Conditions: Respiratory Depression
Keywords: Chronic Pain Ventilatory Response to Hypercapnia (VRH)
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 19
Healthy volunteers: yes

Brief summary:
The purpose of this study is to explore and compare VRH after administration of Belbuca, Oxycodone HCl and Placebo in recreational opioid users. This is a single-center, double -blind, double-dummy , placebo-controlled randomized crossover study in up to 18 men and women self identifying as recreational users. This study will consist of a screening phase, treatment phase (which includes the Naloxone Challenge test) and follow-up visit.

Detailed description:

Arms:
arm 1: Subjects treated with Belbuca 300 µg and oral placebo will be randomized to 1 of 6 treatment sequences in a 1:1:1:1:1:1 ratio. arm 2: Subjects treated with Belbuca 600 µg and oral placebo will be randomized to 1 of 6 treatment sequences in a 1:1:1:1:1:1 ratio. arm 3: Subjects treated with Belbuca 900 µg and oral placebo will be randomized to 1 of 6 treatment sequences in a 1:1:1:1:1:1 ratio. arm 4: Subjects treated with Oxycodone 30 mg and buccal placebo will be randomized to 1 of 6 treatment sequences in a 1:1:1:1:1:1 ratio. arm 5: Subjects treated with Oxycodone 60 mg and buccal placebo will be randomized to 1 of 6 treatment sequences in a 1:1:1:1:1:1 ratio. arm 6: Subjects treated with oral placebo and buccal placebo will be randomized to 1 of 6 treatment sequences in a 1:1:1:1:1:1 ratio.

Interventions: intervention 1: Belbuca 300 µg intervention 2: Belbuca 600 µg intervention 3: Belbuca 900 µg intervention 4: Oxycodone 30 mg intervention 5: Oxycodone 60 mg intervention 6: Placebo
Intervention descriptions: intervention 1: Belbuca 300 µg buccal film intervention 2: Belbuca 600 µg buccal film intervention 3: Belbuca 900 µg buccal film intervention 4: Oxycodone 30 mg capsule intervention 5: Oxycodone 60 mg capsule intervention 6: placebo buccal film and oral placebo

Protocol document:
Prot_000.pdf: 
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PRAHEALTHSCIENCES 
CLINICAL STUDY PROTOCOL 
BUP-401 /BDL673SL-186739 
VERSION 2.0- 6-Aug-2019 
AUTHORIZATION OF CLINICAL STUDY PROTOCOL BY CONTRACT 
RESEARCH ORGANIZATION 
The Sponsor and the Contract Research Organization agree to conduct the study as outlined in this 
CSP. Any modification of the CSP must be agreed upon by the Sponsor and the Contract Research 
Organization and must be documented in writing. 
Name/Position: 
Contract Research Organization: PRA Health Sciences - EDS 
 
 
Signature: 
Strictly Confidential. © 2018, PRA Health Sciences. All rights reserved. 
Page 3 of 57 


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Page 28 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 1 of 112
Model Information
Data Set
WORK.ADXV
Dependent Variable
AVAL
Covariance Structure
Variance Components
Estimation Method
REML
Residual Variance Method
Profile
Fixed Effects SE Method
Model-Based
Degrees of Freedom Method Containment
Class Level Information
Class
LevelsValues
SUBJID
151001 1002 1003 1004 1005 1006 1007 1008 1010 1012 1013 1014 1015 1016 1017
TRTPN
61 2 3 4 5 6
APERIOD
6P1 P2 P3 P4 P5 P6
ARMCD
6ABCEDF BEAFCD CADBFE DCFAEB EFBDAC FDECBA
Dimensions
Covariance Parameters
2
Columns in X
19
Columns in Z
15
Subjects
1
Max Obs per Subject
90
Page 29 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 2 of 112
Number of Observations
Number of Observations Read
90
Number of Observations Used
90
Number of Observations Not Used
0
Iteration History
Iteration Evaluations -2 Res Log Like
Criterion
0
1
425.16851375
1
1
403.50606077 0.00000000
Convergence criteria met.
Covariance Parameter 
Estimates
Cov Parm
Estimate
SUBJID(ARMCD)
5.9883
Residual
6.3569
Fit Statistics
-2 Res Log Likelihood
403.5
AIC (Smaller is Better)
407.5
AICC (Smaller is Better) 407.7
BIC (Smaller is Better)
408.9
Page 30 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 3 of 112
Type 3 Tests of Fixed Effects
Effect
Num 
DF
Den 
DF F Value Pr > F
TRTPN
5 65
2.92 0.0193
APERIOD
5 65
0.49 0.7801
ARMCD
5
9
0.77 0.5916
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
1
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 31 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 4 of 112
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
1
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 32 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 5 of 112
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 33 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 6 of 112
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 34 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 7 of 112
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 35 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 8 of 112
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 36 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 9 of 112
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 37 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 10 of 112
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 38 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 11 of 112
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 39 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 12 of 112
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 40 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 13 of 112
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 41 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 14 of 112
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Estimates
Label
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
Oxy 30 vs Placebo
1.2467
0.924865
1.35
0.1823 0.05 -0.6002
3.0936
Oxy 60 vs Placebo
2.1371
0.924865
2.31
0.0240 0.05 0.2901
3.9840
Bel 300 vs Oxy 30
-2.3279
0.924865
-2.52
0.0143 0.05 -4.1748 -0.4810
Bel 300 vs Oxy 60
-3.2183
0.924865
-3.48
0.0009 0.05 -5.0652 -1.3714
Bel 600 vs Oxy 30
-0.09483
0.922765
-0.10
0.9185 0.05 -1.9376
1.7479
Bel 600 vs Oxy 60
-0.9852
0.924865
-1.07
0.2907 0.05 -2.8321
0.8617
Bel 900 vs Oxy 30
-0.3557
0.924865
-0.38
0.7018 0.05 -2.2026
1.4912
Bel 900 vs Oxy 60
-1.2461
0.922765
-1.35
0.1816 0.05 -3.0888
0.5967
Bel 300 vs Placebo
-1.0812
0.922765
-1.17
0.2455 0.05 -2.9240
0.7615
Bel 600 vs Placebo
1.1519
0.924865
1.25
0.2174 0.05 -0.6950
2.9988
Bel 900 vs Placebo
0.8910
0.924865
0.96
0.3389 0.05 -0.9559
2.7379
Page 42 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 15 of 112
Least Squares Means
Effect
Planned 
Treatment 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
40.6766
0.9195 65
44.24
<.0001 0.05 38.8402 42.5129
TRTPN 2
42.9097
0.9195 65
46.67
<.0001 0.05 41.0733 44.7460
TRTPN 3
42.6488
0.9195 65
46.38
<.0001 0.05 40.8124 44.4851
TRTPN 4
43.0045
0.9195 65
46.77
<.0001 0.05 41.1682 44.8408
TRTPN 5
43.8948
0.9195 65
47.74
<.0001 0.05 42.0585 45.7312
TRTPN 6
41.7578
0.9195 65
45.41
<.0001 0.05 39.9215 43.5941
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
2
-2.2331
0.924865
-2.41
0.0186 0.05 -4.0800 -0.3862
TRTPN 1
3
-1.9722
0.924865
-2.13
0.0367 0.05 -3.8191 -0.1253
TRTPN 1
4
-2.3279
0.924865
-2.52
0.0143 0.05 -4.1748 -0.4810
TRTPN 1
5
-3.2183
0.924865
-3.48
0.0009 0.05 -5.0652 -1.3714
TRTPN 1
6
-1.0812
0.922765
-1.17
0.2455 0.05 -2.9240
0.7615
TRTPN 2
3
0.2609
0.924865
0.28
0.7788 0.05 -1.5860
2.1078
TRTPN 2
4
-0.09483
0.922765
-0.10
0.9185 0.05 -1.9376
1.7479
TRTPN 2
5
-0.9852
0.924865
-1.07
0.2907 0.05 -2.8321
0.8617
TRTPN 2
6
1.1519
0.924865
1.25
0.2174 0.05 -0.6950
2.9988
TRTPN 3
4
-0.3557
0.924865
-0.38
0.7018 0.05 -2.2026
1.4912
TRTPN 3
5
-1.2461
0.922765
-1.35
0.1816 0.05 -3.0888
0.5967
TRTPN 3
6
0.8910
0.924865
0.96
0.3389 0.05 -0.9559
2.7379
TRTPN 4
5
-0.8903
0.924865
-0.96
0.3392 0.05 -2.7372
0.9566
Page 43 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 16 of 112
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 4
6
1.2467
0.924865
1.35
0.1823 0.05 -0.6002
3.0936
TRTPN 5
6
2.1371
0.924865
2.31
0.0240 0.05
0.2901
3.9840
Page 44 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 17 of 112
Model Information
Data Set
WORK.ADXV
Dependent Variable
AVAL
Covariance Structure
Variance Components
Estimation Method
REML
Residual Variance Method
Profile
Fixed Effects SE Method
Model-Based
Degrees of Freedom Method Containment
Class Level Information
Class
LevelsValues
SUBJID
151001 1002 1003 1004 1005 1006 1007 1008 1010 1012 1013 1014 1015 1016 1017
TRTPN
61 2 3 4 5 6
APERIOD
6P1 P2 P3 P4 P5 P6
ARMCD
6ABCEDF BEAFCD CADBFE DCFAEB EFBDAC FDECBA
Dimensions
Covariance Parameters
2
Columns in X
19
Columns in Z
15
Subjects
1
Max Obs per Subject
90
Page 45 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 18 of 112
Number of Observations
Number of Observations Read
90
Number of Observations Used
90
Number of Observations Not Used
0
Iteration History
Iteration Evaluations -2 Res Log Like
Criterion
0
1
1541.87045175
1
1
1532.27894557 0.00000000
Convergence criteria met.
Covariance Parameter 
Estimates
Cov Parm
Estimate
SUBJID(ARMCD) 13297907
Residual
28686215
Fit Statistics
-2 Res Log Likelihood
1532.3
AIC (Smaller is Better)
1536.3
AICC (Smaller is Better) 1536.4
BIC (Smaller is Better)
1537.7
Page 46 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 19 of 112
Type 3 Tests of Fixed Effects
Effect
Num 
DF
Den 
DF F Value Pr > F
TRTPN
5 65
2.93 0.0190
APERIOD
5 65
2.16 0.0699
ARMCD
5
9
0.68 0.6506
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
1
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 47 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 20 of 112
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
1
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 48 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 21 of 112
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 49 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 22 of 112
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 50 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 23 of 112
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 51 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 24 of 112
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 52 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 25 of 112
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 53 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 26 of 112
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 54 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 27 of 112
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 55 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 28 of 112
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 56 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 29 of 112
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 57 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 30 of 112
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Estimates
Label
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
Oxy 30 vs Placebo
-794.77
1964.4965
-0.40
0.6871 0.05 -4718.12
3128.58
Oxy 60 vs Placebo
-5228.92
1964.4965
-2.66
0.0098 0.05 -9152.27 -1305.57
Bel 300 vs Oxy 30
2034.61
1964.4965
1.04
0.3042 0.05 -1888.74
5957.96
Bel 300 vs Oxy 60
6468.76
1964.4965
3.29
0.0016 0.05
2545.41
10392
Bel 600 vs Oxy 30
1022.24
1960.0865
0.52
0.6038 0.05 -2892.31
4936.78
Bel 600 vs Oxy 60
5456.39
1964.4965
2.78
0.0072 0.05
1533.04
9379.74
Bel 900 vs Oxy 30
1726.13
1964.4965
0.88
0.3828 0.05 -2197.22
5649.48
Bel 900 vs Oxy 60
6160.28
1960.0865
3.14
0.0025 0.05
2245.73
10075
Bel 300 vs Placebo
1239.84
1960.0865
0.63
0.5292 0.05 -2674.70
5154.39
Bel 600 vs Placebo
227.47
1964.4965
0.12
0.9082 0.05 -3695.88
4150.82
Bel 900 vs Placebo
931.36
1964.4965
0.47
0.6370 0.05 -2991.99
4854.71
Page 58 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 31 of 112
Least Squares Means
Effect
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha Lower Upper
TRTPN 1
23741
1691.7665
14.03
<.0001 0.05 20362 27120
TRTPN 2
22729
1691.7665
13.43
<.0001 0.05 19350 26107
TRTPN 3
23433
1691.7665
13.85
<.0001 0.05 20054 26811
TRTPN 4
21706
1691.7665
12.83
<.0001 0.05 18328 25085
TRTPN 5
17272
1691.7665
10.21
<.0001 0.05 13894 20651
TRTPN 6
22501
1691.7665
13.30
<.0001 0.05 19123 25880
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
2
1012.37
1964.4965
0.52
0.6081 0.05 -2910.98
4935.72
TRTPN 1
3
308.48
1964.4965
0.16
0.8757 0.05 -3614.87
4231.83
TRTPN 1
4
2034.61
1964.4965
1.04
0.3042 0.05 -1888.74
5957.96
TRTPN 1
5
6468.76
1964.4965
3.29
0.0016 0.05
2545.41
10392
TRTPN 1
6
1239.84
1960.0865
0.63
0.5292 0.05 -2674.70
5154.39
TRTPN 2
3
-703.89
1964.4965
-0.36
0.7213 0.05 -4627.24
3219.46
TRTPN 2
4
1022.24
1960.0865
0.52
0.6038 0.05 -2892.31
4936.78
TRTPN 2
5
5456.39
1964.4965
2.78
0.0072 0.05
1533.04
9379.74
TRTPN 2
6
227.47
1964.4965
0.12
0.9082 0.05 -3695.88
4150.82
TRTPN 3
4
1726.13
1964.4965
0.88
0.3828 0.05 -2197.22
5649.48
TRTPN 3
5
6160.28
1960.0865
3.14
0.0025 0.05
2245.73
10075
TRTPN 3
6
931.36
1964.4965
0.47
0.6370 0.05 -2991.99
4854.71
TRTPN 4
5
4434.15
1964.4965
2.26
0.0274 0.05
510.80
8357.50
Page 59 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 32 of 112
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 4
6
-794.77
1964.4965
-0.40
0.6871 0.05 -4718.12
3128.58
TRTPN 5
6
-5228.92
1964.4965
-2.66
0.0098 0.05 -9152.27 -1305.57
Page 60 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 33 of 112
Model Information
Data Set
WORK.ADXV
Dependent Variable
AVAL
Covariance Structure
Variance Components
Estimation Method
REML
Residual Variance Method
Profile
Fixed Effects SE Method
Model-Based
Degrees of Freedom Method Containment
Class Level Information
Class
LevelsValues
SUBJID
151001 1002 1003 1004 1005 1006 1007 1008 1010 1012 1013 1014 1015 1016 1017
TRTPN
61 2 3 4 5 6
APERIOD
6P1 P2 P3 P4 P5 P6
ARMCD
6ABCEDF BEAFCD CADBFE DCFAEB EFBDAC FDECBA
Dimensions
Covariance Parameters
2
Columns in X
19
Columns in Z
15
Subjects
1
Max Obs per Subject
90
Page 61 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 34 of 112
Number of Observations
Number of Observations Read
90
Number of Observations Used
90
Number of Observations Not Used
0
Iteration History
Iteration Evaluations -2 Res Log Like
Criterion
0
1
668.81167810
1
1
659.34634479 0.00000000
Convergence criteria met.
Covariance Parameter 
Estimates
Cov Parm
Estimate
SUBJID(ARMCD)
99.2034
Residual
216.26
Fit Statistics
-2 Res Log Likelihood
659.3
AIC (Smaller is Better)
663.3
AICC (Smaller is Better) 663.5
BIC (Smaller is Better)
664.8
Page 62 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 35 of 112
Type 3 Tests of Fixed Effects
Effect
Num 
DF
Den 
DF F Value Pr > F
TRTPN
5 65
2.64 0.0313
APERIOD
5 65
2.53 0.0374
ARMCD
5
9
0.58 0.7181
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
1
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 63 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 36 of 112
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
1
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 64 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 37 of 112
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 65 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 38 of 112
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 66 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 39 of 112
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 67 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 40 of 112
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 68 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 41 of 112
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 69 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 42 of 112
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 70 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 43 of 112
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 71 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 44 of 112
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 72 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 45 of 112
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 73 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 46 of 112
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Estimates
Label
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
Oxy 30 vs Placebo
0.01627
5.393965
0.00
0.9976 0.05 -10.7560 10.7886
Oxy 60 vs Placebo
-13.6055
5.393965
-2.52
0.0141 0.05 -24.3778 -2.8332
Bel 300 vs Oxy 30
2.8228
5.393965
0.52
0.6025 0.05
-7.9495 13.5951
Bel 300 vs Oxy 60
16.4446
5.393965
3.05
0.0033 0.05
5.6723 27.2169
Bel 600 vs Oxy 30
1.6470
5.381865
0.31
0.7606 0.05
-9.1012 12.3951
Bel 600 vs Oxy 60
15.2687
5.393965
2.83
0.0062 0.05
4.4964 26.0410
Bel 900 vs Oxy 30
1.9547
5.393965
0.36
0.7182 0.05
-8.8176 12.7270
Bel 900 vs Oxy 60
15.5765
5.381865
2.89
0.0052 0.05
4.8283 26.3246
Bel 300 vs Placebo
2.8391
5.381865
0.53
0.5996 0.05
-7.9090 13.5872
Bel 600 vs Placebo
1.6632
5.393965
0.31
0.7588 0.05
-9.1091 12.4355
Bel 900 vs Placebo
1.9710
5.393965
0.37
0.7160 0.05
-8.8013 12.7433
Page 74 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 47 of 112
Least Squares Means
Effect
Planned 
Treatment 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
62.0303
4.6372 65
13.38
<.0001 0.05 52.7692 71.2915
TRTPN 2
60.8544
4.6372 65
13.12
<.0001 0.05 51.5933 70.1156
TRTPN 3
61.1622
4.6372 65
13.19
<.0001 0.05 51.9011 70.4233
TRTPN 4
59.2075
4.6372 65
12.77
<.0001 0.05 49.9464 68.4686
TRTPN 5
45.5857
4.6372 65
9.83
<.0001 0.05 36.3246 54.8469
TRTPN 6
59.1912
4.6372 65
12.76
<.0001 0.05 49.9301 68.4524
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
2
1.1759
5.393965
0.22
0.8281 0.05
-9.5964 11.9482
TRTPN 1
3
0.8681
5.393965
0.16
0.8726 0.05
-9.9042 11.6404
TRTPN 1
4
2.8228
5.393965
0.52
0.6025 0.05
-7.9495 13.5951
TRTPN 1
5
16.4446
5.393965
3.05
0.0033 0.05
5.6723 27.2169
TRTPN 1
6
2.8391
5.381865
0.53
0.5996 0.05
-7.9090 13.5872
TRTPN 2
3
-0.3078
5.393965
-0.06
0.9547 0.05 -11.0800 10.4645
TRTPN 2
4
1.6470
5.381865
0.31
0.7606 0.05
-9.1012 12.3951
TRTPN 2
5
15.2687
5.393965
2.83
0.0062 0.05
4.4964 26.0410
TRTPN 2
6
1.6632
5.393965
0.31
0.7588 0.05
-9.1091 12.4355
TRTPN 3
4
1.9547
5.393965
0.36
0.7182 0.05
-8.8176 12.7270
TRTPN 3
5
15.5765
5.381865
2.89
0.0052 0.05
4.8283 26.3246
TRTPN 3
6
1.9710
5.393965
0.37
0.7160 0.05
-8.8013 12.7433
TRTPN 4
5
13.6217
5.393965
2.53
0.0140 0.05
2.8495 24.3940
Page 75 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 48 of 112
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 4
6
0.01627
5.393965
0.00
0.9976 0.05 -10.7560 10.7886
TRTPN 5
6
-13.6055
5.393965
-2.52
0.0141 0.05 -24.3778 -2.8332
Page 76 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 49 of 112
Model Information
Data Set
WORK.ADXV
Dependent Variable
AVAL
Covariance Structure
Variance Components
Estimation Method
REML
Residual Variance Method
Profile
Fixed Effects SE Method
Model-Based
Degrees of Freedom Method Containment
Class Level Information
Class
LevelsValues
SUBJID
151001 1002 1003 1004 1005 1006 1007 1008 1010 1012 1013 1014 1015 1016 1017
TRTPN
61 2 3 4 5 6
APERIOD
6P1 P2 P3 P4 P5 P6
ARMCD
6ABCEDF BEAFCD CADBFE DCFAEB EFBDAC FDECBA
Dimensions
Covariance Parameters
2
Columns in X
19
Columns in Z
15
Subjects
1
Max Obs per Subject
90
Page 77 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 50 of 112
Number of Observations
Number of Observations Read
90
Number of Observations Used
90
Number of Observations Not Used
0
Iteration History
Iteration Evaluations -2 Res Log Like
Criterion
0
1
983.84438280
1
1
974.53438815 0.00000000
Convergence criteria met.
Covariance Parameter 
Estimates
Cov Parm
Estimate
SUBJID(ARMCD)
6936.53
Residual
15320
Fit Statistics
-2 Res Log Likelihood
974.5
AIC (Smaller is Better)
978.5
AICC (Smaller is Better) 978.7
BIC (Smaller is Better)
980.0
Page 78 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 51 of 112
Type 3 Tests of Fixed Effects
Effect
Num 
DF
Den 
DF F Value Pr > F
TRTPN
5 65
3.72 0.0051
APERIOD
5 65
2.32 0.0528
ARMCD
5
9
0.89 0.5270
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
1
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 79 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 52 of 112
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
1
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 80 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 53 of 112
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 81 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 54 of 112
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 82 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 55 of 112
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 83 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 56 of 112
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 84 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 57 of 112
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 85 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 58 of 112
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 86 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 59 of 112
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 87 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 60 of 112
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 88 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 61 of 112
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 89 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 62 of 112
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Estimates
Label
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
Oxy 30 vs Placebo
-20.2097
45.399165
-0.45
0.6577 0.05
-110.88
70.4586
Oxy 60 vs Placebo
-129.70
45.399165
-2.86
0.0057 0.05
-220.37 -39.0311
Bel 300 vs Oxy 30
64.5958
45.399165
1.42
0.1596 0.05 -26.0726
155.26
Bel 300 vs Oxy 60
174.09
45.399165
3.83
0.0003 0.05
83.4171
264.75
Bel 600 vs Oxy 30
20.6471
45.297265
0.46
0.6500 0.05 -69.8177
111.11
Bel 600 vs Oxy 60
130.14
45.399165
2.87
0.0056 0.05
39.4684
220.81
Bel 900 vs Oxy 30
49.7034
45.399165
1.09
0.2776 0.05 -40.9650
140.37
Bel 900 vs Oxy 60
159.19
45.297265
3.51
0.0008 0.05
68.7282
249.66
Bel 300 vs Placebo
44.3861
45.297265
0.98
0.3308 0.05 -46.0788
134.85
Bel 600 vs Placebo
0.4374
45.399165
0.01
0.9923 0.05 -90.2310
91.1057
Bel 900 vs Placebo
29.4936
45.399165
0.65
0.5182 0.05 -61.1747
120.16
Page 90 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 63 of 112
Least Squares Means
Effect
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower Upper
TRTPN 1
586.67
38.949265
15.06
<.0001 0.05 508.88 664.46
TRTPN 2
542.72
38.949265
13.93
<.0001 0.05 464.93 620.51
TRTPN 3
571.78
38.949265
14.68
<.0001 0.05 493.99 649.56
TRTPN 4
522.07
38.949265
13.40
<.0001 0.05 444.29 599.86
TRTPN 5
412.58
38.949265
10.59
<.0001 0.05 334.80 490.37
TRTPN 6
542.28
38.949265
13.92
<.0001 0.05 464.50 620.07
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
2
43.9487
45.399165
0.97
0.3366 0.05 -46.7197
134.62
TRTPN 1
3
14.8924
45.399165
0.33
0.7439 0.05 -75.7759
105.56
TRTPN 1
4
64.5958
45.399165
1.42
0.1596 0.05 -26.0726
155.26
TRTPN 1
5
174.09
45.399165
3.83
0.0003 0.05
83.4171
264.75
TRTPN 1
6
44.3861
45.297265
0.98
0.3308 0.05 -46.0788
134.85
TRTPN 2
3
-29.0563
45.399165
-0.64
0.5244 0.05
-119.72
61.6121
TRTPN 2
4
20.6471
45.297265
0.46
0.6500 0.05 -69.8177
111.11
TRTPN 2
5
130.14
45.399165
2.87
0.0056 0.05
39.4684
220.81
TRTPN 2
6
0.4374
45.399165
0.01
0.9923 0.05 -90.2310
91.1057
TRTPN 3
4
49.7034
45.399165
1.09
0.2776 0.05 -40.9650
140.37
TRTPN 3
5
159.19
45.297265
3.51
0.0008 0.05
68.7282
249.66
TRTPN 3
6
29.4936
45.399165
0.65
0.5182 0.05 -61.1747
120.16
TRTPN 4
5
109.49
45.399165
2.41
0.0187 0.05
18.8213
200.16
Page 91 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 64 of 112
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 4
6
-20.2097
45.399165
-0.45
0.6577 0.05
-110.88
70.4586
TRTPN 5
6
-129.70
45.399165
-2.86
0.0057 0.05
-220.37 -39.0311
Page 92 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 65 of 112
Model Information
Data Set
WORK.ADXV
Dependent Variable
AVAL
Covariance Structure
Variance Components
Estimation Method
REML
Residual Variance Method
Profile
Fixed Effects SE Method
Model-Based
Degrees of Freedom Method Containment
Class Level Information
Class
LevelsValues
SUBJID
151001 1002 1003 1004 1005 1006 1007 1008 1010 1012 1013 1014 1015 1016 1017
TRTPN
61 2 3 4 5 6
APERIOD
6P1 P2 P3 P4 P5 P6
ARMCD
6ABCEDF BEAFCD CADBFE DCFAEB EFBDAC FDECBA
Dimensions
Covariance Parameters
2
Columns in X
19
Columns in Z
15
Subjects
1
Max Obs per Subject
90
Page 93 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 66 of 112
Number of Observations
Number of Observations Read
90
Number of Observations Used
90
Number of Observations Not Used
0
Iteration History
Iteration Evaluations -2 Res Log Like
Criterion
0
1
447.68859180
1
1
419.42531502 0.00000000
Convergence criteria met.
