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Clinical Trial Results:
A randomised, double blind, placebo controlled, cross over study of the effects of Buprenorphine Hemiadipate Hydrochloride/Naloxone Hydrochloride Dihydrate intravenous challenges in opioid dependent subjects stabilisied on sublingual Buprenorphine Hydrochloride/Naloxone Hydrochloride Dihydrate (Suboxone)

Summary
EudraCT number	2011-002229-23
Trial protocol	GB
Global end of trial date	11 Oct 2013

Results information
Results version number	v1(current)
This version publication date	28 Sep 2016
First version publication date	28 Sep 2016
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

RB-UK-11-0018

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

Reckitt Benckiser Pharmaceuticals Inc

Sponsor organisation address

10710 Midlothian Turnpike, Suite 430, Richmond, VA, United States, 23235

Public contact

Director of Clinical Operations, Reckitt Benckiser Pharmaceuticals Inc., 01 (804) 594-2029,

Scientific contact

Director of Clinical Operations, Reckitt Benckiser Pharmaceuticals Inc., 01 (804) 594-2029,

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

30 Jan 2015

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

11 Oct 2013

Was the trial ended prematurely?

Main objective of the trial

To compare the behavioural and physiological effects of injecting buprenorphine hemiadipate hydrochloride (HCl)/naloxone HCl dihydrate both alone and in combination at three different dose ratios 1:1, 1:0.5 and 1:0.25, with placebo.

Protection of trial subjects

This study was carried out in accordance with the study protocol, current ICH GCP guidelines, the European Clinical Trials Directive 2001/20/EC, 2005/28/EC, 95/46/EC, and other applicable regulatory and country-specific requirements. Written informed consent was obtained from each subject prior to his/her enrolment in the study. Prior to entering the study, subjects were informed by the principal investigator (PI) or designated sub-investigator about the nature and purpose of the study, procedures, expected duration, alternative therapies available and the benefits and risks involved in study participation. Subjects reviewed consent documents and were given the opportunity to ask questions. Subjects were informed of their right to withdraw from the study at any time without prejudice. It was intended that the potential subject be able to answer simple questions about the study after the ICF was reviewed and explained. After this explanation and before any study specific procedures were performed, the subject voluntarily signed and dated the ICF to indicate desire to participate in the study. The investigator or designee also signed and dated the ICF. The time (hour and minute) the consent was signed was recorded by the subject and the person obtaining the subject’s consent. Prior to participation in the study, the subject received a copy of the signed and dated ICF, along with a card noting site contact information in the event that a medical emergency occurred during the study.

Background therapy

Evidence for comparator

Actual start date of recruitment

31 Jul 2012

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 36

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Screening details

Forty-two subjects were screened.

Period 1 title

Pre-Challenge Period (Day 1 - 7)

Is this the baseline period?

Yes

Allocation method

Not applicable

Blinding used

Not blinded

Overall Pre-Challenge Period

Arm description

A 7-day outpatient period during which subjects received Suboxone. The dose for Day 1 was 8mg, Day 2 was 12mg, and Days 3 to 7 were 16mg.

Arm type

Overall

Investigational medicinal product name

Suboxone

Investigational medicinal product code

Other name

buprenorphine/naloxone

Pharmaceutical forms

Tablet

Routes of administration

Sublingual use

Dosage and administration details

Sublingual Suboxone was administered daily to all subjects, beginning with 8 mg on Day 1, 12 mg on Day 2 and 16 mg of Suboxone on Day 3. Subjects remained on 16 mg/day until the day after the administration of the final challenge.

Number of subjects in period 1	Overall Pre-Challenge Period
Started	36
Completed	31
Not completed	5
Consent withdrawn by subject	1
Adverse event, non-fatal	1
Not specified	3

Period 2 title

Challenge Period (Day 8 - 24)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Blinding implementation details

Based on the randomisation code, the pharmacist dispensed challenge treatment to an unblinded research nurse, who prepared the individual challenge treatments. The challenge treatments were identical in appearance. Under normal circumstances, the blind was not to be broken until all subjects had completed the study and the database was finalised. The blind was allowed to be broken for specific subjects when specific emergency treatment would be dictated by knowing the treatment status.

Overall Challenge Period

Arm description

All subjects received open-label sublingual Suboxone 16 mg from Day 8 until the day after administration of the final challenge. Subjects were administered each of the 8 blinded, intravenously injected challenges in a randomised order, at least 48 hours apart, starting on Study Day 9: A: Placebo B: Buprenorphine hemiadipate HCl 5 mg (delivering 3.7 mg of buprenorphine base) C: Naloxone HCl dihydrate 5 mg (delivering 4.092 mg of naloxone base) D: Buprenorphine hemiadipate HCl 5 mg /naloxone HCl dihydrate 5 mg (delivering 3.7 mg of buprenorphine base and 4.092 mg of naloxone base) E: Buprenorphine hemiadipate HCl 5 mg /naloxone HCl dihydrate 2.5 mg (delivering 3.7 mg of buprenorphine base and 2.046 mg of naloxone base) F: Buprenorphine hemiadipate HCl 5 mg /naloxone HCl dihydrate 1.25 mg (delivering 3.7 mg of buprenorphine base and 1.023 mg of naloxone base) G: Diamorphine HCl 10 mg H: Buprenorphine HCl 4.0 mg (delivering 3.7 mg of buprenorphine base)

Arm type

Overall

Investigational medicinal product name

Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Challenges were administered using either direct puncture or a BD Adsyte Pro 18/20 gauge catheter or similar device over approximately 10 seconds via an IV push. Placebo for IV injection was provided by RBP as identical colourless 2 mL solutions for IV injection. The placebo comprised hydroxypropylbetadex and glucose monohydrate dissolved in water for injection pH adjusted to pH4.

Investigational medicinal product name

Buprenorphine hemiadipate HCl

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for infusion

Routes of administration

Intravenous use

Dosage and administration details

Buprenorphine hemiadipate HCl (2.5 mg/mL) was provided by RBP as a colourless solution identical in appearance to the other challenge treatments. Challenges were administered using either direct puncture or a BD Adsyte Pro 18/20 gauge catheter or similar device (2 mL (total volume for each treatment arm) over approximately 10 seconds via an IV push.

Investigational medicinal product name

Naloxone HCl dihydrate

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Naloxone HCl dihydrate in strengths of 2.5 mg/mL, 1.25 mg/mL, and 0.625 mg/mL was provided by RBP as a colourless solution identical in appearance to the other challenge treatments. Challenges were administered using either direct puncture or a BD Adsyte Pro 18/20 gauge catheter or similar device (2 mL (total volume for each treatment arm) over approximately 10 seconds via an IV push.

Investigational medicinal product name

Diamorphine HCl

Investigational medicinal product code

Other name

Pharmaceutical forms

Solution for injection

Routes of administration

Intravenous use

Dosage and administration details

Diamorphine HCl was sourced commercially and diluted to 5 mg/mL as required. Challenges were administered using either direct puncture or a BD Adsyte Pro 18/20 gauge catheter or similar device (2 mL (total volume for each treatment arm) over approximately 10 seconds via an IV push.

Investigational medicinal product name

Suboxone

Investigational medicinal product code

Other name

buprenorphine/naloxone

Pharmaceutical forms

Tablet

Routes of administration

Sublingual use

Dosage and administration details

Number of subjects in period 2	Overall Challenge Period
Started	31
Completed	24
Not completed	7
Adverse event, non-fatal	1
Not specified	6

Baseline characteristics

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Reporting group title

Pre-Challenge Period (Day 1 - 7)

Reporting group description

Reporting group values	Pre-Challenge Period (Day 1 - 7)	Total
Number of subjects	36	36
Age categorical
Units: Subjects
Adults (18-64 years)	36	36
Age continuous
Units: years
arithmetic mean (standard deviation)	42.9 ( 7.77 )	-
Gender categorical
Units: Subjects
Female	6	6
Male	30	30
Race
Units: Subjects
Asian	1	1
Black or African American	10	10
White	20	20
Asian, White	1	1
Black or African American, White	4	4
Weight
Units: kg
arithmetic mean (standard deviation)	71.51 ( 10.314 )	-
Body Mass Index
Units: kg/m^2
arithmetic mean (standard deviation)	23.41 ( 2.876 )	-

End points

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Reporting group title

Overall Pre-Challenge Period

Reporting group description

A 7-day outpatient period during which subjects received Suboxone. The dose for Day 1 was 8mg, Day 2 was 12mg, and Days 3 to 7 were 16mg.

