An open-label, randomized, single-dose, two-treatment, two-sequence, two-way crossover bioequivalence study of Pramipexole prolonged-release tablet Aristo 1.05 mg, manufactured by Advance Pharma GmbH, Germany (Test) with Sifrol 1.05 mg Retardtabletten (prolonged-release 1.05 mg oral tablets), manufactured by Boehringer Ingelheim Pharma GmbH & Co. KG, Germany (Reference), with at least 07 days washout period between each administration, in healthy, adult, male, human subjects under fasting condition
试验速览
- 阶段
- 1 期
- 状态
- 已完成
- 入组人数
- 46
- 试验地点
- 1
- 主要终点
- To evaluate, whether there exists any bioequivalence between two formulations by means of rate and extent of absorption
研究概览
简要总结
|Name of the Company: Aristo Pharma GmbH, Germany
Name of the Finished Product: 1.05 mg of Pramipexole prolonged-release tablet
Name of the Active Ingredient: Pramipexole
Individual Study Table Referring to Whom it May Concern: Clinical Documentation of the Dossier:
Volume: N/AP
Page: 87
(For Use of National Authority Only)
| --- | --- | --- | --- | --- | --- | --- | |Title of the Study: An open-label, randomized, single-dose, two-treatment, two-sequence, two-way crossover bioequivalence study of Pramipexole prolonged-release tablet Aristo 1.05 mg, manufactured by Advance Pharma GmbH, Germany (Test) with Sifrol 1.05 mg Retardtabletten (prolonged-release 1.05 mg oral tablets), manufactured by Boehringer Ingelheim Pharma GmbH & Co. KG, Germany (Reference), with at least 07 days washout period between each administration, in healthy, adult, male, human subjects under fasting condition.
|Study No.: LBS-014-12
|Date of Final Report: 29-Jan-13
|Principal Investigator
Dr. Mukund Zarapkar
|Analytical Investigator
Dr. Ojitkumar Lukram
|Study Center:
LifeSan Clinical Research
Address:
Centaur House, Near Hotel Grand Hyatt, Santacruz (East), Mumbai – 400055, India.
Phone: +91-22-66499242
Fax: +91-22-66499239
|Total Duration of the Clinical Part:
Stage I – 11 days
Stage II – 11 days
Phase: Bioequivalence study
|Objectives:
Primary Objective
To evaluate, whether there exists any bioequivalence between two formulations i.e. Pramipexole prolonged-release tablet Aristo 1.05 mg, manufactured by Advance Pharma GmbH, Germany (Test) with Sifrol 1.05 mg Retardtabletten (prolonged-release 1.05 mg oral tablets), manufactured by Boehringer Ingelheim Pharma GmbH & Co. KG, Germany (Reference) following single dose administration of one tablet of test or reference formulation in healthy, adult, male, human subjects under fasting condition with at least 07 days washout period by means of rate and extent of absorption based on plasma drug levels of pramipexole.
Secondary Objective
To monitor the safety of the participating subjects in this bioequivalence study of Pramipexole prolonged-release tablet Aristo 1.05 mg, manufactured by Advance Pharma GmbH, Germany (Test) with Sifrol 1.05 mg Retardtabletten (prolonged-release 1.05 mg oral tablets), manufactured by Boehringer Ingelheim Pharma GmbH & Co. KG, Germany (Reference) determined by means of clinical biochemistry, physical examination and AE/SAE monitoring.
|Study Design
· Open-label
· Randomized, single dose.
· Two-treatment, two-sequence, two-way crossover design with a washout period of at least 07 days using two-stage design
· Bioequivalence study.
· In healthy, adult, male, human subjects under fasting condition.
|Planned for Completion:
46 (18 + 28)
|Enrolled and Randomized:
18 (Stage-I) & 28 (Stage-II)
|Dropouts:
00
|Withdrawals:
02
|Completed as Per Protocol:
44
|Analyzed:
46
|Subjected to Pharmacokinetic and Statistical Evaluation:
44 subjects who completed both periods
|Diagnosis and Main Criteria for Inclusion
· Sex: male.
· Age: 18–45 years.
· Healthy, as justified by normal or clinically insignificant findings in clinical and laboratory investigations.
· BMI: 18.5–30.0 kg/m2.
