Trial Outcomes & Findings for Examine Plasma Concentrations of Buprenorphine Following Reapplication of Buprenorphine Transdermal System (BTDS) After Variable Application Site Rest Periods (NCT NCT01259102)

Last Updated: 2012-09-03

Results Overview

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 \[The area under the plasma concentration-time course profile from time = 0 (dosing) through day 3 (to 72 hours)\].

Recruitment status

COMPLETED

Study phase

PHASE1

Target enrollment

70 participants

Primary outcome timeframe

0 to 3 days (72 hours)

Results posted on

2012-09-03

Participant Flow

19-Nov-2000 (first patient, first visit) to 18-Mar-2001 (last patient, last visit) at 1 center in the US, Columbus, OH.

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.

Participant milestones

Participant milestones
Measure	No Rest 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.	7-Day Rest 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.	14-Day Rest 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.	21-Day Rest 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.	28-Day Rest 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.
Overall Study STARTED	13	14	15	14	14
Overall Study COMPLETED	12	14	13	12	13
Overall Study NOT COMPLETED	1	0	2	2	1

Reasons for withdrawal

Reasons for withdrawal
Measure	No Rest 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.	7-Day Rest 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.	14-Day Rest 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.	21-Day Rest 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.	28-Day Rest 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.
Overall Study Adverse Event	1	0	1	1	0
Overall Study Other	0	0	1	1	1

Baseline Characteristics

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

Baseline characteristics by cohort

Baseline characteristics by cohort
Measure	No Rest n=13 Participants 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.	7-Day Rest n=14 Participants 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.	14-Day Rest n=15 Participants 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.	21-Day Rest n=14 Participants 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.	28-Day Rest n=14 Participants 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 n=70 Participants Total of all reporting groups
Age Continuous	28.8 years STANDARD_DEVIATION 1.9 • n=5 Participants	26.2 years STANDARD_DEVIATION 1.6 • n=7 Participants	23.3 years STANDARD_DEVIATION 1.1 • n=5 Participants	26.4 years STANDARD_DEVIATION 1.9 • n=4 Participants	25.1 years STANDARD_DEVIATION 2.3 • n=21 Participants	25.9 years STANDARD_DEVIATION 0.8 • n=8 Participants
Sex: Female, Male Female	2 Participants n=5 Participants	0 Participants n=7 Participants	1 Participants n=5 Participants	1 Participants n=4 Participants	0 Participants n=21 Participants	4 Participants n=8 Participants
Sex: Female, Male Male	11 Participants n=5 Participants	14 Participants n=7 Participants	14 Participants n=5 Participants	13 Participants n=4 Participants	14 Participants n=21 Participants	66 Participants n=8 Participants
Race/Ethnicity, Customized Hispanic	0 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	0 participants n=4 Participants	0 participants n=21 Participants	1 participants n=8 Participants
Race/Ethnicity, Customized Asian	3 participants n=5 Participants	0 participants n=7 Participants	1 participants n=5 Participants	0 participants n=4 Participants	3 participants n=21 Participants	7 participants n=8 Participants
Race/Ethnicity, Customized Black or African American	4 participants n=5 Participants	3 participants n=7 Participants	1 participants n=5 Participants	1 participants n=4 Participants	2 participants n=21 Participants	11 participants n=8 Participants
Race/Ethnicity, Customized White	6 participants n=5 Participants	9 participants n=7 Participants	13 participants n=5 Participants	12 participants n=4 Participants	9 participants n=21 Participants	49 participants n=8 Participants
Race/Ethnicity, Customized Unknown or Not Reported	0 participants n=5 Participants	1 participants n=7 Participants	0 participants n=5 Participants	1 participants n=4 Participants	0 participants n=21 Participants	2 participants n=8 Participants

PRIMARY outcome

Timeframe: 0 to 3 days (72 hours)

Population: 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.

Outcome measures

Outcome measures
Measure	No Rest n=12 Participants 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.	7-Day Rest n=11 Participants 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.	14-Day Rest n=13 Participants 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.	21-Day Rest n=12 Participants 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.	28-Day Rest n=12 Participants 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 1: AUC0-3d	8680 pg/mL*h Standard Error 920	7651 pg/mL*h Standard Error 1514	6465 pg/mL*h Standard Error 1091	12258 pg/mL*h Standard Error 836	8890 pg/mL*h Standard Error 1054

PRIMARY outcome

Timeframe: 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).