Reporting group title

Overall Challenge Period

Reporting group description

Subject analysis set title

A. Placebo

Subject analysis set type

Full analysis

Subject analysis set description

Subjects who completed the placebo challenge consisting of a single intravenous injection of placebo.

Subject analysis set title

B: Buprenorphine hemiadipate HCl

Subject analysis set type

Full analysis

Subject analysis set description

Subjects who completed the challenge consisting of a single intravenous injection of buprenorphine hemiadipate HCl 5 mg.

Subject analysis set title

C: Naloxone HCl dihydrate

Subject analysis set type

Full analysis

Subject analysis set description

Subjects who completed the challenge consisting of a single intravenous injection of naloxone HCl dihydrate 5 mg.

Subject analysis set title

D: BHA/NAL 1:1

Subject analysis set type

Full analysis

Subject analysis set description

Subjects who completed the challenge consisting of a single intravenous injection of buprenorphine hemiadipate HCl 5 mg /naloxone HCl dihydrate 5 mg.

Subject analysis set title

E. BHA/NAL 1:0.5

Subject analysis set type

Full analysis

Subject analysis set description

Subjects who completed the challenge consisting of a single intravenous injection of buprenorphine hemiadipate HCl 5 mg /naloxone HCl dihydrate 2.5 mg.

Subject analysis set title

F. BHA/NAL 1:0.25

Subject analysis set type

Full analysis

Subject analysis set description

Subjects who completed the challenge consisting of a single intravenous injection of buprenorphine hemiadipate HCl 5 mg /naloxone HCl dihydrate 1.25 mg.

Subject analysis set title

G: Diamorphine

Subject analysis set type

Full analysis

Subject analysis set description

Subjects who completed the challenge consisting of a single intravenous injection of diamorphine HCl 10 mg.

Subject analysis set title

H. Buprenorphine HCL

Subject analysis set type

Full analysis

Subject analysis set description

Subjects who completed the challenge consisting of a single intravenous injection of buprenorphine HCl 4.0 mg.

Primary: Change from Baseline in the Clinical Opiate Withdrawal Scale (COWS) Overall Score from 5 Minutes to 60 Minutes During the Challenge Period

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End point title

Change from Baseline in the Clinical Opiate Withdrawal Scale (COWS) Overall Score from 5 Minutes to 60 Minutes During the Challenge Period ^[1]

End point description

The COWS is an 11-item instrument used to assess symptoms of opioid withdrawal (Wesson et al., 1999). The score is the sum of the response to each of the 11 items and cover a range of 0-48. The COWS is commonly used by clinicians treating patients with buprenorphine to monitor the severity of withdrawal. COWS scores below 5 are considered not indicative of withdrawal. Scores from 5 to 12 are considered mild withdrawal; from 13 to 24 moderate withdrawal; 25 to 36 moderate/severe withdrawal, and 37-48 severe withdrawal. A repeated measures model was used to analyse the change from pre-challenge (-10 minutes) over the time frames of interest (assessment times from 5 through 60 minutes post-challenge). The repeated measures mixed model contained terms for the fixed effects for challenge (A to H), period (1 to 8), assessment (5, 15, 30, 45 and 60 minutes post challenge) and the challenge-by-assessment. P-values available in attached file.

End point type

Primary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

Notes
[1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
Justification: The statistical analysis can be found in the attached file.

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24	26	25	27	25	27	26	26
Units: units on a scale
least squares mean (confidence interval 95%)	0.1 (-0.6 to 0.8)	0.1 (-0.6 to 0.8)	3.7 (3.1 to 4.4)	0.9 (0.3 to 1.6)	1 (0.3 to 1.7)	0.2 (-0.5 to 0.9)	0.3 (-0.4 to 1)	0.1 (-0.5 to 0.8)

Attachments

COWS Change from Baseline through 60 minutes

No statistical analyses for this end point

Secondary: Change from Baseline in the Clinical Opiate Withdrawal Scale (COWS) Overall Score from 5 Minutes to 300 Minutes During the Challenge Period

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End point title

Change from Baseline in the Clinical Opiate Withdrawal Scale (COWS) Overall Score from 5 Minutes to 300 Minutes During the Challenge Period

End point description

The COWS is an 11-item instrument used to assess symptoms of opioid withdrawal (Wesson et al., 1999). The score is the sum of the response to each of the 11 items and cover a range of 0-48. The COWS is commonly used by clinicians treating patients with buprenorphine to monitor the severity of withdrawal. COWS scores below 5 are considered not indicative of withdrawal. Scores from 5 to 12 are considered mild withdrawal; from 13 to 24 moderate withdrawal; 25 to 36 moderate/severe withdrawal, and 37-48 severe withdrawal. A repeated measures model was used to analyse the change from pre-challenge (-10 minutes) = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45, 60, 120, 180, 240 and 300 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[2]	26 ^[3]	25 ^[4]	27 ^[5]	25 ^[6]	27 ^[7]	26 ^[8]	26 ^[9]
Units: units on a scale
least squares mean (confidence interval 95%)	0 (-0.6 to 0.5)	0.1 (-0.5 to 0.6)	2.7 (2.2 to 3.3)	0.4 (-0.1 to 1)	0.6 (0 to 1.1)	0 (-0.5 to 0.5)	0 (-0.5 to 0.6)	0 (-0.5 to 0.5)

Attachments

COWS Change from Baseline through 300 minutes

Notes
[2] - Efficacy population
[3] - Efficacy population
[4] - Efficacy population
[5] - Efficacy population
[6] - Efficacy population
[7] - Efficacy population
[8] - Efficacy population
[9] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Clinical Opiate Withdrawal Scale (COWS) Overall Score for Each Post-Baseline Assessment During the Challenge Period

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End point title

Change from Baseline in the Clinical Opiate Withdrawal Scale (COWS) Overall Score for Each Post-Baseline Assessment During the Challenge Period

End point description

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[10]	26 ^[11]	25 ^[12]	27 ^[13]	25 ^[14]	27 ^[15]	26 ^[16]	26 ^[17]
Units: units on a scale
arithmetic mean (standard deviation)
Actual values at baseline (-10 minutes)	0.8 ( 0.94 )	0.7 ( 1.19 )	0.7 ( 1.21 )	0.5 ( 0.64 )	0.5 ( 0.71 )	0.4 ( 0.58 )	0.7 ( 0.94 )	0.6 ( 0.58 )
Change from baseline: 5 minutes	0.1 ( 0.68 )	0.2 ( 0.83 )	0.3 ( 1.25 )	0.5 ( 1.6 )	1.1 ( 2.74 )	0.3 ( 0.95 )	0.2 ( 0.86 )	0.2 ( 0.94 )
Change from baseline: 15 minutes	-0.1 ( 0.93 )	0 ( 1.33 )	1.6 ( 2.43 )	1.3 ( 2.16 )	1.9 ( 2.96 )	0.8 ( 2.03 )	0.3 ( 1.29 )	0.1 ( 0.74 )
Change from baseline: 30 minutes	-0.1 ( 1.08 )	0.1 ( 1.99 )	4.6 ( 4.25 )	1.6 ( 2.45 )	1.1 ( 2.34 )	0.1 ( 1.49 )	0.2 ( 1.12 )	0.2 ( 1.41 )
Change from baseline: 45 minutes	-0.1 ( 1.18 )	0.1 ( 2.15 )	6.7 ( 5.71 )	1.3 ( 2.11 )	0.7 ( 2.39 )	0.1 ( 1.46 )	0.2 ( 1.16 )	0.2 ( 1.36 )
Change from baseline: 60 minutes	-0.2 ( 1.31 )	-0.1 ( 1.76 )	6.2 ( 6.12 )	0.7 ( 1.88 )	0.5 ( 2.8 )	0.2 ( 1.85 )	0 ( 1.34 )	0.2 ( 1.54 )
Change from baseline: 120 minutes	-0.2 ( 1.18 )	0 ( 2.07 )	4 ( 5 )	0 ( 1.19 )	0.1 ( 2.18 )	0.3 ( 1.81 )	-0.2 ( 0.95 )	-0.1 ( 1.32 )
Change from baseline: 180 minutes	-0.4 ( 0.78 )	-0.3 ( 1.76 )	0.8 ( 2.82 )	-0.1 ( 0.89 )	0.1 ( 1.94 )	-0.1 ( 0.86 )	-0.3 ( 0.72 )	-0.1 ( 1.6 )
Change from baseline: 240 minutes	-0.4 ( 0.72 )	-0.2 ( 1.63 )	0.6 ( 3.01 )	-0.1 ( 0.85 )	0 ( 1.81 )	-0.2 ( 0.68 )	-0.3 ( 0.61 )	-0.1 ( 1.31 )
Change from baseline: 300 minutes	-0.3 ( 0.7 )	-0.2 ( 2.05 )	-0.2 ( 1.57 )	-0.3 ( 0.71 )	-0.1 ( 1.63 )	-0.3 ( 0.54 )	-0.3 ( 0.68 )	-0.3 ( 0.75 )