Covariance Parameter 
Estimates
Cov Parm
Estimate
SUBJID(ARMCD)
9.4252
Residual
7.6646
Fit Statistics
-2 Res Log Likelihood
419.4
AIC (Smaller is Better)
423.4
AICC (Smaller is Better) 423.6
BIC (Smaller is Better)
424.8
Page 94 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 67 of 112
Type 3 Tests of Fixed Effects
Effect
Num 
DF
Den 
DF F Value Pr > F
TRTPN
5 65
0.80 0.5523
APERIOD
5 65
1.02 0.4119
ARMCD
5
9
0.61 0.6987
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
1
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 95 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 68 of 112
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
1
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 96 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 69 of 112
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 97 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 70 of 112
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 98 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 71 of 112
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 99 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 72 of 112
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 100 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 73 of 112
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 101 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 74 of 112
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 102 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 75 of 112
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 103 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 76 of 112
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 104 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 77 of 112
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 105 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 78 of 112
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Estimates
Label
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower Upper
Oxy 30 vs Placebo
-1.5420
1.015465
-1.52
0.1337 0.05 -3.5700 0.4860
Oxy 60 vs Placebo
-1.8452
1.015465
-1.82
0.0738 0.05 -3.8732 0.1827
Bel 300 vs Oxy 30
0.4076
1.015465
0.40
0.6894 0.05 -1.6204 2.4356
Bel 300 vs Oxy 60
0.7109
1.015465
0.70
0.4864 0.05 -1.3171 2.7388
Bel 600 vs Oxy 30
0.4711
1.013265
0.46
0.6435 0.05 -1.5524 2.4945
Bel 600 vs Oxy 60
0.7743
1.015465
0.76
0.4485 0.05 -1.2537 2.8023
Bel 900 vs Oxy 30
0.06312
1.015465
0.06
0.9506 0.05 -1.9649 2.0911
Bel 900 vs Oxy 60
0.3664
1.013265
0.36
0.7188 0.05 -1.6571 2.3898
Bel 300 vs Placebo
-1.1344
1.013265
-1.12
0.2670 0.05 -3.1578 0.8890
Bel 600 vs Placebo
-1.0710
1.015465
-1.05
0.2955 0.05 -3.0989 0.9570
Bel 900 vs Placebo
-1.4789
1.015465
-1.46
0.1501 0.05 -3.5069 0.5491
Page 106 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 79 of 112
Least Squares Means
Effect
Planned 
Treatment 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
15.5293
1.0828 65
14.34
<.0001 0.05 13.3667 17.6918
TRTPN 2
15.5927
1.0828 65
14.40
<.0001 0.05 13.4302 17.7552
TRTPN 3
15.1848
1.0828 65
14.02
<.0001 0.05 13.0222 17.3473
TRTPN 4
15.1217
1.0828 65
13.97
<.0001 0.05 12.9591 17.2842
TRTPN 5
14.8184
1.0828 65
13.69
<.0001 0.05 12.6559 16.9809
TRTPN 6
16.6637
1.0828 65
15.39
<.0001 0.05 14.5011 18.8262
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower Upper
TRTPN 1
2
-0.06343
1.015465
-0.06
0.9504 0.05 -2.0914 1.9645
TRTPN 1
3
0.3445
1.015465
0.34
0.7355 0.05 -1.6835 2.3725
TRTPN 1
4
0.4076
1.015465
0.40
0.6894 0.05 -1.6204 2.4356
TRTPN 1
5
0.7109
1.015465
0.70
0.4864 0.05 -1.3171 2.7388
TRTPN 1
6
-1.1344
1.013265
-1.12
0.2670 0.05 -3.1578 0.8890
TRTPN 2
3
0.4079
1.015465
0.40
0.6892 0.05 -1.6201 2.4359
TRTPN 2
4
0.4711
1.013265
0.46
0.6435 0.05 -1.5524 2.4945
TRTPN 2
5
0.7743
1.015465
0.76
0.4485 0.05 -1.2537 2.8023
TRTPN 2
6
-1.0710
1.015465
-1.05
0.2955 0.05 -3.0989 0.9570
TRTPN 3
4
0.06312
1.015465
0.06
0.9506 0.05 -1.9649 2.0911
TRTPN 3
5
0.3664
1.013265
0.36
0.7188 0.05 -1.6571 2.3898
TRTPN 3
6
-1.4789
1.015465
-1.46
0.1501 0.05 -3.5069 0.5491
TRTPN 4
5
0.3032
1.015465
0.30
0.7662 0.05 -1.7247 2.3312
Page 107 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 80 of 112
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower Upper
TRTPN 4
6
-1.5420
1.015465
-1.52
0.1337 0.05 -3.5700 0.4860
TRTPN 5
6
-1.8452
1.015465
-1.82
0.0738 0.05 -3.8732 0.1827
Page 108 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 81 of 112
Model Information
Data Set
WORK.ADXV
Dependent Variable
AVAL
Covariance Structure
Variance Components
Estimation Method
REML
Residual Variance Method
Profile
Fixed Effects SE Method
Model-Based
Degrees of Freedom Method Containment
Class Level Information
Class
LevelsValues
SUBJID
151001 1002 1003 1004 1005 1006 1007 1008 1010 1012 1013 1014 1015 1016 1017
TRTPN
61 2 3 4 5 6
APERIOD
6P1 P2 P3 P4 P5 P6
ARMCD
6ABCEDF BEAFCD CADBFE DCFAEB EFBDAC FDECBA
Dimensions
Covariance Parameters
2
Columns in X
19
Columns in Z
15
Subjects
1
Max Obs per Subject
90
Page 109 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 82 of 112
Number of Observations
Number of Observations Read
90
Number of Observations Used
90
Number of Observations Not Used
0
Iteration History
Iteration Evaluations -2 Res Log Like
Criterion
0
1
1156.00805775
1
1
1151.83225999 0.00000000
Convergence criteria met.
Covariance Parameter 
Estimates
Cov Parm
Estimate
SUBJID(ARMCD)
44274
Residual
176454
Fit Statistics
-2 Res Log Likelihood
1151.8
AIC (Smaller is Better)
1155.8
AICC (Smaller is Better) 1156.0
BIC (Smaller is Better)
1157.2
Page 110 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 83 of 112
Type 3 Tests of Fixed Effects
Effect
Num 
DF
Den 
DF F Value Pr > F
TRTPN
5 65
2.66 0.0299
APERIOD
5 65
3.33 0.0096
ARMCD
5
9
1.24 0.3681
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
1
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 111 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 84 of 112
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
1
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 112 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 85 of 112
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 113 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 86 of 112
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 114 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 87 of 112
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 115 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 88 of 112
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 116 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 89 of 112
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 117 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 90 of 112
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 118 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 91 of 112
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 119 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 92 of 112
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 120 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 93 of 112
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 121 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 94 of 112
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Estimates
Label
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
Oxy 30 vs Placebo
-72.0201
154.0765
-0.47
0.6417 0.05 -379.73
235.69
Oxy 60 vs Placebo
-336.37
154.0765
-2.18
0.0326 0.05 -644.08 -28.6636
Bel 300 vs Oxy 30
200.18
154.0765
1.30
0.1984 0.05 -107.52
507.89
Bel 300 vs Oxy 60
464.53
154.0765
3.01
0.0037 0.05
156.83
772.24
Bel 600 vs Oxy 30
165.60
153.7365
1.08
0.2854 0.05 -141.42
472.62
Bel 600 vs Oxy 60
429.95
154.0765
2.79
0.0069 0.05
122.24
737.66
Bel 900 vs Oxy 30
193.57
154.0765
1.26
0.2135 0.05 -114.14
501.28
Bel 900 vs Oxy 60
457.92
153.7365
2.98
0.0041 0.05
150.90
764.94
Bel 300 vs Placebo
128.16
153.7365
0.83
0.4075 0.05 -178.85
435.18
Bel 600 vs Placebo
93.5803
154.0765
0.61
0.5457 0.05 -214.13
401.29
Bel 900 vs Placebo
121.55
154.0765
0.79
0.4330 0.05 -186.16
429.26
Page 122 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 95 of 112
Least Squares Means
Effect
Planned 
Treatment 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
1272.57
122.47 65
10.39
<.0001 0.05 1027.98 1517.16
TRTPN 2
1237.99
122.47 65
10.11
<.0001 0.05
993.40 1482.58
TRTPN 3
1265.96
122.47 65
10.34
<.0001 0.05 1021.37 1510.55
TRTPN 4
1072.39
122.47 65
8.76
<.0001 0.05
827.80 1316.98
TRTPN 5
808.04
122.47 65
6.60
<.0001 0.05
563.45 1052.63
TRTPN 6
1144.41
122.47 65
9.34
<.0001 0.05
899.82 1389.00
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
2
34.5817
154.0765
0.22
0.8231 0.05
-273.12
342.29
TRTPN 1
3
6.6126
154.0765
0.04
0.9659 0.05
-301.09
314.32
TRTPN 1
4
200.18
154.0765
1.30
0.1984 0.05
-107.52
507.89
TRTPN 1
5
464.53
154.0765
3.01
0.0037 0.05
156.83
772.24
TRTPN 1
6
128.16
153.7365
0.83
0.4075 0.05
-178.85
435.18
TRTPN 2
3
-27.9691
154.0765
-0.18
0.8565 0.05
-335.68
279.74
TRTPN 2
4
165.60
153.7365
1.08
0.2854 0.05
-141.42
472.62
TRTPN 2
5
429.95
154.0765
2.79
0.0069 0.05
122.24
737.66
TRTPN 2
6
93.5803
154.0765
0.61
0.5457 0.05
-214.13
401.29
TRTPN 3
4
193.57
154.0765
1.26
0.2135 0.05
-114.14
501.28
TRTPN 3
5
457.92
153.7365
2.98
0.0041 0.05
150.90
764.94
TRTPN 3
6
121.55
154.0765
0.79
0.4330 0.05
-186.16
429.26
TRTPN 4
5
264.35
154.0765
1.72
0.0910 0.05 -43.3566
572.06
Page 123 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 96 of 112
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 4
6
-72.0201
154.0765
-0.47
0.6417 0.05
-379.73
235.69
TRTPN 5
6
-336.37
154.0765
-2.18
0.0326 0.05
-644.08 -28.6636
Page 124 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 97 of 112
Model Information
Data Set
WORK.ADXV
Dependent Variable
AVAL
Covariance Structure
Variance Components
Estimation Method
REML
Residual Variance Method
Profile
Fixed Effects SE Method
Model-Based
Degrees of Freedom Method Containment
Class Level Information
Class
LevelsValues
SUBJID
151001 1002 1003 1004 1005 1006 1007 1008 1010 1012 1013 1014 1015 1016 1017
TRTPN
61 2 3 4 5 6
APERIOD
6P1 P2 P3 P4 P5 P6
ARMCD
6ABCEDF BEAFCD CADBFE DCFAEB EFBDAC FDECBA
Dimensions
Covariance Parameters
2
Columns in X
19
Columns in Z
15
Subjects
1
Max Obs per Subject
90
Page 125 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 98 of 112
Number of Observations
Number of Observations Read
90
Number of Observations Used
90
Number of Observations Not Used
0
Iteration History
Iteration Evaluations -2 Res Log Like
Criterion
0
1
1214.80530325
1
1
1149.08926784 0.00000000
Convergence criteria met.
Covariance Parameter 
Estimates
Cov Parm
Estimate
SUBJID(ARMCD)
454187
Residual
130654
Fit Statistics
-2 Res Log Likelihood
1149.1
AIC (Smaller is Better)
1153.1
AICC (Smaller is Better) 1153.3
BIC (Smaller is Better)
1154.5
Page 126 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 99 of 112
Type 3 Tests of Fixed Effects
Effect
Num 
DF
Den 
DF F Value Pr > F
TRTPN
5 65
3.21 0.0119
APERIOD
5 65
1.99 0.0923
ARMCD
5
9
0.56 0.7305
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
1
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 127 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 100 of 112
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
1
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 128 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 101 of 112
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 129 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 102 of 112
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 130 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 103 of 112
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 131 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 104 of 112
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 132 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 105 of 112
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 133 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 106 of 112
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 134 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 107 of 112
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 135 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 108 of 112
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 136 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 109 of 112
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 137 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 110 of 112
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Estimates
Label
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower Upper
Oxy 30 vs Placebo
64.4353
132.5865
0.49
0.6286 0.05
-200.34 329.21
Oxy 60 vs Placebo
-258.67
132.5865
-1.95
0.0554 0.05
-523.45 6.1076
Bel 300 vs Oxy 30
135.61
132.5865
1.02
0.3102 0.05
-129.17 400.39
Bel 300 vs Oxy 60
458.72
132.5865
3.46
0.0010 0.05
193.94 723.50
Bel 600 vs Oxy 30
-12.2582
132.2865
-0.09
0.9265 0.05
-276.44 251.93
Bel 600 vs Oxy 60
310.85
132.5865
2.34
0.0221 0.05
46.0695 575.63
Bel 900 vs Oxy 30
128.89
132.5865
0.97
0.3346 0.05
-135.89 393.67
Bel 900 vs Oxy 60
451.99
132.2865
3.42
0.0011 0.05
187.81 716.18
Bel 300 vs Placebo
200.05
132.2865
1.51
0.1353 0.05 -64.1373 464.23
Bel 600 vs Placebo
52.1771
132.5865
0.39
0.6952 0.05
-212.60 316.96
Bel 900 vs Placebo
193.32
132.5865
1.46
0.1496 0.05 -71.4549 458.10
Page 138 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 111 of 112
Least Squares Means
Effect
Planned 
Treatment 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
1959.11
200.92 65
9.75
<.0001 0.05 1557.84 2360.38
TRTPN 2
1811.24
200.92 65
9.01
<.0001 0.05 1409.97 2212.51
TRTPN 3
1952.39
200.92 65
9.72
<.0001 0.05 1551.12 2353.66
TRTPN 4
1823.50
200.92 65
9.08
<.0001 0.05 1422.23 2224.77
TRTPN 5
1500.39
200.92 65
7.47
<.0001 0.05 1099.12 1901.66
TRTPN 6
1759.06
200.92 65
8.75
<.0001 0.05 1357.79 2160.34
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower Upper
TRTPN 1
2
147.87
132.5865
1.12
0.2688 0.05
-116.91 412.65
TRTPN 1
3
6.7232
132.5865
0.05
0.9597 0.05
-258.05 271.50
TRTPN 1
4
135.61
132.5865
1.02
0.3102 0.05
-129.17 400.39
TRTPN 1
5
458.72
132.5865
3.46
0.0010 0.05
193.94 723.50
TRTPN 1
6
200.05
132.2865
1.51
0.1353 0.05 -64.1373 464.23
TRTPN 2
3
-141.15
132.5865
-1.06
0.2910 0.05
-405.92 123.63
TRTPN 2
4
-12.2582
132.2865
-0.09
0.9265 0.05
-276.44 251.93
TRTPN 2
5
310.85
132.5865
2.34
0.0221 0.05
46.0695 575.63
TRTPN 2
6
52.1771
132.5865
0.39
0.6952 0.05
-212.60 316.96
TRTPN 3
4
128.89
132.5865
0.97
0.3346 0.05
-135.89 393.67
TRTPN 3
5
451.99
132.2865
3.42
0.0011 0.05
187.81 716.18
TRTPN 3
6
193.32
132.5865
1.46
0.1496 0.05 -71.4549 458.10
TRTPN 4
5
323.11
132.5865
2.44
0.0176 0.05
58.3277 587.88
Page 139 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.1                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.2                                    
Supporting Table 14.2.2                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio1.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 112 of 112
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower Upper
TRTPN 4
6
64.4353
132.5865
0.49
0.6286 0.05
-200.34 329.21
TRTPN 5
6
-258.67
132.5865
-1.95
0.0554 0.05
-523.45 6.1076
Page 140 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 1 of 112
Model Information
Data Set
WORK.ADXV
Dependent Variable
AVAL
Covariance Structure
Variance Components
Estimation Method
REML
Residual Variance Method
Profile
Fixed Effects SE Method
Model-Based
Degrees of Freedom Method Containment
Class Level Information
Class
LevelsValues
SUBJID
161001 1002 1003 1004 1005 1006 1007 1008 1010 1012 1013 1014 1015 1016 1017 1018
TRTPN
61 2 3 4 5 6
APERIOD
6P1 P2 P3 P4 P5 P6
ARMCD
6ABCEDF BEAFCD CADBFE DCFAEB EFBDAC FDECBA
Dimensions
Covariance Parameters
2
Columns in X
19
Columns in Z
16
Subjects
1
Max Obs per Subject
93
Page 141 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 2 of 112
Number of Observations
Number of Observations Read
93
Number of Observations Used
93
Number of Observations Not Used
0
Iteration History
Iteration Evaluations -2 Res Log Like
Criterion
0
1
445.33349796
1
2
425.58981336 0.00000000
Convergence criteria met.
Covariance Parameter 
Estimates
Cov Parm
Estimate
SUBJID(ARMCD)
5.7636
Residual
6.9739
Fit Statistics
-2 Res Log Likelihood
425.6
AIC (Smaller is Better)
429.6
AICC (Smaller is Better) 429.8
BIC (Smaller is Better)
431.1
Page 142 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 3 of 112
Type 3 Tests of Fixed Effects
Effect
Num 
DF
Den 
DF F Value Pr > F
TRTPN
5 67
3.46 0.0077
APERIOD
5 67
0.49 0.7812
ARMCD
5 10
0.76 0.5997
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
1
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 143 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 4 of 112
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
1
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 144 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 5 of 112
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 145 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 6 of 112
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 146 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 7 of 112
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 147 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 8 of 112
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 148 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 9 of 112
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 149 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 10 of 112
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 150 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 11 of 112
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 151 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 12 of 112
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 152 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 13 of 112
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 153 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 14 of 112
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Estimates
Label
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
Oxy 30 vs Placebo
1.3593
0.955967
1.42
0.1597 0.05 -0.5486
3.2672
Oxy 60 vs Placebo
2.7012
0.937567
2.88
0.0053 0.05 0.8298
4.5725
Bel 300 vs Oxy 30
-2.3356
0.968667
-2.41
0.0186 0.05 -4.2688 -0.4024
Bel 300 vs Oxy 60
-3.6775
0.955867
-3.85
0.0003 0.05 -5.5853 -1.7696
Bel 600 vs Oxy 30
-0.2433
0.956367
-0.25
0.7999 0.05 -2.1521
1.6655
Bel 600 vs Oxy 60
-1.5852
0.937567
-1.69
0.0955 0.05 -3.4564
0.2860
Bel 900 vs Oxy 30
-0.3133
0.968567
-0.32
0.7473 0.05 -2.2464
1.6198
Bel 900 vs Oxy 60
-1.6552
0.956367
-1.73
0.0881 0.05 -3.5639
0.2535
Bel 300 vs Placebo
-0.9763
0.955367
-1.02
0.3105 0.05 -2.8832
0.9305
Bel 600 vs Placebo
1.1159
0.935667
1.19
0.2372 0.05 -0.7515
2.9834
Bel 900 vs Placebo
1.0460
0.955967
1.09
0.2778 0.05 -0.8620
2.9539
Page 154 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 15 of 112
Least Squares Means
Effect
Planned 
Treatment 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
40.7846
0.9218 67
44.24
<.0001
0.1 39.2471 42.3220
TRTPN 2
42.8768
0.9025 67
47.51
<.0001
0.1 41.3715 44.3822
TRTPN 3
42.8069
0.9223 67
46.41
<.0001
0.1 41.2686 44.3451
TRTPN 4
43.1202
0.9223 67
46.75
<.0001
0.1 41.5819 44.6584
TRTPN 5
44.4621
0.9025 67
49.26
<.0001
0.1 42.9567 45.9674
TRTPN 6
41.7609
0.9025 67
46.27
<.0001
0.1 40.2556 43.2662
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
2
-2.0923
0.957867
-2.18
0.0324
0.1 -3.6898
-0.4948
TRTPN 1
3
-2.0223
0.968467
-2.09
0.0406
0.1 -3.6375
-0.4071
TRTPN 1
4
-2.3356
0.968667
-2.41
0.0186
0.1 -3.9511
-0.7201
TRTPN 1
5
-3.6775
0.955867
-3.85
0.0003
0.1 -5.2717
-2.0832
TRTPN 1
6
-0.9763
0.955367
-1.02
0.3105
0.1 -2.5697
0.6171
TRTPN 2
3
0.06998
0.956467
0.07
0.9419
0.1 -1.5253
1.6652
TRTPN 2
4
-0.2433
0.956367
-0.25
0.7999
0.1 -1.8384
1.3517
TRTPN 2
5
-1.5852
0.937567
-1.69
0.0955
0.1 -3.1488 -0.02161
TRTPN 2
6
1.1159
0.935667
1.19
0.2372
0.1 -0.4445
2.6764
TRTPN 3
4
-0.3133
0.968567
-0.32
0.7473
0.1 -1.9286
1.3020
TRTPN 3
5
-1.6552
0.956367
-1.73
0.0881
0.1 -3.2502 -0.06020
TRTPN 3
6
1.0460
0.955967
1.09
0.2778
0.1 -0.5483
2.6403
TRTPN 4
5
-1.3419
0.956367
-1.40
0.1652
0.1 -2.9369
0.2531
Page 155 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=ETCOEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 16 of 112
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 4
6
1.3593
0.955967
1.42
0.1597
0.1 -0.2350
2.9536
TRTPN 5
6
2.7012
0.937567
2.88
0.0053
0.1
1.1374
4.2649
Page 156 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 17 of 112
Model Information
Data Set
WORK.ADXV
Dependent Variable
AVAL
Covariance Structure
Variance Components
Estimation Method
REML
Residual Variance Method
Profile
Fixed Effects SE Method
Model-Based
Degrees of Freedom Method Containment
Class Level Information
Class
LevelsValues
SUBJID
161001 1002 1003 1004 1005 1006 1007 1008 1010 1012 1013 1014 1015 1016 1017 1018
TRTPN
61 2 3 4 5 6
APERIOD
6P1 P2 P3 P4 P5 P6
ARMCD
6ABCEDF BEAFCD CADBFE DCFAEB EFBDAC FDECBA
Dimensions
Covariance Parameters
2
Columns in X
19
Columns in Z
16
Subjects
1
Max Obs per Subject
93
Page 157 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 18 of 112
Number of Observations
Number of Observations Read
93
Number of Observations Used
93
Number of Observations Not Used
0
Iteration History
Iteration Evaluations -2 Res Log Like
Criterion
0
1
1601.99363318
1
2
1591.96490482 0.00000000
Convergence criteria met.
Covariance Parameter 
Estimates
Cov Parm
Estimate
SUBJID(ARMCD) 12903876
Residual
28030184
Fit Statistics
-2 Res Log Likelihood
1592.0
AIC (Smaller is Better)
1596.0
AICC (Smaller is Better) 1596.1
BIC (Smaller is Better)
1597.5
Page 158 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 19 of 112
Type 3 Tests of Fixed Effects
Effect
Num 
DF
Den 
DF F Value Pr > F
TRTPN
5 67
3.06 0.0152
APERIOD
5 67
2.17 0.0677
ARMCD
5 10
0.88 0.5301
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
1
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 159 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 20 of 112
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
1
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 160 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 21 of 112
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 161 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 22 of 112
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 162 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 23 of 112
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 163 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 24 of 112
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 164 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 25 of 112
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 165 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 26 of 112
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 166 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 27 of 112
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 167 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 28 of 112
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 168 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 29 of 112
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 169 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 30 of 112
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Estimates
Label
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
Oxy 30 vs Placebo
-799.96
1915.2867
-0.42
0.6775 0.05 -4622.87
3022.94
Oxy 60 vs Placebo
-5189.06
1879.6067
-2.76
0.0074 0.05 -8940.75 -1437.38
Bel 300 vs Oxy 30
2034.96
1941.7867
1.05
0.2984 0.05 -1840.84
5910.76
Bel 300 vs Oxy 60
6424.06
1915.2267
3.35
0.0013 0.05
2601.26
10247
Bel 600 vs Oxy 30
736.00
1916.0367
0.38
0.7021 0.05 -3088.41
4560.41
Bel 600 vs Oxy 60
5125.10
1879.4567
2.73
0.0082 0.05
1373.69
8876.51
Bel 900 vs Oxy 30
1748.48
1941.6067
0.90
0.3711 0.05 -2126.98
5623.93
Bel 900 vs Oxy 60
6137.58
1915.9867
3.20
0.0021 0.05
2313.27
9961.88
Bel 300 vs Placebo
1234.99
1914.3367
0.65
0.5210 0.05 -2586.03
5056.02
Bel 600 vs Placebo -63.9639
1875.6667
-0.03
0.9729 0.05 -3807.80
3679.88
Bel 900 vs Placebo
948.51
1915.2867
0.50
0.6221 0.05 -2874.40
4771.42
Page 170 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 31 of 112
Least Squares Means
Effect
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha Lower Upper
TRTPN 1
23560
1657.2867
14.22
<.0001
0.1 20795 26324
TRTPN 2
22261
1615.1967
13.78
<.0001
0.1 19567 24955
TRTPN 3
23273
1658.1967
14.04
<.0001
0.1 20507 26039
TRTPN 4
21525
1658.1967
12.98
<.0001
0.1 18759 24290
TRTPN 5
17136
1615.1767
10.61
<.0001
0.1 14442 19830
TRTPN 6
22325
1615.1167
13.82
<.0001
0.1 19631 25019
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
2
1298.96
1919.1467
0.68
0.5008
0.1 -1902.01
4499.93
TRTPN 1
3
286.48
1941.5067
0.15
0.8831
0.1 -2951.78
3524.74
TRTPN 1
4
2034.96
1941.7867
1.05
0.2984
0.1 -1203.76
5273.68
TRTPN 1
5
6424.06
1915.2267
3.35
0.0013
0.1
3229.63
9618.49
TRTPN 1
6
1234.99
1914.3367
0.65
0.5210
0.1 -1957.96
4427.94
TRTPN 2
3
-1012.48
1916.2967
-0.53
0.5990
0.1 -4208.68
2183.73
TRTPN 2
4
736.00
1916.0367
0.38
0.7021
0.1 -2459.77
3931.77
TRTPN 2
5
5125.10
1879.4567
2.73
0.0082
0.1
1990.33
8259.87
TRTPN 2
6
-63.9639
1875.6667
-0.03
0.9729
0.1 -3192.41
3064.49
TRTPN 3
4
1748.48
1941.6067
0.90
0.3711
0.1 -1489.95
4986.91
TRTPN 3
5
6137.58
1915.9867
3.20
0.0021
0.1
2941.89
9333.26
TRTPN 3
6
948.51
1915.2867
0.50
0.6221
0.1 -2246.01
4143.04
TRTPN 4
5
4389.10
1915.9767
2.29
0.0251
0.1
1193.41
7584.79
Page 171 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 32 of 112
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 4
6
-799.96
1915.2867
-0.42
0.6775
0.1 -3994.48
2394.55
TRTPN 5
6
-5189.06
1879.6067
-2.76
0.0074
0.1 -8324.07 -2054.06
Page 172 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 33 of 112
Model Information
Data Set
WORK.ADXV
Dependent Variable
AVAL
Covariance Structure
Variance Components
Estimation Method
REML
Residual Variance Method
Profile
Fixed Effects SE Method
Model-Based
Degrees of Freedom Method Containment
Class Level Information
Class
LevelsValues
SUBJID
161001 1002 1003 1004 1005 1006 1007 1008 1010 1012 1013 1014 1015 1016 1017 1018
TRTPN
61 2 3 4 5 6
APERIOD
6P1 P2 P3 P4 P5 P6
ARMCD
6ABCEDF BEAFCD CADBFE DCFAEB EFBDAC FDECBA
Dimensions
Covariance Parameters
2
Columns in X
19
Columns in Z
16
Subjects
1
Max Obs per Subject
93
Page 173 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 34 of 112
Number of Observations
Number of Observations Read
93
Number of Observations Used
93
Number of Observations Not Used
0
Iteration History
Iteration Evaluations -2 Res Log Like
Criterion
0
1
693.50873069
1
2
683.88329081 0.00000004
2
1
683.88327887 0.00000000
Convergence criteria met.