· Informed consent given in written form.
|Test Formulation
Treatment ID:
T
|Name:
Pramipexole prolonged-release tablets Aristo 1.05 mg
|Strength:
1.05 mg
|Batch number:
12518591
|Mfg. date:
N/AP
|Exp. date:
Jan-2013 [Stage I]
Apr-2013 [Stage II]
|Manufacturer:
Aristo Pharma GmbH, Wallenroder Straße 8-10, 13435 Berlin, Germany
|Dosage form:
Tablets
|Dose administered:
One tablet with 240 mL of water
|Route of administration:
Oral
|Reference Formulation
Treatment ID:
R
|Name:
Sifrol retard 1.05 mg Retardtabletten
|Strength:
1.05 mg
|Lot number:
106692
|Mfg. date:
N/AV
|Exp. date:
Sep-2014
|Manufactured by:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
|Dosage form:
Tablets
|Dose administered:
One tablet with 240 mL of water
|Route of administration:
Oral
|IMP Administration
Period I
25-Sep-12 (Stage-I) and
28-Nov-12 (Stage-II)
|Period II
02-Oct-12 (Stage-I) and
05-Dec-12 (Stage-II)
|Duration of Treatments
Each subject received, in a randomized manner and under fasting condition in each period of the study, one tablet of the test formulation (T) or one tablet of reference formulation (R) with a washout period of at least 07 days between the two study periods.
Time Points
0.00 (predose), 1.00, 2.00, 3.00, 4.00, 4.50, 5.00, 5.50, 6.00, 6.50, 7.00, 7.50, 8.00, 8.50, 9.00, 9.50, 10.00, 12.00, 16.00, 24.00, 48.00 and 72.00 hours post dose.
|Analytical Methods
LC-MS/MS
LLOQ: 20.0 pg/ml (Stage-I & II)
ULOQ: 3996.3 pg/ml (Stage-I) and 3996.6 pg/ml (Stage-II)
Linearity range:
For pramipexole – 20.0pg/ml to 3998.7 pg/ml
|Criteria for Evaluation
Pharmacokinetics:
Analyzed: Pramipexole
Primary target parameters: Log-transformed Cmax andAUC0-t
Secondary target parameters: tmax, Kel, t1/2, and AUC0-inf.
Additional target parameters: MRT, AUCextrap% and Frel
Safety Parameter
Clinical laboratory investigations were performed at the time of screening and post-study safety evaluation.
Vital examinations were performed at the time of admission, discharge, on scheduled vital time points and at post-study safety assessment.
AE/SAE/SUSAR profiles of both test and reference formulations were recorded.
Statistical Methods
ANOVA
The primary pharmacokinetic parameters after logarithmic transformation were subjected to an analysis of variance (ANOVA) using the SAS GLM procedure.
To test the SEQUENCE effect the initial model contained the factors SEQUENCE, SUBJECT nested within SEQUENCE, PERIOD and FORM (drug formulation). The significance of the SEQUENCE effect was tested using the SUBJECT nested within SEQUENCE as the error term applying a 5% level of significance. The significance of the PERIOD and FORM effect were tested with a 5% level of significance.
For the estimation of the least squares means (LSM) for the factor FORM a simplified ANOVA was used comprising of SUBJECT, PERIOD and FORM.
For the analysis of the combined data from the two stages, the factor STAGE was included in the ANOVA model.
The test for normality of the residual distribution were performed on Ln-transformed data using the Shapiro-Wilk procedure using a 5% level of significance.
Because of a two-stage study design an a-adjustment of the significance level had to be done with the method of Pocock. For the calculation of the confidence intervals a = 0.0294 instead of a = 0.05 for the interim and the final statistical analysis had to be used, therefore a 94.12% confidence interval had to be calculated instead of a 90% confidence interval.
Consistent with the two one-sided test for bioequivalence, a-adjusted confidence intervals for the difference between drug formulations least-squares means (LSM) of pramipexole were calculated for the log-transformed parameters AUC0-t, AUC0-∞ and Cmax.
The acceptance range for the a-adjusted confidence band for the ratio of the back-transformed LSMEANS of pramipexole is 80% to 125 % for the parameter AUC0-t and Cmax.
To be inside the acceptance interval the lower bound had to be ≥ 80.00% when rounded to two decimal places and the upper bound had to be ≤ 125.00% when rounded to two decimal places.
In a first step, it was planned to collect data from at least 18 evaluable subjects. If bioequivalence was achieved at stage 1 (interim analysis) the study had to be stopped.
If bioequivalence was not achieved at stage 1 the decision of stopping the study or of continuation of the study with stage 2 had to be based on the sample size re-estimation considering the statistical procedures described in literature.
Because tmax is a discrete variable it is likely that many equal values occur preventing a meaningful analysis the parameter tmax had to be evaluated using the non-parametric Wilcoxon-Mann-Whitney-test.
Confidence Interval [CI]:
The acceptance range for the a-adjusted confidence band for the ratio of the back-transformed LSMEANS of pramipexole had to be 80% to 125 % for the parameter AUC0-t and Cmax.
