48 Hours Post First Dose | 48 hours post first dose | Pain intensity was recorded using the Numerical Pain Rating Scale (NPRS) from 0 to 10, where 0 was no pain and 10 was the worst pain imaginable at hrs: .5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48. As higher pain scores indicate worse pain, a negative Pain Intensity Difference (PID) indicates less pain (improvement from baseline). Thus, SPID scores are expected to be negative if a patient's pain decreases over time, with the lower SPID values indicating greater reduction in pain intensity. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| AVE-901 50 mg Tramadol: IV; 25 mg or 50 mg, given at Hours 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44 | 139 |
| AVE-901 25 mg Tramadol: IV; 25 mg or 50 mg, given at Hours 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44 | 134 |
| Placebo Placebo: IV; Placebo, given at Hours 0, 2, 4, 8, 12, 16, 20, 24, 28, 32, 36, 40, and 44 | 136 |
| Total | 409 |
Baseline characteristics
| Characteristic | AVE-901 50 mg | AVE-901 25 mg | Placebo | Total |
|---|---|---|---|---|
| Age, Continuous | 45.3 years STANDARD_DEVIATION 13.51 | 44.5 years STANDARD_DEVIATION 13.15 | 45.0 years STANDARD_DEVIATION 13.44 | 45.2 years STANDARD_DEVIATION 13.35 |
| American Society of Anesthesiology (ASA) Physical Classification 1 | 70 Participants | 71 Participants | 72 Participants | 213 Participants |
| American Society of Anesthesiology (ASA) Physical Classification 2 | 69 Participants | 63 Participants | 64 Participants | 196 Participants |
| BMI | 27.9 kg/m2 STANDARD_DEVIATION 4.97 | 28.1 kg/m2 STANDARD_DEVIATION 5.48 | 28.3 kg/m2 STANDARD_DEVIATION 4.91 | 28.1 kg/m2 STANDARD_DEVIATION 5.12 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 51 Participants | 46 Participants | 52 Participants | 149 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 88 Participants | 88 Participants | 84 Participants | 260 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Previous opioid history No | 97 Participants | 82 Participants | 89 Participants | 268 Participants |
| Previous opioid history Yes | 42 Participants | 52 Participants | 47 Participants | 141 Participants |
| Qualifying Categorical Pain Score Moderate | 89 Participants | 80 Participants | 75 Participants | 244 Participants |
| Qualifying Categorical Pain Score Severe | 50 Participants | 54 Participants | 61 Participants | 165 Participants |
| Qualifying Numerical Pain Rating Scale (NPRS) | 6.7 score on a scale STANDARD_DEVIATION 1.66 | 6.8 score on a scale STANDARD_DEVIATION 1.39 | 6.9 score on a scale STANDARD_DEVIATION 1.63 | 6.8 score on a scale STANDARD_DEVIATION 1.56 |
| Race (NIH/OMB) American Indian or Alaska Native | 2 Participants | 1 Participants | 4 Participants | 7 Participants |
| Race (NIH/OMB) Asian | 2 Participants | 3 Participants | 4 Participants | 9 Participants |
| Race (NIH/OMB) Black or African American | 29 Participants | 38 Participants | 37 Participants | 104 Participants |
| Race (NIH/OMB) More than one race | 2 Participants | 2 Participants | 3 Participants | 7 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 104 Participants | 88 Participants | 88 Participants | 280 Participants |
| Region of Enrollment United States | 139 Participants | 134 Participants | 136 Participants | 409 Participants |
| Sex: Female, Male Female | 120 Participants | 116 Participants | 113 Participants | 349 Participants |
| Sex: Female, Male Male | 19 Participants | 18 Participants | 23 Participants | 60 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 140 | 0 / 133 | 0 / 136 |
| other Total, other adverse events | 93 / 140 | 56 / 133 | 60 / 136 |
| serious Total, serious adverse events | 0 / 140 | 1 / 133 | 0 / 136 |
Outcome results
Primary
The Sum of Pain Intensity Differences (SPID) Through 48 Hours Post First Dose
Pain intensity was recorded using the Numerical Pain Rating Scale (NPRS) from 0 to 10, where 0 was no pain and 10 was the worst pain imaginable at hrs: .5, 1, 2, 3, 4, 5, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 44, 46, 48. As higher pain scores indicate worse pain, a negative Pain Intensity Difference (PID) indicates less pain (improvement from baseline). Thus, SPID scores are expected to be negative if a patient's pain decreases over time, with the lower SPID values indicating greater reduction in pain intensity.
Time frame: 48 hours post first dose
Population: One patient was randomized to tramadol 25 mg but received tramadol 50 mg in error.
| Arm | Measure | Value (LEAST_SQUARES_MEAN) |
|---|---|---|
| AVE-901 50 mg | The Sum of Pain Intensity Differences (SPID) Through 48 Hours Post First Dose | -122.8 score on a scale |
| AVE-901 25 mg | The Sum of Pain Intensity Differences (SPID) Through 48 Hours Post First Dose | -110.9 score on a scale |
| Placebo | The Sum of Pain Intensity Differences (SPID) Through 48 Hours Post First Dose | -97.8 score on a scale |
p-value: <0.005ANCOVA