Healthy
Conditions
Brief summary
This study aims to demonstrate the bioequivalence between the formulation of 5 mg/mL Tramadol Hydrochloride Oral Solution (08P1902F0) Relative to the reference product Contramal® (100 mg/mL Oral Solution).
Interventions
DRUGTramadol Hydrochloride 5 MG/ML Oral Solution
50mg (10mL) single dose
DRUGTramadol Hydrochloride 100 MG/ML Oral Solution (Contramal(r))
50mg (20 drops) single dose
Sponsors
International Pharmaceutical Research Center
Unither Pharmaceuticals, France
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Open-label, randomized, single dose, two-sequence, two-period crossover study
Eligibility
Sex/Gender
ALL
Age
18 Years to 50 Years
Healthy volunteers
Yes
Inclusion criteria
* Male and non-pregnant female human subjects, age 18-50 years * Body mass index between 18.5-30 Kg/m² * Subject with normal findings * Willingness to follow the protocol requirements
Exclusion criteria
* History of hypersensitivity to tramadol hydrochloride * Significant history of asthma, thyrotoxicosis, tumours, peptic or gastric ulcer, gastrointestinal malabsorption or haemorrhage in the gastro-intestinal tract, sinusitis, pharyngitis, renal disorder (impaired renal function), hepatic disorder (impaired hepatic function), cardiovascular disorder (ex. severe heart failure), neurological disease such as epilepsy, haematological disorders or diabetes, psychiatric, dermatologic or immunological disorders * Presence of any clinically significant results from laboratory tests, * lactating female or woman of childbearing potential unwilling to use an effective contraception
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Cmax of Tramadol Hydrochloride for the Test and the Reference Products | predose, 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours | The maximum concentration in plasma among observed concentrations at pre-specified time points |
| AUC0-t of Tramadol Hydrochloride for the Test and the Reference Products | predose, 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours | The area under the plasma concentration versus time curve from time 0 to the last measured concentration |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Kel of Tramadol Hydrochloride for the Test and the Reference Products | predose, 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours | The elimination rate constant |
| Tmax of Tramadol Hydrochloride for the Test and the Reference Products | predose, 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours | Time of the maximum measured plasma concentration. Determined directly from the plasma concentration-time curve. If the maximum value occurs at more than one time point, tmax is defined as the first time point with this value. |
| Number of Treatment-related Adverse Events | Day 1 to Day 11 (end of study) | Occurence and severity of adverse events (serious and non serious adverse events) |
| T1/2 of Tramadol Hydrochloride for the Test and the Reference Products | predose, 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours | Plasma Elimination Half-Life |
| AUC0-infinity of Tramadol Hydrochloride for the Test and the Reference Products | predose, 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours | The area under the plasma concentration versus time curve from time 0 to to infinite time |
Other
| Measure | Time frame | Description |
|---|---|---|
| Palatability Questionnaire | 0 and 2 minutes | 5 point scale: from 1 : very bad after taste to 5 : very good after taste |
Countries
Jordan
Participant flow
Pre-assignment details
cross-over study.
Participants by arm
| Arm | Count |
|---|---|
| Tramadol HCl 5mg/mL Oral Solution IMP08P1902F0 Then Tramadol HCl 100mg/mL Oral Solution Contramal(r) Participants first received Tramadol Hydrochloride 5 MG/ML Oral Solution: 50mg (10mL) single dose (IMP 08P1902F0) manufactured by Unither Liquid Manufacturing in a fasting state. After a washout period of 1 week, they received Tramadol HCl 100mg/mL oral solution Contramal(r) manufactured by Grunenthal GmbH in a fasting state | 12 |
| Tramadol HCl 100mg/mL Oral Solution Contramal(r) Then Tramadol HCl 5mg/mL Oral Solution IMP08P1902F0 Participants first received Tramadol HCl 100mg/mL oral solution Contramal(r) manufactured by Grunenthal GmbH in a fasting state. After a washout period of 1 week, they received Tramadol Hydrochloride 5 MG/ML Oral Solution: 50mg (10mL) single dose (IMP 08P1902F0) manufactured by Unither Liquid Manufacturing in a fasting state. | 12 |
| Total | 24 |
Baseline characteristics
| Characteristic | Tramadol HCl 100mg/mL Oral Solution Contramal(r) Then Tramadol HCl 5mg/mL Oral Solution IMP08P1902F0 | Total | Tramadol HCl 5mg/mL Oral Solution IMP08P1902F0 Then Tramadol HCl 100mg/mL Oral Solution Contramal(r) |
|---|---|---|---|
| Age, Continuous | 29 years STANDARD_DEVIATION 7.3 | 27 years STANDARD_DEVIATION 7.08 | 25 years STANDARD_DEVIATION 6.6 |
| Race and Ethnicity Not Collected | — | 0 Participants | — |
| Region of Enrollment Jordan | 12 Participants | 24 Participants | 12 Participants |
| Sex: Female, Male Female | 0 Participants | 0 Participants | 0 Participants |
| Sex: Female, Male Male | 12 Participants | 24 Participants | 12 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 24 | 0 / 24 |
| other Total, other adverse events | 0 / 24 | 0 / 24 |
| serious Total, serious adverse events | 0 / 24 | 0 / 24 |
Outcome results
Primary
AUC0-t of Tramadol Hydrochloride for the Test and the Reference Products
The area under the plasma concentration versus time curve from time 0 to the last measured concentration
Time frame: predose, 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | AUC0-t of Tramadol Hydrochloride for the Test and the Reference Products | 902.01 ng*h/mL | Standard Deviation 339.22 |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | AUC0-t of Tramadol Hydrochloride for the Test and the Reference Products | 812.63 ng*h/mL | Standard Deviation 301.24 |
Primary
Cmax of Tramadol Hydrochloride for the Test and the Reference Products
