Examine Plasma Concentrations of Buprenorphine Following Reapplication of Buprenorphine Transdermal System (BTDS) After Variable Application Site Rest Periods

• Sponsor: Purdue Pharma LP (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01259102
• Collaborator: (none)
• Enrollment: 70
• Location: 1
• Arms: 5
• Duration (Months): 3.9
• Patients Per Site Per Month: 17.8

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the pharmacokinetics of BTDS following same-site patch reapplication after rest intervals.

Condition or Disease	Intervention/Treatment	Phase
Healthy	Drug: Buprenorphine transdermal patch	Phase 1

Detailed Description

The purpose of this study is to determine the minimum application site rest period that ensures that reapplication of BTDS 10 to the same site in the deltoid region does not result in increased absorption of drug in normal healthy subjects.

Study Design

• Study Type: Interventional
• Actual Enrollment: 70 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Official Title: A Parallel Open-Label Study to Examine Plasma Concentrations of Buprenorphine Following Reapplication of 10-mg Buprenorphine Transdermal System (BTDS) After Variable Application Site Rest Periods in Healthy Subjects
• Study Start Date: Nov 1, 2000
• Actual Primary Completion Date: Mar 1, 2001
• Actual Study Completion Date: Mar 1, 2001

Arms and Interventions

Arm	Intervention/Treatment
Experimental: No Rest BTDS 10 with no application site rest period prior to application of second BTDS	Drug: Buprenorphine transdermal patch; Buprenorphine 10 mcg/hour patch applied transdermally for 7-day wear.; Other Names: Butrans™
Experimental: 7-Day Rest BTDS 10 with 7-day rest period prior to application of second BTDS	Drug: Buprenorphine transdermal patch; Buprenorphine 10 mcg/hour patch applied transdermally for 7-day wear.; Other Names: Butrans™
Experimental: 14-Day Rest BTDS 10 with 14-day rest period prior to application of second BTDS	Drug: Buprenorphine transdermal patch; Buprenorphine 10 mcg/hour patch applied transdermally for 7-day wear.; Other Names: Butrans™
Experimental: 21-Day Rest BTDS 10 with 21-day rest period prior to application of second BTDS	Drug: Buprenorphine transdermal patch; Buprenorphine 10 mcg/hour patch applied transdermally for 7-day wear.; Other Names: Butrans™
Experimental: 28-Day Rest BTDS 10 with 28-day rest period prior to application of second BTDS	Drug: Buprenorphine transdermal patch; Buprenorphine 10 mcg/hour patch applied transdermally for 7-day wear.; Other Names: Butrans™

Outcome Measures

Primary Outcome Measures

1. Period 1: AUC0-3d [0 to 3 days (72 hours)]

   Period 1 was the first application of BTDS 10: To determine the minimum application site rest periods that ensured that the reapplication of BTDS to the same site in the deltoid region did not result in increased absorption of the drug as measured by AUC0-3d [The area under the plasma concentration-time course profile from time = 0 (dosing) through day 3 (to 72 hours)].

2. Period 2: AUC0-3d. [0 to 3 days]

   Period 2 was the second application of BTDS 10: To determine the minimum application site rest periods that ensured that the reapplication of BTDS to the same site in the deltoid region did not result in increased absorption of the drug as measured by AUC0-3d. AUC0-3d - The area under the plasma concentration-time course profile from time = 0 (dosing) through day 3 (to 72 hours).

3. Period 1: Cmax0-3d [0 to 3 days]

   Period 1 was the first application of BTDS 10: To determine the minimum application site rest periods that ensured that the reapplication of BTDS to the same site in the deltoid region did not result in increased absorption of the drug as measured by Cmax0-3d. Cmax0-3d - The maximum observed concentration taken directly from the plasma concentration-time course profile from time = 0 (dosing) through day 3 (to 72 hours). This was considered an index of maximum (peak) exposure to the study drug.

4. Period 2: Cmax0-3d [0 to 3 days]

   Period 2 was the second application of BTDS 10: To determine the minimum application site rest periods that ensured that the reapplication of BTDS to the same site in the deltoid region did not result in increased absorption of the drug as measured by Cmax0-3d. Cmax0-3d (pg/mL) - The maximum observed concentration taken directly from the plasma concentration-time course profile from time = 0 (dosing) through day 3 (to 72 hours). This was considered an index of maximum (peak) exposure to the study drug.