To be inside the acceptance interval the lower bound had to be ≥ 80.00% when rounded to two decimal places and the upper bound had to be ≤ 125.00% when rounded to two decimal places.
Acceptance criteria:
LnCmax: 80-125% (α-adjusted)
LnAUC0-t: 80-125% (α-adjusted)
|Results
Pharmacokinetics:
| Table 1: Summary of pharmacokinetic parameters |
|Parameters
**Pramipexole (**mean ± SD)
| Test (T)
Reference (R)
|Cmax (pg/mL)
1482.86 ± 287.258
1569.00 ± 378.955
|AUC0-t (pg.h/mL)
36273.95 ± 8485.625
39340.71 ± 10991.376
|AUC0-inf (pg.h/mL)
36994.70 ± 8717.462
39979.05 ± 11052.846
|
tmax (h)
7.05 ± 3.052
8.86 ± 4.126
|Kel (h-1)
0.07 ± 0.012
0.07 ± 0.010
|t1/2 (h)
10.57 ± 1.891
10.04 ±1.364
Statistical analysis:
The bioequivalence evaluation was based on the log-transformed values of Cmax and AUC0-t ratios (test vs. reference formulation) of pramipexole.
The ratios of the estimated least square means (and 94.12% CIs) of the test to reference formulation (TR) of pramipexole were 95.38% (89.22-101.96%) for LnCmax and 93.04% (84.86-102.00%) for LnAUC0-t respectively.
The intra-subject CVs for pramipexole for LnCmax, LnAUC0-t and LnAUC0-inf were 16.19%, 22.45%, and 22.15%, respectively.
The a-adjusted confidence and for the ratio of the back-transformed LSMEANS of pramipexole (test/reference) for the primary target parameters of Cmax and AUC0-t were within the acceptance interval of 80–125%, thus establishing bioequivalence as per the CPMP note for guidance for Investigation of Bioavailability and Bioequivalence (CPMP/EWP/QWP/1401/98, REV1, CORR. COMMITTEE, January 2010).
| Table 2: ANOVA-log coefficients of variation of the intra-individual ratios |
|Pharmacokinetic parameter
Comparison
Estimated geometric mean ratio
Lower 94,12% CI
Upper 94,12% CI
Intra-subject CV%
|LnCmax
T vs. R
95.38
89.22
101.96
16.19
|LnAUC0-t
T vs. R
93.04
84.86
102.00
22.45
|Safety Assessment:
During the clinical conduct of the study, twenty-nine (n=29) AE [12 AE in stage-I and 17 AE in stage-II] were recorded, irrespective of the nature of the treatment administered [test or reference]. The subjects were treated appropriately for the AE and it was seen that all the AEs were recovered without any sequel.
Two subjects [S-2 in stage-I & S-39 in stage-II] were withdrawn from the study on account of AE and concomitant medication.
Four more (n=4) AE (2 AEs in stage-I and 2 AE in stage-II) were noted in the clinical laboratory values of the post-study safety assessment.
|Conclusion
· The study was performed according to the protocol and the ICH-GCP guidelines.
· As per the regulations of “CPMP/EWP/QWP/1401/98, REV.1, CORR. COMMITTEE, January 2010†the a-adjusted confidence band for the ratio of the back-transformed LSMEANS of AUC0-t and Cmax for pramipexole were within the acceptance limits of 80–125%. Hence, it can be concluded that the “Test†formulation, i.e. Pramipexole prolonged-release tablet Aristo 1.05 mg, manufactured by Advance Pharma GmbH, Germany is bioequivalent with the reference formulation i.e. Sifrol 1.05 mg Retardtabletten (prolonged-release 1.05 mg oral tablets) manufactured by Boehringer Ingelheim Pharma GmbH & Co. KG, Germany in terms of the primary target parameters of Cmax and AUC0-t following single dose administration in fasting condition.
· There were thirty-three [33] adverse events (29 in clinical conduct and 4 in post-study safety assessment), which were managed appropriately till complete resolution without any sequel.
· Two subjects [S-2 in stage-I & S-39 in stage-II] were withdrawn from the study on account of AE and concomitant medication.
· Since this study was intended to assess the bioequivalence between test and reference formulations along with the safety of participating the subjects; no statistical comparison of the adverse event profile between test and reference formulation was considered necessary. Apparently, in 13 out of 14 adverse events happened after consuming the reference formulation had some relationship determined with the pramipexole, whereas relationship with Pramipexole could be concluded in 14 out of 15 adverse events that happened after consuming the test formulation. There was no relationship of two AE with the study drug [AE-12 – sequence TR in period II of stage-I was not related with reference formulation & AE-10 – sequence TR in period II of stage-II which was not related with test formulation]. All the adverse events noted in this study were in accordance with the SmPC of Sifrol 1.05 mg Retardtabletten (prolonged-release 1.05 mg oral tablets) and therefore, no new safety related finding could be elicited.
