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Bioequivalence of Two Transdermal Clonidine Administrations in Healthy Volunteers

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ClinicalTrials.gov Identifier: NCT02096744
Recruitment Status : Completed
First Posted : March 26, 2014
Results First Posted : July 16, 2015
Last Update Posted : July 16, 2015
Sponsor:
Information provided by (Responsible Party):
Boehringer Ingelheim

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Crossover Assignment;   Masking: Double;   Primary Purpose: Treatment
Condition Healthy
Interventions Drug: Catapres-TTS-1
Drug: Intervention 1: Catapres-TTS-3
Drug: Intervention 2: Catapres-TTS-3
Enrollment 56
Recruitment Details This study was conducted in three separate groups.
Pre-assignment Details  
Arm/Group Title Catapres®-TTS-3 Crossover 1: TTS-3 Oppanol Then TTS-3 Vistanex Catapres®-TTS-3 Crossover 2: TTS-3 Vistanex Then TTS-3 Oppanol
Hide Arm/Group Description Catapres®-TTS(Transdermal Therapeutic System)-3 (0.3 mg/24 hr) Oppanol® (T1) first, followed by Catapres®-TTS-3 (0.3 mg/24 hr) Vistanex™ (R1). Followed by simultaneous administration of TTS-1 Oppanol® (T2) and TTS-1 Vistanex™ (R2) patches each delivering 0.1mg clinidine/24h. Catapres®-TTS-3 (0.3 mg/24 hr) Vistanex™ (R1) first, followed by Catapres®-TTS-3 (0.3 mg/24 hr) Oppanol® (T1). Followed by simultaneous administration of TTS-1 Oppanol® (T2) and TTS-1 Vistanex™ (R2) patches each delivering 0.1mg clinidine/24h.
Period Title: Treatment Period 1(7 Days)
Started 29 29
Completed 28 28
Not Completed 1 1
Reason Not Completed
Accidental early removal of the patch             0             1
Non compliance with the site rule             1             0
Period Title: Washout Period 1(7 Days)
Started 28 28
Completed 28 28
Not Completed 0 0
Period Title: Treatment Period 2 (7 Days)
Started 28 28
Completed 28 28
Not Completed 0 0
Period Title: Washout Period 2 (3 Days)
Started 28 28
Completed 28 28
Not Completed 0 0
Period Title: Treatment Period 3 (7 Days)
Started 28 28
Completed 28 27
Not Completed 0 1
Reason Not Completed
Withdrawal by Subject             0             1
Arm/Group Title Overall Study
Hide Arm/Group Description

A randomised, double-blind, 2-way crossover design, followed by a period for assessment of adhesive properties of the clonidine patch.

In the crossover part of the trial, subjects were treated with either Catapres®-TTS delivering 0.3 mg clonidine/24 h (TTS-3) in the Oppanol® formulation (test treatment T1) or Catapres®-TTS-3 (0.3 mg/24 h) with Vistanex™ formulation (reference treatment R1) in each period. In the adhesion phase of the trial, subjects were treated simultaneously with Oppanol® (test treatment T2) and Vistanex™ (reference treatment R2) patches, each delivering 0.1 mg clonidine/24 h (TTS-1).