Notes
[10] - Efficacy population
[11] - Efficacy population
[12] - Efficacy population
[13] - Efficacy population
[14] - Efficacy population
[15] - Efficacy population
[16] - Efficacy population n=25 for the diamorphine challenge at 240 mins and 300 mins.
[17] - Efficacy population

No statistical analyses for this end point

Secondary: Visual Analogue Scale Good Effect (VAS-G) Repeated Measures Analysis of Variance from 5 Minutes to 60 Minutes During the Challenge Period

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End point title

Visual Analogue Scale Good Effect (VAS-G) Repeated Measures Analysis of Variance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Visual Analogue Scale (VAS)-B, VAS-G, and VAS-high: 100 mm visual analogue scales assessing subject reported ‘bad’, ‘good’, and ‘high’ effects respectively. The scales are anchored with the terms none on the zero end and most ever on the 100 mm end. Repeated Measures Model: Post Challenge = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, and Challenge x Period, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

5, 15, 30, 45, and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[18]	26 ^[19]	25 ^[20]	27 ^[21]	25 ^[22]	27 ^[23]	26 ^[24]	26 ^[25]
Units: units on a scale
least squares mean (confidence interval 95%)	2.7 (-4.9 to 10.2)	6.9 (-0.3 to 14)	3.3 (-3.6 to 10.3)	4.9 (-1.9 to 11.7)	5.2 (-1.9 to 12.4)	4.8 (-2 to 11.6)	7.5 (0.4 to 14.6)	12.4 (5.5 to 19.2)

Attachments

VAS-G through 60 minutes

Notes
[18] - Efficacy population
[19] - Efficacy population
[20] - Efficacy population
[21] - Efficacy population
[22] - Efficacy population
[23] - Efficacy population
[24] - Efficacy population
[25] - Efficacy population

No statistical analyses for this end point

Secondary: Visual Analogue Scale Good Effect (VAS-G) Repeated Measures Analysis of Variance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Visual Analogue Scale Good Effect (VAS-G) Repeated Measures Analysis of Variance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Visual Analogue Scale (VAS)-B, VAS-G, and VAS-high: 100 mm visual analogue scales assessing subject reported ‘bad’, ‘good’, and ‘high’ effects respectively. The scales are anchored with the terms none on the zero end and most ever on the 100 mm end. Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

5, 15, 30, 45, 60, 120, 180, 240 and 300 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[26]	26 ^[27]	25 ^[28]	27 ^[29]	25 ^[30]	27 ^[31]	26 ^[32]	26 ^[33]
Units: units on a scale
least squares mean (confidence interval 95%)	2.5 (-3.2 to 8.1)	4.3 (-1.1 to 9.7)	2.2 (-3 to 7.4)	3.2 (-1.9 to 8.2)	4.1 (-1.3 to 9.4)	4 (-1 to 9.1)	5.7 (0.4 to 11)	8.5 (3.3 to 13.6)

Attachments

VAS-G through 300 minutes

Notes
[26] - Efficacy population
[27] - Efficacy population
[28] - Efficacy population
[29] - Efficacy population
[30] - Efficacy population
[31] - Efficacy population
[32] - Efficacy population
[33] - Efficacy population

No statistical analyses for this end point

Secondary: Visual Analogue Scale Bad Effect (VAS-B) Repeated Measures Analysis of Variance from 5 Minutes to 60 Minutes During the Challenge Period

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End point title

Visual Analogue Scale Bad Effect (VAS-B) Repeated Measures Analysis of Variance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

End point type

Secondary

End point timeframe

5, 15, 30, 45, and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[34]	26 ^[35]	25 ^[36]	27 ^[37]	25 ^[38]	27 ^[39]	26 ^[40]	26 ^[41]
Units: units on a scale
least squares mean (confidence interval 95%)	-0.1 (-3.6 to 3.5)	0.3 (-3.1 to 3.6)	19.7 (16.4 to 22.9)	2.6 (-0.5 to 5.8)	2.1 (-1.2 to 5.4)	0.5 (-2.7 to 3.6)	0.9 (-2.4 to 4.2)	1.1 (-2.1 to 4.3)

Attachments

VAS-B through 60 minutes

Notes
[34] - Efficacy population
[35] - Efficacy population
[36] - Efficacy population
[37] - Efficacy population
[38] - Efficacy population
[39] - Efficacy population
[40] - Efficacy population
[41] - Efficacy population

No statistical analyses for this end point

Secondary: Visual Analogue Scale Bad Effect (VAS-B) Repeated Measures Analysis of Variance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Visual Analogue Scale Bad Effect (VAS-B) Repeated Measures Analysis of Variance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Visual Analogue Scale (VAS)-B, VAS-G, and VAS-high: 100 mm visual analogue scales assessing subject reported ‘bad’, ‘good’, and ‘high’ effects respectively. The scales are anchored with the terms none on the zero end and most ever on the 100 mm end. Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

5, 15, 30, 45, 60, 120, 180, 240 and 300 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[42]	26 ^[43]	25 ^[44]	27 ^[45]	25 ^[46]	27 ^[47]	26 ^[48]	26 ^[49]
Units: units on a scale
least squares mean (confidence interval 95%)	0 (-2.7 to 2.7)	0.2 (-2.4 to 2.7)	16 (13.5 to 18.5)	1.4 (-1 to 3.8)	1.3 (-1.2 to 3.8)	0.3 (-2.1 to 2.7)	0.3 (-2.2 to 2.9)	1.4 (-1 to 3.8)

Attachments

VAS-B through 300 minutes

Notes
[42] - Efficacy population
[43] - Efficacy population
[44] - Efficacy population
[45] - Efficacy population
[46] - Efficacy population
[47] - Efficacy population
[48] - Efficacy population
[49] - Efficacy population

No statistical analyses for this end point

Secondary: Visual Analogue Scale High Effect (VAS-H) Repeated Measures Analysis of Variance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Visual Analogue Scale High Effect (VAS-H) Repeated Measures Analysis of Variance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

End point type

Secondary

End point timeframe

5, 15, 30, 45, and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[50]	26 ^[51]	25 ^[52]	27 ^[53]	25 ^[54]	27 ^[55]	26 ^[56]	26 ^[57]
Units: units on a scale
least squares mean (confidence interval 95%)	1.5 (-4.7 to 7.8)	7.3 (1.3 to 13.3)	4.7 (-1.2 to 10.6)	4.5 (-1.3 to 10.2)	4.9 (-1.1 to 10.9)	3.3 (-2.5 to 9)	4.4 (-1.5 to 10.4)	10.8 (5 to 16.6)

Attachments

VAS-H through 60 minutes

Notes
[50] - Efficacy population
[51] - Efficacy population
[52] - Efficacy population
[53] - Efficacy population
[54] - Efficacy population
[55] - Efficacy population
[56] - Efficacy population
[57] - Efficacy population

No statistical analyses for this end point

Secondary: Visual Analogue Scale High Effect (VAS-H) Repeated Measures Analysis of Variance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Visual Analogue Scale High Effect (VAS-H) Repeated Measures Analysis of Variance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Visual Analogue Scale (VAS)-B, VAS-G, and VAS-high: 100 mm visual analogue scales assessing subject reported ‘bad’, ‘good’, and ‘high’ effects respectively. The scales are anchored with the terms none on the zero end and most ever on the 100 mm end. Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