Outcome measures

Outcome measures
Measure	No Rest n=12 Participants 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.	7-Day Rest n=11 Participants 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.	14-Day Rest n=13 Participants 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.	21-Day Rest n=12 Participants 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.	28-Day Rest n=12 Participants 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 2: AUC0-3d.	12316 pg/mL*h Standard Error 1062	14733 pg/mL*h Standard Error 2255	13571 pg/mL*h Standard Error 1671	12931 pg/mL*h Standard Error 908	9056 pg/mL*h Standard Error 888

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	No Rest n=12 Participants 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.	7-Day Rest n=11 Participants 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.	14-Day Rest n=13 Participants 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.	21-Day Rest n=12 Participants 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.	28-Day Rest n=12 Participants 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 1: Cmax0-3d	183 pg/mL Standard Error 17	193 pg/mL Standard Error 50	151 pg/mL Standard Error 24	241 pg/mL Standard Error 15	185 pg/mL Standard Error 16

PRIMARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	No Rest n=12 Participants 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.	7-Day Rest n=11 Participants 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.	14-Day Rest n=13 Participants 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.	21-Day Rest n=12 Participants 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.	28-Day Rest n=12 Participants 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 2: Cmax0-3d	216 pg/mL Standard Error 17	300 pg/mL Standard Error 52	262 pg/mL Standard Error 31	278 pg/mL Standard Error 41	182 pg/mL Standard Error 14

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	No Rest n=12 Participants 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.	7-Day Rest n=11 Participants 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.	14-Day Rest n=13 Participants 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.	21-Day Rest n=12 Participants 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.	28-Day Rest n=12 Participants 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 1: AUC0-7d.	21946 pg/mL*h Standard Error 1686	20541 pg/mL*h Standard Error 2645	14707 pg/mL*h Standard Error 1851	27040 pg/mL*h Standard Error 1298	22086 pg/mL*h Standard Error 1591

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	No Rest n=12 Participants 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.	7-Day Rest n=11 Participants 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.	14-Day Rest n=13 Participants 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.	21-Day Rest n=12 Participants 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.	28-Day Rest n=12 Participants 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 2: AUC0-7d	25126 pg/mL*h Standard Error 2285	27543 pg/mL*h Standard Error 3093	26174 pg/mL*h Standard Error 2414	27123 pg/mL*h Standard Error 1475	21790 pg/mL*h Standard Error 1365

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	No Rest n=12 Participants 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.	7-Day Rest n=11 Participants 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.	14-Day Rest n=13 Participants 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.	21-Day Rest n=12 Participants 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.	28-Day Rest n=12 Participants 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 1: Cmax0-7	188 pg/mL Standard Error 16	206 pg/mL Standard Error 48	160 pg/mL Standard Error 22	245 pg/mL Standard Error 14	192 pg/mL Standard Error 15

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	No Rest n=12 Participants 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.	7-Day Rest n=11 Participants 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.	14-Day Rest n=13 Participants 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.	21-Day Rest n=12 Participants 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.	28-Day Rest n=12 Participants 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 2: Cmax0-7d	216 pg/mL Standard Error 17	300 pg/mL Standard Error 52	262 pg/mL Standard Error 31	278 pg/mL Standard Error 41	202 pg/mL Standard Error 18

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	No Rest n=12 Participants 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.	7-Day Rest n=11 Participants 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.	14-Day Rest n=13 Participants 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.	21-Day Rest n=12 Participants 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.	28-Day Rest n=12 Participants 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 1: Tmax0-7d.	74 hour Standard Error 7	86 hour Standard Error 6	78 hour Standard Error 15	55 hour Standard Error 6	76 hour Standard Error 11

SECONDARY outcome

Timeframe: 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.

Outcome measures

Outcome measures
Measure	No Rest n=12 Participants 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.	7-Day Rest n=11 Participants 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.	14-Day Rest n=13 Participants 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.	21-Day Rest n=12 Participants 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.	28-Day Rest n=12 Participants 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 2: Tmax0-7d.	42 hour Standard Error 3	38 hour Standard Error 6	36 hour Standard Error 5	46 hour Standard Error 4	63 hour Standard Error 10

Adverse Events

No Rest

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

7-Day Rest

Serious events: 1 serious events

Other events: 14 other events

Deaths: 0 deaths

14-Day Rest

Serious events: 0 serious events

Other events: 13 other events

Deaths: 0 deaths

21-Day Rest

Serious events: 0 serious events

Other events: 10 other events

Deaths: 0 deaths

28-Day Rest

Serious events: 0 serious events

Other events: 11 other events

Deaths: 0 deaths

Serious adverse events

Serious adverse events
Measure	No Rest n=13 participants at risk 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.	7-Day Rest n=14 participants at risk 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.	14-Day Rest n=15 participants at risk 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.	21-Day Rest n=14 participants at risk 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.	28-Day Rest n=14 participants at risk 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.
Hepatobiliary disorders Neutropenia	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • Number of events 1 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.