Covariance Parameter 
Estimates
Cov Parm
Estimate
SUBJID(ARMCD)
94.1104
Residual
212.55
Fit Statistics
-2 Res Log Likelihood
683.9
AIC (Smaller is Better)
687.9
AICC (Smaller is Better) 688.0
BIC (Smaller is Better)
689.4
Page 174 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 35 of 112
Type 3 Tests of Fixed Effects
Effect
Num 
DF
Den 
DF F Value Pr > F
TRTPN
5 67
2.58 0.0339
APERIOD
5 67
2.60 0.0327
ARMCD
5 10
0.62 0.6898
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
1
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 175 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 36 of 112
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
1
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 176 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 37 of 112
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 177 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 38 of 112
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 178 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 39 of 112
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 179 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 40 of 112
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 180 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 41 of 112
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 181 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 42 of 112
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 182 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 43 of 112
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 183 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 44 of 112
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 184 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 45 of 112
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 185 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 46 of 112
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Estimates
Label
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
Oxy 30 vs Placebo
0.2197
5.273867
0.04
0.9669 0.05 -10.3069 10.7464
Oxy 60 vs Placebo
-12.9112
5.175867
-2.49
0.0151 0.05 -23.2422 -2.5803
Bel 300 vs Oxy 30
2.8091
5.347067
0.53
0.6011 0.05
-7.8636 13.4818
Bel 300 vs Oxy 60
15.9401
5.273767
3.02
0.0035 0.05
5.4138 26.4664
Bel 600 vs Oxy 30
0.8329
5.275967
0.16
0.8750 0.05
-9.6978 11.3636
Bel 600 vs Oxy 60
13.9639
5.175467
2.70
0.0088 0.05
3.6337 24.2941
Bel 900 vs Oxy 30
2.0449
5.346567
0.38
0.7033 0.05
-8.6269 12.7166
Bel 900 vs Oxy 60
15.1758
5.275767
2.88
0.0054 0.05
4.6454 25.7063
Bel 300 vs Placebo
3.0289
5.271367
0.57
0.5675 0.05
-7.4926 13.5504
Bel 600 vs Placebo
1.0527
5.165067
0.20
0.8391 0.05
-9.2567 11.3620
Bel 900 vs Placebo
2.2646
5.273867
0.43
0.6690 0.05
-8.2620 12.7912
Page 186 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 47 of 112
Least Squares Means
Effect
Planned 
Treatment 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
61.5830
4.5368 67
13.57
<.0001
0.1 54.0160 69.1499
TRTPN 2
59.6068
4.4204 67
13.48
<.0001
0.1 52.2339 66.9796
TRTPN 3
60.8187
4.5393 67
13.40
<.0001
0.1 53.2476 68.3899
TRTPN 4
58.7739
4.5393 67
12.95
<.0001
0.1 51.2027 66.3450
TRTPN 5
45.6429
4.4204 67
10.33
<.0001
0.1 38.2701 53.0157
TRTPN 6
58.5541
4.4202 67
13.25
<.0001
0.1 51.1816 65.9266
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
2
1.9762
5.284567
0.37
0.7096
0.1
-6.8379 10.7903
TRTPN 1
3
0.7643
5.346367
0.14
0.8868
0.1
-8.1529 9.6814
TRTPN 1
4
2.8091
5.347067
0.53
0.6011
0.1
-6.1093 11.7275
TRTPN 1
5
15.9401
5.273767
3.02
0.0035
0.1
7.1440 24.7362
TRTPN 1
6
3.0289
5.271367
0.57
0.5675
0.1
-5.7632 11.8209
TRTPN 2
3
-1.2120
5.276667
-0.23
0.8190
0.1 -10.0129 7.5890
TRTPN 2
4
0.8329
5.275967
0.16
0.8750
0.1
-7.9668 9.6326
TRTPN 2
5
13.9639
5.175467
2.70
0.0088
0.1
5.3317 22.5960
TRTPN 2
6
1.0527
5.165067
0.20
0.8391
0.1
-7.5621 9.6674
TRTPN 3
4
2.0449
5.346567
0.38
0.7033
0.1
-6.8727 10.9624
TRTPN 3
5
15.1758
5.275767
2.88
0.0054
0.1
6.3764 23.9753
TRTPN 3
6
2.2646
5.273867
0.43
0.6690
0.1
-6.5317 11.0609
TRTPN 4
5
13.1310
5.275767
2.49
0.0153
0.1
4.3315 21.9305
Page 187 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=PEFMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 48 of 112
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 4
6
0.2197
5.273867
0.04
0.9669
0.1
-8.5766 9.0161
TRTPN 5
6
-12.9112
5.175867
-2.49
0.0151
0.1 -21.5440 -4.2785
Page 188 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 49 of 112
Model Information
Data Set
WORK.ADXV
Dependent Variable
AVAL
Covariance Structure
Variance Components
Estimation Method
REML
Residual Variance Method
Profile
Fixed Effects SE Method
Model-Based
Degrees of Freedom Method Containment
Class Level Information
Class
LevelsValues
SUBJID
161001 1002 1003 1004 1005 1006 1007 1008 1010 1012 1013 1014 1015 1016 1017 1018
TRTPN
61 2 3 4 5 6
APERIOD
6P1 P2 P3 P4 P5 P6
ARMCD
6ABCEDF BEAFCD CADBFE DCFAEB EFBDAC FDECBA
Dimensions
Covariance Parameters
2
Columns in X
19
Columns in Z
16
Subjects
1
Max Obs per Subject
93
Page 189 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 50 of 112
Number of Observations
Number of Observations Read
93
Number of Observations Used
93
Number of Observations Not Used
0
Iteration History
Iteration Evaluations -2 Res Log Like
Criterion
0
1
1021.29677444
1
2
1011.48017988 0.00000000
Convergence criteria met.
Covariance Parameter 
Estimates
Cov Parm
Estimate
SUBJID(ARMCD)
6773.79
Residual
14934
Fit Statistics
-2 Res Log Likelihood
1011.5
AIC (Smaller is Better)
1015.5
AICC (Smaller is Better) 1015.6
BIC (Smaller is Better)
1017.0
Page 190 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 51 of 112
Type 3 Tests of Fixed Effects
Effect
Num 
DF
Den 
DF F Value Pr > F
TRTPN
5 67
4.01 0.0030
APERIOD
5 67
2.31 0.0537
ARMCD
5 10
1.12 0.4076
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
1
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 191 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 52 of 112
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
1
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 192 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 53 of 112
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 193 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 54 of 112
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 194 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 55 of 112
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 195 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 56 of 112
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 196 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 57 of 112
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 197 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 58 of 112
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 198 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 59 of 112
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 199 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 60 of 112
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 200 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 61 of 112
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 201 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 62 of 112
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Estimates
Label
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
Oxy 30 vs Placebo
-21.2343
44.208467
-0.48
0.6326 0.05
-109.47
67.0060
Oxy 60 vs Placebo
-131.81
43.385567
-3.04
0.0034 0.05
-218.41 -45.2147
Bel 300 vs Oxy 30
64.6649
44.820767
1.44
0.1538 0.05 -24.7977
154.13
Bel 300 vs Oxy 60
175.24
44.207267
3.96
0.0002 0.05
87.0052
263.48
Bel 600 vs Oxy 30
14.7699
44.225767
0.33
0.7394 0.05 -73.5049
103.04
Bel 600 vs Oxy 60
125.35
43.382267
2.89
0.0052 0.05
38.7567
211.94
Bel 900 vs Oxy 30
50.0157
44.816867
1.12
0.2684 0.05 -39.4390
139.47
Bel 900 vs Oxy 60
160.59
44.224567
3.63
0.0005 0.05
72.3214
248.87
Bel 300 vs Placebo
43.4306
44.186867
0.98
0.3292 0.05 -44.7665
131.63
Bel 600 vs Placebo
-6.4645
43.294767
-0.15
0.8818 0.05 -92.8811
79.9522
Bel 900 vs Placebo
28.7813
44.208567
0.65
0.5172 0.05 -59.4592
117.02
Page 202 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 63 of 112
Least Squares Means
Effect
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower Upper
TRTPN 1
582.53
38.167267
15.26
<.0001
0.1 518.87 646.19
TRTPN 2
532.64
37.194267
14.32
<.0001
0.1 470.60 594.67
TRTPN 3
567.88
38.188367
14.87
<.0001
0.1 504.19 631.58
TRTPN 4
517.87
38.188267
13.56
<.0001
0.1 454.17 581.56
TRTPN 5
407.29
37.193867
10.95
<.0001
0.1 345.25 469.33
TRTPN 6
539.10
37.192367
14.49
<.0001
0.1 477.07 601.14
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
2
49.8950
44.297767
1.13
0.2640
0.1 -23.9897
123.78
TRTPN 1
3
14.6493
44.814567
0.33
0.7448
0.1 -60.0975
89.3960
TRTPN 1
4
64.6649
44.820767
1.44
0.1538
0.1 -10.0923
139.42
TRTPN 1
5
175.24
44.207267
3.96
0.0002
0.1
101.51
248.98
TRTPN 1
6
43.4306
44.186867
0.98
0.3292
0.1 -30.2692
117.13
TRTPN 2
3
-35.2458
44.231767
-0.80
0.4284
0.1
-109.02
38.5290
TRTPN 2
4
14.7699
44.225767
0.33
0.7394
0.1 -58.9948
88.5345
TRTPN 2
5
125.35
43.382267
2.89
0.0052
0.1
52.9901
197.71
TRTPN 2
6
-6.4645
43.294767
-0.15
0.8818
0.1 -78.6764
65.7475
TRTPN 3
4
50.0157
44.816867
1.12
0.2684
0.1 -24.7350
124.77
TRTPN 3
5
160.59
44.224567
3.63
0.0005
0.1
86.8311
234.36
TRTPN 3
6
28.7813
44.208567
0.65
0.5172
0.1 -44.9547
102.52
TRTPN 4
5
110.58
44.224467
2.50
0.0149
0.1
36.8155
184.34
Page 203 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=REMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 64 of 112
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 4
6
-21.2343
44.208467
-0.48
0.6326
0.1 -94.9702
52.5016
TRTPN 5
6
-131.81
43.385567
-3.04
0.0034
0.1
-204.18 -59.4492
Page 204 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 65 of 112
Model Information
Data Set
WORK.ADXV
Dependent Variable
AVAL
Covariance Structure
Variance Components
Estimation Method
REML
Residual Variance Method
Profile
Fixed Effects SE Method
Model-Based
Degrees of Freedom Method Containment
Class Level Information
Class
LevelsValues
SUBJID
161001 1002 1003 1004 1005 1006 1007 1008 1010 1012 1013 1014 1015 1016 1017 1018
TRTPN
61 2 3 4 5 6
APERIOD
6P1 P2 P3 P4 P5 P6
ARMCD
6ABCEDF BEAFCD CADBFE DCFAEB EFBDAC FDECBA
Dimensions
Covariance Parameters
2
Columns in X
19
Columns in Z
16
Subjects
1
Max Obs per Subject
93
Page 205 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 66 of 112
Number of Observations
Number of Observations Read
93
Number of Observations Used
93
Number of Observations Not Used
0
Iteration History
Iteration Evaluations -2 Res Log Like
Criterion
0
1
462.41208316
1
3
434.25316146 0.00000768
2
1
434.25201500 0.00000001
Convergence criteria met.
Covariance Parameter 
Estimates
Cov Parm
Estimate
SUBJID(ARMCD)
8.5079
Residual
7.5427
Fit Statistics
-2 Res Log Likelihood
434.3
AIC (Smaller is Better)
438.3
AICC (Smaller is Better) 438.4
BIC (Smaller is Better)
439.8
Page 206 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 67 of 112
Type 3 Tests of Fixed Effects
Effect
Num 
DF
Den 
DF F Value Pr > F
TRTPN
5 67
1.08 0.3818
APERIOD
5 67
1.12 0.3558
ARMCD
5 10
0.81 0.5698
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
1
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 207 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 68 of 112
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
1
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 208 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 69 of 112
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 209 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 70 of 112
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 210 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 71 of 112
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 211 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 72 of 112
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 212 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 73 of 112
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 213 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 74 of 112
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 214 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 75 of 112
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 215 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 76 of 112
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 216 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 77 of 112
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 217 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 78 of 112
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Estimates
Label
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
Oxy 30 vs Placebo
-1.6707
0.994367
-1.68
0.0976 0.05 -3.6554
0.3140
Oxy 60 vs Placebo
-2.1015
0.975067
-2.16
0.0347 0.05 -4.0476 -0.1553
Bel 300 vs Oxy 30
0.4163
1.007367
0.41
0.6807 0.05 -1.5943
2.4268
Bel 300 vs Oxy 60
0.8470
0.994367
0.85
0.3973 0.05 -1.1376
2.8316
Bel 600 vs Oxy 30
0.4418
0.994867
0.44
0.6584 0.05 -1.5438
2.4275
Bel 600 vs Oxy 60
0.8726
0.974967
0.89
0.3740 0.05 -1.0734
2.8186
Bel 900 vs Oxy 30
0.05551
1.007267
0.06
0.9562 0.05 -1.9548
2.0659
Bel 900 vs Oxy 60
0.4862
0.994867
0.49
0.6266 0.05 -1.4993
2.4718
Bel 300 vs Placebo
-1.2544
0.993767
-1.26
0.2112 0.05 -3.2379
0.7291
Bel 600 vs Placebo
-1.2289
0.973067
-1.26
0.2110 0.05 -3.1710
0.7132
Bel 900 vs Placebo
-1.6152
0.994367
-1.62
0.1090 0.05 -3.5999
0.3695
Page 218 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 79 of 112
Least Squares Means
Effect
Planned 
Treatment 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
15.4944
1.0329 67
15.00
<.0001
0.1 13.7716 17.2171
TRTPN 2
15.5199
1.0141 67
15.30
<.0001
0.1 13.8285 17.2114
TRTPN 3
15.1336
1.0334 67
14.64
<.0001
0.1 13.4100 16.8572
TRTPN 4
15.0781
1.0334 67
14.59
<.0001
0.1 13.3545 16.8017
TRTPN 5
14.6473
1.0141 67
14.44
<.0001
0.1 12.9559 16.3388
TRTPN 6
16.7488
1.0141 67
16.52
<.0001
0.1 15.0574 18.4402
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
2
-0.02556
0.996367
-0.03
0.9796
0.1 -1.6873
1.6362
TRTPN 1
3
0.3608
1.007167
0.36
0.7213
0.1 -1.3191
2.0406
TRTPN 1
4
0.4163
1.007367
0.41
0.6807
0.1 -1.2638
2.0963
TRTPN 1
5
0.8470
0.994367
0.85
0.3973
0.1 -0.8114
2.5054
TRTPN 1
6
-1.2544
0.993767
-1.26
0.2112
0.1 -2.9119
0.4030
TRTPN 2
3
0.3863
0.995067
0.39
0.6990
0.1 -1.2732
2.0458
TRTPN 2
4
0.4418
0.994867
0.44
0.6584
0.1 -1.2174
2.1011
TRTPN 2
5
0.8726
0.974967
0.89
0.3740
0.1 -0.7536
2.4987
TRTPN 2
6
-1.2289
0.973067
-1.26
0.2110
0.1 -2.8517
0.3940
TRTPN 3
4
0.05551
1.007267
0.06
0.9562
0.1 -1.6244
1.7354
TRTPN 3
5
0.4862
0.994867
0.49
0.6266
0.1 -1.1730
2.1455
TRTPN 3
6
-1.6152
0.994367
-1.62
0.1090
0.1 -3.2737
0.04324
TRTPN 4
5
0.4307
0.994867
0.43
0.6664
0.1 -1.2285
2.0900
Page 219 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=RRSPEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 80 of 112
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 4
6
-1.6707
0.994367
-1.68
0.0976
0.1 -3.3292 -0.01227
TRTPN 5
6
-2.1015
0.975067
-2.16
0.0347
0.1 -3.7277
-0.4752
Page 220 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 81 of 112
Model Information
Data Set
WORK.ADXV
Dependent Variable
AVAL
Covariance Structure
Variance Components
Estimation Method
REML
Residual Variance Method
Profile
Fixed Effects SE Method
Model-Based
Degrees of Freedom Method Containment
Class Level Information
Class
LevelsValues
SUBJID
161001 1002 1003 1004 1005 1006 1007 1008 1010 1012 1013 1014 1015 1016 1017 1018
TRTPN
61 2 3 4 5 6
APERIOD
6P1 P2 P3 P4 P5 P6
ARMCD
6ABCEDF BEAFCD CADBFE DCFAEB EFBDAC FDECBA
Dimensions
Covariance Parameters
2
Columns in X
19
Columns in Z
16
Subjects
1
Max Obs per Subject
93
Page 221 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 82 of 112
Number of Observations
Number of Observations Read
93
Number of Observations Used
93
Number of Observations Not Used
0
Iteration History
Iteration Evaluations -2 Res Log Like
Criterion
0
1
1200.55113258
1
2
1196.44710417 0.00000001
2
1
1196.44709777 0.00000000
Convergence criteria met.
Covariance Parameter 
Estimates
Cov Parm
Estimate
SUBJID(ARMCD)
41275
Residual
174256
Fit Statistics
-2 Res Log Likelihood
1196.4
AIC (Smaller is Better)
1200.4
AICC (Smaller is Better) 1200.6
BIC (Smaller is Better)
1202.0
Page 222 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 83 of 112
Type 3 Tests of Fixed Effects
Effect
Num 
DF
Den 
DF F Value Pr > F
TRTPN
5 67
3.07 0.0149
APERIOD
5 67
3.41 0.0083
ARMCD
5 10
1.21 0.3725
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
1
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 223 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 84 of 112
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
1
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 224 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 85 of 112
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 225 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 86 of 112
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 226 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 87 of 112
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 227 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 88 of 112
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 228 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 89 of 112
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 229 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 90 of 112
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 230 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 91 of 112
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 231 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 92 of 112
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 232 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 93 of 112
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
ARMCD
CADBFE
ARMCD
DCFAEB
Page 233 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 94 of 112
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
EFBDAC
ARMCD
FDECBA
Estimates
Label
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
Oxy 30 vs Placebo
-100.13
150.9067
-0.66
0.5093 0.05 -401.34
201.08
Oxy 60 vs Placebo
-379.92
148.2067
-2.56
0.0126 0.05 -675.72 -84.1134
Bel 300 vs Oxy 30
202.07
153.1067
1.32
0.1914 0.05 -103.52
507.66
Bel 300 vs Oxy 60
481.86
150.9067
3.19
0.0021 0.05
180.66
783.06
Bel 600 vs Oxy 30
173.86
150.9567
1.15
0.2535 0.05 -127.43
475.16
Bel 600 vs Oxy 60
453.65
148.1967
3.06
0.0032 0.05
157.87
749.44
Bel 900 vs Oxy 30
191.81
153.0967
1.25
0.2146 0.05 -113.76
497.37
Bel 900 vs Oxy 60
471.60
150.9567
3.12
0.0026 0.05
170.31
772.89
Bel 300 vs Placebo
101.94
150.8467
0.68
0.5015 0.05 -199.15
403.03
Bel 600 vs Placebo
73.7326
147.8967
0.50
0.6197 0.05 -221.45
368.92
Bel 900 vs Placebo
91.6771
150.9067
0.61
0.5456 0.05 -209.53
392.88
Page 234 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 95 of 112
Least Squares Means
Effect
Planned 
Treatment 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
1281.33
120.51 67
10.63
<.0001
0.1 1080.33 1482.32
TRTPN 2
1253.12
117.02 67
10.71
<.0001
0.1 1057.94 1448.30
TRTPN 3
1271.06
120.57 67
10.54
<.0001
0.1 1069.97 1472.16
TRTPN 4
1079.26
120.57 67
8.95
<.0001
0.1
878.16 1280.36
TRTPN 5
799.47
117.02 67
6.83
<.0001
0.1
604.29 994.65
TRTPN 6
1179.39
117.02 67
10.08
<.0001
0.1
984.22 1374.56
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
2
28.2077
151.2167
0.19
0.8526
0.1
-224.00 280.41
TRTPN 1
3
10.2632
153.0867
0.07
0.9467
0.1
-245.06 265.59
TRTPN 1
4
202.07
153.1067
1.32
0.1914
0.1 -53.2914 457.43
TRTPN 1
5
481.86
150.9067
3.19
0.0021
0.1
230.17 733.55
TRTPN 1
6
101.94
150.8467
0.68
0.5015
0.1
-149.66 353.54
TRTPN 2
3
-17.9445
150.9767
-0.12
0.9057
0.1
-269.75 233.86
TRTPN 2
4
173.86
150.9567
1.15
0.2535
0.1 -77.9097 425.63
TRTPN 2
5
453.65
148.1967
3.06
0.0032
0.1
206.49 700.82
TRTPN 2
6
73.7326
147.8967
0.50
0.6197
0.1
-172.93 320.40
TRTPN 3
4
191.81
153.0967
1.25
0.2146
0.1 -63.5327 447.14
TRTPN 3
5
471.60
150.9567
3.12
0.0026
0.1
219.83 723.36
TRTPN 3
6
91.6771
150.9067
0.61
0.5456
0.1
-160.02 343.37
TRTPN 4
5
279.79
150.9567
1.85
0.0682
0.1
28.0255 531.56
Page 235 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=SEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 96 of 112
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 4
6
-100.13
150.9067
-0.66
0.5093
0.1
-351.82 151.57
TRTPN 5
6
-379.92
148.2067
-2.56
0.0126
0.1
-627.10 -132.74
Page 236 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 97 of 112
Model Information
Data Set
WORK.ADXV
Dependent Variable
AVAL
Covariance Structure
Variance Components
Estimation Method
REML
Residual Variance Method
Profile
Fixed Effects SE Method
Model-Based
Degrees of Freedom Method Containment
Class Level Information
Class
LevelsValues
SUBJID
161001 1002 1003 1004 1005 1006 1007 1008 1010 1012 1013 1014 1015 1016 1017 1018
TRTPN
61 2 3 4 5 6
APERIOD
6P1 P2 P3 P4 P5 P6
ARMCD
6ABCEDF BEAFCD CADBFE DCFAEB EFBDAC FDECBA
Dimensions
Covariance Parameters
2
Columns in X
19
Columns in Z
16
Subjects
1
Max Obs per Subject
93
Page 237 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 98 of 112
Number of Observations
Number of Observations Read
93
Number of Observations Used
93
Number of Observations Not Used
0
Iteration History
Iteration Evaluations -2 Res Log Like
Criterion
0
1
1262.49257037
1
3
1199.66035259 0.00000852
2
1
1199.65567545 0.00000003
3
1
1199.65566003 0.00000000
Convergence criteria met.