Overall Number of Baseline Participants 58
Hide Baseline Analysis Population Description
All enrolled subjects in the trial were treated and were included in the treated set (TS).
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 58 participants
41.3  (13.0)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 58 participants
Female
30
  51.7%
Male
28
  48.3%
1.Primary Outcome
Title AUC0-168 (Area Under the Concentration-time Curve of Clonidine in Plasma Over the Time Interval From 0 to 168 h)
Hide Description AUC0-168 (area under the concentration-time curve of clonidine in plasma over the time interval from 0 to 168 h) The values for geometric mean and geometric coefficient of variation (gCV) are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.
Time Frame 1 hour (h) before patch administration and 12h, 24h, 48h, 72h, 96h, 120h, 144h, 168h after patch administration
Hide Outcome Measure Data
Hide Analysis Population Description
PKS included all treated subjects who provided at least one observation for at least one primary endpoint without protocol violations with respect to the statistical evaluation of PK endpoints.
Arm/Group Title Catapres®-TTS-3 With Oppanol® Catapres®-TTS-3 With Vistanex™
Hide Arm/Group Description:
Subject to receive 0.3 mg/24 hr Catapres®-TTS-3 Oppanol® (T1)
Subject to receive 0.3 mg/24 hr Catapres®-TTS-3 Vistanex™ (R1)
Overall Number of Participants Analyzed 52 50
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: pg*h/mL
82517.99
(19.0%)
80641.47
(19.0%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Catapres®-TTS-3 With Oppanol®, Catapres®-TTS-3 With Vistanex™
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The assessment of bioequivalence was based upon 2-sided 90% confidence intervals (CIs) for the ratios of the geometric means Catapres-TTS-3(Oppanol/Vistanex) using an acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments ANOVA on the logarithmic scale including effects for 'Group', ‘sequence’, ‘subjects within sequences’, ‘period’, and ‘treatment’.
Method of Estimation Estimation Parameter Adjusted Geometric Mean ratio
Estimated Value 102.33
Confidence Interval (2-Sided) 90%
95.74 to 109.37
Parameter Dispersion
Type: Standard Error of the mean
Value: 19.0
Estimation Comments

The estimated value is actually the ratio of Catapres-TTS-3 with Oppanol and Catapres-TTS-3 with Vistanex.

The value in parameter dispersion type and dispersion value is actually the intra-individual gCV.

2.Primary Outcome
Title Cavg (Average of Measured Concentrations of Clonidine in Plasma on Days 5, 6, and 7)
Hide Description Cavg (average of measured concentrations of clonidine in plasma on Days 5, 6, and 7) The values for geometric mean and gCV are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.
Time Frame 1 hour (h) before patch administration and 12h, 24h, 48h, 72h, 96h, 120h, 144h, 168h, 192h, 216h, 240h after patch administration
Hide Outcome Measure Data
Hide Analysis Population Description
PKS included all treated subjects who provided at least one observation for at least one primary endpoint without protocol violations with respect to the statistical evaluation of PK endpoints.
Arm/Group Title Catapres®-TTS-3 With Oppanol® Catapres®-TTS-3 With Vistanex™
Hide Arm/Group Description:
Subject to receive 0.3 mg/24 hr Catapres®-TTS-3 Oppanol® (T1)
Subject to receive 0.3 mg/24 hr Catapres®-TTS-3 Vistanex™ (R1)
Overall Number of Participants Analyzed 52 50
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: pg/mL
697.327
(16.6%)
668.893
(16.6%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Catapres®-TTS-3 With Oppanol®, Catapres®-TTS-3 With Vistanex™
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The assessment of bioequivalence was based upon 2-sided 90% confidence intervals (CIs) for the ratios of the geometric means Catapres-TTS-3(Oppanol/Vistanex) using an acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments ANOVA on the logarithmic scale including effects for 'Group', ‘sequence’, ‘subjects within sequences’, ‘period’, and ‘treatment’.
Method of Estimation Estimation Parameter Adjusted Geometric Means ratio
Estimated Value 104.25
Confidence Interval (2-Sided) 90%
98.367 to 110.487
Parameter Dispersion
Type: Standard Error of the mean
Value: 16.6
Estimation Comments

The estimated value is actually the ratio of Catapres-TTS-3 with Oppanol and Catapres-TTS-3 with Vistanex.

The value in parameter dispersion type and dispersion value is actually the intra-individual gCV.