Other adverse events

Other adverse events
Measure	No Rest n=13 participants at risk 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.	7-Day Rest n=14 participants at risk 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.	14-Day Rest n=15 participants at risk 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.	21-Day Rest n=14 participants at risk 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.	28-Day Rest n=14 participants at risk 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.
Renal and urinary disorders Abnormal ejaculation	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Reproductive system and breast disorders Breast pain	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Cardiac disorders Phlebitis	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	14.3% 2/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Gastrointestinal disorders Anorexia	30.8% 4/13 • 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. AEs were learned of by spontaneous reports and subject interview.	35.7% 5/14 • 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. AEs were learned of by spontaneous reports and subject interview.	13.3% 2/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	21.4% 3/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Gastrointestinal disorders Constipation	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	14.3% 2/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Gastrointestinal disorders Diarrhea	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	14.3% 2/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Gastrointestinal disorders Nausea	53.8% 7/13 • 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. AEs were learned of by spontaneous reports and subject interview.	21.4% 3/14 • 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. AEs were learned of by spontaneous reports and subject interview.	46.7% 7/15 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	14.3% 2/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Gastrointestinal disorders Vomiting	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	6.7% 1/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	14.3% 2/14 • 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. AEs were learned of by spontaneous reports and subject interview.
General disorders Asthenia	53.8% 7/13 • 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. AEs were learned of by spontaneous reports and subject interview.	14.3% 2/14 • 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. AEs were learned of by spontaneous reports and subject interview.	26.7% 4/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	14.3% 2/14 • 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. AEs were learned of by spontaneous reports and subject interview.
General disorders Headache	46.2% 6/13 • 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. AEs were learned of by spontaneous reports and subject interview.	57.1% 8/14 • 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. AEs were learned of by spontaneous reports and subject interview.	66.7% 10/15 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	42.9% 6/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Metabolism and nutrition disorders Thirst	23.1% 3/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Nervous system disorders Dizziness	15.4% 2/13 • 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. AEs were learned of by spontaneous reports and subject interview.	14.3% 2/14 • 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. AEs were learned of by spontaneous reports and subject interview.	6.7% 1/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Nervous system disorders Nervousness	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Nervous system disorders Vertigo	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	14.3% 2/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Psychiatric disorders Thinking abnormally	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	14.3% 2/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Respiratory, thoracic and mediastinal disorders Pharyngitis	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	21.4% 3/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Skin and subcutaneous tissue disorders Prutitus at site	38.5% 5/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	20.0% 3/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	14.3% 2/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Renal and urinary disorders Polyuria	15.4% 2/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
General disorders Accidental injury	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
General disorders Back pain	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
General disorders Chest pain substernal	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
General disorders Infection	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
General disorders Infection bacterial	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
General disorders Pain	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.
General disorders Reaction unevaluable	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Cardiac disorders Electrocardiogram abnormal	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Cardiac disorders Palpitation	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Cardiac disorders Vasodilatation	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Gastrointestinal disorders Dyspepsia	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Gastrointestinal disorders Eructation	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Gastrointestinal disorders Flatulence	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	6.7% 1/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Blood and lymphatic system disorders Leukopenia	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Metabolism and nutrition disorders Bilirubinemia	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Nervous system disorders Agitation	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Nervous system disorders Somnolence	38.5% 5/13 • 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. AEs were learned of by spontaneous reports and subject interview.	35.7% 5/14 • 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. AEs were learned of by spontaneous reports and subject interview.	33.3% 5/15 • 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. AEs were learned of by spontaneous reports and subject interview.	35.7% 5/14 • 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. AEs were learned of by spontaneous reports and subject interview.	35.7% 5/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Nervous system disorders Tremor	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Respiratory, thoracic and mediastinal disorders Cough increased	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Respiratory, thoracic and mediastinal disorders Rhinitis	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Skin and subcutaneous tissue disorders Erythema at site	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	6.7% 1/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Skin and subcutaneous tissue disorders Other site reactions	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Eye disorders Amblyopia	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Eye disorders Conjunctivitis	0.00% 0/13 • 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. AEs were learned of by spontaneous reports and subject interview.	7.1% 1/14 • 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. AEs were learned of by spontaneous reports and subject interview.	6.7% 1/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Eye disorders Photophobia	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	6.7% 1/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.
Renal and urinary disorders Nocturia	7.7% 1/13 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/15 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.	0.00% 0/14 • 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. AEs were learned of by spontaneous reports and subject interview.

Additional Information

Executive Medical Director, Clinical Pharmacology

Purdue Pharma L.P.

Phone: 800-733-1333

Results disclosure agreements

Principal investigator is a sponsor employee
Publication restrictions are in place

Restriction type: GT60