Covariance Parameter 
Estimates
Cov Parm
Estimate
SUBJID(ARMCD)
414683
Residual
139616
Fit Statistics
-2 Res Log Likelihood
1199.7
AIC (Smaller is Better)
1203.7
AICC (Smaller is Better) 1203.8
BIC (Smaller is Better)
1205.2
Page 238 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 99 of 112
Type 3 Tests of Fixed Effects
Effect
Num 
DF
Den 
DF F Value Pr > F
TRTPN
5 67
2.55 0.0361
APERIOD
5 67
2.30 0.0541
ARMCD
5 10
0.58 0.7139
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
1
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
Page 239 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 100 of 112
Coefficients for Oxy 30 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
CADBFE
ARMCD
DCFAEB
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
1
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
Page 240 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 101 of 112
Coefficients for Oxy 60 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
CADBFE
ARMCD
DCFAEB
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
Page 241 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 102 of 112
Coefficients for Bel 300 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
CADBFE
ARMCD
DCFAEB
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
Page 242 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 103 of 112
Coefficients for Bel 300 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
CADBFE
ARMCD
DCFAEB
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
Page 243 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 104 of 112
Coefficients for Bel 600 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
CADBFE
ARMCD
DCFAEB
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
Page 244 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 105 of 112
Coefficients for Bel 600 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
CADBFE
ARMCD
DCFAEB
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
-1
TRTPN
5
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
Page 245 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 106 of 112
Coefficients for Bel 900 vs Oxy 30
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
CADBFE
ARMCD
DCFAEB
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
-1
TRTPN
6
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
Page 246 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 107 of 112
Coefficients for Bel 900 vs Oxy 60
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
CADBFE
ARMCD
DCFAEB
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
1
TRTPN
2
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
Page 247 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 108 of 112
Coefficients for Bel 300 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
CADBFE
ARMCD
DCFAEB
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
1
TRTPN
3
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
Page 248 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 109 of 112
Coefficients for Bel 600 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
CADBFE
ARMCD
DCFAEB
ARMCD
EFBDAC
ARMCD
FDECBA
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
Intercept
TRTPN
1
TRTPN
2
TRTPN
3
1
TRTPN
4
TRTPN
5
TRTPN
6
-1
APERIOD
P1
APERIOD
P2
APERIOD
P3
APERIOD
P4
APERIOD
P5
APERIOD
P6
ARMCD
ABCEDF
ARMCD
BEAFCD
Page 249 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 110 of 112
Coefficients for Bel 900 vs Placebo
Effect
APERIOD
Planned 
Arm 
Code
Planned 
Treatment 
(N)
Row1
ARMCD
CADBFE
ARMCD
DCFAEB
ARMCD
EFBDAC
ARMCD
FDECBA
Estimates
Label
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
Oxy 30 vs Placebo
85.6321
135.3567
0.63
0.5291 0.05
-184.52 355.79
Oxy 60 vs Placebo
-187.67
132.6567
-1.41
0.1618 0.05
-452.45 77.1076
Bel 300 vs Oxy 30
134.18
137.0467
0.98
0.3310 0.05
-139.36 407.72
Bel 300 vs Oxy 60
407.48
135.3467
3.01
0.0037 0.05
137.34 677.63
Bel 600 vs Oxy 30
-38.2811
135.4267
-0.28
0.7783 0.05
-308.59 232.03
Bel 600 vs Oxy 60
235.02
132.6467
1.77
0.0810 0.05 -29.7354 499.78
Bel 900 vs Oxy 30
134.25
137.0367
0.98
0.3308 0.05
-139.26 407.76
Bel 900 vs Oxy 60
407.55
135.4267
3.01
0.0037 0.05
137.25 677.85
Bel 300 vs Placebo
219.81
135.2667
1.63
0.1088 0.05 -50.1648 489.79
Bel 600 vs Placebo
47.3510
132.3867
0.36
0.7217 0.05
-216.87 311.58
Bel 900 vs Placebo
219.88
135.3567
1.62
0.1090 0.05 -50.2740 490.04
Page 250 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 111 of 112
Least Squares Means
Effect
Planned 
Treatment 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
1937.48
190.88 67
10.15
<.0001
0.1 1619.11 2255.84
TRTPN 2
1765.02
188.96 67
9.34
<.0001
0.1 1449.85 2080.19
TRTPN 3
1937.55
190.93 67
10.15
<.0001
0.1 1619.09 2256.01
TRTPN 4
1803.30
190.93 67
9.44
<.0001
0.1 1484.84 2121.76
TRTPN 5
1529.99
188.96 67
8.10
<.0001
0.1 1214.82 1845.16
TRTPN 6
1717.67
188.96 67
9.09
<.0001
0.1 1402.50 2032.83
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 1
2
172.46
135.6267
1.27
0.2079
0.1 -53.7416 398.66
TRTPN 1
3
-0.06905
137.0267
-0.00
0.9996
0.1
-228.61 228.47
TRTPN 1
4
134.18
137.0467
0.98
0.3310
0.1 -94.3961 362.75
TRTPN 1
5
407.48
135.3467
3.01
0.0037
0.1
181.74 633.22
TRTPN 1
6
219.81
135.2667
1.63
0.1088
0.1
-5.7877 445.41
TRTPN 2
3
-172.53
135.4467
-1.27
0.2071
0.1
-398.44 53.3775
TRTPN 2
4
-38.2811
135.4267
-0.28
0.7783
0.1
-264.16 187.59
TRTPN 2
5
235.02
132.6467
1.77
0.0810
0.1
13.7839 456.26
TRTPN 2
6
47.3510
132.3867
0.36
0.7217
0.1
-173.44 268.14
TRTPN 3
4
134.25
137.0367
0.98
0.3308
0.1 -94.3054 362.80
TRTPN 3
5
407.55
135.4267
3.01
0.0037
0.1
181.68 633.42
TRTPN 3
6
219.88
135.3567
1.62
0.1090
0.1
-5.8676 445.63
TRTPN 4
5
273.30
135.4267
2.02
0.0476
0.1
47.4358 499.17
Page 251 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.2                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.3                                    
Supporting Table 14.2.3                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=TVEMEMAX
____________________________________________________________________________________________________________________________________
Program: A_Bio2.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 112 of 112
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Planned 
Treatment 
(N)
Estimate
Standard
ErrorDF t Value Pr > |t| Alpha
Lower
Upper
TRTPN 4
6
85.6321
135.3567
0.63
0.5291
0.1
-140.12 311.38
TRTPN 5
6
-187.67
132.6567
-1.41
0.1618
0.1
-408.93 33.5848
Page 252 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 1 of 31
Model Information
Data Set
WORK.ADXV
Dependent Variable
AVAL
Covariance Structure
Compound Symmetry
Subject Effect
SUBJID
Estimation Method
REML
Residual Variance Method
Profile
Fixed Effects SE Method
Model-Based
Degrees of Freedom Method Between-Within
Class Level Information
Class
LevelsValues
SUBJID
151001 1002 1003 1004 1005 1006 1007 1008 1010 1012 1013 1014 1015 1016 1017
TRTPN
6Bel300 Bel600 Bel900 Oxy30 Oxy60 Plac
APERIOD
6P1 P2 P3 P4 P5 P6
ARMCD
6ABCEDF BEAFCD CADBFE DCFAEB EFBDAC FDECBA
ATPTN
60 0.5 1 2 3 4
Dimensions
Covariance Parameters
2
Columns in X
55
Columns in Z
0
Subjects
15
Max Obs per Subject
36
Page 253 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 2 of 31
Number of Observations
Number of Observations Read
527
Number of Observations Used
527
Number of Observations Not Used
0
Iteration History
Iteration Evaluations -2 Res Log Like
Criterion
0
1
9845.22756633
1
2
9742.18466751 0.00000000
Convergence criteria met.
Covariance Parameter 
Estimates
Cov Parm Subject Estimate
CS
SUBJID
12122276
Residual
26084275
Fit Statistics
-2 Res Log Likelihood
9742.2
AIC (Smaller is Better)
9746.2
AICC (Smaller is Better) 9746.2
BIC (Smaller is Better)
9747.6
Page 254 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 3 of 31
Null Model Likelihood 
Ratio Test
DF Chi-Square Pr > ChiSq
1
103.04
<.0001
Type 3 Tests of Fixed Effects
Effect
Num 
DF
Den 
DF F Value Pr > F
TRTPN
5 70
7.48 <.0001
APERIOD
5 70
5.76 0.0002
ARMCD
5
9
0.87 0.5343
TRTPN*ATPTN
30407
2.21 0.0003
Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha Lower Upper
TRTPN*ATPTN Bel300
0
20100
1607.72407
12.50
<.0001 0.05 16940 23261
TRTPN*ATPTN Bel300
0.5
21760
1607.72407
13.53
<.0001 0.05 18599 24920
TRTPN*ATPTN Bel300
1
19847
1607.72407
12.35
<.0001 0.05 16687 23008
TRTPN*ATPTN Bel300
2
19992
1607.72407
12.43
<.0001 0.05 16831 23152
TRTPN*ATPTN Bel300
3
15579
1607.72407
9.69
<.0001 0.05 12418 18739
TRTPN*ATPTN Bel300
4
16134
1607.72407
10.04
<.0001 0.05 12974 19295
TRTPN*ATPTN Bel600
0
19868
1646.63407
12.07
<.0001 0.05 16631 23105
TRTPN*ATPTN Bel600
0.5
20768
1646.63407
12.61
<.0001 0.05 17531 24005
TRTPN*ATPTN Bel600
1
19400
1607.76407
12.07
<.0001 0.05 16240 22561
TRTPN*ATPTN Bel600
2
17831
1607.76407
11.09
<.0001 0.05 14670 20991
Page 255 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 4 of 31
Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha Lower Upper
TRTPN*ATPTN Bel600
3
17241
1607.76407
10.72
<.0001 0.05 14081 20402
TRTPN*ATPTN Bel600
4
17258
1607.76407
10.73
<.0001 0.05 14097 20418
TRTPN*ATPTN Bel900
0
21445
1646.60407
13.02
<.0001 0.05 18208 24682
TRTPN*ATPTN Bel900
0.5
22890
1607.73407
14.24
<.0001 0.05 19730 26051
TRTPN*ATPTN Bel900
1
20071
1607.73407
12.48
<.0001 0.05 16910 23231
TRTPN*ATPTN Bel900
2
18313
1607.73407
11.39
<.0001 0.05 15152 21473
TRTPN*ATPTN Bel900
3
17633
1607.73407
10.97
<.0001 0.05 14472 20793
TRTPN*ATPTN Bel900
4
16584
1607.73407
10.32
<.0001 0.05 13424 19745
TRTPN*ATPTN Oxy30
0
20238
1691.50407
11.96
<.0001 0.05 16913 23563
TRTPN*ATPTN Oxy30
0.5
17966
1691.50407
10.62
<.0001 0.05 14641 21291
TRTPN*ATPTN Oxy30
1
16113
1646.66407
9.79
<.0001 0.05 12876 19350
TRTPN*ATPTN Oxy30
2
16969
1607.77407
10.55
<.0001 0.05 13808 20129
TRTPN*ATPTN Oxy30
3
18564
1607.77407
11.55
<.0001 0.05 15403 21724
TRTPN*ATPTN Oxy30
4
18784
1607.77407
11.68
<.0001 0.05 15624 21945
TRTPN*ATPTN Oxy60
0
19149
1692.33407
11.32
<.0001 0.05 15823 22476
TRTPN*ATPTN Oxy60
0.5
16780
1692.33407
9.92
<.0001 0.05 13453 20106
TRTPN*ATPTN Oxy60
1
14484
1648.55407
8.79
<.0001 0.05 11243 17724
TRTPN*ATPTN Oxy60
2
13262
1607.78407
8.25
<.0001 0.05 10101 16422
TRTPN*ATPTN Oxy60
3
13811
1607.78407
8.59
<.0001 0.05 10650 16972
TRTPN*ATPTN Oxy60
4
13931
1607.78407
8.66
<.0001 0.05 10771 17092
TRTPN*ATPTN Plac
0
18548
1607.72407
11.54
<.0001 0.05 15388 21709
TRTPN*ATPTN Plac
0.5
20129
1607.72407
12.52
<.0001 0.05 16968 23289
TRTPN*ATPTN Plac
1
21018
1607.72407
13.07
<.0001 0.05 17857 24178
TRTPN*ATPTN Plac
2
17212
1607.72407
10.71
<.0001 0.05 14052 20373
Page 256 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 5 of 31
Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha Lower Upper
TRTPN*ATPTN Plac
3
17014
1607.72407
10.58
<.0001 0.05 13854 20175
TRTPN*ATPTN Plac
4
18407
1607.72407
11.45
<.0001 0.05 15247 21568
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
0
Bel300
0.5
-1659.32
1864.91 407
-0.89
0.3741 0.05 -5325.39
2006.74
TRTPN*ATPTN Bel300
0
Bel300
1
252.85
1864.91 407
0.14
0.8922 0.05 -3413.21
3918.92
TRTPN*ATPTN Bel300
0
Bel300
2
108.37
1864.91 407
0.06
0.9537 0.05 -3557.70
3774.43
TRTPN*ATPTN Bel300
0
Bel300
3
4521.35
1864.91 407
2.42
0.0158 0.05
855.29
8187.42
TRTPN*ATPTN Bel300
0
Bel300
4
3966.17
1864.91 407
2.13
0.0340 0.05
300.11
7632.24
TRTPN*ATPTN Bel300
0
Bel600
0
232.42
1899.90 407
0.12
0.9027 0.05 -3502.42
3967.27
TRTPN*ATPTN Bel300
0
Bel600
0.5
-668.08
1899.90 407
-0.35
0.7253 0.05 -4402.92
3066.77
TRTPN*ATPTN Bel300
0
Bel600
1
699.98
1866.36 407
0.38
0.7078 0.05 -2968.93
4368.88
TRTPN*ATPTN Bel300
0
Bel600
2
2269.65
1866.36 407
1.22
0.2247 0.05 -1399.26
5938.55
TRTPN*ATPTN Bel300
0
Bel600
3
2858.87
1866.36 407
1.53
0.1264 0.05
-810.04
6527.77
TRTPN*ATPTN Bel300
0
Bel600
4
2842.61
1866.36 407
1.52
0.1285 0.05
-826.30
6511.51
TRTPN*ATPTN Bel300
0
Bel900
0
-1344.38
1899.87 407
-0.71
0.4796 0.05 -5079.16
2390.40
TRTPN*ATPTN Bel300
0
Bel900
0.5
-2789.80
1866.33 407
-1.49
0.1357 0.05 -6458.65
879.04
TRTPN*ATPTN Bel300
0
Bel900
1
29.6690
1866.33 407
0.02
0.9873 0.05 -3639.18
3698.51
TRTPN*ATPTN Bel300
0
Bel900
2
1787.42
1866.33 407
0.96
0.3388 0.05 -1881.42
5456.27
TRTPN*ATPTN Bel300
0
Bel900
3
2467.69
1866.33 407
1.32
0.1868 0.05 -1201.16
6136.53
TRTPN*ATPTN Bel300
0
Bel900
4
3516.18
1866.33 407
1.88
0.0603 0.05
-152.67
7185.02
Page 257 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 6 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
0
Oxy30
0
-137.82
1938.87 407
-0.07
0.9434 0.05 -3949.28
3673.64
TRTPN*ATPTN Bel300
0
Oxy30
0.5
2134.33
1938.87 407
1.10
0.2716 0.05 -1677.13
5945.78
TRTPN*ATPTN Bel300
0
Oxy30
1
3987.34
1899.93 407
2.10
0.0365 0.05
252.43
7722.24
TRTPN*ATPTN Bel300
0
Oxy30
2
3131.59
1866.36 407
1.68
0.0941 0.05
-537.33
6800.51
TRTPN*ATPTN Bel300
0
Oxy30
3
1536.75
1866.36 407
0.82
0.4108 0.05 -2132.16
5205.67
TRTPN*ATPTN Bel300
0
Oxy30
4
1316.00
1866.36 407
0.71
0.4811 0.05 -2352.92
4984.92
TRTPN*ATPTN Bel300
0
Oxy60
0
950.87
1939.56 407
0.49
0.6242 0.05 -2861.94
4763.68
TRTPN*ATPTN Bel300
0
Oxy60
0.5
3320.72
1939.56 407
1.71
0.0876 0.05
-492.09
7133.53
TRTPN*ATPTN Bel300
0
Oxy60
1
5616.58
1900.77 407
2.95
0.0033 0.05
1880.02
9353.14
TRTPN*ATPTN Bel300
0
Oxy60
2
6838.81
1866.36 407
3.66
0.0003 0.05
3169.89
10508
TRTPN*ATPTN Bel300
0
Oxy60
3
6289.34
1866.36 407
3.37
0.0008 0.05
2620.42
9958.26
TRTPN*ATPTN Bel300
0
Oxy60
4
6169.20
1866.36 407
3.31
0.0010 0.05
2500.29
9838.12
TRTPN*ATPTN Bel300
0
Plac
0
1552.01
1865.61 407
0.83
0.4059 0.05 -2115.42
5219.44
TRTPN*ATPTN Bel300
0
Plac
0.5
-28.3753
1865.61 407
-0.02
0.9879 0.05 -3695.80
3639.05
TRTPN*ATPTN Bel300
0
Plac
1
-917.63
1865.61 407
-0.49
0.6231 0.05 -4585.06
2749.79
TRTPN*ATPTN Bel300
0
Plac
2
2887.83
1865.61 407
1.55
0.1224 0.05
-779.60
6555.26
TRTPN*ATPTN Bel300
0
Plac
3
3085.85
1865.61 407
1.65
0.0989 0.05
-581.58
6753.28
TRTPN*ATPTN Bel300
0
Plac
4
1693.01
1865.61 407
0.91
0.3647 0.05 -1974.42
5360.43
TRTPN*ATPTN Bel300
0.5
Bel300
1
1912.18
1864.91 407
1.03
0.3058 0.05 -1753.89
5578.24
TRTPN*ATPTN Bel300
0.5
Bel300
2
1767.69
1864.91 407
0.95
0.3438 0.05 -1898.38
5433.75
TRTPN*ATPTN Bel300
0.5
Bel300
3
6180.67
1864.91 407
3.31
0.0010 0.05
2514.61
9846.74
TRTPN*ATPTN Bel300
0.5
Bel300
4
5625.50
1864.91 407
3.02
0.0027 0.05
1959.43
9291.56
TRTPN*ATPTN Bel300
0.5
Bel600
0
1891.74
1899.90 407
1.00
0.3200 0.05 -1843.10
5626.59
TRTPN*ATPTN Bel300
0.5
Bel600
0.5
991.25
1899.90 407
0.52
0.6021 0.05 -2743.60
4726.09
TRTPN*ATPTN Bel300
0.5
Bel600
1
2359.30
1866.36 407
1.26
0.2069 0.05 -1309.61
6028.20
Page 258 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 7 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
0.5
Bel600
2
3928.97
1866.36 407
2.11
0.0359 0.05
260.07
7597.88
TRTPN*ATPTN Bel300
0.5
Bel600
3
4518.19
1866.36 407
2.42
0.0159 0.05
849.28
8187.09
TRTPN*ATPTN Bel300
0.5
Bel600
4
4501.93
1866.36 407
2.41
0.0163 0.05
833.02
8170.83
TRTPN*ATPTN Bel300
0.5
Bel900
0
314.94
1899.87 407
0.17
0.8684 0.05 -3419.84
4049.73
TRTPN*ATPTN Bel300
0.5
Bel900
0.5
-1130.48
1866.33 407
-0.61
0.5450 0.05 -4799.33
2538.36
TRTPN*ATPTN Bel300
0.5
Bel900
1
1688.99
1866.33 407
0.90
0.3660 0.05 -1979.86
5357.84
TRTPN*ATPTN Bel300
0.5
Bel900
2
3446.74
1866.33 407
1.85
0.0655 0.05
-222.10
7115.59
TRTPN*ATPTN Bel300
0.5
Bel900
3
4127.01
1866.33 407
2.21
0.0276 0.05
458.16
7795.85
TRTPN*ATPTN Bel300
0.5
Bel900
4
5175.50
1866.33 407
2.77
0.0058 0.05
1506.65
8844.34
TRTPN*ATPTN Bel300
0.5
Oxy30
0
1521.50
1938.87 407
0.78
0.4331 0.05 -2289.96
5332.96
TRTPN*ATPTN Bel300
0.5
Oxy30
0.5
3793.65
1938.87 407
1.96
0.0511 0.05 -17.8074
7605.10
TRTPN*ATPTN Bel300
0.5
Oxy30
1
5646.66
1899.93 407
2.97
0.0031 0.05
1911.76
9381.56
TRTPN*ATPTN Bel300
0.5
Oxy30
2
4790.91
1866.36 407
2.57
0.0106 0.05
1121.99
8459.83
TRTPN*ATPTN Bel300
0.5
Oxy30
3
3196.07
1866.36 407
1.71
0.0876 0.05
-472.84
6864.99
TRTPN*ATPTN Bel300
0.5
Oxy30
4
2975.32
1866.36 407
1.59
0.1117 0.05
-693.60
6644.24
TRTPN*ATPTN Bel300
0.5
Oxy60
0
2610.19
1939.56 407
1.35
0.1791 0.05 -1202.62
6423.01
TRTPN*ATPTN Bel300
0.5
Oxy60
0.5
4980.04
1939.56 407
2.57
0.0106 0.05
1167.23
8792.85
TRTPN*ATPTN Bel300
0.5
Oxy60
1
7275.90
1900.77 407
3.83
0.0001 0.05
3539.34
11012
TRTPN*ATPTN Bel300
0.5
Oxy60
2
8498.13
1866.36 407
4.55
<.0001 0.05
4829.22
12167
TRTPN*ATPTN Bel300
0.5
Oxy60
3
7948.66
1866.36 407
4.26
<.0001 0.05
4279.74
11618
TRTPN*ATPTN Bel300
0.5
Oxy60
4
7828.52
1866.36 407
4.19
<.0001 0.05
4159.61
11497
TRTPN*ATPTN Bel300
0.5
Plac
0
3211.33
1865.61 407
1.72
0.0860 0.05
-456.10
6878.76
TRTPN*ATPTN Bel300
0.5
Plac
0.5
1630.95
1865.61 407
0.87
0.3825 0.05 -2036.48
5298.37
TRTPN*ATPTN Bel300
0.5
Plac
1
741.69
1865.61 407
0.40
0.6912 0.05 -2925.74
4409.12
TRTPN*ATPTN Bel300
0.5
Plac
2
4547.15
1865.61 407
2.44
0.0152 0.05
879.72
8214.58
Page 259 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 8 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
0.5
Plac
3
4745.17
1865.61 407
2.54
0.0113 0.05
1077.74
8412.60
TRTPN*ATPTN Bel300
0.5
Plac
4
3352.33
1865.61 407
1.80
0.0731 0.05
-315.10
7019.76