Secondary Outcome Measures

1. Period 1: AUC0-7d. [0 to 7 days]

   Period 1 was the first application of BTDS 10: The time for absorption to return to normal measured by AUC0-7d. AUC0-7d - The area under the plasma concentration-time course profile from time = 0 (dosing) to BTDS removal.

2. Period 2: AUC0-7d [0 to 7 days]

   Period 2 was the second application of BTDS 10: The time for absorption to return to normal measured by AUC0-7d. AUC0-7d - The area under the plasma concentration-time course profile from time = 0 (dosing) to BTDS removal.

3. Period 1: Cmax0-7 [0 to 7 days]

   Period 1 was the first application of BTDS 10: The time for absorption to return to normal measured by Cmax0-7. Cmax0-7d - The maximum observed concentration taken directly from the plasma concentration-time course profile.

4. Period 2: Cmax0-7d [0 to 7 days]

   Period 2 was the second application of BTDS 10: The time for absorption to return to normal measured by Cmax0-7d. Cmax0-7d - The maximum observed concentration taken directly from the plasma concentration-time course profile.

5. Period 1: Tmax0-7d. [0 to 7days]

   Period 1 was the first application of BTDS 10: The time for absorption to return to normal measured by Tmax0-7d. Tmax0-7d - The time from dosing to the maximum observed concentration was taken directly from the plasma concentration-time course profile. If the maximum plasma concentration was observed at 2 or more consecutive time points, the earliest time point was used for Tmax.

6. Period 2: Tmax0-7d. [0 to 7 days]

   Period 2 was the second application of BTDS 10: The time for absorption to return to normal measured by Tmax0-7d. Tmax0-7d - The time from dosing to the maximum observed concentration was taken directly from the plasma concentration-time course profile. If the maximum plasma concentration was observed at 2 or more consecutive time points, the earliest time point was used for Tmax.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 45 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: Yes

Inclusion Criteria Include:

• Males and females 18 to 45 years of age, inclusive.

• Weight of 60 to 100 kilograms (kg) [132-220 pounds (lb)] and within 15% of optimum for height and body frame.

• In good health, evidenced by a lack of significantly abnormal findings on medical history, physical examination, clinical laboratory tests, vital signs, and electrocardiogram (ECG).

• Willing to discontinue and abstain from any medications, including vitamins or mineral supplements, throughout the study.

• Willing to follow dietary restrictions, including abstention from caffeine and xanthine-containing beverages for the duration of the study.

• Did not smoke or chew tobacco for at least 45 days prior to administration of study drugs, and agree not to use tobacco products during the study

Exclusion Criteria Include:

• A history of hypersensitivity to opioid or psychotropic drugs.

• A history of recurrent seizures or syncope.

• Any medical or surgical conditions which might interfere with transdermal absorption, distribution, metabolism, or excretion of drugs.

• Any other significant active medical illness such as: history or presence of liver disease or liver injury that is indicated by an abnormal liver function profile such as aspartate transaminase (AST), alanine transaminase (ALT), or serum bilirubin; history or presence of impaired renal function that is indicated by abnormal creatinine or blood urea nitrogen (BUN) values or abnormal urinary constituents (eg, albuminuria); history of neutropenia (absolute neutrophil count [ANC] <1000/mm3 or thrombocytopenia (platelet <150,000/mm3).

• Positive results of urine drug screen or urine cotinine (consistent with active smoking).

• A history of substance or alcohol abuse within the past 5 years.

• Females who are nursing.

• Females who are pregnant as confirmed by a positive serum human chorionic gonadotropin (bHCG) test.

Other protocol-specific exclusion/inclusion criteria may apply.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	The Ohio State University Department of Pharmacology	Columbus	Ohio	United States	43210

Sponsors and Collaborators

• Purdue Pharma LP

Investigators

None specified.

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Product Information

Publications

None provided.

• Responsible Party: Purdue Pharma LP
• ClinicalTrials.gov Identifier: NCT01259102
• Other Study ID Numbers: BUP1002
• First Posted: Dec 13, 2010
• Last Update Posted: Sep 3, 2012
• Last Verified: Aug 1, 2012

• Keywords provided by Purdue Pharma LP: Healthy subjects; Opioid; Transdermal
• Additional relevant MeSH terms: Buprenorphine

Study Results

Participant Flow

Recruitment Details	19-Nov-2000 (first patient, first visit) to 18-Mar-2001 (last patient, last visit) at 1 center in the US, Columbus, OH.
Pre-assignment Detail	Subjects were assigned into 1 of 5 treatment groups with different recovery periods, ranging from 0 to 4 weeks. For the 5 treatment groups, the rest period was 0, 7, 14, 21, or 28 days, respectively, between the removal of the first buprenorphine transdermal system (BTDS) and placement of the second BTDS in exactly the same location.