5, 15, 30, 45, 60, 120, 180, 240 and 300 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[58]	26 ^[59]	25 ^[60]	27 ^[61]	25 ^[62]	27 ^[63]	26 ^[64]	26 ^[65]
Units: units on a scale
least squares mean (confidence interval 95%)	0.9 (-3.6 to 5.4)	4.5 (0.1 to 8.8)	3 (-1.2 to 7.2)	2.5 (-1.7 to 6.6)	3.3 (-1 to 7.6)	2.2 (-1.9 to 6.3)	3.3 (-1 to 7.6)	7.3 (3.1 to 11.5)

Attachments

VAS-H through 300 minutes

Notes
[58] - Efficacy population
[59] - Efficacy population
[60] - Efficacy population
[61] - Efficacy population
[62] - Efficacy population
[63] - Efficacy population
[64] - Efficacy population
[65] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Flushing Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Flushing Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Flushing Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[66]	26 ^[67]	25 ^[68]	27 ^[69]	25 ^[70]	27 ^[71]	26 ^[72]	26 ^[73]
Units: units on a scale
least squares mean (confidence interval 95%)	0.1 (-0.1 to 0.3)	0.1 (-0.1 to 0.3)	0.7 (0.5 to 0.9)	0.4 (0.2 to 0.6)	0.3 (0.1 to 0.5)	0.2 (0 to 0.3)	0.2 (0 to 0.4)	0.2 (0.1 to 0.4)

Attachments

AEC Flushing 60 min

Notes
[66] - Efficacy population
[67] - Efficacy population
[68] - Efficacy population
[69] - Efficacy population
[70] - Efficacy population
[71] - Efficacy population
[72] - Efficacy population
[73] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Flushing Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Flushing Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[74]	26 ^[75]	25 ^[76]	27 ^[77]	25 ^[78]	27 ^[79]	26 ^[80]	26 ^[81]
Units: units on a scale
least squares mean (confidence interval 95%)	0.1 (-0.1 to 0.2)	0.1 (0 to 0.2)	0.5 (0.4 to 0.6)	0.2 (0.1 to 0.3)	0.2 (0.1 to 0.3)	0.1 (0 to 0.2)	0.1 (0 to 0.2)	0.2 (0.1 to 0.3)

Attachments

AEC Flushing 300 min

Notes
[74] - Efficacy population
[75] - Efficacy population
[76] - Efficacy population
[77] - Efficacy population
[78] - Efficacy population
[79] - Efficacy population
[80] - Efficacy population
[81] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Itchy Skin Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Itchy Skin Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Itchy skin Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[82]	26 ^[83]	25 ^[84]	27 ^[85]	25 ^[86]	27 ^[87]	26 ^[88]	26 ^[89]
Units: units on a scale
least squares mean (confidence interval 95%)	0.1 (-0.1 to 0.3)	0.1 (-0.1 to 0.2)	0.1 (-0.1 to 0.2)	0.1 (-0.1 to 0.2)	0.1 (-0.1 to 0.2)	0 (-0.2 to 0.1)	0.4 (0.3 to 0.6)	0.2 (0 to 0.3)

Attachments

AEC Itchy Skin 60 min

Notes
[82] - Efficacy population
[83] - Efficacy population
[84] - Efficacy population
[85] - Efficacy population
[86] - Efficacy population
[87] - Efficacy population
[88] - Efficacy population
[89] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Itchy Skin Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Itchy Skin Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Itchy skin Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[90]	26 ^[91]	25 ^[92]	27 ^[93]	25 ^[94]	27 ^[95]	26 ^[96]	26 ^[97]
Units: units on a scale
least squares mean (confidence interval 95%)	0.1 (0 to 0.2)	0.1 (0 to 0.2)	0 (-0.1 to 0.1)	0 (-0.1 to 0.2)	0.1 (-0.1 to 0.2)	0 (-0.1 to 0.1)	0.3 (0.2 to 0.4)	0.2 (0.1 to 0.3)

Attachments

AEC Itchy Skin 300 min

Notes
[90] - Efficacy population
[91] - Efficacy population
[92] - Efficacy population
[93] - Efficacy population
[94] - Efficacy population
[95] - Efficacy population
[96] - Efficacy population
[97] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Nausea Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Nausea Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Nausea Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[98]	26 ^[99]	25 ^[100]	27 ^[101]	25 ^[102]	27 ^[103]	26 ^[104]	26 ^[105]
Units: units on a scale
least squares mean (confidence interval 95%)	0.1 (0 to 0.2)	0.1 (-0.1 to 0.2)	0.4 (0.3 to 0.5)	0.1 (0 to 0.2)	0.1 (0 to 0.2)	0 (-0.1 to 0.1)	0 (-0.1 to 0.1)	0 (-0.1 to 0.2)

Attachments

AEC Nausea 60 min

Notes
[98] - Efficacy population
[99] - Efficacy population
[100] - Efficacy population
[101] - Efficacy population
[102] - Efficacy population
[103] - Efficacy population
[104] - Efficacy population
[105] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Nausea Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Nausea Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Nausea Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[106]	26 ^[107]	25 ^[108]	27 ^[109]	25 ^[110]	27 ^[111]	26 ^[112]	26 ^[113]
Units: units on a scale
least squares mean (confidence interval 95%)	0 (0 to 0.1)	0 (0 to 0.1)	0.3 (0.2 to 0.4)	0.1 (0 to 0.1)	0.1 (0 to 0.1)	0 (0 to 0.1)	0 (0 to 0.1)	0.1 (0 to 0.1)

Attachments

AEC Nausea 300 min

Notes
[106] - Efficacy population
[107] - Efficacy population
[108] - Efficacy population
[109] - Efficacy population
[110] - Efficacy population
[111] - Efficacy population
[112] - Efficacy population
[113] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Nodding Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Nodding Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Nodding Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[114]	26 ^[115]	25 ^[116]	27 ^[117]	25 ^[118]	27 ^[119]	26 ^[120]	26 ^[121]
Units: units on a scale
least squares mean (confidence interval 95%)	0 (-0.1 to 0.1)	0.1 (-0.1 to 0.2)	0.1 (-0.1 to 0.2)	0.2 (0.1 to 0.3)	0.1 (0 to 0.3)	0.1 (0 to 0.3)	0.1 (0 to 0.3)	0.1 (0 to 0.3)

Attachments

AEC Nodding 60 min

Notes
[114] - Efficacy population
[115] - Efficacy population
[116] - Efficacy population
[117] - Efficacy population
[118] - Efficacy population
[119] - Efficacy population
[120] - Efficacy population
[121] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Nodding Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Nodding Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Nodding Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[122]	26 ^[123]	25 ^[124]	27 ^[125]	25 ^[126]	27 ^[127]	26 ^[128]	26 ^[129]
Units: units on a scale
least squares mean (confidence interval 95%)	0 (-0.1 to 0.1)	0.1 (0 to 0.1)	0.1 (0 to 0.2)	0.1 (0 to 0.2)	0.1 (0 to 0.2)	0.1 (0 to 0.2)	0.1 (0 to 0.2)	0.1 (0 to 0.2)

Attachments

AEC Nodding 300 min

Notes
[122] - Efficacy population
[123] - Efficacy population
[124] - Efficacy population
[125] - Efficacy population
[126] - Efficacy population
[127] - Efficacy population
[128] - Efficacy population
[129] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Relaxed Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Relaxed Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Relaxed Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[130]	26 ^[131]	25 ^[132]	27 ^[133]	25 ^[134]	27 ^[135]	26 ^[136]	26 ^[137]
Units: units on a scale
least squares mean (confidence interval 95%)	0.1 (-0.2 to 0.4)	0.3 (0 to 0.6)	-0.3 (-0.6 to 0)	0 (-0.3 to 0.3)	0 (-0.3 to 0.3)	0.1 (-0.2 to 0.4)	0.2 (-0.1 to 0.5)	0.4 (0.2 to 0.7)

Attachments

AEC Relaxed 60 min

Notes
[130] - Efficacy population
[131] - Efficacy population
[132] - Efficacy population
[133] - Efficacy population
[134] - Efficacy population
[135] - Efficacy population
[136] - Efficacy population
[137] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Relaxed Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Relaxed Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Relaxed Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[138]	26 ^[139]	25 ^[140]	27 ^[141]	25 ^[142]	27 ^[143]	26 ^[144]	26 ^[145]
Units: units on a scale
least squares mean (confidence interval 95%)	0.1 (-0.2 to 0.3)	0.2 (-0.1 to 0.5)	-0.4 (-0.6 to -0.1)	0 (-0.3 to 0.2)	0 (-0.3 to 0.2)	0 (-0.2 to 0.3)	0.1 (-0.2 to 0.3)	0.4 (0.1 to 0.6)