TRTPN*ATPTN Bel300
1
Bel300
2
-144.49
1864.91 407
-0.08
0.9383 0.05 -3810.56
3521.58
TRTPN*ATPTN Bel300
1
Bel300
3
4268.50
1864.91 407
2.29
0.0226 0.05
602.43
7934.56
TRTPN*ATPTN Bel300
1
Bel300
4
3713.32
1864.91 407
1.99
0.0471 0.05
47.2543
7379.39
TRTPN*ATPTN Bel300
1
Bel600
0
-20.4327
1899.90 407
-0.01
0.9914 0.05 -3755.28
3714.41
TRTPN*ATPTN Bel300
1
Bel600
0.5
-920.93
1899.90 407
-0.48
0.6281 0.05 -4655.78
2813.92
TRTPN*ATPTN Bel300
1
Bel600
1
447.12
1866.36 407
0.24
0.8108 0.05 -3221.78
4116.03
TRTPN*ATPTN Bel300
1
Bel600
2
2016.79
1866.36 407
1.08
0.2805 0.05 -1652.11
5685.70
TRTPN*ATPTN Bel300
1
Bel600
3
2606.01
1866.36 407
1.40
0.1634 0.05 -1062.89
6274.92
TRTPN*ATPTN Bel300
1
Bel600
4
2589.75
1866.36 407
1.39
0.1660 0.05 -1079.15
6258.66
TRTPN*ATPTN Bel300
1
Bel900
0
-1597.23
1899.87 407
-0.84
0.4010 0.05 -5332.01
2137.55
TRTPN*ATPTN Bel300
1
Bel900
0.5
-3042.66
1866.33 407
-1.63
0.1038 0.05 -6711.50
626.19
TRTPN*ATPTN Bel300
1
Bel900
1
-223.19
1866.33 407
-0.12
0.9049 0.05 -3892.03
3445.66
TRTPN*ATPTN Bel300
1
Bel900
2
1534.57
1866.33 407
0.82
0.4114 0.05 -2134.28
5203.41
TRTPN*ATPTN Bel300
1
Bel900
3
2214.83
1866.33 407
1.19
0.2360 0.05 -1454.01
5883.68
TRTPN*ATPTN Bel300
1
Bel900
4
3263.32
1866.33 407
1.75
0.0811 0.05
-405.52
6932.17
TRTPN*ATPTN Bel300
1
Oxy30
0
-390.68
1938.87 407
-0.20
0.8404 0.05 -4202.13
3420.78
TRTPN*ATPTN Bel300
1
Oxy30
0.5
1881.47
1938.87 407
0.97
0.3324 0.05 -1929.98
5692.93
TRTPN*ATPTN Bel300
1
Oxy30
1
3734.48
1899.93 407
1.97
0.0500 0.05
-0.4199
7469.38
TRTPN*ATPTN Bel300
1
Oxy30
2
2878.74
1866.36 407
1.54
0.1237 0.05
-790.18
6547.65
TRTPN*ATPTN Bel300
1
Oxy30
3
1283.90
1866.36 407
0.69
0.4919 0.05 -2385.02
4952.82
TRTPN*ATPTN Bel300
1
Oxy30
4
1063.15
1866.36 407
0.57
0.5692 0.05 -2605.77
4732.06
TRTPN*ATPTN Bel300
1
Oxy60
0
698.02
1939.56 407
0.36
0.7191 0.05 -3114.79
4510.83
TRTPN*ATPTN Bel300
1
Oxy60
0.5
3067.86
1939.56 407
1.58
0.1145 0.05
-744.95
6880.67
Page 260 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 9 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
1
Oxy60
1
5363.73
1900.77 407
2.82
0.0050 0.05
1627.16
9100.29
TRTPN*ATPTN Bel300
1
Oxy60
2
6585.96
1866.36 407
3.53
0.0005 0.05
2917.04
10255
TRTPN*ATPTN Bel300
1
Oxy60
3
6036.48
1866.36 407
3.23
0.0013 0.05
2367.57
9705.40
TRTPN*ATPTN Bel300
1
Oxy60
4
5916.35
1866.36 407
3.17
0.0016 0.05
2247.43
9585.27
TRTPN*ATPTN Bel300
1
Plac
0
1299.16
1865.61 407
0.70
0.4866 0.05 -2368.27
4966.59
TRTPN*ATPTN Bel300
1
Plac
0.5
-281.23
1865.61 407
-0.15
0.8803 0.05 -3948.66
3386.20
TRTPN*ATPTN Bel300
1
Plac
1
-1170.49
1865.61 407
-0.63
0.5307 0.05 -4837.92
2496.94
TRTPN*ATPTN Bel300
1
Plac
2
2634.97
1865.61 407
1.41
0.1586 0.05 -1032.46
6302.40
TRTPN*ATPTN Bel300
1
Plac
3
2832.99
1865.61 407
1.52
0.1297 0.05
-834.43
6500.42
TRTPN*ATPTN Bel300
1
Plac
4
1440.15
1865.61 407
0.77
0.4406 0.05 -2227.28
5107.58
TRTPN*ATPTN Bel300
2
Bel300
3
4412.99
1864.91 407
2.37
0.0184 0.05
746.92
8079.05
TRTPN*ATPTN Bel300
2
Bel300
4
3857.81
1864.91 407
2.07
0.0392 0.05
191.74
7523.88
TRTPN*ATPTN Bel300
2
Bel600
0
124.06
1899.90 407
0.07
0.9480 0.05 -3610.79
3858.90
TRTPN*ATPTN Bel300
2
Bel600
0.5
-776.44
1899.90 407
-0.41
0.6830 0.05 -4511.29
2958.41
TRTPN*ATPTN Bel300
2
Bel600
1
591.61
1866.36 407
0.32
0.7514 0.05 -3077.29
4260.52
TRTPN*ATPTN Bel300
2
Bel600
2
2161.28
1866.36 407
1.16
0.2475 0.05 -1507.62
5830.19
TRTPN*ATPTN Bel300
2
Bel600
3
2750.50
1866.36 407
1.47
0.1413 0.05
-918.40
6419.41
TRTPN*ATPTN Bel300
2
Bel600
4
2734.24
1866.36 407
1.47
0.1437 0.05
-934.66
6403.15
TRTPN*ATPTN Bel300
2
Bel900
0
-1452.74
1899.87 407
-0.76
0.4449 0.05 -5187.53
2282.04
TRTPN*ATPTN Bel300
2
Bel900
0.5
-2898.17
1866.33 407
-1.55
0.1212 0.05 -6567.01
770.68
TRTPN*ATPTN Bel300
2
Bel900
1
-78.6961
1866.33 407
-0.04
0.9664 0.05 -3747.54
3590.15
TRTPN*ATPTN Bel300
2
Bel900
2
1679.06
1866.33 407
0.90
0.3688 0.05 -1989.79
5347.90
TRTPN*ATPTN Bel300
2
Bel900
3
2359.32
1866.33 407
1.26
0.2069 0.05 -1309.52
6028.17
TRTPN*ATPTN Bel300
2
Bel900
4
3407.81
1866.33 407
1.83
0.0686 0.05
-261.03
7076.66
TRTPN*ATPTN Bel300
2
Oxy30
0
-246.19
1938.87 407
-0.13
0.8990 0.05 -4057.64
3565.27
Page 261 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 10 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
2
Oxy30
0.5
2025.96
1938.87 407
1.04
0.2967 0.05 -1785.49
5837.42
TRTPN*ATPTN Bel300
2
Oxy30
1
3878.97
1899.93 407
2.04
0.0418 0.05
144.07
7613.87
TRTPN*ATPTN Bel300
2
Oxy30
2
3023.23
1866.36 407
1.62
0.1060 0.05
-645.69
6692.14
TRTPN*ATPTN Bel300
2
Oxy30
3
1428.39
1866.36 407
0.77
0.4445 0.05 -2240.53
5097.31
TRTPN*ATPTN Bel300
2
Oxy30
4
1207.64
1866.36 407
0.65
0.5180 0.05 -2461.28
4876.55
TRTPN*ATPTN Bel300
2
Oxy60
0
842.51
1939.56 407
0.43
0.6642 0.05 -2970.30
4655.32
TRTPN*ATPTN Bel300
2
Oxy60
0.5
3212.35
1939.56 407
1.66
0.0984 0.05
-600.46
7025.16
TRTPN*ATPTN Bel300
2
Oxy60
1
5508.22
1900.77 407
2.90
0.0040 0.05
1771.65
9244.78
TRTPN*ATPTN Bel300
2
Oxy60
2
6730.45
1866.36 407
3.61
0.0003 0.05
3061.53
10399
TRTPN*ATPTN Bel300
2
Oxy60
3
6180.97
1866.36 407
3.31
0.0010 0.05
2512.06
9849.89
TRTPN*ATPTN Bel300
2
Oxy60
4
6060.84
1866.36 407
3.25
0.0013 0.05
2391.92
9729.76
TRTPN*ATPTN Bel300
2
Plac
0
1443.65
1865.61 407
0.77
0.4395 0.05 -2223.78
5111.08
TRTPN*ATPTN Bel300
2
Plac
0.5
-136.74
1865.61 407
-0.07
0.9416 0.05 -3804.17
3530.69
TRTPN*ATPTN Bel300
2
Plac
1
-1026.00
1865.61 407
-0.55
0.5827 0.05 -4693.43
2641.43
TRTPN*ATPTN Bel300
2
Plac
2
2779.46
1865.61 407
1.49
0.1370 0.05
-887.97
6446.89
TRTPN*ATPTN Bel300
2
Plac
3
2977.48
1865.61 407
1.60
0.1113 0.05
-689.95
6644.91
TRTPN*ATPTN Bel300
2
Plac
4
1584.64
1865.61 407
0.85
0.3962 0.05 -2082.79
5252.07
TRTPN*ATPTN Bel300
3
Bel300
4
-555.18
1864.91 407
-0.30
0.7661 0.05 -4221.24
3110.89
TRTPN*ATPTN Bel300
3
Bel600
0
-4288.93
1899.90 407
-2.26
0.0245 0.05 -8023.78
-554.08
TRTPN*ATPTN Bel300
3
Bel600
0.5
-5189.43
1899.90 407
-2.73
0.0066 0.05 -8924.27 -1454.58
TRTPN*ATPTN Bel300
3
Bel600
1
-3821.38
1866.36 407
-2.05
0.0413 0.05 -7490.28
-152.47
TRTPN*ATPTN Bel300
3
Bel600
2
-2251.70
1866.36 407
-1.21
0.2283 0.05 -5920.61
1417.20
TRTPN*ATPTN Bel300
3
Bel600
3
-1662.49
1866.36 407
-0.89
0.3736 0.05 -5331.39
2006.42
TRTPN*ATPTN Bel300
3
Bel600
4
-1678.75
1866.36 407
-0.90
0.3689 0.05 -5347.65
1990.16
TRTPN*ATPTN Bel300
3
Bel900
0
-5865.73
1899.87 407
-3.09
0.0022 0.05 -9600.51 -2130.95
Page 262 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 11 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
3
Bel900
0.5
-7311.16
1866.33 407
-3.92
0.0001 0.05
-10980 -3642.31
TRTPN*ATPTN Bel300
3
Bel900
1
-4491.68
1866.33 407
-2.41
0.0165 0.05 -8160.53
-822.84
TRTPN*ATPTN Bel300
3
Bel900
2
-2733.93
1866.33 407
-1.46
0.1437 0.05 -6402.78
934.92
TRTPN*ATPTN Bel300
3
Bel900
3
-2053.67
1866.33 407
-1.10
0.2718 0.05 -5722.51
1615.18
TRTPN*ATPTN Bel300
3
Bel900
4
-1005.18
1866.33 407
-0.54
0.5905 0.05 -4674.02
2663.67
TRTPN*ATPTN Bel300
3
Oxy30
0
-4659.17
1938.87 407
-2.40
0.0167 0.05 -8470.63
-847.72
TRTPN*ATPTN Bel300
3
Oxy30
0.5
-2387.03
1938.87 407
-1.23
0.2190 0.05 -6198.48
1424.43
TRTPN*ATPTN Bel300
3
Oxy30
1
-534.02
1899.93 407
-0.28
0.7788 0.05 -4268.92
3200.88
TRTPN*ATPTN Bel300
3
Oxy30
2
-1389.76
1866.36 407
-0.74
0.4569 0.05 -5058.68
2279.16
TRTPN*ATPTN Bel300
3
Oxy30
3
-2984.60
1866.36 407
-1.60
0.1106 0.05 -6653.52
684.32
TRTPN*ATPTN Bel300
3
Oxy30
4
-3205.35
1866.36 407
-1.72
0.0867 0.05 -6874.27
463.57
TRTPN*ATPTN Bel300
3
Oxy60
0
-3570.48
1939.56 407
-1.84
0.0664 0.05 -7383.29
242.33
TRTPN*ATPTN Bel300
3
Oxy60
0.5
-1200.64
1939.56 407
-0.62
0.5362 0.05 -5013.45
2612.18
TRTPN*ATPTN Bel300
3
Oxy60
1
1095.23
1900.77 407
0.58
0.5648 0.05 -2641.33
4831.79
TRTPN*ATPTN Bel300
3
Oxy60
2
2317.46
1866.36 407
1.24
0.2151 0.05 -1351.46
5986.38
TRTPN*ATPTN Bel300
3
Oxy60
3
1767.99
1866.36 407
0.95
0.3441 0.05 -1900.93
5436.90
TRTPN*ATPTN Bel300
3
Oxy60
4
1647.85
1866.36 407
0.88
0.3778 0.05 -2021.07
5316.77
TRTPN*ATPTN Bel300
3
Plac
0
-2969.34
1865.61 407
-1.59
0.1122 0.05 -6636.77
698.09
TRTPN*ATPTN Bel300
3
Plac
0.5
-4549.73
1865.61 407
-2.44
0.0152 0.05 -8217.16
-882.30
TRTPN*ATPTN Bel300
3
Plac
1
-5438.99
1865.61 407
-2.92
0.0037 0.05 -9106.42 -1771.56
TRTPN*ATPTN Bel300
3
Plac
2
-1633.53
1865.61 407
-0.88
0.3818 0.05 -5300.95
2033.90
TRTPN*ATPTN Bel300
3
Plac
3
-1435.50
1865.61 407
-0.77
0.4421 0.05 -5102.93
2231.93
TRTPN*ATPTN Bel300
3
Plac
4
-2828.35
1865.61 407
-1.52
0.1303 0.05 -6495.78
839.08
TRTPN*ATPTN Bel300
4
Bel600
0
-3733.75
1899.90 407
-1.97
0.0501 0.05 -7468.60
1.0934
TRTPN*ATPTN Bel300
4
Bel600
0.5
-4634.25
1899.90 407
-2.44
0.0151 0.05 -8369.10
-899.40
Page 263 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 12 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
4
Bel600
1
-3266.20
1866.36 407
-1.75
0.0809 0.05 -6935.10
402.71
TRTPN*ATPTN Bel300
4
Bel600
2
-1696.53
1866.36 407
-0.91
0.3639 0.05 -5365.43
1972.38
TRTPN*ATPTN Bel300
4
Bel600
3
-1107.31
1866.36 407
-0.59
0.5533 0.05 -4776.21
2561.60
TRTPN*ATPTN Bel300
4
Bel600
4
-1123.57
1866.36 407
-0.60
0.5475 0.05 -4792.47
2545.34
TRTPN*ATPTN Bel300
4
Bel900
0
-5310.55
1899.87 407
-2.80
0.0054 0.05 -9045.33 -1575.77
TRTPN*ATPTN Bel300
4
Bel900
0.5
-6755.98
1866.33 407
-3.62
0.0003 0.05
-10425 -3087.13
TRTPN*ATPTN Bel300
4
Bel900
1
-3936.51
1866.33 407
-2.11
0.0355 0.05 -7605.35
-267.66
TRTPN*ATPTN Bel300
4
Bel900
2
-2178.75
1866.33 407
-1.17
0.2437 0.05 -5847.60
1490.09
TRTPN*ATPTN Bel300
4
Bel900
3
-1498.49
1866.33 407
-0.80
0.4225 0.05 -5167.33
2170.36
TRTPN*ATPTN Bel300
4
Bel900
4
-450.00
1866.33 407
-0.24
0.8096 0.05 -4118.84
3218.85
TRTPN*ATPTN Bel300
4
Oxy30
0
-4104.00
1938.87 407
-2.12
0.0349 0.05 -7915.45
-292.54
TRTPN*ATPTN Bel300
4
Oxy30
0.5
-1831.85
1938.87 407
-0.94
0.3453 0.05 -5643.30
1979.61
TRTPN*ATPTN Bel300
4
Oxy30
1
21.1604
1899.93 407
0.01
0.9911 0.05 -3713.74
3756.06
TRTPN*ATPTN Bel300
4
Oxy30
2
-834.58
1866.36 407
-0.45
0.6550 0.05 -4503.50
2834.33
TRTPN*ATPTN Bel300
4
Oxy30
3
-2429.42
1866.36 407
-1.30
0.1938 0.05 -6098.34
1239.50
TRTPN*ATPTN Bel300
4
Oxy30
4
-2650.17
1866.36 407
-1.42
0.1564 0.05 -6319.09
1018.74
TRTPN*ATPTN Bel300
4
Oxy60
0
-3015.30
1939.56 407
-1.55
0.1208 0.05 -6828.11
797.51
TRTPN*ATPTN Bel300
4
Oxy60
0.5
-645.46
1939.56 407
-0.33
0.7395 0.05 -4458.27
3167.35
TRTPN*ATPTN Bel300
4
Oxy60
1
1650.41
1900.77 407
0.87
0.3858 0.05 -2086.16
5386.97
TRTPN*ATPTN Bel300
4
Oxy60
2
2872.64
1866.36 407
1.54
0.1245 0.05
-796.28
6541.55
TRTPN*ATPTN Bel300
4
Oxy60
3
2323.16
1866.36 407
1.24
0.2139 0.05 -1345.75
5992.08
TRTPN*ATPTN Bel300
4
Oxy60
4
2203.03
1866.36 407
1.18
0.2385 0.05 -1465.89
5871.95
TRTPN*ATPTN Bel300
4
Plac
0
-2414.16
1865.61 407
-1.29
0.1964 0.05 -6081.59
1253.27
TRTPN*ATPTN Bel300
4
Plac
0.5
-3994.55
1865.61 407
-2.14
0.0329 0.05 -7661.98
-327.12
TRTPN*ATPTN Bel300
4
Plac
1
-4883.81
1865.61 407
-2.62
0.0092 0.05 -8551.24 -1216.38
Page 264 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 13 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
4
Plac
2
-1078.35
1865.61 407
-0.58
0.5636 0.05 -4745.78
2589.08
TRTPN*ATPTN Bel300
4
Plac
3
-880.33
1865.61 407
-0.47
0.6373 0.05 -4547.75
2787.10
TRTPN*ATPTN Bel300
4
Plac
4
-2273.17
1865.61 407
-1.22
0.2238 0.05 -5940.60
1394.26
TRTPN*ATPTN Bel600
0
Bel600
0.5
-900.50
1930.37 407
-0.47
0.6411 0.05 -4695.24
2894.24
TRTPN*ATPTN Bel600
0
Bel600
1
467.56
1899.21 407
0.25
0.8057 0.05 -3265.93
4201.04
TRTPN*ATPTN Bel600
0
Bel600
2
2037.23
1899.21 407
1.07
0.2841 0.05 -1696.26
5770.71
TRTPN*ATPTN Bel600
0
Bel600
3
2626.45
1899.21 407
1.38
0.1674 0.05 -1107.04
6359.93
TRTPN*ATPTN Bel600
0
Bel600
4
2610.19
1899.21 407
1.37
0.1701 0.05 -1123.30
6343.67
TRTPN*ATPTN Bel600
0
Bel900
0
-1576.80
1933.90 407
-0.82
0.4154 0.05 -5378.48
2224.88
TRTPN*ATPTN Bel600
0
Bel900
0.5
-3022.23
1899.91 407
-1.59
0.1124 0.05 -6757.09
712.64
TRTPN*ATPTN Bel600
0
Bel900
1
-202.75
1899.91 407
-0.11
0.9151 0.05 -3937.62
3532.11
TRTPN*ATPTN Bel600
0
Bel900
2
1555.00
1899.91 407
0.82
0.4136 0.05 -2179.86
5289.86
TRTPN*ATPTN Bel600
0
Bel900
3
2235.27
1899.91 407
1.18
0.2401 0.05 -1499.60
5970.13
TRTPN*ATPTN Bel600
0
Bel900
4
3283.75
1899.91 407
1.73
0.0847 0.05
-451.11
7018.62
TRTPN*ATPTN Bel600
0
Oxy30
0
-370.24
1971.65 407
-0.19
0.8511 0.05 -4246.13
3505.65
TRTPN*ATPTN Bel600
0
Oxy30
0.5
1901.91
1971.65 407
0.96
0.3353 0.05 -1973.99
5777.80
TRTPN*ATPTN Bel600
0
Oxy30
1
3754.91
1933.14 407
1.94
0.0528 0.05 -45.2754
7555.10
TRTPN*ATPTN Bel600
0
Oxy30
2
2899.17
1899.96 407
1.53
0.1278 0.05
-835.79
6634.13
TRTPN*ATPTN Bel600
0
Oxy30
3
1304.33
1899.96 407
0.69
0.4928 0.05 -2430.63
5039.29
TRTPN*ATPTN Bel600
0
Oxy30
4
1083.58
1899.96 407
0.57
0.5688 0.05 -2651.38
4818.53
TRTPN*ATPTN Bel600
0
Oxy60
0
718.45
1973.27 407
0.36
0.7160 0.05 -3160.62
4597.53
TRTPN*ATPTN Bel600
0
Oxy60
0.5
3088.30
1973.27 407
1.57
0.1183 0.05
-790.78
6967.37
TRTPN*ATPTN Bel600
0
Oxy60
1
5384.16
1935.61 407
2.78
0.0057 0.05
1579.12
9189.20
TRTPN*ATPTN Bel600
0
Oxy60
2
6606.39
1900.72 407
3.48
0.0006 0.05
2869.93
10343
TRTPN*ATPTN Bel600
0
Oxy60
3
6056.92
1900.72 407
3.19
0.0016 0.05
2320.46
9793.38
Page 265 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 14 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel600
0
Oxy60
4
5936.78
1900.72 407
3.12
0.0019 0.05
2200.32
9673.24
TRTPN*ATPTN Bel600
0
Plac
0
1319.59
1899.90 407
0.69
0.4877 0.05 -2415.26
5054.44
TRTPN*ATPTN Bel600
0
Plac
0.5
-260.80
1899.90 407
-0.14
0.8909 0.05 -3995.64
3474.05
TRTPN*ATPTN Bel600
0
Plac
1
-1150.06
1899.90 407
-0.61
0.5453 0.05 -4884.90
2584.79
TRTPN*ATPTN Bel600
0
Plac
2
2655.41
1899.90 407
1.40
0.1630 0.05 -1079.44
6390.25
TRTPN*ATPTN Bel600
0
Plac
3
2853.43
1899.90 407
1.50
0.1339 0.05
-881.42
6588.27
TRTPN*ATPTN Bel600
0
Plac
4
1460.58
1899.90 407
0.77
0.4425 0.05 -2274.26
5195.43
TRTPN*ATPTN Bel600
0.5
Bel600
1
1368.05
1899.21 407
0.72
0.4717 0.05 -2365.43
5101.54
TRTPN*ATPTN Bel600
0.5
Bel600
2
2937.73
1899.21 407
1.55
0.1227 0.05
-795.76
6671.21
TRTPN*ATPTN Bel600
0.5
Bel600
3
3526.94
1899.21 407
1.86
0.0640 0.05
-206.54
7260.43
TRTPN*ATPTN Bel600
0.5
Bel600
4
3510.68
1899.21 407
1.85
0.0653 0.05
-222.80
7244.17
TRTPN*ATPTN Bel600
0.5
Bel900
0
-676.30
1933.90 407
-0.35
0.7267 0.05 -4477.98
3125.38
TRTPN*ATPTN Bel600
0.5
Bel900
0.5
-2121.73
1899.91 407
-1.12
0.2648 0.05 -5856.59
1613.13
TRTPN*ATPTN Bel600
0.5
Bel900
1
697.74
1899.91 407
0.37
0.7136 0.05 -3037.12
4432.61
TRTPN*ATPTN Bel600
0.5
Bel900
2
2455.50
1899.91 407
1.29
0.1969 0.05 -1279.36
6190.36
TRTPN*ATPTN Bel600
0.5
Bel900
3
3135.76
1899.91 407
1.65
0.0996 0.05
-599.10
6870.63
TRTPN*ATPTN Bel600
0.5
Bel900
4
4184.25
1899.91 407
2.20
0.0282 0.05
449.39
7919.11
TRTPN*ATPTN Bel600
0.5
Oxy30
0
530.25
1971.65 407
0.27
0.7881 0.05 -3345.64
4406.15
TRTPN*ATPTN Bel600
0.5
Oxy30
0.5
2802.40
1971.65 407
1.42
0.1560 0.05 -1073.49
6678.29
TRTPN*ATPTN Bel600
0.5
Oxy30
1
4655.41
1933.14 407
2.41
0.0165 0.05
855.22
8455.60
TRTPN*ATPTN Bel600
0.5
Oxy30
2
3799.67
1899.96 407
2.00
0.0462 0.05
64.7109
7534.62
TRTPN*ATPTN Bel600
0.5
Oxy30
3
2204.83
1899.96 407
1.16
0.2465 0.05 -1530.13
5939.78
TRTPN*ATPTN Bel600
0.5
Oxy30
4
1984.08
1899.96 407
1.04
0.2970 0.05 -1750.88
5719.03
TRTPN*ATPTN Bel600
0.5
Oxy60
0
1618.95
1973.27 407
0.82
0.4124 0.05 -2260.13
5498.03
TRTPN*ATPTN Bel600
0.5
Oxy60
0.5
3988.79
1973.27 407
2.02
0.0439 0.05
109.72
7867.87
Page 266 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 15 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel600
0.5
Oxy60
1
6284.66
1935.61 407
3.25
0.0013 0.05
2479.62
10090
TRTPN*ATPTN Bel600
0.5
Oxy60
2
7506.89
1900.72 407
3.95
<.0001 0.05
3770.43
11243
TRTPN*ATPTN Bel600
0.5
Oxy60
3
6957.41
1900.72 407
3.66
0.0003 0.05
3220.95
10694
TRTPN*ATPTN Bel600
0.5
Oxy60
4
6837.28
1900.72 407
3.60
0.0004 0.05
3100.82
10574
TRTPN*ATPTN Bel600
0.5
Plac
0
2220.09
1899.90 407
1.17
0.2433 0.05 -1514.76
5954.93
TRTPN*ATPTN Bel600
0.5
Plac
0.5
639.70
1899.90 407
0.34
0.7365 0.05 -3095.15
4374.55
TRTPN*ATPTN Bel600
0.5
Plac
1
-249.56
1899.90 407
-0.13
0.8956 0.05 -3984.41
3485.29
TRTPN*ATPTN Bel600
0.5
Plac
2
3555.90
1899.90 407
1.87
0.0620 0.05
-178.94
7290.75
TRTPN*ATPTN Bel600
0.5
Plac
3
3753.92
1899.90 407
1.98
0.0488 0.05
19.0786
7488.77
TRTPN*ATPTN Bel600
0.5
Plac
4
2361.08
1899.90 407
1.24
0.2147 0.05 -1373.77
6095.93
TRTPN*ATPTN Bel600
1
Bel600
2
1569.67
1864.91 407
0.84
0.4005 0.05 -2096.39
5235.74
TRTPN*ATPTN Bel600
1
Bel600
3
2158.89
1864.91 407
1.16
0.2477 0.05 -1507.18
5824.96
TRTPN*ATPTN Bel600
1
Bel600
4
2142.63
1864.91 407
1.15
0.2513 0.05 -1523.44
5808.70
TRTPN*ATPTN Bel600
1
Bel900
0
-2044.36
1900.65 407
-1.08
0.2827 0.05 -5780.66
1691.95
TRTPN*ATPTN Bel600
1
Bel900
0.5
-3489.78
1866.36 407
-1.87
0.0622 0.05 -7158.69
179.13
TRTPN*ATPTN Bel600
1
Bel900
1
-670.31
1866.36 407
-0.36
0.7197 0.05 -4339.22
2998.60
TRTPN*ATPTN Bel600
1
Bel900
2
1087.45
1866.36 407
0.58
0.5604 0.05 -2581.47
4756.36
TRTPN*ATPTN Bel600
1
Bel900
3
1767.71
1866.36 407
0.95
0.3441 0.05 -1901.20
5436.62
TRTPN*ATPTN Bel600
1
Bel900
4
2816.20
1866.36 407
1.51
0.1321 0.05
-852.71
6485.11
TRTPN*ATPTN Bel600
1
Oxy30
