Healthy
Conditions
Brief summary
The main objective of this trial is to establish the bioequivalence of Sifrol® tablets manufactured at two different sites.
Interventions
DRUGPramipexole manufactured in Ingelheim
1 tablet Sifrol® (pramipexole) manufactured in Ingelheim containing 0.088 mg pramipexole taken orally after an overnight fast of at least 10 hours.
DRUGPramipexole manufactured in Ennigerloh
1 tablet Sifrol® (pramipexole) manufactured in Ennigerloh containing 0.088 mg pramipexole taken orally after an overnight fast of at least 10 hours.
Sponsors
Boehringer Ingelheim
Study design
Allocation
RANDOMIZED
Intervention model
CROSSOVER
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 55 Years
Healthy volunteers
Yes
Inclusion criteria
1. Healthy male or female subjects according to the assessment of the investigator, as based on a complete medical histo1y including a physical examination, vital signs (blood pressure (BP), pulse rate (PR)), 12-lead electrocardiogram (ECG), and clinical laboratory tests 2. Age of 18 to 55 years (inclusive) 3. Body mass index (BMI) of 18.5 to 29.9 kg/m² (inclusive) 4. Signed and dated written informed consent in accordance with ICH-GCP and local legislation prior to admission to the trial Further inclusion criteria apply.
Exclusion criteria
1. Any finding in the medical examination (including BP, PR or ECG) deviating from normal and assessed as clinically relevant by the investigator 2. Repeated measurement of systolic blood pressure outside the range of 90 to 140 mmHg, diastolic blood pressure outside the range of 50 to 90 mmHg, or pulse rate outside the range of 45 to 90 beats per minute (bpm) 3. Any laboratory value outside the reference range that the investigator considers to be of clinical relevance 4. Any evidence of a concomitant disease assessed as clinically relevant by the investigator Further
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of Pramipexole in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | Within 3 hours prior to drug administration and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 34 and 48 hours following administration. | Area under the concentration-time curve of pramipexole in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). Data was derived from an Analysis of variance (ANOVA) on the logarithmic scale including effects for sequence, subjects nested within sequences, period and treatment. The effect 'subjects within sequences' were considered as random, whereas the other effects were considered as fixed. CIs were calculated based on the residual error from the ANOVA and quantiles from the t-distribution. These quantities were then back-transformed to the original scale to provide the point estimate and 90% CIs for each endpoint. |
| Maximum Measured Concentration of Pramipexole in Plasma (Cmax) | Within 3 hours prior to drug administration and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 34 and 48 hours following administration. | Maximum measured concentration of pramipexole in plasma (Cmax). Data was derived from an Analysis of variance (ANOVA) on the logarithmic scale including effects for sequence, subjects nested within sequences, period and treatment. The effect 'subjects within sequences' were considered as random, whereas the other effects were considered as fixed. CIs were calculated based on the residual error from the ANOVA and quantiles from the t-distribution. These quantities were then back-transformed to the original scale to provide the point estimate and 90% CIs for each endpoint. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Area Under the Concentration-time Curve of Pramipexole in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | Within 3 hours prior to drug administration and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 34 and 48 hours following administration. | Area under the concentration-time curve of pramipexole in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). Data was derived from an Analysis of variance (ANOVA) on the logarithmic scale including effects for sequence, subjects nested within sequences, period and treatment. The effect 'subjects within sequences' were considered as random, whereas the other effects were considered as fixed. CIs were calculated based on the residual error from the ANOVA and quantiles from the t-distribution. These quantities were then back-transformed to the original scale to provide the point estimate and 90% CIs for each endpoint. |
Countries
Germany
Participant flow
Recruitment details
This was a randomized, open-label, two-way crossover design trial.
Pre-assignment details
All subjects were screened for eligibility prior to participation in the trial. Subjects attended a specialist site which ensured that they (the subjects) 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
Participants by arm
| Arm | Count |
|---|---|
| Reference - Test Subjects received the reference product followed by the test product, the treatments were separated by a wash-out phase of at least 3 days.
Reference product: Healthy subjects received 1 tablet Sifrol® (pramipexole) manufactured in Ingelheim containing 0.088 mg pramipexole taken orally after an overnight fast of at least 10 hours.
Test product: Healthy subjects received 1 tablet Sifrol® (pramipexole) manufactured in Ennigerloh containing 0.088 mg pramipexole taken orally after an overnight fast of at least 10 hours. | 14 |
| Test - Reference Subjects received the test product followed by the reference product, the treatments were separated by a wash-out phase of at least 3 days.
Test product: Healthy subjects received 1 tablet Sifrol® (pramipexole) manufactured in Ennigerloh containing 0.088 mg pramipexole taken orally after an overnight fast of at least 10 hours.