Attachments

AEC Relaxed 300 min

Notes
[138] - Efficacy population
[139] - Efficacy population
[140] - Efficacy population
[141] - Efficacy population
[142] - Efficacy population
[143] - Efficacy population
[144] - Efficacy population
[145] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Pleasant Sick Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Pleasant Sick Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Pleasant Sick Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[146]	26 ^[147]	25 ^[148]	27 ^[149]	25 ^[150]	27 ^[151]	26 ^[152]	26 ^[153]
Units: units on a scale
least squares mean (confidence interval 95%)	0 (-0.1 to 0.1)	0 (0 to 0.1)	0.1 (0.1 to 0.2)	0.1 (0 to 0.1)	0 (0 to 0.1)	0 (-0.1 to 0.1)	0 (0 to 0.1)	0 (0 to 0.1)

Attachments

AEC Pleasand Sick 60 min

Notes
[146] - Efficacy population
[147] - Efficacy population
[148] - Efficacy population
[149] - Efficacy population
[150] - Efficacy population
[151] - Efficacy population
[152] - Efficacy population
[153] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Pleasant Sick Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Pleasant Sick Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Pleasant Sick Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[154]	26 ^[155]	25 ^[156]	27 ^[157]	25 ^[158]	27 ^[159]	26 ^[160]	26 ^[161]
Units: units on a scale
least squares mean (confidence interval 95%)	0 (-0.1 to 0)	0 (0 to 0.1)	0.1 (0.1 to 0.2)	0 (0 to 0.1)	0 (0 to 0.1)	0 (0 to 0.1)	0 (0 to 0.1)	0 (0 to 0.1)

Attachments

AEC Pleasant Sick 300 min

Notes
[154] - Efficacy population
[155] - Efficacy population
[156] - Efficacy population
[157] - Efficacy population
[158] - Efficacy population
[159] - Efficacy population
[160] - Efficacy population
[161] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Coasting or Spaced Out Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Coasting or Spaced Out Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Coasting or Spaced Out Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[162]	26 ^[163]	25 ^[164]	27 ^[165]	25 ^[166]	27 ^[167]	26 ^[168]	26 ^[169]
Units: units on a scale
least squares mean (confidence interval 95%)	0.1 (-0.1 to 0.4)	0.4 (0.1 to 0.6)	0.3 (0.1 to 0.5)	0.2 (-0.1 to 0.4)	0.2 (0 to 0.5)	0.2 (0 to 0.4)	0.3 (0 to 0.5)	0.5 (0.3 to 0.7)

Attachments

AEC Coasting/Spaced Out 60 min

Notes
[162] - Efficacy population
[163] - Efficacy population
[164] - Efficacy population
[165] - Efficacy population
[166] - Efficacy population
[167] - Efficacy population
[168] - Efficacy population
[169] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Coasting or Spaced Out Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Coasting or Spaced Out Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Coasting or Spaced Out Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[170]	26 ^[171]	25 ^[172]	27 ^[173]	25 ^[174]	27 ^[175]	26 ^[176]	26 ^[177]
Units: units on a scale
least squares mean (confidence interval 95%)	0.1 (-0.1 to 0.2)	0.2 (0.1 to 0.3)	0.2 (0 to 0.3)	0.1 (-0.1 to 0.2)	0.1 (0 to 0.3)	0.1 (0 to 0.3)	0.2 (0 to 0.3)	0.3 (0.2 to 0.5)

Attachments

AEC Coasting/Spaced Out 300 min

Notes
[170] - Efficacy population
[171] - Efficacy population
[172] - Efficacy population
[173] - Efficacy population
[174] - Efficacy population
[175] - Efficacy population
[176] - Efficacy population
[177] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Talkative Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Talkative Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Talkative Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[178]	26 ^[179]	25 ^[180]	27 ^[181]	25 ^[182]	27 ^[183]	26 ^[184]	26 ^[185]
Units: units on a scale
least squares mean (confidence interval 95%)	0 (-0.2 to 0.2)	0.2 (0 to 0.4)	-0.3 (-0.5 to -0.1)	-0.1 (-0.3 to 0.1)	0.1 (-0.1 to 0.3)	-0.1 (-0.3 to 0.1)	0.1 (-0.1 to 0.3)	0.1 (0 to 0.3)

Attachments

AEC Talkative 60 min

Notes
[178] - Efficacy population
[179] - Efficacy population
[180] - Efficacy population
[181] - Efficacy population
[182] - Efficacy population
[183] - Efficacy population
[184] - Efficacy population
[185] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Talkative Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Talkative Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Talkative Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[186]	26 ^[187]	25 ^[188]	27 ^[189]	25 ^[190]	27 ^[191]	26 ^[192]	26 ^[193]
Units: units on a scale
least squares mean (confidence interval 95%)	0 (-0.2 to 0.2)	0.2 (0 to 0.4)	-0.3 (-0.5 to -0.1)	-0.1 (-0.3 to 0.1)	0.1 (-0.1 to 0.3)	0 (-0.2 to 0.2)	0 (-0.2 to 0.2)	0.1 (-0.1 to 0.3)

Attachments

AEC Talkative 300 min

Notes
[186] - Efficacy population
[187] - Efficacy population
[188] - Efficacy population
[189] - Efficacy population
[190] - Efficacy population
[191] - Efficacy population
[192] - Efficacy population
[193] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Heavy or Sluggish Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Heavy or Sluggish Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Heavy or Sluggish Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[194]	26 ^[195]	25 ^[196]	27 ^[197]	25 ^[198]	27 ^[199]	26 ^[200]	26 ^[201]
Units: units on a scale
least squares mean (confidence interval 95%)	0.2 (-0.1 to 0.4)	0.2 (-0.1 to 0.4)	0.7 (0.5 to 1)	0.5 (0.2 to 0.7)	0.2 (0 to 0.5)	0.2 (0 to 0.5)	0.2 (-0.1 to 0.5)	0.3 (0 to 0.5)

Attachments

AEC Heavy/Sluggsh 60 min

Notes
[194] - Efficacy population
[195] - Efficacy population
[196] - Efficacy population
[197] - Efficacy population
[198] - Efficacy population
[199] - Efficacy population
[200] - Efficacy population
[201] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Heavy or Sluggish Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Heavy or Sluggish Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Heavy or Sluggish Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[202]	26 ^[203]	25 ^[204]	27 ^[205]	25 ^[206]	27 ^[207]	26 ^[208]	26 ^[209]
Units: units on a scale
least squares mean (confidence interval 95%)	0.1 (-0.1 to 0.4)	0.1 (-0.1 to 0.3)	0.6 (0.3 to 0.8)	0.3 (0.1 to 0.5)	0.1 (-0.1 to 0.4)	0.1 (-0.1 to 0.3)	0.2 (-0.1 to 0.4)	0.2 (0 to 0.4)

Attachments

AEC Heavy/Sluggsh 300 min

Notes
[202] - Efficacy population
[203] - Efficacy population
[204] - Efficacy population
[205] - Efficacy population
[206] - Efficacy population
[207] - Efficacy population
[208] - Efficacy population
[209] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Dry Mouth Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Dry Mouth Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Dry Mouth Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[210]	26 ^[211]	25 ^[212]	27 ^[213]	25 ^[214]	27 ^[215]	26 ^[216]	26 ^[217]
Units: units on a scale
least squares mean (confidence interval 95%)	0.2 (0 to 0.3)	0.1 (-0.1 to 0.2)	0.1 (0 to 0.3)	0 (-0.1 to 0.2)	0.1 (0 to 0.3)	0.1 (-0.1 to 0.2)	0.1 (0 to 0.2)	0.4 (0.2 to 0.5)