0
-837.80
1939.83 407
-0.43
0.6660 0.05 -4651.14
2975.54
TRTPN*ATPTN Bel600
1
Oxy30
0.5
1434.35
1939.83 407
0.74
0.4601 0.05 -2378.99
5247.69
TRTPN*ATPTN Bel600
1
Oxy30
1
3287.36
1900.00 407
1.73
0.0844 0.05
-447.69
7022.40
TRTPN*ATPTN Bel600
1
Oxy30
2
2431.61
1865.62 407
1.30
0.1932 0.05 -1235.83
6099.06
TRTPN*ATPTN Bel600
1
Oxy30
3
836.78
1865.62 407
0.45
0.6540 0.05 -2830.67
4504.22
TRTPN*ATPTN Bel600
1
Oxy30
4
616.02
1865.62 407
0.33
0.7414 0.05 -3051.42
4283.47
Page 267 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 16 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel600
1
Oxy60
0
250.90
1940.37 407
0.13
0.8972 0.05 -3563.50
4065.30
TRTPN*ATPTN Bel600
1
Oxy60
0.5
2620.74
1940.37 407
1.35
0.1776 0.05 -1193.66
6435.14
TRTPN*ATPTN Bel600
1
Oxy60
1
4916.60
1901.48 407
2.59
0.0101 0.05
1178.66
8654.55
TRTPN*ATPTN Bel600
1
Oxy60
2
6138.83
1866.33 407
3.29
0.0011 0.05
2469.98
9807.69
TRTPN*ATPTN Bel600
1
Oxy60
3
5589.36
1866.33 407
2.99
0.0029 0.05
1920.50
9258.22
TRTPN*ATPTN Bel600
1
Oxy60
4
5469.23
1866.33 407
2.93
0.0036 0.05
1800.37
9138.08
TRTPN*ATPTN Bel600
1
Plac
0
852.03
1866.36 407
0.46
0.6483 0.05 -2816.87
4520.94
TRTPN*ATPTN Bel600
1
Plac
0.5
-728.35
1866.36 407
-0.39
0.6966 0.05 -4397.26
2940.55
TRTPN*ATPTN Bel600
1
Plac
1
-1617.61
1866.36 407
-0.87
0.3866 0.05 -5286.52
2051.29
TRTPN*ATPTN Bel600
1
Plac
2
2187.85
1866.36 407
1.17
0.2418 0.05 -1481.05
5856.75
TRTPN*ATPTN Bel600
1
Plac
3
2385.87
1866.36 407
1.28
0.2019 0.05 -1283.03
6054.78
TRTPN*ATPTN Bel600
1
Plac
4
993.03
1866.36 407
0.53
0.5950 0.05 -2675.88
4661.93
TRTPN*ATPTN Bel600
2
Bel600
3
589.22
1864.91 407
0.32
0.7522 0.05 -3076.85
4255.28
TRTPN*ATPTN Bel600
2
Bel600
4
572.96
1864.91 407
0.31
0.7588 0.05 -3093.11
4239.02
TRTPN*ATPTN Bel600
2
Bel900
0
-3614.03
1900.65 407
-1.90
0.0579 0.05 -7350.33
122.28
TRTPN*ATPTN Bel600
2
Bel900
0.5
-5059.45
1866.36 407
-2.71
0.0070 0.05 -8728.37 -1390.54
TRTPN*ATPTN Bel600
2
Bel900
1
-2239.98
1866.36 407
-1.20
0.2308 0.05 -5908.89
1428.93
TRTPN*ATPTN Bel600
2
Bel900
2
-482.23
1866.36 407
-0.26
0.7962 0.05 -4151.14
3186.69
TRTPN*ATPTN Bel600
2
Bel900
3
198.04
1866.36 407
0.11
0.9155 0.05 -3470.87
3866.95
TRTPN*ATPTN Bel600
2
Bel900
4
1246.53
1866.36 407
0.67
0.5046 0.05 -2422.39
4915.44
TRTPN*ATPTN Bel600
2
Oxy30
0
-2407.47
1939.83 407
-1.24
0.2153 0.05 -6220.81
1405.87
TRTPN*ATPTN Bel600
2
Oxy30
0.5
-135.32
1939.83 407
-0.07
0.9444 0.05 -3948.66
3678.02
TRTPN*ATPTN Bel600
2
Oxy30
1
1717.69
1900.00 407
0.90
0.3665 0.05 -2017.36
5452.73
TRTPN*ATPTN Bel600
2
Oxy30
2
861.94
1865.62 407
0.46
0.6443 0.05 -2805.51
4529.39
TRTPN*ATPTN Bel600
2
Oxy30
3
-732.90
1865.62 407
-0.39
0.6946 0.05 -4400.34
2934.55
Page 268 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 17 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel600
2
Oxy30
4
-953.65
1865.62 407
-0.51
0.6095 0.05 -4621.10
2713.80
TRTPN*ATPTN Bel600
2
Oxy60
0
-1318.78
1940.37 407
-0.68
0.4971 0.05 -5133.18
2495.63
TRTPN*ATPTN Bel600
2
Oxy60
0.5
1051.07
1940.37 407
0.54
0.5883 0.05 -2763.33
4865.47
TRTPN*ATPTN Bel600
2
Oxy60
1
3346.93
1901.48 407
1.76
0.0791 0.05
-391.02
7084.88
TRTPN*ATPTN Bel600
2
Oxy60
2
4569.16
1866.33 407
2.45
0.0148 0.05
900.31
8238.02
TRTPN*ATPTN Bel600
2
Oxy60
3
4019.69
1866.33 407
2.15
0.0318 0.05
350.83
7688.54
TRTPN*ATPTN Bel600
2
Oxy60
4
3899.55
1866.33 407
2.09
0.0373 0.05
230.70
7568.41
TRTPN*ATPTN Bel600
2
Plac
0
-717.64
1866.36 407
-0.38
0.7008 0.05 -4386.54
2951.27
TRTPN*ATPTN Bel600
2
Plac
0.5
-2298.02
1866.36 407
-1.23
0.2189 0.05 -5966.93
1370.88
TRTPN*ATPTN Bel600
2
Plac
1
-3187.28
1866.36 407
-1.71
0.0884 0.05 -6856.19
481.62
TRTPN*ATPTN Bel600
2
Plac
2
618.18
1866.36 407
0.33
0.7406 0.05 -3050.73
4287.08
TRTPN*ATPTN Bel600
2
Plac
3
816.20
1866.36 407
0.44
0.6621 0.05 -2852.71
4485.10
TRTPN*ATPTN Bel600
2
Plac
4
-576.64
1866.36 407
-0.31
0.7575 0.05 -4245.55
3092.26
TRTPN*ATPTN Bel600
3
Bel600
4
-16.2605
1864.91 407
-0.01
0.9930 0.05 -3682.33
3649.81
TRTPN*ATPTN Bel600
3
Bel900
0
-4203.25
1900.65 407
-2.21
0.0276 0.05 -7939.55
-466.94
TRTPN*ATPTN Bel600
3
Bel900
0.5
-5648.67
1866.36 407
-3.03
0.0026 0.05 -9317.58 -1979.76
TRTPN*ATPTN Bel600
3
Bel900
1
-2829.20
1866.36 407
-1.52
0.1303 0.05 -6498.11
839.71
TRTPN*ATPTN Bel600
3
Bel900
2
-1071.44
1866.36 407
-0.57
0.5662 0.05 -4740.36
2597.47
TRTPN*ATPTN Bel600
3
Bel900
3
-391.18
1866.36 407
-0.21
0.8341 0.05 -4060.09
3277.73
TRTPN*ATPTN Bel600
3
Bel900
4
657.31
1866.36 407
0.35
0.7249 0.05 -3011.60
4326.22
TRTPN*ATPTN Bel600
3
Oxy30
0
-2996.69
1939.83 407
-1.54
0.1232 0.05 -6810.03
816.65
TRTPN*ATPTN Bel600
3
Oxy30
0.5
-724.54
1939.83 407
-0.37
0.7090 0.05 -4537.88
3088.80
TRTPN*ATPTN Bel600
3
Oxy30
1
1128.47
1900.00 407
0.59
0.5529 0.05 -2606.58
4863.51
TRTPN*ATPTN Bel600
3
Oxy30
2
272.72
1865.62 407
0.15
0.8838 0.05 -3394.72
3940.17
TRTPN*ATPTN Bel600
3
Oxy30
3
-1322.11
1865.62 407
-0.71
0.4789 0.05 -4989.56
2345.33
Page 269 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 18 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel600
3
Oxy30
4
-1542.87
1865.62 407
-0.83
0.4087 0.05 -5210.31
2124.58
TRTPN*ATPTN Bel600
3
Oxy60
0
-1907.99
1940.37 407
-0.98
0.3260 0.05 -5722.39
1906.41
TRTPN*ATPTN Bel600
3
Oxy60
0.5
461.85
1940.37 407
0.24
0.8120 0.05 -3352.55
4276.25
TRTPN*ATPTN Bel600
3
Oxy60
1
2757.71
1901.48 407
1.45
0.1477 0.05
-980.23
6495.66
TRTPN*ATPTN Bel600
3
Oxy60
2
3979.94
1866.33 407
2.13
0.0336 0.05
311.09
7648.80
TRTPN*ATPTN Bel600
3
Oxy60
3
3430.47
1866.33 407
1.84
0.0668 0.05
-238.39
7099.33
TRTPN*ATPTN Bel600
3
Oxy60
4
3310.34
1866.33 407
1.77
0.0769 0.05
-358.52
6979.19
TRTPN*ATPTN Bel600
3
Plac
0
-1306.86
1866.36 407
-0.70
0.4842 0.05 -4975.76
2362.05
TRTPN*ATPTN Bel600
3
Plac
0.5
-2887.24
1866.36 407
-1.55
0.1226 0.05 -6556.15
781.66
TRTPN*ATPTN Bel600
3
Plac
1
-3776.50
1866.36 407
-2.02
0.0437 0.05 -7445.41
-107.60
TRTPN*ATPTN Bel600
3
Plac
2
28.9600
1866.36 407
0.02
0.9876 0.05 -3639.94
3697.86
TRTPN*ATPTN Bel600
3
Plac
3
226.98
1866.36 407
0.12
0.9033 0.05 -3441.92
3895.89
TRTPN*ATPTN Bel600
3
Plac
4
-1165.86
1866.36 407
-0.62
0.5325 0.05 -4834.77
2503.04
TRTPN*ATPTN Bel600
4
Bel900
0
-4186.98
1900.65 407
-2.20
0.0282 0.05 -7923.29
-450.68
TRTPN*ATPTN Bel600
4
Bel900
0.5
-5632.41
1866.36 407
-3.02
0.0027 0.05 -9301.32 -1963.50
TRTPN*ATPTN Bel600
4
Bel900
1
-2812.94
1866.36 407
-1.51
0.1325 0.05 -6481.85
855.97
TRTPN*ATPTN Bel600
4
Bel900
2
-1055.18
1866.36 407
-0.57
0.5721 0.05 -4724.10
2613.73
TRTPN*ATPTN Bel600
4
Bel900
3
-374.92
1866.36 407
-0.20
0.8409 0.05 -4043.83
3293.99
TRTPN*ATPTN Bel600
4
Bel900
4
673.57
1866.36 407
0.36
0.7184 0.05 -2995.34
4342.48
TRTPN*ATPTN Bel600
4
Oxy30
0
-2980.43
1939.83 407
-1.54
0.1252 0.05 -6793.77
832.91
TRTPN*ATPTN Bel600
4
Oxy30
0.5
-708.28
1939.83 407
-0.37
0.7152 0.05 -4521.62
3105.06
TRTPN*ATPTN Bel600
4
Oxy30
1
1144.73
1900.00 407
0.60
0.5472 0.05 -2590.32
4879.77
TRTPN*ATPTN Bel600
4
Oxy30
2
288.98
1865.62 407
0.15
0.8770 0.05 -3378.46
3956.43
TRTPN*ATPTN Bel600
4
Oxy30
3
-1305.85
1865.62 407
-0.70
0.4844 0.05 -4973.30
2361.59
TRTPN*ATPTN Bel600
4
Oxy30
4
-1526.61
1865.62 407
-0.82
0.4137 0.05 -5194.05
2140.84
Page 270 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 19 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel600
4
Oxy60
0
-1891.73
1940.37 407
-0.97
0.3302 0.05 -5706.13
1922.67
TRTPN*ATPTN Bel600
4
Oxy60
0.5
478.11
1940.37 407
0.25
0.8055 0.05 -3336.29
4292.51
TRTPN*ATPTN Bel600
4
Oxy60
1
2773.97
1901.48 407
1.46
0.1454 0.05
-963.97
6511.92
TRTPN*ATPTN Bel600
4
Oxy60
2
3996.20
1866.33 407
2.14
0.0329 0.05
327.35
7665.06
TRTPN*ATPTN Bel600
4
Oxy60
3
3446.73
1866.33 407
1.85
0.0655 0.05
-222.12
7115.59
TRTPN*ATPTN Bel600
4
Oxy60
4
3326.60
1866.33 407
1.78
0.0754 0.05
-342.26
6995.45
TRTPN*ATPTN Bel600
4
Plac
0
-1290.60
1866.36 407
-0.69
0.4896 0.05 -4959.50
2378.31
TRTPN*ATPTN Bel600
4
Plac
0.5
-2870.98
1866.36 407
-1.54
0.1248 0.05 -6539.89
797.92
TRTPN*ATPTN Bel600
4
Plac
1
-3760.24
1866.36 407
-2.01
0.0446 0.05 -7429.15 -91.3370
TRTPN*ATPTN Bel600
4
Plac
2
45.2205
1866.36 407
0.02
0.9807 0.05 -3623.68
3714.13
TRTPN*ATPTN Bel600
4
Plac
3
243.24
1866.36 407
0.13
0.8964 0.05 -3425.66
3912.15
TRTPN*ATPTN Bel600
4
Plac
4
-1149.60
1866.36 407
-0.62
0.5383 0.05 -4818.51
2519.30
TRTPN*ATPTN Bel900
0
Bel900
0.5
-1445.43
1899.15 407
-0.76
0.4470 0.05 -5178.80
2287.94
TRTPN*ATPTN Bel900
0
Bel900
1
1374.05
1899.15 407
0.72
0.4698 0.05 -2359.32
5107.42
TRTPN*ATPTN Bel900
0
Bel900
2
3131.80
1899.15 407
1.65
0.0999 0.05
-601.57
6865.17
TRTPN*ATPTN Bel900
0
Bel900
3
3812.07
1899.15 407
2.01
0.0454 0.05
78.6944
7545.44
TRTPN*ATPTN Bel900
0
Bel900
4
4860.55
1899.15 407
2.56
0.0108 0.05
1127.18
8593.93
TRTPN*ATPTN Bel900
0
Oxy30
0
1206.56
1972.55 407
0.61
0.5411 0.05 -2671.09
5084.21
TRTPN*ATPTN Bel900
0
Oxy30
0.5
3478.71
1972.55 407
1.76
0.0786 0.05
-398.94
7356.35
TRTPN*ATPTN Bel900
0
Oxy30
1
5331.71
1933.93 407
2.76
0.0061 0.05
1529.98
9133.44
TRTPN*ATPTN Bel900
0
Oxy30
2
4475.97
1900.64 407
2.35
0.0190 0.05
739.68
8212.26
TRTPN*ATPTN Bel900
0
Oxy30
3
2881.13
1900.64 407
1.52
0.1303 0.05
-855.16
6617.42
TRTPN*ATPTN Bel900
0
Oxy30
4
2660.38
1900.64 407
1.40
0.1624 0.05 -1075.92
6396.67
TRTPN*ATPTN Bel900
0
Oxy60
0
2295.25
1970.63 407
1.16
0.2448 0.05 -1578.63
6169.13
TRTPN*ATPTN Bel900
0
Oxy60
0.5
4665.10
1970.63 407
2.37
0.0184 0.05
791.22
8538.98
Page 271 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 20 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel900
0
Oxy60
1
6960.96
1933.11 407
3.60
0.0004 0.05
3160.84
10761
TRTPN*ATPTN Bel900
0
Oxy60
2
8183.19
1899.14 407
4.31
<.0001 0.05
4449.84
11917
TRTPN*ATPTN Bel900
0
Oxy60
3
7633.72
1899.14 407
4.02
<.0001 0.05
3900.36
11367
TRTPN*ATPTN Bel900
0
Oxy60
4
7513.58
1899.14 407
3.96
<.0001 0.05
3780.23
11247
TRTPN*ATPTN Bel900
0
Plac
0
2896.39
1899.87 407
1.52
0.1282 0.05
-838.39
6631.17
TRTPN*ATPTN Bel900
0
Plac
0.5
1316.00
1899.87 407
0.69
0.4889 0.05 -2418.78
5050.78
TRTPN*ATPTN Bel900
0
Plac
1
426.74
1899.87 407
0.22
0.8224 0.05 -3308.04
4161.53
TRTPN*ATPTN Bel900
0
Plac
2
4232.21
1899.87 407
2.23
0.0265 0.05
497.42
7966.99
TRTPN*ATPTN Bel900
0
Plac
3
4430.23
1899.87 407
2.33
0.0202 0.05
695.44
8165.01
TRTPN*ATPTN Bel900
0
Plac
4
3037.38
1899.87 407
1.60
0.1107 0.05
-697.40
6772.17
TRTPN*ATPTN Bel900
0.5
Bel900
1
2819.47
1864.91 407
1.51
0.1313 0.05
-846.59
6485.54
TRTPN*ATPTN Bel900
0.5
Bel900
2
4577.23
1864.91 407
2.45
0.0145 0.05
911.16
8243.29
TRTPN*ATPTN Bel900
0.5
Bel900
3
5257.49
1864.91 407
2.82
0.0051 0.05
1591.43
8923.56
TRTPN*ATPTN Bel900
0.5
Bel900
4
6305.98
1864.91 407
3.38
0.0008 0.05
2639.92
9972.05
TRTPN*ATPTN Bel900
0.5
Oxy30
0
2651.98
1938.86 407
1.37
0.1721 0.05 -1159.45
6463.42
TRTPN*ATPTN Bel900
0.5
Oxy30
0.5
4924.13
1938.86 407
2.54
0.0115 0.05
1112.69
8735.57
TRTPN*ATPTN Bel900
0.5
Oxy30
1
6777.14
1899.92 407
3.57
0.0004 0.05
3042.26
10512
TRTPN*ATPTN Bel900
0.5
Oxy30
2
5921.40
1866.35 407
3.17
0.0016 0.05
2252.51
9590.28
TRTPN*ATPTN Bel900
0.5
Oxy30
3
4326.56
1866.35 407
2.32
0.0209 0.05
657.67
7995.44
TRTPN*ATPTN Bel900
0.5
Oxy30
4
4105.80
1866.35 407
2.20
0.0284 0.05
436.92
7774.69
TRTPN*ATPTN Bel900
0.5
Oxy60
0
3740.68
1937.93 407
1.93
0.0543 0.05 -68.9214
7550.28
TRTPN*ATPTN Bel900
0.5
Oxy60
0.5
6110.52
1937.93 407
3.15
0.0017 0.05
2300.92
9920.12
TRTPN*ATPTN Bel900
0.5
Oxy60
1
8406.39
1900.81 407
4.42
<.0001 0.05
4669.76
12143
TRTPN*ATPTN Bel900
0.5
Oxy60
2
9628.62
1865.66 407
5.16
<.0001 0.05
5961.08
13296
TRTPN*ATPTN Bel900
0.5
Oxy60
3
9079.14
1865.66 407
4.87
<.0001 0.05
5411.61
12747
Page 272 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 21 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel900
0.5
Oxy60
4
8959.01
1865.66 407
4.80
<.0001 0.05
5291.47
12627
TRTPN*ATPTN Bel900
0.5
Plac
0
4341.82
1866.33 407
2.33
0.0205 0.05
672.97
8010.66
TRTPN*ATPTN Bel900
0.5
Plac
0.5
2761.43
1866.33 407
1.48
0.1398 0.05
-907.42
6430.27
TRTPN*ATPTN Bel900
0.5
Plac
1
1872.17
1866.33 407
1.00
0.3164 0.05 -1796.68
5541.02
TRTPN*ATPTN Bel900
0.5
Plac
2
5677.63
1866.33 407
3.04
0.0025 0.05
2008.79
9346.48
TRTPN*ATPTN Bel900
0.5
Plac
3
5875.65
1866.33 407
3.15
0.0018 0.05
2206.81
9544.50
TRTPN*ATPTN Bel900
0.5
Plac
4
4482.81
1866.33 407
2.40
0.0168 0.05
813.96
8151.66
TRTPN*ATPTN Bel900
1
Bel900
2
1757.75
1864.91 407
0.94
0.3465 0.05 -1908.31
5423.82
TRTPN*ATPTN Bel900
1
Bel900
3
2438.02
1864.91 407
1.31
0.1918 0.05 -1228.05
6104.08
TRTPN*ATPTN Bel900
1
Bel900
4
3486.51
1864.91 407
1.87
0.0623 0.05
-179.56
7152.57
TRTPN*ATPTN Bel900
1
Oxy30
0
-167.49
1938.86 407
-0.09
0.9312 0.05 -3978.93
3643.95
TRTPN*ATPTN Bel900
1
Oxy30
0.5
2104.66
1938.86 407
1.09
0.2783 0.05 -1706.78
5916.10
TRTPN*ATPTN Bel900
1
Oxy30
1
3957.67
1899.92 407
2.08
0.0379 0.05
222.79
7692.54
TRTPN*ATPTN Bel900
1
Oxy30
2
3101.92
1866.35 407
1.66
0.0973 0.05
-566.96
6770.81
TRTPN*ATPTN Bel900
1
Oxy30
3
1507.08
1866.35 407
0.81
0.4198 0.05 -2161.80
5175.97
TRTPN*ATPTN Bel900
1
Oxy30
4
1286.33
1866.35 407
0.69
0.4911 0.05 -2382.56
4955.22
TRTPN*ATPTN Bel900
1
Oxy60
0
921.20
1937.93 407
0.48
0.6348 0.05 -2888.39
4730.80
TRTPN*ATPTN Bel900
1
Oxy60
0.5
3291.05
1937.93 407
1.70
0.0902 0.05
-518.55
7100.65
TRTPN*ATPTN Bel900
1
Oxy60
1
5586.91
1900.81 407
2.94
0.0035 0.05
1850.29
9323.53
TRTPN*ATPTN Bel900
1
Oxy60
2
6809.14
1865.66 407
3.65
0.0003 0.05
3141.61
10477
TRTPN*ATPTN Bel900
1
Oxy60
3
6259.67
1865.66 407
3.36
0.0009 0.05
2592.14
9927.20
TRTPN*ATPTN Bel900
1
Oxy60
4
6139.53
1865.66 407
3.29
0.0011 0.05
2472.00
9807.07
TRTPN*ATPTN Bel900
1
Plac
0
1522.34
1866.33 407
0.82
0.4152 0.05 -2146.50
5191.19
TRTPN*ATPTN Bel900
1
Plac
0.5
-58.0443
1866.33 407
-0.03
0.9752 0.05 -3726.89
3610.80
TRTPN*ATPTN Bel900
1
Plac
1
-947.30
1866.33 407
-0.51
0.6120 0.05 -4616.15
2721.54
Page 273 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 22 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel900
1
Plac
2
2858.16
1866.33 407
1.53
0.1264 0.05
-810.69
6527.00
TRTPN*ATPTN Bel900
1
Plac
3
3056.18
1866.33 407
1.64
0.1023 0.05
-612.67
6725.03
TRTPN*ATPTN Bel900
1
Plac
4
1663.34
1866.33 407
0.89
0.3733 0.05 -2005.51
5332.18
TRTPN*ATPTN Bel900
2
Bel900
3
680.26
1864.91 407
0.36
0.7155 0.05 -2985.80
4346.33
TRTPN*ATPTN Bel900
2
Bel900
4
1728.75
1864.91 407
0.93
0.3545 0.05 -1937.31
5394.82
TRTPN*ATPTN Bel900
2
Oxy30
0
-1925.24
1938.86 407
-0.99
0.3213 0.05 -5736.68
1886.19
TRTPN*ATPTN Bel900
2
Oxy30
0.5
346.90
1938.86 407
0.18
0.8581 0.05 -3464.53
4158.34
TRTPN*ATPTN Bel900
2
Oxy30
1
2199.91
1899.92 407
1.16
0.2476 0.05 -1534.96
5934.79
TRTPN*ATPTN Bel900
2
Oxy30
2
1344.17
1866.35 407
0.72
0.4718 0.05 -2324.72
5013.06
TRTPN*ATPTN Bel900
2
Oxy30
3
-250.67
1866.35 407
-0.13
0.8932 0.05 -3919.56
3418.22
TRTPN*ATPTN Bel900
2
Oxy30
4
-471.42
1866.35 407
-0.25
0.8007 0.05 -4140.31
3197.46
TRTPN*ATPTN Bel900
2
Oxy60
0
-836.55
1937.93 407
-0.43
0.6662 0.05 -4646.15
2973.05
TRTPN*ATPTN Bel900
2
Oxy60
0.5
1533.29
1937.93 407
0.79
0.4293 0.05 -2276.31
5342.89
TRTPN*ATPTN Bel900
2
Oxy60
1
3829.16
1900.81 407
2.01
0.0446 0.05
92.5345
7565.78
TRTPN*ATPTN Bel900
2
Oxy60
2
5051.39
1865.66 407
2.71
0.0071 0.05
1383.85
8718.92
TRTPN*ATPTN Bel900
2
Oxy60
3
4501.91
1865.66 407
2.41
0.0163 0.05
834.38
8169.45
TRTPN*ATPTN Bel900
2
Oxy60
4
4381.78
1865.66 407
2.35
0.0193 0.05
714.25
8049.31
TRTPN*ATPTN Bel900
2
Plac
0
-235.41
1866.33 407
-0.13
0.8997 0.05 -3904.26
3433.43
TRTPN*ATPTN Bel900
2
Plac
0.5
-1815.80
1866.33 407
-0.97
0.3312 0.05 -5484.64
1853.05
TRTPN*ATPTN Bel900
2
Plac
1
-2705.06
1866.33 407
-1.45
0.1480 0.05 -6373.90
963.79
TRTPN*ATPTN Bel900
2
Plac
2
1100.40
1866.33 407
0.59
0.5558 0.05 -2568.44
4769.25
TRTPN*ATPTN Bel900
2
Plac
3
1298.43
1866.33 407
0.70
0.4870 0.05 -2370.42
4967.27
TRTPN*ATPTN Bel900
2
Plac
4
-94.4181
1866.33 407
-0.05
0.9597 0.05 -3763.26
3574.43
TRTPN*ATPTN Bel900
3
Bel900
4
1048.49
1864.91 407
0.56
0.5743 0.05 -2617.58
4714.55
TRTPN*ATPTN Bel900
3
Oxy30
0
-2605.51
1938.86 407
-1.34
0.1798 0.05 -6416.95
1205.93
Page 274 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 23 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel900
3
Oxy30
0.5
-333.36
1938.86 407
-0.17
0.8636 0.05 -4144.80
3478.08
TRTPN*ATPTN Bel900
3
Oxy30
1
1519.65
1899.92 407
0.80
0.4243 0.05 -2215.23
5254.52
TRTPN*ATPTN Bel900
3
Oxy30
2
663.90
1866.35 407
0.36
0.7222 0.05 -3004.98
4332.79
TRTPN*ATPTN Bel900
3
Oxy30
3
-930.93
1866.35 407
-0.50
0.6182 0.05 -4599.82
2737.95
TRTPN*ATPTN Bel900
3
Oxy30
4
-1151.69
1866.35 407
-0.62
0.5375 0.05 -4820.57
2517.20
TRTPN*ATPTN Bel900
3
Oxy60
0
-1516.81
1937.93 407
-0.78
0.4343 0.05 -5326.41
2292.79
TRTPN*ATPTN Bel900
3
Oxy60
0.5
853.03
1937.93 407
0.44
0.6600 0.05 -2956.57
4662.63
TRTPN*ATPTN Bel900
3
Oxy60
1
3148.89
1900.81 407
1.66
0.0984 0.05
-587.73
6885.52
TRTPN*ATPTN Bel900
3
Oxy60
2
4371.12
1865.66 407
2.34
0.0196 0.05
703.59
8038.66
TRTPN*ATPTN Bel900
3
Oxy60
3
3821.65
1865.66 407
2.05
0.0412 0.05
154.12
7489.18
TRTPN*ATPTN Bel900
3
Oxy60
4
3701.52
1865.66 407
1.98
0.0479 0.05
33.9823
7369.05
TRTPN*ATPTN Bel900
3
Plac
0
-915.68
1866.33 407
-0.49
0.6240 0.05 -4584.52
2753.17