Arm/Group Title	No Rest	7-Day Rest	14-Day Rest	21-Day Rest	28-Day Rest
Arm/Group Description	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 0 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 7 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 14 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 21 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 28 days between the removal of BTDS and placement of the second BTDS in the same location.
Period Title: Overall Study
STARTED	13	14	15	14	14
COMPLETED	12	14	13	12	13
NOT COMPLETED	1	0	2	2	1

Baseline Characteristics

Arm/Group Title	No Rest	7-Day Rest	14-Day Rest	21-Day Rest	28-Day Rest	Total
Arm/Group Description	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 0 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 7 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 14 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 21 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 28 days between the removal of BTDS and placement of the second BTDS in the same location.	Total of all reporting groups
Overall Participants	13	14	15	14	14	70
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	28.8 (1.9)	26.2 (1.6)	23.3 (1.1)	26.4 (1.9)	25.1 (2.3)	25.9 (0.8)
Sex: Female, Male (Count of Participants)
Female	2 15.4%	0 0%	1 6.7%	1 7.1%	0 0%	4 5.7%
Male	11 84.6%	14 100%	14 93.3%	13 92.9%	14 100%	66 94.3%
Race/Ethnicity, Customized (participants) [Number]
Hispanic	0 0%	1 7.1%	0 0%	0 0%	0 0%	1 1.4%
Asian	3 23.1%	0 0%	1 6.7%	0 0%	3 21.4%	7 10%
Black or African American	4 30.8%	3 21.4%	1 6.7%	1 7.1%	2 14.3%	11 15.7%
White	6 46.2%	9 64.3%	13 86.7%	12 85.7%	9 64.3%	49 70%
Unknown or Not Reported	0 0%	1 7.1%	0 0%	1 7.1%	0 0%	2 2.9%

Outcome Measures

1. Primary Outcome

Title	Period 1: AUC0-3d
Description	Period 1 was the first application of BTDS 10: To determine the minimum application site rest periods that ensured that the reapplication of BTDS to the same site in the deltoid region did not result in increased absorption of the drug as measured by AUC0-3d [The area under the plasma concentration-time course profile from time = 0 (dosing) through day 3 (to 72 hours)].
Time Frame	0 to 3 days (72 hours)

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: All subjects who satisfied the inclusion/exclusion criteria, received both applications of BTDS, and submitted to postbaseline phlebotomy through at least the 72-hour time point of both applications.

Arm/Group Title	No Rest	7-Day Rest	14-Day Rest	21-Day Rest	28-Day Rest
Arm/Group Description	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 0 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 7 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 14 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 21 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 28 days between the removal of BTDS and placement of the second BTDS in the same location.
Measure Participants	12	11	13	12	12
Mean (Standard Error) [pg/mL*h]	8680 (920)	7651 (1514)	6465 (1091)	12258 (836)	8890 (1054)

2. Primary Outcome

Title	Period 2: AUC0-3d.
Description	Period 2 was the second application of BTDS 10: To determine the minimum application site rest periods that ensured that the reapplication of BTDS to the same site in the deltoid region did not result in increased absorption of the drug as measured by AUC0-3d. AUC0-3d - The area under the plasma concentration-time course profile from time = 0 (dosing) through day 3 (to 72 hours).
Time Frame	0 to 3 days

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: All subjects who satisfied the inclusion/exclusion criteria, received both applications of BTDS, and submitted to postbaseline phlebotomy through at least the 72-hour time point of both applications.

Arm/Group Title	No Rest	7-Day Rest	14-Day Rest	21-Day Rest	28-Day Rest
Arm/Group Description	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 0 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 7 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 14 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 21 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 28 days between the removal of BTDS and placement of the second BTDS in the same location.
Measure Participants	12	11	13	12	12
Mean (Standard Error) [pg/mL*h]	12316 (1062)	14733 (2255)	13571 (1671)	12931 (908)	9056 (888)

3. Primary Outcome

Title	Period 1: Cmax0-3d
Description	Period 1 was the first application of BTDS 10: To determine the minimum application site rest periods that ensured that the reapplication of BTDS to the same site in the deltoid region did not result in increased absorption of the drug as measured by Cmax0-3d. Cmax0-3d - The maximum observed concentration taken directly from the plasma concentration-time course profile from time = 0 (dosing) through day 3 (to 72 hours). This was considered an index of maximum (peak) exposure to the study drug.
Time Frame	0 to 3 days

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: All subjects who satisfied the inclusion/exclusion criteria, received both applications of BTDS, and submitted to postbaseline phlebotomy through at least the 72-hour time point of both applications.