Attachments

AEC Dry Mouth 60 min

Notes
[210] - Efficacy population
[211] - Efficacy population
[212] - Efficacy population
[213] - Efficacy population
[214] - Efficacy population
[215] - Efficacy population
[216] - Efficacy population
[217] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Dry Mouth Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Dry Mouth Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Dry Mouth Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[218]	26 ^[219]	25 ^[220]	27 ^[221]	25 ^[222]	27 ^[223]	26 ^[224]	26 ^[225]
Units: units on a scale
least squares mean (confidence interval 95%)	0.1 (0 to 0.2)	0 (-0.1 to 0.2)	0.1 (0 to 0.2)	0 (-0.1 to 0.1)	0.1 (0 to 0.2)	0 (-0.1 to 0.1)	0 (-0.1 to 0.2)	0.3 (0.2 to 0.4)

Attachments

AEC Dry Mouth 300 min

Notes
[218] - Efficacy population
[219] - Efficacy population
[220] - Efficacy population
[221] - Efficacy population
[222] - Efficacy population
[223] - Efficacy population
[224] - Efficacy population
[225] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Drive Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Drive Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Drive Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[226]	26 ^[227]	25 ^[228]	27 ^[229]	25 ^[230]	27 ^[231]	26 ^[232]	26 ^[233]
Units: units on a scale
least squares mean (confidence interval 95%)	-0.1 (-0.3 to 0.1)	-0.1 (-0.3 to 0.1)	-0.6 (-0.8 to -0.4)	-0.2 (-0.4 to 0)	-0.2 (-0.4 to 0)	-0.1 (-0.3 to 0.1)	-0.2 (-0.4 to 0)	0.1 (-0.1 to 0.2)

Attachments

AEC Drive 60 min

Notes
[226] - Efficacy population
[227] - Efficacy population
[228] - Efficacy population
[229] - Efficacy population
[230] - Efficacy population
[231] - Efficacy population
[232] - Efficacy population
[233] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Drive Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Drive Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Drive Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[234]	26 ^[235]	25 ^[236]	27 ^[237]	25 ^[238]	27 ^[239]	26 ^[240]	26 ^[241]
Units: units on a scale
least squares mean (confidence interval 95%)	-0.1 (-0.3 to 0.2)	-0.1 (-0.4 to 0.1)	-0.5 (-0.7 to -0.3)	-0.2 (-0.4 to 0)	-0.2 (-0.4 to 0)	-0.2 (-0.4 to 0.1)	-0.2 (-0.4 to 0)	0 (-0.2 to 0.2)

Attachments

AEC Drive 300 min

Notes
[234] - Efficacy population
[235] - Efficacy population
[236] - Efficacy population
[237] - Efficacy population
[238] - Efficacy population
[239] - Efficacy population
[240] - Efficacy population
[241] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Sleepy Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Sleepy Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Sleepy Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[242]	26 ^[243]	25 ^[244]	27 ^[245]	25 ^[246]	27 ^[247]	26 ^[248]	26 ^[249]
Units: units on a scale
least squares mean (confidence interval 95%)	0.1 (-0.2 to 0.3)	0 (-0.3 to 0.2)	0.8 (0.5 to 1)	0.4 (0.1 to 0.6)	0.1 (-0.1 to 0.4)	0.2 (0 to 0.4)	0.2 (0 to 0.4)	0.2 (-0.1 to 0.4)

Attachments

AEC Sleepy 60 min

Notes
[242] - Efficacy population
[243] - Efficacy population
[244] - Efficacy population
[245] - Efficacy population
[246] - Efficacy population
[247] - Efficacy population
[248] - Efficacy population
[249] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Sleepy Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Sleepy Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Sleepy Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[250]	26 ^[251]	25 ^[252]	27 ^[253]	25 ^[254]	27 ^[255]	26 ^[256]	26 ^[257]
Units: units on a scale
least squares mean (confidence interval 95%)	0.1 (-0.1 to 0.3)	0 (-0.2 to 0.2)	0.7 (0.5 to 0.9)	0.2 (0 to 0.4)	0 (-0.2 to 0.3)	0.1 (0 to 0.3)	0.2 (0 to 0.4)	0.2 (0 to 0.4)

Attachments

AEC Sleepy 300 min

Notes
[250] - Efficacy population
[251] - Efficacy population
[252] - Efficacy population
[253] - Efficacy population
[254] - Efficacy population
[255] - Efficacy population
[256] - Efficacy population
[257] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Carefree Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Carefree Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Carefree Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[258]	26 ^[259]	25 ^[260]	27 ^[261]	25 ^[262]	27 ^[263]	26 ^[264]	26 ^[265]
Units: units on a scale
least squares mean (confidence interval 95%)	-0.1 (-0.4 to 0.3)	0.2 (-0.1 to 0.5)	-0.3 (-0.6 to 0)	-0.1 (-0.4 to 0.3)	-0.1 (-0.4 to 0.3)	0.1 (-0.2 to 0.4)	0.1 (-0.2 to 0.4)	0.4 (0.1 to 0.7)

Attachments

AEC Carefree 60 min

Notes
[258] - Efficacy population
[259] - Efficacy population
[260] - Efficacy population
[261] - Efficacy population
[262] - Efficacy population
[263] - Efficacy population
[264] - Efficacy population
[265] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Carefree Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Carefree Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Carefree Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[266]	26 ^[267]	25 ^[268]	27 ^[269]	25 ^[270]	27 ^[271]	26 ^[272]	26 ^[273]
Units: units on a scale
least squares mean (confidence interval 95%)	-0.1 (-0.4 to 0.2)	0.1 (-0.2 to 0.4)	-0.3 (-0.6 to 0)	0 (-0.3 to 0.3)	0 (-0.3 to 0.3)	0 (-0.3 to 0.3)	0.1 (-0.2 to 0.4)	0.3 (0 to 0.6)

Attachments

AEC Carefree 300 min

Notes
[266] - Efficacy population
[267] - Efficacy population
[268] - Efficacy population
[269] - Efficacy population
[270] - Efficacy population
[271] - Efficacy population
[272] - Efficacy population
[273] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Drunken Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Drunken Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Drunken Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[274]	26 ^[275]	25 ^[276]	27 ^[277]	25 ^[278]	27 ^[279]	26 ^[280]	26 ^[281]
Units: units on a scale
least squares mean (confidence interval 95%)	-0.1 (-0.2 to 0.1)	0.1 (-0.1 to 0.2)	0 (-0.1 to 0.2)	0 (-0.1 to 0.2)	0.1 (0 to 0.3)	0.1 (0 to 0.2)	0 (-0.1 to 0.2)	0.2 (0 to 0.3)

Attachments

AEC Drunken 60 min

Notes
[274] - Efficacy population
[275] - Efficacy population
[276] - Efficacy population
[277] - Efficacy population
[278] - Efficacy population
[279] - Efficacy population
[280] - Efficacy population
[281] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Drunken Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Drunken Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Drunken Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[282]	26 ^[283]	25 ^[284]	27 ^[285]	25 ^[286]	27 ^[287]	26 ^[288]	26 ^[289]
Units: units on a scale
least squares mean (confidence interval 95%)	-0.1 (-0.2 to 0.1)	0.1 (0 to 0.2)	0 (-0.1 to 0.1)	0 (-0.1 to 0.1)	0.1 (0 to 0.2)	0 (-0.1 to 0.1)	0 (-0.1 to 0.1)	0.1 (0 to 0.2)

Attachments

AEC Drunken 300 min

Notes
[282] - Efficacy population
[283] - Efficacy population
[284] - Efficacy population
[285] - Efficacy population
[286] - Efficacy population
[287] - Efficacy population
[288] - Efficacy population
[289] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Good Mood Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Good Mood Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Good Mood Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[290]	26 ^[291]	25 ^[292]	27 ^[293]	25 ^[294]	27 ^[295]	26 ^[296]	26 ^[297]
Units: units on a scale
least squares mean (confidence interval 95%)	-0.1 (-0.4 to 0.2)	0.2 (-0.1 to 0.5)	-0.5 (-0.8 to -0.3)	-0.2 (-0.4 to 0.1)	-0.1 (-0.4 to 0.1)	-0.1 (-0.3 to 0.2)	0.1 (-0.2 to 0.4)	0.3 (0.1 to 0.6)