3.Secondary Outcome
Title AUC0-inf(Area Under the Concentration-time Curve of Clonidine in Plasma Over the Time Interval From 0 to Infinity)
Hide Description AUC 0-inf(area under the concentration-time curve of clonidine in plasma over the time interval from 0 to infinity) The values for geometric mean and gCV are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.
Time Frame 1 hour (h) before patch administration and 12h, 24h, 48h, 72h, 96h, 120h, 144h, 168h, 192h, 216h, 240h after patch administration
Hide Outcome Measure Data
Hide Analysis Population Description
PKS included all treated subjects who provided at least one observation for at least one primary endpoint without protocol violations with respect to the statistical evaluation of PK endpoints.
Arm/Group Title Catapres®-TTS-3 With Oppanol® Catapres-TTS-3 With Vistanex™
Hide Arm/Group Description:
Subject to receive 0.3 mg/24 hr Catapres®-TTS-3 Oppanol® (T1)
Subject to receive 0.3 mg/24 hr Catapres-TTS-3 Vistanex™ (R1)
Overall Number of Participants Analyzed 52 50
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: pg*h/mL
119127.55
(15.8%)
115903.34
(15.8%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Catapres®-TTS-3 With Oppanol®, Catapres-TTS-3 With Vistanex™
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The assessment of bioequivalence was based upon 2-sided 90% confidence intervals (CIs) for the ratios of the geometric means Catapres-TTS-3(Oppanol/Vistanex) using an acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments ANOVA on the logarithmic scale including effects for 'Group', ‘sequence’, ‘subjects within sequences’, ‘period’, and ‘treatment’.
Method of Estimation Estimation Parameter Adjusted Geometric Means ratio
Estimated Value 102.78
Confidence Interval (2-Sided) 90%
97.25 to 108.63
Parameter Dispersion
Type: Standard Error of the mean
Value: 15.8
Estimation Comments

The estimated value is actually the ratio of Catapres-TTS-3 with Oppanol and Catapres-TTS-3 with Vistanex.

The value in parameter dispersion type and dispersion value is actually the intra-individual gCV.

4.Secondary Outcome
Title Cmax (Maximum Concentration of Clonidine in Plasma)
Hide Description Cmax (maximum concentration of clonidine in plasma) The values for geometric mean and gCV are actually adjusted geometric means and adjusted intra-individual gCVs, respectively.
Time Frame 1 hour (h) before patch administration and 12h, 24h, 48h, 72h, 96h, 120h, 144h, 168h, 192h, 216h, 240h after patch administration
Hide Outcome Measure Data
Hide Analysis Population Description
PKS included all treated subjects who provided at least one observation for at least one primary endpoint without protocol violations with respect to the statistical evaluation of PK endpoints.
Arm/Group Title Catapres®-TTS-3 With Oppanol® Catapres®-TTS-3 With Vistanex™
Hide Arm/Group Description:
Subject to receive 0.3 mg/24 hr Catapres®-TTS-3 Oppanol® (T1)
Subject to receive 0.3 mg/24 hr Catapres®-TTS-3 Vistanex™ (R1)
Overall Number of Participants Analyzed 52 50
Geometric Mean (Geometric Coefficient of Variation)
Unit of Measure: pg/mL
813.516
(16.7%)
781.896
(16.7%)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Catapres®-TTS-3 With Oppanol®, Catapres®-TTS-3 With Vistanex™
Comments [Not Specified]
Type of Statistical Test Non-Inferiority or Equivalence
Comments The assessment of bioequivalence was based upon 2-sided 90% confidence intervals (CIs) for the ratios of the geometric means Catapres-TTS-3(Oppanol/Vistanex) using an acceptance range of 80.00 to 125.00%.
Statistical Test of Hypothesis P-Value <0.0001
Comments [Not Specified]
Method ANOVA
Comments ANOVA on the logarithmic scale including effects for 'Group',‘sequence’, ‘subjects within sequences’, ‘period’, and ‘treatment’.
Method of Estimation Estimation Parameter Adjusted Geometric Means ratio
Estimated Value 104.04
Confidence Interval (2-Sided) 90%
98.148 to 110.294
Parameter Dispersion
Type: Standard Error of the mean
Value: 16.7
Estimation Comments

The estimated value is actually the ratio of Catapres-TTS-3 with Oppanol and Catapres-TTS-3 with Vistanex.