TRTPN*ATPTN Bel900
3
Plac
0.5
-2496.06
1866.33 407
-1.34
0.1818 0.05 -6164.91
1172.78
TRTPN*ATPTN Bel900
3
Plac
1
-3385.32
1866.33 407
-1.81
0.0704 0.05 -7054.17
283.52
TRTPN*ATPTN Bel900
3
Plac
2
420.14
1866.33 407
0.23
0.8220 0.05 -3248.71
4088.99
TRTPN*ATPTN Bel900
3
Plac
3
618.16
1866.33 407
0.33
0.7407 0.05 -3050.68
4287.01
TRTPN*ATPTN Bel900
3
Plac
4
-774.68
1866.33 407
-0.42
0.6783 0.05 -4443.53
2894.16
TRTPN*ATPTN Bel900
4
Oxy30
0
-3654.00
1938.86 407
-1.88
0.0602 0.05 -7465.44
157.44
TRTPN*ATPTN Bel900
4
Oxy30
0.5
-1381.85
1938.86 407
-0.71
0.4764 0.05 -5193.29
2429.59
TRTPN*ATPTN Bel900
4
Oxy30
1
471.16
1899.92 407
0.25
0.8043 0.05 -3263.72
4206.03
TRTPN*ATPTN Bel900
4
Oxy30
2
-384.59
1866.35 407
-0.21
0.8368 0.05 -4053.47
3284.30
TRTPN*ATPTN Bel900
4
Oxy30
3
-1979.42
1866.35 407
-1.06
0.2895 0.05 -5648.31
1689.46
TRTPN*ATPTN Bel900
4
Oxy30
4
-2200.18
1866.35 407
-1.18
0.2391 0.05 -5869.06
1468.71
TRTPN*ATPTN Bel900
4
Oxy60
0
-2565.30
1937.93 407
-1.32
0.1863 0.05 -6374.90
1244.30
TRTPN*ATPTN Bel900
4
Oxy60
0.5
-195.46
1937.93 407
-0.10
0.9197 0.05 -4005.06
3614.14
Page 275 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 24 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel900
4
Oxy60
1
2100.40
1900.81 407
1.11
0.2698 0.05 -1636.22
5837.03
TRTPN*ATPTN Bel900
4
Oxy60
2
3322.64
1865.66 407
1.78
0.0757 0.05
-344.90
6990.17
TRTPN*ATPTN Bel900
4
Oxy60
3
2773.16
1865.66 407
1.49
0.1379 0.05
-894.37
6440.69
TRTPN*ATPTN Bel900
4
Oxy60
4
2653.03
1865.66 407
1.42
0.1558 0.05 -1014.51
6320.56
TRTPN*ATPTN Bel900
4
Plac
0
-1964.16
1866.33 407
-1.05
0.2932 0.05 -5633.01
1704.68
TRTPN*ATPTN Bel900
4
Plac
0.5
-3544.55
1866.33 407
-1.90
0.0582 0.05 -7213.40
124.29
TRTPN*ATPTN Bel900
4
Plac
1
-4433.81
1866.33 407
-2.38
0.0180 0.05 -8102.66
-764.97
TRTPN*ATPTN Bel900
4
Plac
2
-628.35
1866.33 407
-0.34
0.7365 0.05 -4297.19
3040.50
TRTPN*ATPTN Bel900
4
Plac
3
-430.33
1866.33 407
-0.23
0.8178 0.05 -4099.17
3238.52
TRTPN*ATPTN Bel900
4
Plac
4
-1823.17
1866.33 407
-0.98
0.3292 0.05 -5492.02
1845.67
TRTPN*ATPTN Oxy30
0
Oxy30
0.5
2272.15
2003.24 407
1.13
0.2574 0.05 -1665.84
6210.13
TRTPN*ATPTN Oxy30
0
Oxy30
1
4125.16
1968.65 407
2.10
0.0368 0.05
255.17
7995.14
TRTPN*ATPTN Oxy30
0
Oxy30
2
3269.41
1939.06 407
1.69
0.0925 0.05
-542.40
7081.23
TRTPN*ATPTN Oxy30
0
Oxy30
3
1674.57
1939.06 407
0.86
0.3883 0.05 -2137.24
5486.39
TRTPN*ATPTN Oxy30
0
Oxy30
4
1453.82
1939.06 407
0.75
0.4538 0.05 -2357.99
5265.63
TRTPN*ATPTN Oxy30
0
Oxy60
0
1088.69
2010.59 407
0.54
0.5885 0.05 -2863.74
5041.13
TRTPN*ATPTN Oxy30
0
Oxy60
0.5
3458.54
2010.59 407
1.72
0.0862 0.05
-493.90
7410.98
TRTPN*ATPTN Oxy30
0
Oxy60
1
5754.40
1975.27 407
2.91
0.0038 0.05
1871.40
9637.40
TRTPN*ATPTN Oxy30
0
Oxy60
2
6976.63
1940.65 407
3.59
0.0004 0.05
3161.68
10792
TRTPN*ATPTN Oxy30
0
Oxy60
3
6427.16
1940.65 407
3.31
0.0010 0.05
2612.20
10242
TRTPN*ATPTN Oxy30
0
Oxy60
4
6307.02
1940.65 407
3.25
0.0013 0.05
2492.07
10122
TRTPN*ATPTN Oxy30
0
Plac
0
1689.83
1938.87 407
0.87
0.3840 0.05 -2121.62
5501.29
TRTPN*ATPTN Oxy30
0
Plac
0.5
109.45
1938.87 407
0.06
0.9550 0.05 -3702.01
3920.90
TRTPN*ATPTN Oxy30
0
Plac
1
-779.81
1938.87 407
-0.40
0.6877 0.05 -4591.27
3031.64
TRTPN*ATPTN Oxy30
0
Plac
2
3025.65
1938.87 407
1.56
0.1194 0.05
-785.81
6837.10
Page 276 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 25 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Oxy30
0
Plac
3
3223.67
1938.87 407
1.66
0.0972 0.05
-587.79
7035.13
TRTPN*ATPTN Oxy30
0
Plac
4
1830.83
1938.87 407
0.94
0.3456 0.05 -1980.63
5642.28
TRTPN*ATPTN Oxy30
0.5
Oxy30
1
1853.01
1968.65 407
0.94
0.3471 0.05 -2016.98
5722.99
TRTPN*ATPTN Oxy30
0.5
Oxy30
2
997.26
1939.06 407
0.51
0.6073 0.05 -2814.55
4809.08
TRTPN*ATPTN Oxy30
0.5
Oxy30
3
-597.57
1939.06 407
-0.31
0.7581 0.05 -4409.39
3214.24
TRTPN*ATPTN Oxy30
0.5
Oxy30
4
-818.33
1939.06 407
-0.42
0.6732 0.05 -4630.14
2993.49
TRTPN*ATPTN Oxy30
0.5
Oxy60
0
-1183.45
2010.59 407
-0.59
0.5564 0.05 -5135.89
2768.98
TRTPN*ATPTN Oxy30
0.5
Oxy60
0.5
1186.39
2010.59 407
0.59
0.5555 0.05 -2766.05
5138.83
TRTPN*ATPTN Oxy30
0.5
Oxy60
1
3482.25
1975.27 407
1.76
0.0787 0.05
-400.75
7365.26
TRTPN*ATPTN Oxy30
0.5
Oxy60
2
4704.48
1940.65 407
2.42
0.0158 0.05
889.53
8519.44
TRTPN*ATPTN Oxy30
0.5
Oxy60
3
4155.01
1940.65 407
2.14
0.0329 0.05
340.05
7969.97
TRTPN*ATPTN Oxy30
0.5
Oxy60
4
4034.88
1940.65 407
2.08
0.0382 0.05
219.92
7849.83
TRTPN*ATPTN Oxy30
0.5
Plac
0
-582.32
1938.87 407
-0.30
0.7641 0.05 -4393.77
3229.14
TRTPN*ATPTN Oxy30
0.5
Plac
0.5
-2162.70
1938.87 407
-1.12
0.2653 0.05 -5974.16
1648.75
TRTPN*ATPTN Oxy30
0.5
Plac
1
-3051.96
1938.87 407
-1.57
0.1162 0.05 -6863.42
759.49
TRTPN*ATPTN Oxy30
0.5
Plac
2
753.50
1938.87 407
0.39
0.6978 0.05 -3057.96
4564.96
TRTPN*ATPTN Oxy30
0.5
Plac
3
951.52
1938.87 407
0.49
0.6239 0.05 -2859.93
4762.98
TRTPN*ATPTN Oxy30
0.5
Plac
4
-441.32
1938.87 407
-0.23
0.8201 0.05 -4252.78
3370.13
TRTPN*ATPTN Oxy30
1
Oxy30
2
-855.74
1899.26 407
-0.45
0.6525 0.05 -4589.34
2877.85
TRTPN*ATPTN Oxy30
1
Oxy30
3
-2450.58
1899.26 407
-1.29
0.1977 0.05 -6184.17
1283.01
TRTPN*ATPTN Oxy30
1
Oxy30
4
-2671.33
1899.26 407
-1.41
0.1603 0.05 -6404.93
1062.26
TRTPN*ATPTN Oxy30
1
Oxy60
0
-3036.46
1972.42 407
-1.54
0.1245 0.05 -6913.87
840.94
TRTPN*ATPTN Oxy30
1
Oxy60
0.5
-666.62
1972.42 407
-0.34
0.7356 0.05 -4544.02
3210.79
TRTPN*ATPTN Oxy30
1
Oxy60
1
1629.25
1935.67 407
0.84
0.4005 0.05 -2175.91
5434.40
TRTPN*ATPTN Oxy30
1
Oxy60
2
2851.48
1900.76 407
1.50
0.1343 0.05
-885.06
6588.02
Page 277 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 26 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Oxy30
1
Oxy60
3
2302.00
1900.76 407
1.21
0.2266 0.05 -1434.54
6038.54
TRTPN*ATPTN Oxy30
1
Oxy60
4
2181.87
1900.76 407
1.15
0.2517 0.05 -1554.67
5918.41
TRTPN*ATPTN Oxy30
1
Plac
0
-2435.32
1899.93 407
-1.28
0.2006 0.05 -6170.22
1299.58
TRTPN*ATPTN Oxy30
1
Plac
0.5
-4015.71
1899.93 407
-2.11
0.0352 0.05 -7750.61
-280.81
TRTPN*ATPTN Oxy30
1
Plac
1
-4904.97
1899.93 407
-2.58
0.0102 0.05 -8639.87 -1170.07
TRTPN*ATPTN Oxy30
1
Plac
2
-1099.51
1899.93 407
-0.58
0.5631 0.05 -4834.41
2635.39
TRTPN*ATPTN Oxy30
1
Plac
3
-901.49
1899.93 407
-0.47
0.6354 0.05 -4636.39
2833.41
TRTPN*ATPTN Oxy30
1
Plac
4
-2294.33
1899.93 407
-1.21
0.2279 0.05 -6029.23
1440.57
TRTPN*ATPTN Oxy30
2
Oxy30
3
-1594.84
1864.91 407
-0.86
0.3930 0.05 -5260.90
2071.23
TRTPN*ATPTN Oxy30
2
Oxy30
4
-1815.59
1864.91 407
-0.97
0.3309 0.05 -5481.66
1850.47
TRTPN*ATPTN Oxy30
2
Oxy60
0
-2180.72
1939.53 407
-1.12
0.2615 0.05 -5993.46
1632.03
TRTPN*ATPTN Oxy30
2
Oxy60
0.5
189.13
1939.53 407
0.10
0.9224 0.05 -3623.62
4001.87
TRTPN*ATPTN Oxy30
2
Oxy60
1
2484.99
1901.48 407
1.31
0.1920 0.05 -1252.95
6222.93
TRTPN*ATPTN Oxy30
2
Oxy60
2
3707.22
1866.32 407
1.99
0.0477 0.05
38.3874
7376.05
TRTPN*ATPTN Oxy30
2
Oxy60
3
3157.75
1866.32 407
1.69
0.0914 0.05
-511.09
6826.58
TRTPN*ATPTN Oxy30
2
Oxy60
4
3037.61
1866.32 407
1.63
0.1044 0.05
-631.22
6706.45
TRTPN*ATPTN Oxy30
2
Plac
0
-1579.58
1866.36 407
-0.85
0.3979 0.05 -5248.50
2089.34
TRTPN*ATPTN Oxy30
2
Plac
0.5
-3159.97
1866.36 407
-1.69
0.0912 0.05 -6828.88
508.95
TRTPN*ATPTN Oxy30
2
Plac
1
-4049.23
1866.36 407
-2.17
0.0306 0.05 -7718.14
-380.31
TRTPN*ATPTN Oxy30
2
Plac
2
-243.76
1866.36 407
-0.13
0.8961 0.05 -3912.68
3425.15
TRTPN*ATPTN Oxy30
2
Plac
3
-45.7422
1866.36 407
-0.02
0.9805 0.05 -3714.66
3623.18
TRTPN*ATPTN Oxy30
2
Plac
4
-1438.59
1866.36 407
-0.77
0.4413 0.05 -5107.50
2230.33
TRTPN*ATPTN Oxy30
3
Oxy30
4
-220.75
1864.91 407
-0.12
0.9058 0.05 -3886.82
3445.31
TRTPN*ATPTN Oxy30
3
Oxy60
0
-585.88
1939.53 407
-0.30
0.7628 0.05 -4398.63
3226.87
TRTPN*ATPTN Oxy30
3
Oxy60
0.5
1783.96
1939.53 407
0.92
0.3582 0.05 -2028.78
5596.71
Page 278 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 27 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Oxy30
3
Oxy60
1
4079.83
1901.48 407
2.15
0.0325 0.05
341.89
7817.77
TRTPN*ATPTN Oxy30
3
Oxy60
2
5302.06
1866.32 407
2.84
0.0047 0.05
1633.23
8970.89
TRTPN*ATPTN Oxy30
3
Oxy60
3
4752.59
1866.32 407
2.55
0.0112 0.05
1083.75
8421.42
TRTPN*ATPTN Oxy30
3
Oxy60
4
4632.45
1866.32 407
2.48
0.0135 0.05
963.62
8301.28
TRTPN*ATPTN Oxy30
3
Plac
0
15.2591
1866.36 407
0.01
0.9935 0.05 -3653.66
3684.18
TRTPN*ATPTN Oxy30
3
Plac
0.5
-1565.13
1866.36 407
-0.84
0.4022 0.05 -5234.05
2103.79
TRTPN*ATPTN Oxy30
3
Plac
1
-2454.39
1866.36 407
-1.32
0.1892 0.05 -6123.31
1214.53
TRTPN*ATPTN Oxy30
3
Plac
2
1351.07
1866.36 407
0.72
0.4695 0.05 -2317.84
5019.99
TRTPN*ATPTN Oxy30
3
Plac
3
1549.10
1866.36 407
0.83
0.4070 0.05 -2119.82
5218.01
TRTPN*ATPTN Oxy30
3
Plac
4
156.25
1866.36 407
0.08
0.9333 0.05 -3512.67
3825.17
TRTPN*ATPTN Oxy30
4
Oxy60
0
-365.13
1939.53 407
-0.19
0.8508 0.05 -4177.87
3447.62
TRTPN*ATPTN Oxy30
4
Oxy60
0.5
2004.72
1939.53 407
1.03
0.3019 0.05 -1808.03
5817.46
TRTPN*ATPTN Oxy30
4
Oxy60
1
4300.58
1901.48 407
2.26
0.0242 0.05
562.64
8038.52
TRTPN*ATPTN Oxy30
4
Oxy60
2
5522.81
1866.32 407
2.96
0.0033 0.05
1853.98
9191.64
TRTPN*ATPTN Oxy30
4
Oxy60
3
4973.34
1866.32 407
2.66
0.0080 0.05
1304.50
8642.17
TRTPN*ATPTN Oxy30
4
Oxy60
4
4853.20
1866.32 407
2.60
0.0097 0.05
1184.37
8522.04
TRTPN*ATPTN Oxy30
4
Plac
0
236.01
1866.36 407
0.13
0.8994 0.05 -3432.91
3904.93
TRTPN*ATPTN Oxy30
4
Plac
0.5
-1344.38
1866.36 407
-0.72
0.4717 0.05 -5013.29
2324.54
TRTPN*ATPTN Oxy30
4
Plac
1
-2233.63
1866.36 407
-1.20
0.2321 0.05 -5902.55
1435.28
TRTPN*ATPTN Oxy30
4
Plac
2
1571.83
1866.36 407
0.84
0.4002 0.05 -2097.09
5240.75
TRTPN*ATPTN Oxy30
4
Plac
3
1769.85
1866.36 407
0.95
0.3435 0.05 -1899.07
5438.77
TRTPN*ATPTN Oxy30
4
Plac
4
377.01
1866.36 407
0.20
0.8400 0.05 -3291.91
4045.92
TRTPN*ATPTN Oxy60
0
Oxy60
0.5
2369.84
2003.24 407
1.18
0.2375 0.05 -1568.14
6307.83
TRTPN*ATPTN Oxy60
0
Oxy60
1
4665.71
1971.54 407
2.37
0.0184 0.05
790.04
8541.38
TRTPN*ATPTN Oxy60
0
Oxy60
2
5887.94
1937.96 407
3.04
0.0025 0.05
2078.28
9697.60
Page 279 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 28 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Oxy60
0
Oxy60
3
5338.46
1937.96 407
2.75
0.0061 0.05
1528.80
9148.12
TRTPN*ATPTN Oxy60
0
Oxy60
4
5218.33
1937.96 407
2.69
0.0074 0.05
1408.67
9027.99
TRTPN*ATPTN Oxy60
0
Plac
0
601.14
1939.56 407
0.31
0.7568 0.05 -3211.67
4413.95
TRTPN*ATPTN Oxy60
0
Plac
0.5
-979.25
1939.56 407
-0.50
0.6139 0.05 -4792.06
2833.56
TRTPN*ATPTN Oxy60
0
Plac
1
-1868.51
1939.56 407
-0.96
0.3359 0.05 -5681.32
1944.30
TRTPN*ATPTN Oxy60
0
Plac
2
1936.95
1939.56 407
1.00
0.3186 0.05 -1875.86
5749.76
TRTPN*ATPTN Oxy60
0
Plac
3
2134.98
1939.56 407
1.10
0.2717 0.05 -1677.84
5947.79
TRTPN*ATPTN Oxy60
0
Plac
4
742.13
1939.56 407
0.38
0.7022 0.05 -3070.68
4554.94
TRTPN*ATPTN Oxy60
0.5
Oxy60
1
2295.86
1971.54 407
1.16
0.2449 0.05 -1579.81
6171.53
TRTPN*ATPTN Oxy60
0.5
Oxy60
2
3518.09
1937.96 407
1.82
0.0702 0.05
-291.57
7327.75
TRTPN*ATPTN Oxy60
0.5
Oxy60
3
2968.62
1937.96 407
1.53
0.1263 0.05
-841.04
6778.28
TRTPN*ATPTN Oxy60
0.5
Oxy60
4
2848.49
1937.96 407
1.47
0.1424 0.05
-961.17
6658.15
TRTPN*ATPTN Oxy60
0.5
Plac
0
-1768.71
1939.56 407
-0.91
0.3624 0.05 -5581.52
2044.11
TRTPN*ATPTN Oxy60
0.5
Plac
0.5
-3349.09
1939.56 407
-1.73
0.0850 0.05 -7161.90
463.72
TRTPN*ATPTN Oxy60
0.5
Plac
1
-4238.35
1939.56 407
-2.19
0.0294 0.05 -8051.16
-425.54
TRTPN*ATPTN Oxy60
0.5
Plac
2
-432.89
1939.56 407
-0.22
0.8235 0.05 -4245.70
3379.92
TRTPN*ATPTN Oxy60
0.5
Plac
3
-234.87
1939.56 407
-0.12
0.9037 0.05 -4047.68
3577.94
TRTPN*ATPTN Oxy60
0.5
Plac
4
-1627.71
1939.56 407
-0.84
0.4018 0.05 -5440.52
2185.10
TRTPN*ATPTN Oxy60
1
Oxy60
2
1222.23
1899.22 407
0.64
0.5202 0.05 -2511.28
4955.74
TRTPN*ATPTN Oxy60
1
Oxy60
3
672.76
1899.22 407
0.35
0.7234 0.05 -3060.75
4406.26
TRTPN*ATPTN Oxy60
1
Oxy60
4
552.62
1899.22 407
0.29
0.7712 0.05 -3180.88
4286.13
TRTPN*ATPTN Oxy60
1
Plac
0
-4064.57
1900.77 407
-2.14
0.0331 0.05 -7801.13
-328.01
TRTPN*ATPTN Oxy60
1
Plac
0.5
-5644.96
1900.77 407
-2.97
0.0032 0.05 -9381.52 -1908.39
TRTPN*ATPTN Oxy60
1
Plac
1
-6534.22
1900.77 407
-3.44
0.0006 0.05
-10271 -2797.65
TRTPN*ATPTN Oxy60
1
Plac
2
-2728.75
1900.77 407
-1.44
0.1519 0.05 -6465.31
1007.81
Page 280 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 29 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Oxy60
1
Plac
3
-2530.73
1900.77 407
-1.33
0.1838 0.05 -6267.29
1205.83
TRTPN*ATPTN Oxy60
1
Plac
4
-3923.58
1900.77 407
-2.06
0.0396 0.05 -7660.14
-187.01
TRTPN*ATPTN Oxy60
2
Oxy60
3
-549.47
1864.91 407
-0.29
0.7684 0.05 -4215.54
3116.59
TRTPN*ATPTN Oxy60
2
Oxy60
4
-669.61
1864.91 407
-0.36
0.7197 0.05 -4335.67
2996.46
TRTPN*ATPTN Oxy60
2
Plac
0
-5286.80
1866.36 407
-2.83
0.0048 0.05 -8955.72 -1617.88
TRTPN*ATPTN Oxy60
2
Plac
0.5
-6867.19
1866.36 407
-3.68
0.0003 0.05
-10536 -3198.27
TRTPN*ATPTN Oxy60
2
Plac
1
-7756.45
1866.36 407
-4.16
<.0001 0.05
-11425 -4087.53
TRTPN*ATPTN Oxy60
2
Plac
2
-3950.98
1866.36 407
-2.12
0.0349 0.05 -7619.90
-282.07
TRTPN*ATPTN Oxy60
2
Plac
3
-3752.96
1866.36 407
-2.01
0.0450 0.05 -7421.88 -84.0457
TRTPN*ATPTN Oxy60
2
Plac
4
-5145.81
1866.36 407
-2.76
0.0061 0.05 -8814.72 -1476.89
TRTPN*ATPTN Oxy60
3
Oxy60
4
-120.13
1864.91 407
-0.06
0.9487 0.05 -3786.20
3545.93
TRTPN*ATPTN Oxy60
3
Plac
0
-4737.33
1866.36 407
-2.54
0.0115 0.05 -8406.24 -1068.41
TRTPN*ATPTN Oxy60
3
Plac
0.5
-6317.71
1866.36 407
-3.39
0.0008 0.05 -9986.63 -2648.80
TRTPN*ATPTN Oxy60
3
Plac
1
-7206.97
1866.36 407
-3.86
0.0001 0.05
-10876 -3538.06
TRTPN*ATPTN Oxy60
3
Plac
2
-3401.51
1866.36 407
-1.82
0.0691 0.05 -7070.43
267.41
TRTPN*ATPTN Oxy60
3
Plac
3
-3203.49
1866.36 407
-1.72
0.0868 0.05 -6872.41
465.43
TRTPN*ATPTN Oxy60
3
Plac
4
-4596.33
1866.36 407
-2.46
0.0142 0.05 -8265.25
-927.42
TRTPN*ATPTN Oxy60
4
Plac
0
-4617.19
1866.36 407
-2.47
0.0138 0.05 -8286.11
-948.27
TRTPN*ATPTN Oxy60
4
Plac
0.5
-6197.58
1866.36 407
-3.32
0.0010 0.05 -9866.50 -2528.66
TRTPN*ATPTN Oxy60
4
Plac
1
-7086.84
1866.36 407
-3.80
0.0002 0.05
-10756 -3417.92
TRTPN*ATPTN Oxy60
4
Plac
2
-3281.38
1866.36 407
-1.76
0.0795 0.05 -6950.29
387.54
TRTPN*ATPTN Oxy60
4
Plac
3
-3083.35
1866.36 407
-1.65
0.0993 0.05 -6752.27
585.56
TRTPN*ATPTN Oxy60
4
Plac
4
-4476.20
1866.36 407
-2.40
0.0169 0.05 -8145.12
-807.28
TRTPN*ATPTN Plac
0
Plac
0.5
-1580.39
1864.91 407
-0.85
0.3973 0.05 -5246.45
2085.68
TRTPN*ATPTN Plac
0
Plac
1
-2469.65
1864.91 407
-1.32
0.1862 0.05 -6135.71
1196.42
Page 281 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 30 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Plac
0
Plac
2
1335.82
1864.91 407
0.72
0.4742 0.05 -2330.25
5001.88
TRTPN*ATPTN Plac
0
Plac
3
1533.84
1864.91 407
0.82
0.4113 0.05 -2132.23
5199.90
TRTPN*ATPTN Plac
0
Plac
4
140.99
1864.91 407
0.08
0.9398 0.05 -3525.07
3807.06
TRTPN*ATPTN Plac
0.5
Plac
1
-889.26
1864.91 407
-0.48
0.6337 0.05 -4555.32
2776.81
TRTPN*ATPTN Plac
0.5
Plac
2
2916.20
1864.91 407
1.56
0.1187 0.05
-749.86
6582.27
TRTPN*ATPTN Plac
0.5
Plac
3
3114.22
1864.91 407
1.67
0.0957 0.05
-551.84
6780.29
TRTPN*ATPTN Plac
0.5
Plac
4
1721.38
1864.91 407
0.92
0.3565 0.05 -1944.68
5387.45
TRTPN*ATPTN Plac
1
Plac
2
3805.46
1864.91 407
2.04
0.0419 0.05
139.40
7471.53
TRTPN*ATPTN Plac
1
Plac
3
4003.48
1864.91 407
2.15
0.0324 0.05
337.42
7669.55
TRTPN*ATPTN Plac
1
Plac
4
2610.64
1864.91 407
1.40
0.1623 0.05 -1055.43
6276.71
TRTPN*ATPTN Plac
2
Plac
3
198.02
1864.91 407
0.11
0.9155 0.05 -3468.04
3864.09
TRTPN*ATPTN Plac
2
Plac
4
-1194.82
1864.91 407
-0.64
0.5221 0.05 -4860.89
2471.24
TRTPN*ATPTN Plac
3
Plac
4
-1392.84
1864.91 407
-0.75
0.4556 0.05 -5058.91
2273.22
Tests of Effect Slices
Effect
Analysis 
Timepoint 
(N)
Num 
DF
Den 
DF F Value Pr > F
TRTPN*ATPTN 0
5407
0.54 0.7480
TRTPN*ATPTN 0.5
5407
2.80 0.0168
TRTPN*ATPTN 1
5407
3.65 0.0031
TRTPN*ATPTN 2
5407
2.87 0.0147
TRTPN*ATPTN 3
5407
1.64 0.1471
TRTPN*ATPTN 4
5407
1.77 0.1173
Page 282 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.3                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.4                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio3.sas  Created: 02APR2020  7:35 POSTLOCK             
Page 31 of 31
Page 283 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 1 of 31
Model Information
Data Set
WORK.ADXV
Dependent Variable
AVAL
Covariance Structure
Compound Symmetry
Subject Effect
SUBJID
Estimation Method
REML
Residual Variance Method
Profile
Fixed Effects SE Method
Model-Based
Degrees of Freedom Method Between-Within
Class Level Information
Class
LevelsValues
SUBJID
161001 1002 1003 1004 1005 1006 1007 1008 1010 1012 1013 1014 1015 1016 1017 1018
TRTPN
6Bel300 Bel600 Bel900 Oxy30 Oxy60 Plac
APERIOD
6P1 P2 P3 P4 P5 P6
ARMCD
6ABCEDF BEAFCD CADBFE DCFAEB EFBDAC FDECBA
ATPTN
60 0.5 1 2 3 4
Dimensions
Covariance Parameters
2
Columns in X
55
Columns in Z
0
Subjects
16
Max Obs per Subject
36
Page 284 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 2 of 31
Number of Observations
Number of Observations Read
545
Number of Observations Used
545
Number of Observations Not Used
0
Iteration History
Iteration Evaluations -2 Res Log Like
Criterion
0
1
10201.54397027
1
2
10095.46515998 0.00000006
2
1
10095.46488411 0.00000000
Convergence criteria met.