Attachments

AEC Good Mood 60 min

Notes
[290] - Efficacy population
[291] - Efficacy population
[292] - Efficacy population
[293] - Efficacy population
[294] - Efficacy population
[295] - Efficacy population
[296] - Efficacy population
[297] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Good Mood Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Good Mood Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Good Mood Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[298]	26 ^[299]	25 ^[300]	27 ^[301]	25 ^[302]	27 ^[303]	26 ^[304]	26 ^[305]
Units: units on a scale
least squares mean (confidence interval 95%)	-0.1 (-0.4 to 0.1)	0.1 (-0.1 to 0.4)	-0.6 (-0.8 to -0.3)	-0.2 (-0.4 to 0.1)	-0.1 (-0.4 to 0.2)	-0.1 (-0.4 to 0.2)	0 (-0.3 to 0.3)	0.2 (0 to 0.5)

Attachments

AEC Good Mood 300 min

Notes
[298] - Efficacy population
[299] - Efficacy population
[300] - Efficacy population
[301] - Efficacy population
[302] - Efficacy population
[303] - Efficacy population
[304] - Efficacy population
[305] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Tingling Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Tingling Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Tingling Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[306]	26 ^[307]	25 ^[308]	27 ^[309]	25 ^[310]	27 ^[311]	26 ^[312]	26 ^[313]
Units: units on a scale
least squares mean (confidence interval 95%)	0 (-0.1 to 0.2)	0.1 (0 to 0.3)	0.2 (0 to 0.3)	0 (-0.1 to 0.2)	0 (-0.1 to 0.2)	0.2 (0 to 0.3)	0.2 (0 to 0.3)	0.2 (0 to 0.3)

Attachments

AEC Tingling 60 min

Notes
[306] - Efficacy population
[307] - Efficacy population
[308] - Efficacy population
[309] - Efficacy population
[310] - Efficacy population
[311] - Efficacy population
[312] - Efficacy population
[313] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Tingling Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Tingling Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Tingling Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[314]	26 ^[315]	25 ^[316]	27 ^[317]	25 ^[318]	27 ^[319]	26 ^[320]	26 ^[321]
Units: units on a scale
least squares mean (confidence interval 95%)	0 (-0.1 to 0.1)	0.1 (0 to 0.2)	0.1 (0 to 0.2)	0 (-0.1 to 0.1)	0 (0 to 0.1)	0.1 (0 to 0.2)	0.1 (0 to 0.2)	0.1 (0.1 to 0.2)

Attachments

AEC Tingling 300 min

Notes
[314] - Efficacy population
[315] - Efficacy population
[316] - Efficacy population
[317] - Efficacy population
[318] - Efficacy population
[319] - Efficacy population
[320] - Efficacy population
[321] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Energetic Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Energetic Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Energetic Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

-10 minutes (pre-dose), 5, 15, 30, 45 and 60 minutes post dose on dosing days during the challenge period (Study days 9, 11, 13, 15, 17, 19, 21 , 23, dependent upon randomization order)

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[322]	26 ^[323]	25 ^[324]	27 ^[325]	25 ^[326]	27 ^[327]	26 ^[328]	26 ^[329]
Units: units on a scale
least squares mean (confidence interval 95%)	0 (-0.2 to 0.2)	0 (-0.2 to 0.2)	-0.4 (-0.6 to -0.2)	-0.2 (-0.4 to 0)	-0.1 (-0.3 to 0.1)	0.1 (-0.1 to 0.2)	-0.2 (-0.4 to 0)	0.1 (-0.1 to 0.3)

Attachments

AEC Energetic 60 min

Notes
[322] - Efficacy population
[323] - Efficacy population
[324] - Efficacy population
[325] - Efficacy population
[326] - Efficacy population
[327] - Efficacy population
[328] - Efficacy population
[329] - Efficacy population

No statistical analyses for this end point

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Energetic Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Top of page

End point title

Change from Baseline in the Agonist Effects Checklist (AEC) Energetic Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

End point description

Agonist Effects Checklist (AEC): a 17 item, subject completed checklist consisting of terms and phrases typical of opioid agonist effects. Subjects rated each of the following items on a 5-point scale from 0 (no effect) to 4 (maximum effect): flushing, itchy skin, nausea, nodding, relaxed, pleasant sick, coasting or spaced out, talkative, heavy or sluggish, dry mouth, drive, sleepy, carefree, drunken, good mood, tingling and energetic. This item: Energetic Repeated Measures Model: Change from Baseline = Challenge, Period, Assessment Time, Challenge x Assessment Time, Period x Assessment Time, Challenge x Period and Within Period Baseline Value, using the Toeplitz covariance structure for repeating Assessment Time for Challenge within subject, and subject as a random effect. P-values available in attached file.

End point type

Secondary

End point timeframe

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[330]	26 ^[331]	25 ^[332]	27 ^[333]	25 ^[334]	27 ^[335]	26 ^[336]	26 ^[337]
Units: units on a scale
least squares mean (confidence interval 95%)	0 (-0.2 to 0.2)	0 (-0.2 to 0.2)	-0.4 (-0.6 to -0.2)	-0.1 (-0.3 to 0.1)	0 (-0.3 to 0.2)	0 (-0.2 to 0.3)	-0.2 (-0.4 to 0.1)	0.1 (-0.2 to 0.3)

Attachments

AEC Energetic 300 min

Notes
[330] - Efficacy population
[331] - Efficacy population
[332] - Efficacy population
[333] - Efficacy population
[334] - Efficacy population
[335] - Efficacy population
[336] - Efficacy population
[337] - Efficacy population

No statistical analyses for this end point

Secondary: Patients with Treatment-Emergent Adverse Events (TEAEs)

Top of page

End point title

Patients with Treatment-Emergent Adverse Events (TEAEs)

End point description

An AE was defined as any untoward medical occurrence in a patient or clinical investigation subject administered a pharmaceutical product and which did not necessarily have to have a causal relationship with this treatment. TEAE: Treatment-Emergent Adverse Event is a new adverse event or an event that worsens in intensity after the first dose of Suboxone is administered. An adverse event is associated with a challenge if the onset of the AE occurs after the start of the administration of the challenge but prior to the start of the administration of the next challenge. Relation to study treatment was assessed by the investigator. Serious AE Criteria: 1 = Results in death 2 = Is life-threatening 3 = Requires in-patient hospitalisation or prolongation of existing hospitalisation 4 = Results in persistent or significant disability/incapacity 5 = Is a congenital anomaly/birth defect

End point type

Secondary

End point timeframe

Days 1-24

End point values	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Number of subjects analysed	24 ^[338]	23 ^[339]	22 ^[340]	23 ^[341]	23 ^[342]	22 ^[343]	23 ^[344]	22 ^[345]
Units: patients
Any TEAE	2	5	5	1	5	4	5	3
Related TEAE	1	3	2	1	0	1	1	0
Serious TEAE	0	0	0	0	0	0	0	0
Serious Related TEAE	0	0	0	0	0	0	0	0
TEAE leading to d/c of treatment	0	0	0	0	0	0	0	0
TEAE leading to death	0	0	0	0	0	0	0	0

Notes
[338] - Safety population
[339] - Safety population
[340] - Safety population
[341] - Safety population
[342] - Safety population
[343] - Safety population
[344] - Safety population
[345] - Safety population

No statistical analyses for this end point

Adverse events

Top of page

Timeframe for reporting adverse events

Day 1 - 24

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

15.0

Reporting group title

Pre-Challenge Period (Day 1 - 7)

Reporting group description

A 7-day outpatient period during which subjects received Suboxone. The dose for Day 1 was 8mg, Day 2 was 12mg, and Days 3 to 7 was 16mg.

Reporting group title

A. Placebo

Reporting group description

Subjects who completed the placebo challenge consisting of a single intravenous injection of placebo. The time frame for the Challenge Period was between days 8-24 during which patients continued taking 16mg of Suboxone daily.

Reporting group title

B: Buprenorphine hemiadipate HCl

Reporting group description

Subjects who completed the challenge consisting of a single intravenous injection of buprenorphine hemiadipate HCl 5 mg. The time frame for the Challenge Period was between days 8-24 during which patients continued taking 16mg of Suboxone daily.

Reporting group title

C: Naloxone HCl dihydrate

Reporting group description

Subjects who completed the challenge consisting of a single intravenous injection of naloxone HCl dihydrate 5 mg. The time frame for the Challenge Period was between days 8-24 during which patients continued taking 16mg of Suboxone daily.

Reporting group title

D: BHA/NAL 1:1

Reporting group description

Subjects who completed the challenge consisting of a single intravenous injection of buprenorphine hemiadipate HCl 5 mg /naloxone HCl dihydrate 5 mg. The time frame for the Challenge Period was between days 8-24 during which patients continued taking 16mg of Suboxone daily.