Reference product: Healthy subjects received 1 tablet Sifrol® (pramipexole) manufactured in Ingelheim containing 0.088 mg pramipexole taken orally after an overnight fast of at least 10 hours. | 14 |
| Total | 28 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Washout | Adverse Event | 0 | 2 |
Baseline characteristics
| Characteristic | Test - Reference | Total | Reference - Test |
|---|---|---|---|
| Age, Continuous | 40.1 years STANDARD_DEVIATION 9.7 | 39.0 years STANDARD_DEVIATION 9.2 | 37.9 years STANDARD_DEVIATION 8.9 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 14 Participants | 28 Participants | 14 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 | 1 Participants | 1 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 | 14 Participants | 27 Participants | 13 Participants |
| Sex: Female, Male Female | 7 Participants | 16 Participants | 9 Participants |
| Sex: Female, Male Male | 7 Participants | 12 Participants | 5 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 26 | 0 / 28 |
| other Total, other adverse events | 7 / 26 | 5 / 28 |
| serious Total, serious adverse events | 0 / 26 | 0 / 28 |
Outcome results
Primary
Area Under the Concentration-time Curve of Pramipexole in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz)
Area under the concentration-time curve of pramipexole in plasma over the time interval from 0 to the last quantifiable data point (AUC0-tz). Data was derived from an Analysis of variance (ANOVA) on the logarithmic scale including effects for sequence, subjects nested within sequences, period and treatment. The effect 'subjects within sequences' were considered as random, whereas the other effects were considered as fixed. CIs were calculated based on the residual error from the ANOVA and quantiles from the t-distribution. These quantities were then back-transformed to the original scale to provide the point estimate and 90% CIs for each endpoint.
Time frame: Within 3 hours prior to drug administration and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 34 and 48 hours following administration.
Population: Pharmacokinetic set (PKS): all subjects in the TS who provided at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK nonevaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Reference - Sifrol® (Pramipexole) Manufactured in Ingelheim | Area Under the Concentration-time Curve of Pramipexole in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 3573 hour * picogram per milliliter |
| Test - Sifrol® (Pramipexole) Manufactured in Ennigerloh | Area Under the Concentration-time Curve of Pramipexole in Plasma Over the Time Interval From 0 to the Last Quantifiable Data Point (AUC0-tz) | 3632 hour * picogram per milliliter |
Comparison: Analysis of variance (ANOVA) on the logarithmic scale included effects for sequence, subjects nested within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. confidence intervals (CIs) were calculated based on the residual error from the ANOVA and quantiles from the t-distribution. These quantities were then back-transformed to the original scale to provide the point estimate and 90% CIs.90% CI: [98.4, 105]
Primary
Maximum Measured Concentration of Pramipexole in Plasma (Cmax)
Maximum measured concentration of pramipexole in plasma (Cmax). Data was derived from an Analysis of variance (ANOVA) on the logarithmic scale including effects for sequence, subjects nested within sequences, period and treatment. The effect 'subjects within sequences' were considered as random, whereas the other effects were considered as fixed. CIs were calculated based on the residual error from the ANOVA and quantiles from the t-distribution. These quantities were then back-transformed to the original scale to provide the point estimate and 90% CIs for each endpoint.
Time frame: Within 3 hours prior to drug administration and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 34 and 48 hours following administration.
Population: Pharmacokinetic set (PKS): all subjects in the TS who provided at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK nonevaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Reference - Sifrol® (Pramipexole) Manufactured in Ingelheim | Maximum Measured Concentration of Pramipexole in Plasma (Cmax) | 285 picogram per milliliter |
| Test - Sifrol® (Pramipexole) Manufactured in Ennigerloh | Maximum Measured Concentration of Pramipexole in Plasma (Cmax) | 280 picogram per milliliter |
Comparison: Analysis of variance (ANOVA) on the logarithmic scale included effects for sequence, subjects nested within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. confidence intervals (CIs) were calculated based on the residual error from the ANOVA and quantiles from the t-distribution. These quantities were then back-transformed to the original scale to provide the point estimate and 90% CIs.90% CI: [91.6, 105.5]
Secondary
Area Under the Concentration-time Curve of Pramipexole in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞)
Area under the concentration-time curve of pramipexole in plasma over the time interval from 0 extrapolated to infinity (AUC0-∞). Data was derived from an Analysis of variance (ANOVA) on the logarithmic scale including effects for sequence, subjects nested within sequences, period and treatment. The effect 'subjects within sequences' were considered as random, whereas the other effects were considered as fixed. CIs were calculated based on the residual error from the ANOVA and quantiles from the t-distribution. These quantities were then back-transformed to the original scale to provide the point estimate and 90% CIs for each endpoint.
Time frame: Within 3 hours prior to drug administration and 0.25, 0.5, 1, 1.5, 2, 3, 4, 5, 6, 8, 10, 12, 24, 34 and 48 hours following administration.
Population: Pharmacokinetic set (PKS): all subjects in the TS who provided at least one PK endpoint that was defined as primary or secondary and was not excluded due to a protocol deviation relevant to the evaluation of PK or due to PK nonevaluability.
| Arm | Measure | Value (GEOMETRIC_LEAST_SQUARES_MEAN) |
|---|---|---|
| Reference - Sifrol® (Pramipexole) Manufactured in Ingelheim | Area Under the Concentration-time Curve of Pramipexole in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 3730 hour * picogram per milliliter |
| Test - Sifrol® (Pramipexole) Manufactured in Ennigerloh | Area Under the Concentration-time Curve of Pramipexole in Plasma Over the Time Interval From 0 Extrapolated to Infinity (AUC0-∞) | 3788 hour * picogram per milliliter |
Comparison: Analysis of variance (ANOVA) on the logarithmic scale included effects for sequence, subjects nested within sequences, period and treatment. The effect 'subjects within sequences' was considered as random, whereas the other effects were considered as fixed. confidence intervals (CIs) were calculated based on the residual error from the ANOVA and quantiles from the t-distribution. These quantities were then back-transformed to the original scale to provide the point estimate and 90% CIs.90% CI: [98.2, 105]