Arm/Group Title	No Rest	7-Day Rest	14-Day Rest	21-Day Rest	28-Day Rest
Arm/Group Description	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 0 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 7 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 14 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 21 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 28 days between the removal of BTDS and placement of the second BTDS in the same location.
Measure Participants	12	11	13	12	12
Mean (Standard Error) [pg/mL]	183 (17)	193 (50)	151 (24)	241 (15)	185 (16)

4. Primary Outcome

Title	Period 2: Cmax0-3d
Description	Period 2 was the second application of BTDS 10: To determine the minimum application site rest periods that ensured that the reapplication of BTDS to the same site in the deltoid region did not result in increased absorption of the drug as measured by Cmax0-3d. Cmax0-3d (pg/mL) - The maximum observed concentration taken directly from the plasma concentration-time course profile from time = 0 (dosing) through day 3 (to 72 hours). This was considered an index of maximum (peak) exposure to the study drug.
Time Frame	0 to 3 days

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: All subjects who satisfied the inclusion/exclusion criteria, received both applications of BTDS, and submitted to postbaseline phlebotomy through at least the 72-hour time point of both applications.

Arm/Group Title	No Rest	7-Day Rest	14-Day Rest	21-Day Rest	28-Day Rest
Arm/Group Description	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 0 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 7 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 14 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 21 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 28 days between the removal of BTDS and placement of the second BTDS in the same location.
Measure Participants	12	11	13	12	12
Mean (Standard Error) [pg/mL]	216 (17)	300 (52)	262 (31)	278 (41)	182 (14)

5. Secondary Outcome

Title	Period 1: AUC0-7d.
Description	Period 1 was the first application of BTDS 10: The time for absorption to return to normal measured by AUC0-7d. AUC0-7d - The area under the plasma concentration-time course profile from time = 0 (dosing) to BTDS removal.
Time Frame	0 to 7 days

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: All subjects who satisfied the inclusion/exclusion criteria, received both applications of BTDS, and submitted to postbaseline phlebotomy through at least the 72-hour time point of both applications.

Arm/Group Title	No Rest	7-Day Rest	14-Day Rest	21-Day Rest	28-Day Rest
Arm/Group Description	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 0 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 7 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 14 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 21 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 28 days between the removal of BTDS and placement of the second BTDS in the same location.
Measure Participants	12	11	13	12	12
Mean (Standard Error) [pg/mL*h]	21946 (1686)	20541 (2645)	14707 (1851)	27040 (1298)	22086 (1591)

6. Secondary Outcome

Title	Period 2: AUC0-7d
Description	Period 2 was the second application of BTDS 10: The time for absorption to return to normal measured by AUC0-7d. AUC0-7d - The area under the plasma concentration-time course profile from time = 0 (dosing) to BTDS removal.
Time Frame	0 to 7 days

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: All subjects who satisfied the inclusion/exclusion criteria, received both applications of BTDS, and submitted to postbaseline phlebotomy through at least the 72-hour time point of both applications.

Arm/Group Title	No Rest	7-Day Rest	14-Day Rest	21-Day Rest	28-Day Rest
Arm/Group Description	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 0 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 7 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 14 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 21 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 28 days between the removal of BTDS and placement of the second BTDS in the same location.
Measure Participants	12	11	13	12	12
Mean (Standard Error) [pg/mL*h]	25126 (2285)	27543 (3093)	26174 (2414)	27123 (1475)	21790 (1365)

7. Secondary Outcome

Title	Period 1: Cmax0-7
Description	Period 1 was the first application of BTDS 10: The time for absorption to return to normal measured by Cmax0-7. Cmax0-7d - The maximum observed concentration taken directly from the plasma concentration-time course profile.
Time Frame	0 to 7 days

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: All subjects who satisfied the inclusion/exclusion criteria, received both applications of BTDS, and submitted to postbaseline phlebotomy through at least the 72-hour time point of both applications.