Reporting group title

E. BHA/NAL 1:0.5

Reporting group description

Subjects who completed the challenge consisting of a single intravenous injection of buprenorphine hemiadipate HCl 5 mg /naloxone HCl dihydrate 2.5 mg. The time frame for the Challenge Period was between days 8-24 during which patients continued taking 16mg of Suboxone daily.

Reporting group title

F. BHA/NAL 1:0.25

Reporting group description

Subjects who completed the challenge consisting of a single intravenous injection of buprenorphine hemiadipate HCl 5 mg /naloxone HCl dihydrate 1.25 mg. The time frame for the Challenge Period was between days 8-24 during which patients continued taking 16mg of Suboxone daily.

Reporting group title

G: Diamorphine

Reporting group description

Subjects who completed the challenge consisting of a single intravenous injection of diamorphine HCl 10 mg. The time frame for the Challenge Period was between days 8-24 during which patients continued taking 16mg of Suboxone daily.

Reporting group title

H. Buprenorphine HCL

Reporting group description

Subjects who completed the challenge consisting of a single intravenous injection of buprenorphine HCl 4.0 mg. The time frame for the Challenge Period was between days 8-24 during which patients continued taking 16mg of Suboxone daily.

Serious adverse events	Pre-Challenge Period (Day 1 - 7)	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Total subjects affected by serious adverse events
subjects affected / exposed	0 / 36 (0.00%)	0 / 24 (0.00%)	0 / 26 (0.00%)	0 / 25 (0.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 27 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)
number of deaths (all causes)	0	0	0	0	0	0	0	0	0
number of deaths resulting from adverse events

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Pre-Challenge Period (Day 1 - 7)	A. Placebo	B: Buprenorphine hemiadipate HCl	C: Naloxone HCl dihydrate	D: BHA/NAL 1:1	E. BHA/NAL 1:0.5	F. BHA/NAL 1:0.25	G: Diamorphine	H. Buprenorphine HCL
Total subjects affected by non serious adverse events
subjects affected / exposed	5 / 36 (13.89%)	0 / 24 (0.00%)	4 / 26 (15.38%)	3 / 25 (12.00%)	1 / 27 (3.70%)	1 / 25 (4.00%)	1 / 27 (3.70%)	1 / 26 (3.85%)	0 / 26 (0.00%)
Nervous system disorders
Headache
subjects affected / exposed	1 / 36 (2.78%)	0 / 24 (0.00%)	3 / 26 (11.54%)	1 / 25 (4.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	1 / 27 (3.70%)	1 / 26 (3.85%)	0 / 26 (0.00%)
occurrences all number	1	0	3	1	0	0	1	1	0
Gastrointestinal disorders
Constipation
subjects affected / exposed	4 / 36 (11.11%)	0 / 24 (0.00%)	1 / 26 (3.85%)	0 / 25 (0.00%)	1 / 27 (3.70%)	1 / 25 (4.00%)	0 / 27 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	4	0	1	0	1	1	0	0	0
Skin and subcutaneous tissue disorders
Dry skin
subjects affected / exposed	0 / 36 (0.00%)	0 / 24 (0.00%)	0 / 26 (0.00%)	2 / 25 (8.00%)	0 / 27 (0.00%)	0 / 25 (0.00%)	0 / 27 (0.00%)	0 / 26 (0.00%)	0 / 26 (0.00%)
occurrences all number	0	0	0	2	0	0	0	0	0

More information

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Were there any global substantial amendments to the protocol? Yes

14 Feb 2012

• Exclusion criteria 7, 9, 12 and 13 were revised. • Definition and reporting of AEs and SAEs were revised. • Pregnancy related section was added to the study procedures. • Prohibited medications were described.

19 Jul 2012

• A clarification was provided regarding the administration of the first challenge dose. It was clarified that the first challenge could be administered on a Monday if it was not possible to administer it on the weekend. It was also clarified that the investigator was allowed to use discretion to dispense sublingual Suboxone for 2 days to cover the weekend dose. • It was clarified that clinical laboratory safety tests would be performed 21-24 hours prior to the first challenge dose and at 24 h after the final challenge. The schedule of these tests was revised to Day -14 to Day -1, Day 1, Day 8 (“first challenge day -1”), the day after the final challenge (“final challenge day +1”) and at Follow-up. • The dose of test product on Day 3 was revised to 16 mg and it was clarified that the duration of the dose would be extended until the day after the last challenge administration. • It was clarified that subjects would receive Suboxone from Day 1 until the day after the last challenge administration (inclusive). • Figure 1 was corrected with the clarification of Screening visit to be Day-14 to Day-1 and that Day 8 was considered Challenge Day -1. The timing of the challenges was changed to be between 9 and 11 AM. • Duration of participation for each subject was changed to 43 days; the out patient period was changed to 7 days; the duration of the residential period was changed to a minimum of 17 days which was allowed to be extended up to 28 days if the subject was kept in house during the out patient period. • Inclusion criterion No. 9 was modified to include subjects who continued to abuse opioids at least 3 times per week. • The method of administration of challenges was modified to include either direct puncture or a BD Adsyte Pro 18/20 gauge catheter or similar device over approximately 10 seconds via an IV push. • Other changes were also made.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change from Baseline in the Clinical Opiate Withdrawal Scale (COWS) Overall Score from 5 Minutes to 60 Minutes During the Challenge Period

Primary: Change from Baseline in the Clinical Opiate Withdrawal Scale (COWS) Overall Score from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Clinical Opiate Withdrawal Scale (COWS) Overall Score from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Clinical Opiate Withdrawal Scale (COWS) Overall Score from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Clinical Opiate Withdrawal Scale (COWS) Overall Score for Each Post-Baseline Assessment During the Challenge Period

Secondary: Change from Baseline in the Clinical Opiate Withdrawal Scale (COWS) Overall Score for Each Post-Baseline Assessment During the Challenge Period

Secondary: Visual Analogue Scale Good Effect (VAS-G) Repeated Measures Analysis of Variance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Visual Analogue Scale Good Effect (VAS-G) Repeated Measures Analysis of Variance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Visual Analogue Scale Good Effect (VAS-G) Repeated Measures Analysis of Variance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Visual Analogue Scale Good Effect (VAS-G) Repeated Measures Analysis of Variance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Visual Analogue Scale Bad Effect (VAS-B) Repeated Measures Analysis of Variance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Visual Analogue Scale Bad Effect (VAS-B) Repeated Measures Analysis of Variance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Visual Analogue Scale Bad Effect (VAS-B) Repeated Measures Analysis of Variance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Visual Analogue Scale Bad Effect (VAS-B) Repeated Measures Analysis of Variance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Visual Analogue Scale High Effect (VAS-H) Repeated Measures Analysis of Variance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Visual Analogue Scale High Effect (VAS-H) Repeated Measures Analysis of Variance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Visual Analogue Scale High Effect (VAS-H) Repeated Measures Analysis of Variance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Visual Analogue Scale High Effect (VAS-H) Repeated Measures Analysis of Variance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Flushing Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Flushing Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Flushing Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Flushing Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Itchy Skin Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Itchy Skin Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Itchy Skin Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Itchy Skin Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Nausea Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Nausea Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Nausea Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Nausea Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Nodding Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Nodding Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Nodding Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Nodding Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Relaxed Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Relaxed Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Relaxed Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Relaxed Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Pleasant Sick Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Pleasant Sick Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Pleasant Sick Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Pleasant Sick Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Coasting or Spaced Out Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Coasting or Spaced Out Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Coasting or Spaced Out Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Coasting or Spaced Out Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Talkative Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Talkative Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Talkative Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Talkative Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Heavy or Sluggish Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Heavy or Sluggish Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Heavy or Sluggish Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Heavy or Sluggish Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Dry Mouth Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Dry Mouth Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Dry Mouth Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Dry Mouth Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Drive Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Drive Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Drive Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Drive Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Sleepy Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Sleepy Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Sleepy Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Sleepy Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Carefree Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Carefree Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Carefree Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Carefree Repeated Measures Analysis of Covariance from 5 Minutes to 300 Minutes During the Challenge Period

Secondary: Change from Baseline in the Agonist Effects Checklist (AEC) Drunken Repeated Measures Analysis of Covariance from 5 Minutes to 60 Minutes During the Challenge Period