The maximum concentration in plasma among observed concentrations at pre-specified time points
Time frame: predose, 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | Cmax of Tramadol Hydrochloride for the Test and the Reference Products | 139.65 ng/mL | Standard Deviation 53.01 |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | Cmax of Tramadol Hydrochloride for the Test and the Reference Products | 123.90 ng/mL | Standard Deviation 36.02 |
Secondary
AUC0-infinity of Tramadol Hydrochloride for the Test and the Reference Products
The area under the plasma concentration versus time curve from time 0 to to infinite time
Time frame: predose, 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | AUC0-infinity of Tramadol Hydrochloride for the Test and the Reference Products | 965.92 ng*h/mL | Standard Deviation 385.19 |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | AUC0-infinity of Tramadol Hydrochloride for the Test and the Reference Products | 873.74 ng*h/mL | Standard Deviation 344.86 |
Secondary
Kel of Tramadol Hydrochloride for the Test and the Reference Products
The elimination rate constant
Time frame: predose, 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | Kel of Tramadol Hydrochloride for the Test and the Reference Products | 0.1344 L/h | Standard Deviation 0.04 |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | Kel of Tramadol Hydrochloride for the Test and the Reference Products | 0.1294 L/h | Standard Deviation 0.03 |
Secondary
Number of Treatment-related Adverse Events
Occurence and severity of adverse events (serious and non serious adverse events)
Time frame: Day 1 to Day 11 (end of study)
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | Number of Treatment-related Adverse Events | 0 adverse events |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | Number of Treatment-related Adverse Events | 0 adverse events |
Secondary
T1/2 of Tramadol Hydrochloride for the Test and the Reference Products
Plasma Elimination Half-Life
Time frame: predose, 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | T1/2 of Tramadol Hydrochloride for the Test and the Reference Products | 5.48 h | Standard Deviation 1.33 |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | T1/2 of Tramadol Hydrochloride for the Test and the Reference Products | 5.71 h | Standard Deviation 1.48 |
Secondary
Tmax of Tramadol Hydrochloride for the Test and the Reference Products
Time of the maximum measured plasma concentration. Determined directly from the plasma concentration-time curve. If the maximum value occurs at more than one time point, tmax is defined as the first time point with this value.
Time frame: predose, 0.25, 0.50, 0.75, 1.00, 1.50, 2.00, 2.50, 3.00, 3.50, 4.00, 5.00, 6.00, 8.00, 10.00, 12.00, 16.00 and 24.00 hours
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | Tmax of Tramadol Hydrochloride for the Test and the Reference Products | 1.5 h |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | Tmax of Tramadol Hydrochloride for the Test and the Reference Products | 1 h |
Other Pre-specified
Palatability Questionnaire
5 point scale: from 1 : very bad after taste to 5 : very good after taste
Time frame: 0 and 2 minutes
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | Palatability Questionnaire | no taste at 0 min | 0 percentage of participant |
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | Palatability Questionnaire | bad taste at 0 min | 12.5 percentage of participant |
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | Palatability Questionnaire | very bad taste at 0 min | 4.17 percentage of participant |
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | Palatability Questionnaire | good taste at 0 min | 66.67 percentage of participant |
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | Palatability Questionnaire | very good taste at 0 min | 16.67 percentage of participant |
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | Palatability Questionnaire | Very bad after taste at 2 min | 0 percentage of participant |
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | Palatability Questionnaire | bad after taste at 2 min | 4.17 percentage of participant |
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | Palatability Questionnaire | no after taste at 2 min | 4.17 percentage of participant |
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | Palatability Questionnaire | good after taste at 2 min | 66.67 percentage of participant |
| Tramadol Hydrochloride 5mg/mL Oral Solution (IMP 08P1902F0) | Palatability Questionnaire | very good after taste at 2 min | 25 percentage of participant |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | Palatability Questionnaire | no after taste at 2 min | 20.83 percentage of participant |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | Palatability Questionnaire | Very bad after taste at 2 min | 4.17 percentage of participant |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | Palatability Questionnaire | very good after taste at 2 min | 4.17 percentage of participant |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | Palatability Questionnaire | very bad taste at 0 min | 4.17 percentage of participant |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | Palatability Questionnaire | bad taste at 0 min | 33.33 percentage of participant |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | Palatability Questionnaire | no taste at 0 min | 0 percentage of participant |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | Palatability Questionnaire | bad after taste at 2 min | 29.17 percentage of participant |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | Palatability Questionnaire | good taste at 0 min | 54.17 percentage of participant |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | Palatability Questionnaire | good after taste at 2 min | 41.67 percentage of participant |
| Tramadol Hydrochloride 100mg/mL Oral Solution (Contramal(r)) | Palatability Questionnaire | very good taste at 0 min | 8.33 percentage of participant |