The value in parameter dispersion type and dispersion value is actually the intra-individual gCV.

Time Frame From patch administration until at most 7 days after patch removal, i.e., up to 14 days
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title TTS-3: Oppanol® (T1) TTS-3: Vistanex™ (R1) TTS-1: Vistanex™ (R2) + Oppanol® (T2)
Hide Arm/Group Description Administration of TTS-3 with Oppanol® Administration of TTS-3 with Vistanex™ Simultaneous administration of TTS-1 with Oppanol® and TTS-1 with Vistanex™
All-Cause Mortality
TTS-3: Oppanol® (T1) TTS-3: Vistanex™ (R1) TTS-1: Vistanex™ (R2) + Oppanol® (T2)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
TTS-3: Oppanol® (T1) TTS-3: Vistanex™ (R1) TTS-1: Vistanex™ (R2) + Oppanol® (T2)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   0/57 (0.00%)   0/57 (0.00%)   0/56 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 5%
TTS-3: Oppanol® (T1) TTS-3: Vistanex™ (R1) TTS-1: Vistanex™ (R2) + Oppanol® (T2)
Affected / at Risk (%) Affected / at Risk (%) Affected / at Risk (%)
Total   46/57 (80.70%)   45/57 (78.95%)   23/56 (41.07%) 
Gastrointestinal disorders       
Diarrhoea  1  3/57 (5.26%)  0/57 (0.00%)  0/56 (0.00%) 
Dry mouth  1  6/57 (10.53%)  4/57 (7.02%)  0/56 (0.00%) 
Infrequent bowel movements  1  6/57 (10.53%)  8/57 (14.04%)  0/56 (0.00%) 
Nausea  1  3/57 (5.26%)  1/57 (1.75%)  1/56 (1.79%) 
General disorders       
Application site erythema  1  23/57 (40.35%)  19/57 (33.33%)  10/56 (17.86%) 
Application site papules  1  12/57 (21.05%)  8/57 (14.04%)  6/56 (10.71%) 
Application site pruritus  1  5/57 (8.77%)  4/57 (7.02%)  0/56 (0.00%) 
Fatigue  1  3/57 (5.26%)  3/57 (5.26%)  0/56 (0.00%) 
Nervous system disorders       
Dizziness  1  4/57 (7.02%)  6/57 (10.53%)  3/56 (5.36%) 
Headache  1  8/57 (14.04%)  7/57 (12.28%)  3/56 (5.36%) 
Psychiatric disorders       
Insomnia  1  2/57 (3.51%)  4/57 (7.02%)  0/56 (0.00%) 
Vascular disorders       
Orthostatic hypotension  1  11/57 (19.30%)  3/57 (5.26%)  0/56 (0.00%) 
Indicates events were collected by systematic assessment
1
Term from vocabulary, MedDRA 17.0
Certain Agreements
Principal Investigators are NOT employed by the organization sponsoring the study.
There IS an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.
Boehringer Ingelheim (BI) acknowledges that investigators have the right to publish the study results. Investigators shall provide BI with a copy of any publication or presentation for review prior to any submission. Such review will be done with regard to proprietary information, information related to patentable inventions, medical, scientific, and statistical accuracy within 60 days. BI may request a delay of the publication in order to protect BI’s intellectual property rights.
Results Point of Contact
Layout table for Results Point of Contact information
Name/Title: Boehringer Ingelheim Call Center
Organization: Boehringer Ingelheim
Phone: 1-800-243-0127
EMail: clintriage.rdg@boehringer-ingelheim.com
Layout table for additonal information
Responsible Party: Boehringer Ingelheim
ClinicalTrials.gov Identifier: NCT02096744     History of Changes
Other Study ID Numbers: 253.2486
First Submitted: March 24, 2014
First Posted: March 26, 2014
Results First Submitted: June 19, 2015
Results First Posted: July 16, 2015
Last Update Posted: July 16, 2015