Arm/Group Title	No Rest	7-Day Rest	14-Day Rest	21-Day Rest	28-Day Rest
Arm/Group Description	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 0 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 7 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 14 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 21 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 28 days between the removal of BTDS and placement of the second BTDS in the same location.
Measure Participants	12	11	13	12	12
Mean (Standard Error) [pg/mL]	188 (16)	206 (48)	160 (22)	245 (14)	192 (15)

8. Secondary Outcome

Title	Period 2: Cmax0-7d
Description	Period 2 was the second application of BTDS 10: The time for absorption to return to normal measured by Cmax0-7d. Cmax0-7d - The maximum observed concentration taken directly from the plasma concentration-time course profile.
Time Frame	0 to 7 days

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: All subjects who satisfied the inclusion/exclusion criteria, received both applications of BTDS, and submitted to postbaseline phlebotomy through at least the 72-hour time point of both applications.

Arm/Group Title	No Rest	7-Day Rest	14-Day Rest	21-Day Rest	28-Day Rest
Arm/Group Description	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 0 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 7 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 14 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 21 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 28 days between the removal of BTDS and placement of the second BTDS in the same location.
Measure Participants	12	11	13	12	12
Mean (Standard Error) [pg/mL]	216 (17)	300 (52)	262 (31)	278 (41)	202 (18)

9. Secondary Outcome

Title	Period 1: Tmax0-7d.
Description	Period 1 was the first application of BTDS 10: The time for absorption to return to normal measured by Tmax0-7d. Tmax0-7d - The time from dosing to the maximum observed concentration was taken directly from the plasma concentration-time course profile. If the maximum plasma concentration was observed at 2 or more consecutive time points, the earliest time point was used for Tmax.
Time Frame	0 to 7days

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: All subjects who satisfied the inclusion/exclusion criteria, received both applications of BTDS, and submitted to postbaseline phlebotomy through at least the 72-hour time point of both applications.

Arm/Group Title	No Rest	7-Day Rest	14-Day Rest	21-Day Rest	28-Day Rest
Arm/Group Description	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 0 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 7 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 14 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 21 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 28 days between the removal of BTDS and placement of the second BTDS in the same location.
Measure Participants	12	11	13	12	12
Mean (Standard Error) [hour]	74 (7)	86 (6)	78 (15)	55 (6)	76 (11)

10. Secondary Outcome

Title	Period 2: Tmax0-7d.
Description	Period 2 was the second application of BTDS 10: The time for absorption to return to normal measured by Tmax0-7d. Tmax0-7d - The time from dosing to the maximum observed concentration was taken directly from the plasma concentration-time course profile. If the maximum plasma concentration was observed at 2 or more consecutive time points, the earliest time point was used for Tmax.
Time Frame	0 to 7 days

Outcome Measure Data

Analysis Population Description

Pharmacokinetic Population: All subjects who satisfied the inclusion/exclusion criteria, received both applications of BTDS, and submitted to postbaseline phlebotomy through at least the 72-hour time point of both applications.

Arm/Group Title	No Rest	7-Day Rest	14-Day Rest	21-Day Rest	28-Day Rest
Arm/Group Description	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 0 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 7 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 14 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 21 days between the removal of BTDS and placement of the second BTDS in the same location.	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 28 days between the removal of BTDS and placement of the second BTDS in the same location.
Measure Participants	12	11	13	12	12
Mean (Standard Error) [hour]	42 (3)	38 (6)	36 (5)	46 (4)	63 (10)