研究设计
- 研究类型
- Interventional
- 分配方式
- Computer generated randomization
- 盲法
- Open Label
入排标准
- 年龄范围
- 18.00 Year(s) 至 45.00 Year(s)（—）
- 性别
- Male
入选标准
- •(i)Healthy, Asian, male, human volunteer aged from 18 to 45 years.
- •(ii)Weight: 65 kg to 85 kg (iii)Body Mass Index (BMI) should be within 18.5-30.0 kg/m
- •(iv)Voluntarily willing and capable to give written and signed informed consent prior to participation in the study, according to the form attached in appendix
- •(v)Availability for the entire study period and willingness to adhere to protocol and study requirements.
- •(vi)Volunteers willing to undergo pre and post-study physical examinations and laboratory investigations.
- •(vii)Having no significant disease or abnormal laboratory values on laboratory examination with no clinical relevance, medical history or physical examination during screening.
- •(viii)12-lead ECG in resting position and vital signs are within normal limits or showing abnormalities, which the investigator does not consider of clinical relevance.
- •(ix)Normal chest X-ray findings or findings that have no clinical correlation.
- •(x)Non-smokers or ex-smokers who gave up smoking for at least 2 years prior to the study.
- •(xi)Having not consumed alcohol at least 48 hours prior to IMP administration justified by negative breath-alcohol test and who agree not to consume any amount of alcohol throughout the conduct of the study.
- •(xii)The subject agrees to abstain from coffee and other food and drinks containing methylxanthines (tea, cola, chocolate), grapefruit-containing food and beverages and chewing gum for 48 hours prior to the study drug administration and during each study period.
- •(xiii)Negative urine test for drug of abuse (amphetamine, barbiturate, tetrahydrocanabinoids, morphine, cocaine, benzodiazepine).
排除标准
- •(i)History of allergy or hypersensitivity to pramipexole or history of any drug hypersensitivity or intolerance, which, in the opinion of the investigator, would compromise the safety of the subject or the study.
- •(ii)History of or signs or symptoms of Parkinson’s disease.
- •(iii)History of diseases of liver or hepatic impairment within last one (1) year (iv)Elevated serum transaminases (SGOT/ SGPT) or alkaline phosphatase (at least 1.5 times of upper normal range).
- •(v)History of mania or hypomania.
- •(vi)Serious, uncontrolled disease (including serious psychological disorders) likely to interfere with the study and/or likely to cause death within the study duration.
- •(vii)Participation in another clinical study or a blood donation program or have had blood loss of more than 350 ml during the last 90 days.
- •(viii)Renal insufficiency (serum creatinine more than twofold of the > 3 mg/dL).
- •(ix)Seropositive for VDRL, HIV or hepatitis B or C infection.
- •(x)Any clinically significant abnormality (to be determined by the investigator) following review of screening laboratory data and full physical examination.
- •(xi)Vital sign abnormalities (systolic blood pressure in supine position lower than 90 or higher than 140 mm Hg or diastolic blood pressure lower than 50 or higher than 100 mm Hg or heart rate less than 50 bpm or more than 120 bpm) at screening and at pre-admission physical examination.
- •(xii)Having suffered any illness within a week of starting the study or who have been hospitalized within the 3 months preceding the start of the study.
- •(xiii)Having taken over the counter (OTC) or prescribed medications, including any antihypertensive drugs, enzyme-modifying drugs or any systemic medication within the 07 days prior to the study (However, paracetamol may be permitted up to 03 days prior to the start of the study).
- •(xiv)Have a history of substance abuse within the last 5 years.
- •(xv)Consumption of methylxanthine-containing derivatives (coffee, tea, cola drinks, chocolate) within 48 hrs before IMP administration and grapefruit or orange juice for at least 48 hrs prior to IMP administration.
- •(xvi)Habit of chewing or inhaling nicotine-containing products (e.g. tobacco) currently or within last six months prior to the study.
- •(xvii)Abnormal INR combined with clinical manifestation.
- •(xviii)Subject is vegetarian or follows particular diets.
结局指标
主要结局
To evaluate, whether there exists any bioequivalence between two formulations by means of rate and extent of absorption
时间窗: To evaluate, whether there exists any bioequivalence between two formulations by means of rate and extent of absorption
次要结局
- To monitor the safety of the participating subjects(At the time of admission, Predose, at 1.00, 3.00, 5.00, 9.00, 13.00, 25.00, 37.00, 48.00 and 72.00 hrs post-dose and anytime throughout the study as and when the necessity is felt by the medical officer)