Adverse Events

Time Frame	All adverse events, whether spontaneously reported or elicited on direct questioning, that occurred after administration of the first dose of study drug and on or before the final visit were reported on the adverse event form.
Adverse Event Reporting Description	AEs were learned of by spontaneous reports and subject interview.
Arm/Group Title	No Rest		7-Day Rest		14-Day Rest		21-Day Rest		28-Day Rest
Arm/Group Description	Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 0 days between the removal of BTDS and placement of the second BTDS in the same location.		Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 7 days between the removal of BTDS and placement of the second BTDS in the same location.		Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 14 days between the removal of BTDS and placement of the second BTDS in the same location.		Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 21 days between the removal of BTDS and placement of the second BTDS in the same location.		Each subject applied BTDS (10 mcg/h) on 2 occasions and wore it for 7 days (168 hours). Subjects were assigned to 1 of 5 treatment groups with different application site rest periods from 0 to 4 weeks. For this group, the rest period was 28 days between the removal of BTDS and placement of the second BTDS in the same location.
All Cause Mortality
	No Rest		7-Day Rest		14-Day Rest		21-Day Rest		28-Day Rest
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	No Rest		7-Day Rest		14-Day Rest		21-Day Rest		28-Day Rest
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/13 (0%)		1/14 (7.1%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Hepatobiliary disorders
Neutropenia	0/13 (0%)	0	1/14 (7.1%)	1	0/15 (0%)	0	0/14 (0%)	0	0/14 (0%)	0
Other (Not Including Serious) Adverse Events
	No Rest		7-Day Rest		14-Day Rest		21-Day Rest		28-Day Rest
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	11/13 (84.6%)		14/14 (100%)		13/15 (86.7%)		10/14 (71.4%)		11/14 (78.6%)
Blood and lymphatic system disorders
Leukopenia	0/13 (0%)		1/14 (7.1%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Cardiac disorders
Phlebitis	0/13 (0%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		2/14 (14.3%)
Electrocardiogram abnormal	1/13 (7.7%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Palpitation	0/13 (0%)		0/14 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Vasodilatation	0/13 (0%)		0/14 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Eye disorders
Amblyopia	1/13 (7.7%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Conjunctivitis	0/13 (0%)		1/14 (7.1%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Photophobia	1/13 (7.7%)		0/14 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Gastrointestinal disorders
Anorexia	4/13 (30.8%)		5/14 (35.7%)		2/15 (13.3%)		0/14 (0%)		3/14 (21.4%)
Constipation	1/13 (7.7%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		2/14 (14.3%)
Diarrhea	0/13 (0%)		0/14 (0%)		0/15 (0%)		1/14 (7.1%)		2/14 (14.3%)
Nausea	7/13 (53.8%)		3/14 (21.4%)		7/15 (46.7%)		1/14 (7.1%)		2/14 (14.3%)
Vomiting	1/13 (7.7%)		0/14 (0%)		1/15 (6.7%)		0/14 (0%)		2/14 (14.3%)
Dyspepsia	0/13 (0%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Eructation	1/13 (7.7%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Flatulence	0/13 (0%)		0/14 (0%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
General disorders
Asthenia	7/13 (53.8%)		2/14 (14.3%)		4/15 (26.7%)		0/14 (0%)		2/14 (14.3%)
Headache	6/13 (46.2%)		8/14 (57.1%)		10/15 (66.7%)		1/14 (7.1%)		6/14 (42.9%)
Accidental injury	0/13 (0%)		1/14 (7.1%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Back pain	1/13 (7.7%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Chest pain substernal	1/13 (7.7%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Infection	0/13 (0%)		0/14 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Infection bacterial	0/13 (0%)		0/14 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Pain	1/13 (7.7%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Reaction unevaluable	1/13 (7.7%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Metabolism and nutrition disorders
Thirst	3/13 (23.1%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Bilirubinemia	0/13 (0%)		1/14 (7.1%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Nervous system disorders
Dizziness	2/13 (15.4%)		2/14 (14.3%)		1/15 (6.7%)		0/14 (0%)		1/14 (7.1%)
Nervousness	1/13 (7.7%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Vertigo	0/13 (0%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		2/14 (14.3%)
Agitation	0/13 (0%)		1/14 (7.1%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Somnolence	5/13 (38.5%)		5/14 (35.7%)		5/15 (33.3%)		5/14 (35.7%)		5/14 (35.7%)
Tremor	1/13 (7.7%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Psychiatric disorders
Thinking abnormally	1/13 (7.7%)		1/14 (7.1%)		0/15 (0%)		2/14 (14.3%)		0/14 (0%)
Renal and urinary disorders
Polyuria	2/13 (15.4%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Abnormal ejaculation	0/13 (0%)		0/14 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Nocturia	1/13 (7.7%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		0/14 (0%)
Reproductive system and breast disorders
Breast pain	0/13 (0%)		0/14 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Respiratory, thoracic and mediastinal disorders
Pharyngitis	0/13 (0%)		0/14 (0%)		0/15 (0%)		1/14 (7.1%)		3/14 (21.4%)
Cough increased	1/13 (7.7%)		0/14 (0%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)
Rhinitis	1/13 (7.7%)		0/14 (0%)		0/15 (0%)		0/14 (0%)		1/14 (7.1%)
Skin and subcutaneous tissue disorders
Prutitus at site	5/13 (38.5%)		0/14 (0%)		3/15 (20%)		0/14 (0%)		2/14 (14.3%)
Erythema at site	0/13 (0%)		1/14 (7.1%)		1/15 (6.7%)		0/14 (0%)		0/14 (0%)
Other site reactions	1/13 (7.7%)		1/14 (7.1%)		0/15 (0%)		1/14 (7.1%)		0/14 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is more than 60 days but less than or equal to 180 days. The sponsor cannot require changes to the communication and cannot extend the embargo.