Covariance Parameter 
Estimates
Cov Parm Subject Estimate
CS
SUBJID
11371173
Residual
25636473
Fit Statistics
-2 Res Log Likelihood
10095.5
AIC (Smaller is Better)
10099.5
AICC (Smaller is Better) 10099.5
BIC (Smaller is Better)
10101.0
Page 285 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 3 of 31
Null Model Likelihood 
Ratio Test
DF Chi-Square Pr > ChiSq
1
106.08
<.0001
Type 3 Tests of Fixed Effects
Effect
Num 
DF
Den 
DF F Value Pr > F
TRTPN
5 72
7.88 <.0001
APERIOD
5 72
5.82 0.0001
ARMCD
5 10
1.34 0.3239
TRTPN*ATPTN
30422
2.22 0.0003
Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha Lower Upper
TRTPN*ATPTN Bel300
0
19956
1566.43422
12.74
<.0001 0.05 16877 23035
TRTPN*ATPTN Bel300
0.5
21615
1566.43422
13.80
<.0001 0.05 18536 24694
TRTPN*ATPTN Bel300
1
19703
1566.43422
12.58
<.0001 0.05 16624 22782
TRTPN*ATPTN Bel300
2
19848
1566.43422
12.67
<.0001 0.05 16769 22927
TRTPN*ATPTN Bel300
3
15435
1566.43422
9.85
<.0001 0.05 12356 18514
TRTPN*ATPTN Bel300
4
15990
1566.43422
10.21
<.0001 0.05 12911 19069
TRTPN*ATPTN Bel600
0
19546
1565.91422
12.48
<.0001 0.05 16468 22624
TRTPN*ATPTN Bel600
0.5
20533
1565.91422
13.11
<.0001 0.05 17455 23611
TRTPN*ATPTN Bel600
1
19148
1530.53422
12.51
<.0001 0.05 16140 22156
TRTPN*ATPTN Bel600
2
17543
1530.53422
11.46
<.0001 0.05 14534 20551
Page 286 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 4 of 31
Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha Lower Upper
TRTPN*ATPTN Bel600
3
16703
1530.53422
10.91
<.0001 0.05 13695 19712
TRTPN*ATPTN Bel600
4
16887
1530.53422
11.03
<.0001 0.05 13878 19895
TRTPN*ATPTN Bel900
0
21316
1605.83422
13.27
<.0001 0.05 18160 24473
TRTPN*ATPTN Bel900
0.5
22751
1566.65422
14.52
<.0001 0.05 19672 25831
TRTPN*ATPTN Bel900
1
19932
1566.65422
12.72
<.0001 0.05 16852 23011
TRTPN*ATPTN Bel900
2
18174
1566.65422
11.60
<.0001 0.05 15094 21253
TRTPN*ATPTN Bel900
3
17494
1566.65422
11.17
<.0001 0.05 14414 20573
TRTPN*ATPTN Bel900
4
16445
1566.65422
10.50
<.0001 0.05 13366 19525
TRTPN*ATPTN Oxy30
0
20087
1651.59422
12.16
<.0001 0.05 16841 23334
TRTPN*ATPTN Oxy30
0.5
17815
1651.59422
10.79
<.0001 0.05 14569 21061
TRTPN*ATPTN Oxy30
1
15960
1606.15422
9.94
<.0001 0.05 12803 19117
TRTPN*ATPTN Oxy30
2
16815
1566.67422
10.73
<.0001 0.05 13736 19895
TRTPN*ATPTN Oxy30
3
18410
1566.67422
11.75
<.0001 0.05 15331 21490
TRTPN*ATPTN Oxy30
4
18631
1566.67422
11.89
<.0001 0.05 15552 21711
TRTPN*ATPTN Oxy60
0
18627
1607.20422
11.59
<.0001 0.05 15468 21786
TRTPN*ATPTN Oxy60
0.5
16395
1607.20422
10.20
<.0001 0.05 13236 19554
TRTPN*ATPTN Oxy60
1
14303
1567.67422
9.12
<.0001 0.05 11222 17385
TRTPN*ATPTN Oxy60
2
13311
1530.56422
8.70
<.0001 0.05 10302 16319
TRTPN*ATPTN Oxy60
3
13978
1530.56422
9.13
<.0001 0.05 10969 16986
TRTPN*ATPTN Oxy60
4
14097
1530.56422
9.21
<.0001 0.05 11088 17105
TRTPN*ATPTN Plac
0
18495
1530.50422
12.08
<.0001 0.05 15487 21503
TRTPN*ATPTN Plac
0.5
20021
1530.50422
13.08
<.0001 0.05 17012 23029
TRTPN*ATPTN Plac
1
20972
1530.50422
13.70
<.0001 0.05 17964 23981
TRTPN*ATPTN Plac
2
16906
1530.50422
11.05
<.0001 0.05 13897 19914
Page 287 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 5 of 31
Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha Lower Upper
TRTPN*ATPTN Plac
3
17320
1530.50422
11.32
<.0001 0.05 14312 20328
TRTPN*ATPTN Plac
4
18499
1530.50422
12.09
<.0001 0.05 15491 21508
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
0
Bel300
0.5
-1659.32
1848.84 422
-0.90
0.3700 0.05 -5293.40
1974.75
TRTPN*ATPTN Bel300
0
Bel300
1
252.85
1848.84 422
0.14
0.8913 0.05 -3381.22
3886.93
TRTPN*ATPTN Bel300
0
Bel300
2
108.37
1848.84 422
0.06
0.9533 0.05 -3525.71
3742.44
TRTPN*ATPTN Bel300
0
Bel300
3
4521.35
1848.84 422
2.45
0.0149 0.05
887.28
8155.43
TRTPN*ATPTN Bel300
0
Bel300
4
3966.17
1848.84 422
2.15
0.0325 0.05
332.10
7600.25
TRTPN*ATPTN Bel300
0
Bel600
0
410.18
1852.53 422
0.22
0.8249 0.05 -3231.15
4051.51
TRTPN*ATPTN Bel300
0
Bel600
0.5
-576.54
1852.53 422
-0.31
0.7558 0.05 -4217.87
3064.79
TRTPN*ATPTN Bel300
0
Bel600
1
808.09
1822.76 422
0.44
0.6578 0.05 -2774.72
4390.90
TRTPN*ATPTN Bel300
0
Bel600
2
2413.31
1822.76 422
1.32
0.1862 0.05 -1169.50
5996.12
TRTPN*ATPTN Bel300
0
Bel600
3
3252.96
1822.76 422
1.78
0.0750 0.05
-329.85
6835.77
TRTPN*ATPTN Bel300
0
Bel600
4
3069.51
1822.76 422
1.68
0.0929 0.05
-513.30
6652.32
TRTPN*ATPTN Bel300
0
Bel900
0
-1360.31
1883.44 422
-0.72
0.4705 0.05 -5062.40
2341.78
TRTPN*ATPTN Bel300
0
Bel900
0.5
-2794.98
1850.18 422
-1.51
0.1316 0.05 -6431.69
841.73
TRTPN*ATPTN Bel300
0
Bel900
1
24.4926
1850.18 422
0.01
0.9894 0.05 -3612.22
3661.20
TRTPN*ATPTN Bel300
0
Bel900
2
1782.25
1850.18 422
0.96
0.3360 0.05 -1854.46
5418.96
TRTPN*ATPTN Bel300
0
Bel900
3
2462.51
1850.18 422
1.33
0.1839 0.05 -1174.20
6099.22
TRTPN*ATPTN Bel300
0
Bel900
4
3511.00
1850.18 422
1.90
0.0584 0.05
-125.71
7147.71
Page 288 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 6 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
0
Oxy30
0
-131.08
1922.13 422
-0.07
0.9457 0.05 -3909.22
3647.07
TRTPN*ATPTN Bel300
0
Oxy30
0.5
2141.07
1922.13 422
1.11
0.2660 0.05 -1637.08
5919.22
TRTPN*ATPTN Bel300
0
Oxy30
1
3995.79
1883.53 422
2.12
0.0345 0.05
293.52
7698.06
TRTPN*ATPTN Bel300
0
Oxy30
2
3140.64
1850.26 422
1.70
0.0904 0.05
-496.23
6777.51
TRTPN*ATPTN Bel300
0
Oxy30
3
1545.80
1850.26 422
0.84
0.4039 0.05 -2091.07
5182.67
TRTPN*ATPTN Bel300
0
Oxy30
4
1325.05
1850.26 422
0.72
0.4743 0.05 -2311.82
4961.92
TRTPN*ATPTN Bel300
0
Oxy60
0
1329.04
1886.80 422
0.70
0.4816 0.05 -2379.67
5037.74
TRTPN*ATPTN Bel300
0
Oxy60
0.5
3561.27
1886.80 422
1.89
0.0598 0.05
-147.43
7269.97
TRTPN*ATPTN Bel300
0
Oxy60
1
5652.80
1852.83 422
3.05
0.0024 0.05
2010.86
9294.73
TRTPN*ATPTN Bel300
0
Oxy60
2
6645.35
1822.14 422
3.65
0.0003 0.05
3063.75
10227
TRTPN*ATPTN Bel300
0
Oxy60
3
5978.53
1822.14 422
3.28
0.0011 0.05
2396.93
9560.13
TRTPN*ATPTN Bel300
0
Oxy60
4
5859.39
1822.14 422
3.22
0.0014 0.05
2277.79
9440.99
TRTPN*ATPTN Bel300
0
Plac
0
1461.12
1821.91 422
0.80
0.4230 0.05 -2120.03
5042.26
TRTPN*ATPTN Bel300
0
Plac
0.5
-64.5111
1821.91 422
-0.04
0.9718 0.05 -3645.65
3516.63
TRTPN*ATPTN Bel300
0
Plac
1
-1016.01
1821.91 422
-0.56
0.5774 0.05 -4597.16
2565.13
TRTPN*ATPTN Bel300
0
Plac
2
3050.29
1821.91 422
1.67
0.0948 0.05
-530.86
6631.43
TRTPN*ATPTN Bel300
0
Plac
3
2636.22
1821.91 422
1.45
0.1487 0.05
-944.92
6217.36
TRTPN*ATPTN Bel300
0
Plac
4
1456.98
1821.91 422
0.80
0.4243 0.05 -2124.16
5038.13
TRTPN*ATPTN Bel300
0.5
Bel300
1
1912.18
1848.84 422
1.03
0.3016 0.05 -1721.90
5546.25
TRTPN*ATPTN Bel300
0.5
Bel300
2
1767.69
1848.84 422
0.96
0.3396 0.05 -1866.39
5401.76
TRTPN*ATPTN Bel300
0.5
Bel300
3
6180.67
1848.84 422
3.34
0.0009 0.05
2546.60
9814.75
TRTPN*ATPTN Bel300
0.5
Bel300
4
5625.50
1848.84 422
3.04
0.0025 0.05
1991.42
9259.57
TRTPN*ATPTN Bel300
0.5
Bel600
0
2069.50
1852.53 422
1.12
0.2646 0.05 -1571.83
5710.83
TRTPN*ATPTN Bel300
0.5
Bel600
0.5
1082.78
1852.53 422
0.58
0.5592 0.05 -2558.55
4724.11
TRTPN*ATPTN Bel300
0.5
Bel600
1
2467.41
1822.76 422
1.35
0.1766 0.05 -1115.40
6050.22
Page 289 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 7 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
0.5
Bel600
2
4072.63
1822.76 422
2.23
0.0260 0.05
489.82
7655.44
TRTPN*ATPTN Bel300
0.5
Bel600
3
4912.28
1822.76 422
2.69
0.0073 0.05
1329.47
8495.09
TRTPN*ATPTN Bel300
0.5
Bel600
4
4728.84
1822.76 422
2.59
0.0098 0.05
1146.03
8311.65
TRTPN*ATPTN Bel300
0.5
Bel900
0
299.01
1883.44 422
0.16
0.8739 0.05 -3403.08
4001.10
TRTPN*ATPTN Bel300
0.5
Bel900
0.5
-1135.66
1850.18 422
-0.61
0.5397 0.05 -4772.37
2501.05
TRTPN*ATPTN Bel300
0.5
Bel900
1
1683.81
1850.18 422
0.91
0.3633 0.05 -1952.89
5320.52
TRTPN*ATPTN Bel300
0.5
Bel900
2
3441.57
1850.18 422
1.86
0.0636 0.05
-195.14
7078.28
TRTPN*ATPTN Bel300
0.5
Bel900
3
4121.83
1850.18 422
2.23
0.0264 0.05
485.12
7758.54
TRTPN*ATPTN Bel300
0.5
Bel900
4
5170.32
1850.18 422
2.79
0.0054 0.05
1533.61
8807.03
TRTPN*ATPTN Bel300
0.5
Oxy30
0
1528.24
1922.13 422
0.80
0.4270 0.05 -2249.90
5306.39
TRTPN*ATPTN Bel300
0.5
Oxy30
0.5
3800.39
1922.13 422
1.98
0.0487 0.05
22.2455
7578.54
TRTPN*ATPTN Bel300
0.5
Oxy30
1
5655.11
1883.53 422
3.00
0.0028 0.05
1952.84
9357.38
TRTPN*ATPTN Bel300
0.5
Oxy30
2
4799.96
1850.26 422
2.59
0.0098 0.05
1163.09
8436.83
TRTPN*ATPTN Bel300
0.5
Oxy30
3
3205.12
1850.26 422
1.73
0.0840 0.05
-431.74
6841.99
TRTPN*ATPTN Bel300
0.5
Oxy30
4
2984.37
1850.26 422
1.61
0.1075 0.05
-652.50
6621.24
TRTPN*ATPTN Bel300
0.5
Oxy60
0
2988.36
1886.80 422
1.58
0.1140 0.05
-720.34
6697.06
TRTPN*ATPTN Bel300
0.5
Oxy60
0.5
5220.59
1886.80 422
2.77
0.0059 0.05
1511.89
8929.29
TRTPN*ATPTN Bel300
0.5
Oxy60
1
7312.12
1852.83 422
3.95
<.0001 0.05
3670.18
10954
TRTPN*ATPTN Bel300
0.5
Oxy60
2
8304.67
1822.14 422
4.56
<.0001 0.05
4723.07
11886
TRTPN*ATPTN Bel300
0.5
Oxy60
3
7637.85
1822.14 422
4.19
<.0001 0.05
4056.25
11219
TRTPN*ATPTN Bel300
0.5
Oxy60
4
7518.71
1822.14 422
4.13
<.0001 0.05
3937.11
11100
TRTPN*ATPTN Bel300
0.5
Plac
0
3120.44
1821.91 422
1.71
0.0875 0.05
-460.71
6701.58
TRTPN*ATPTN Bel300
0.5
Plac
0.5
1594.81
1821.91 422
0.88
0.3819 0.05 -1986.33
5175.95
TRTPN*ATPTN Bel300
0.5
Plac
1
643.31
1821.91 422
0.35
0.7242 0.05 -2937.84
4224.45
TRTPN*ATPTN Bel300
0.5
Plac
2
4709.61
1821.91 422
2.58
0.0101 0.05
1128.46
8290.75
Page 290 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 8 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
0.5
Plac
3
4295.54
1821.91 422
2.36
0.0188 0.05
714.40
7876.68
TRTPN*ATPTN Bel300
0.5
Plac
4
3116.30
1821.91 422
1.71
0.0879 0.05
-464.84
6697.45
TRTPN*ATPTN Bel300
1
Bel300
2
-144.49
1848.84 422
-0.08
0.9377 0.05 -3778.57
3489.59
TRTPN*ATPTN Bel300
1
Bel300
3
4268.50
1848.84 422
2.31
0.0214 0.05
634.42
7902.57
TRTPN*ATPTN Bel300
1
Bel300
4
3713.32
1848.84 422
2.01
0.0452 0.05
79.2444
7347.40
TRTPN*ATPTN Bel300
1
Bel600
0
157.33
1852.53 422
0.08
0.9324 0.05 -3484.00
3798.66
TRTPN*ATPTN Bel300
1
Bel600
0.5
-829.40
1852.53 422
-0.45
0.6546 0.05 -4470.73
2811.94
TRTPN*ATPTN Bel300
1
Bel600
1
555.23
1822.76 422
0.30
0.7608 0.05 -3027.58
4138.04
TRTPN*ATPTN Bel300
1
Bel600
2
2160.46
1822.76 422
1.19
0.2366 0.05 -1422.35
5743.27
TRTPN*ATPTN Bel300
1
Bel600
3
3000.10
1822.76 422
1.65
0.1005 0.05
-582.71
6582.91
TRTPN*ATPTN Bel300
1
Bel600
4
2816.66
1822.76 422
1.55
0.1230 0.05
-766.15
6399.47
TRTPN*ATPTN Bel300
1
Bel900
0
-1613.16
1883.44 422
-0.86
0.3922 0.05 -5315.25
2088.92
TRTPN*ATPTN Bel300
1
Bel900
0.5
-3047.84
1850.18 422
-1.65
0.1002 0.05 -6684.54
588.87
TRTPN*ATPTN Bel300
1
Bel900
1
-228.36
1850.18 422
-0.12
0.9018 0.05 -3865.07
3408.35
TRTPN*ATPTN Bel300
1
Bel900
2
1529.39
1850.18 422
0.83
0.4089 0.05 -2107.32
5166.10
TRTPN*ATPTN Bel300
1
Bel900
3
2209.66
1850.18 422
1.19
0.2330 0.05 -1427.05
5846.36
TRTPN*ATPTN Bel300
1
Bel900
4
3258.15
1850.18 422
1.76
0.0790 0.05
-378.56
6894.85
TRTPN*ATPTN Bel300
1
Oxy30
0
-383.93
1922.13 422
-0.20
0.8418 0.05 -4162.08
3394.21
TRTPN*ATPTN Bel300
1
Oxy30
0.5
1888.22
1922.13 422
0.98
0.3265 0.05 -1889.93
5666.36
TRTPN*ATPTN Bel300
1
Oxy30
1
3742.94
1883.53 422
1.99
0.0475 0.05
40.6684
7445.20
TRTPN*ATPTN Bel300
1
Oxy30
2
2887.79
1850.26 422
1.56
0.1193 0.05
-749.08
6524.65
TRTPN*ATPTN Bel300
1
Oxy30
3
1292.95
1850.26 422
0.70
0.4851 0.05 -2343.92
4929.82
TRTPN*ATPTN Bel300
1
Oxy30
4
1072.20
1850.26 422
0.58
0.5626 0.05 -2564.67
4709.06
TRTPN*ATPTN Bel300
1
Oxy60
0
1076.18
1886.80 422
0.57
0.5687 0.05 -2632.52
4784.88
TRTPN*ATPTN Bel300
1
Oxy60
0.5
3308.42
1886.80 422
1.75
0.0803 0.05
-400.29
7017.12
Page 291 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 9 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
1
Oxy60
1
5399.94
1852.83 422
2.91
0.0038 0.05
1758.01
9041.88
TRTPN*ATPTN Bel300
1
Oxy60
2
6392.49
1822.14 422
3.51
0.0005 0.05
2810.89
9974.09
TRTPN*ATPTN Bel300
1
Oxy60
3
5725.68
1822.14 422
3.14
0.0018 0.05
2144.08
9307.28
TRTPN*ATPTN Bel300
1
Oxy60
4
5606.54
1822.14 422
3.08
0.0022 0.05
2024.94
9188.14
TRTPN*ATPTN Bel300
1
Plac
0
1208.26
1821.91 422
0.66
0.5076 0.05 -2372.88
4789.40
TRTPN*ATPTN Bel300
1
Plac
0.5
-317.37
1821.91 422
-0.17
0.8618 0.05 -3898.51
3263.78
TRTPN*ATPTN Bel300
1
Plac
1
-1268.87
1821.91 422
-0.70
0.4865 0.05 -4850.01
2312.27
TRTPN*ATPTN Bel300
1
Plac
2
2797.43
1821.91 422
1.54
0.1254 0.05
-783.71
6378.57
TRTPN*ATPTN Bel300
1
Plac
3
2383.36
1821.91 422
1.31
0.1915 0.05 -1197.78
5964.50
TRTPN*ATPTN Bel300
1
Plac
4
1204.13
1821.91 422
0.66
0.5090 0.05 -2377.01
4785.27
TRTPN*ATPTN Bel300
2
Bel300
3
4412.99
1848.84 422
2.39
0.0174 0.05
778.91
8047.06
TRTPN*ATPTN Bel300
2
Bel300
4
3857.81
1848.84 422
2.09
0.0375 0.05
223.73
7491.89
TRTPN*ATPTN Bel300
2
Bel600
0
301.82
1852.53 422
0.16
0.8707 0.05 -3339.51
3943.15
TRTPN*ATPTN Bel300
2
Bel600
0.5
-684.91
1852.53 422
-0.37
0.7118 0.05 -4326.24
2956.43
TRTPN*ATPTN Bel300
2
Bel600
1
699.72
1822.76 422
0.38
0.7013 0.05 -2883.09
4282.53
TRTPN*ATPTN Bel300
2
Bel600
2
2304.95
1822.76 422
1.26
0.2067 0.05 -1277.86
5887.76
TRTPN*ATPTN Bel300
2
Bel600
3
3144.59
1822.76 422
1.73
0.0852 0.05
-438.22
6727.40
TRTPN*ATPTN Bel300
2
Bel600
4
2961.15
1822.76 422
1.62
0.1050 0.05
-621.66
6543.96
TRTPN*ATPTN Bel300
2
Bel900
0
-1468.68
1883.44 422
-0.78
0.4360 0.05 -5170.76
2233.41
TRTPN*ATPTN Bel300
2
Bel900
0.5
-2903.35
1850.18 422
-1.57
0.1173 0.05 -6540.05
733.36
TRTPN*ATPTN Bel300
2
Bel900
1
-83.8725
1850.18 422
-0.05
0.9639 0.05 -3720.58
3552.84
TRTPN*ATPTN Bel300
2
Bel900
2
1673.88
1850.18 422
0.90
0.3661 0.05 -1962.83
5310.59
TRTPN*ATPTN Bel300
2
Bel900
3
2354.15
1850.18 422
1.27
0.2039 0.05 -1282.56
5990.85
TRTPN*ATPTN Bel300
2
Bel900
4
3402.64
1850.18 422
1.84
0.0666 0.05
-234.07
7039.34
TRTPN*ATPTN Bel300
2
Oxy30
0
-239.44
1922.13 422
-0.12
0.9009 0.05 -4017.59
3538.70
Page 292 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 10 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
2
Oxy30
0.5
2032.71
1922.13 422
1.06
0.2909 0.05 -1745.44
5810.85
TRTPN*ATPTN Bel300
2
Oxy30
1
3887.43
1883.53 422
2.06
0.0396 0.05
185.16
7589.69
TRTPN*ATPTN Bel300
2
Oxy30
2
3032.28
1850.26 422
1.64
0.1020 0.05
-604.59
6669.14
TRTPN*ATPTN Bel300
2
Oxy30
3
1437.44
1850.26 422
0.78
0.4377 0.05 -2199.43
5074.31
TRTPN*ATPTN Bel300
2
Oxy30
4
1216.68
1850.26 422
0.66
0.5112 0.05 -2420.18
4853.55
TRTPN*ATPTN Bel300
2
Oxy60
0
1220.67
1886.80 422
0.65
0.5180 0.05 -2488.03
4929.37
TRTPN*ATPTN Bel300
2
Oxy60
0.5
3452.91
1886.80 422
1.83
0.0680 0.05
-255.80
7161.61
TRTPN*ATPTN Bel300
2
Oxy60
1
5544.43
1852.83 422
2.99
0.0029 0.05
1902.50
9186.37
TRTPN*ATPTN Bel300
2
Oxy60
2
6536.98
1822.14 422
3.59
0.0004 0.05
2955.38
10119
TRTPN*ATPTN Bel300
2
Oxy60
3
5870.17
1822.14 422
3.22
0.0014 0.05
2288.57
9451.77
TRTPN*ATPTN Bel300
2
Oxy60
4
5751.03
1822.14 422
3.16
0.0017 0.05
2169.43
9332.63
TRTPN*ATPTN Bel300
2
Plac
0
1352.75
1821.91 422
0.74
0.4582 0.05 -2228.39
4933.89
TRTPN*ATPTN Bel300
2
Plac
0.5
-172.88
1821.91 422
-0.09
0.9244 0.05 -3754.02
3408.27
TRTPN*ATPTN Bel300
2
Plac
1
-1124.38
1821.91 422
-0.62
0.5375 0.05 -4705.52
2456.76
TRTPN*ATPTN Bel300
2
Plac
2
2941.92
1821.91 422
1.61
0.1071 0.05
-639.22
6523.06
TRTPN*ATPTN Bel300
2
Plac
3
2527.85
1821.91 422
1.39
0.1660 0.05 -1053.29
6108.99
TRTPN*ATPTN Bel300
2
Plac
4
1348.62
1821.91 422
0.74
0.4596 0.05 -2232.52
4929.76
TRTPN*ATPTN Bel300
3
Bel300
4
-555.18
1848.84 422
-0.30
0.7641 0.05 -4189.25
3078.90
TRTPN*ATPTN Bel300
3
Bel600
0
-4111.17
1852.53 422
-2.22
0.0270 0.05 -7752.50
-469.84
TRTPN*ATPTN Bel300
3
Bel600
0.5
-5097.89
1852.53 422
-2.75
0.0062 0.05 -8739.22 -1456.56
TRTPN*ATPTN Bel300
3
Bel600
1
-3713.27
1822.76 422
-2.04
0.0423 0.05 -7296.08
-130.46
TRTPN*ATPTN Bel300
3
Bel600
2
-2108.04
1822.76 422
-1.16
0.2481 0.05 -5690.85
1474.77
TRTPN*ATPTN Bel300
3
Bel600
3
-1268.39
1822.76 422
-0.70
0.4869 0.05 -4851.20
2314.42
TRTPN*ATPTN Bel300
3
Bel600
4
-1451.84
1822.76 422
-0.80
0.4262 0.05 -5034.65
2130.97
TRTPN*ATPTN Bel300
3
Bel900
0
-5881.66
1883.44 422
-3.12
0.0019 0.05 -9583.75 -2179.57
Page 293 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 11 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
3
Bel900
0.5
-7316.33
1850.18 422
-3.95
<.0001 0.05
-10953 -3679.63
TRTPN*ATPTN Bel300
3
Bel900
1
-4496.86
1850.18 422
-2.43
0.0155 0.05 -8133.57
-860.15
TRTPN*ATPTN Bel300
3
Bel900
2
-2739.11
1850.18 422
-1.48
0.1395 0.05 -6375.81
897.60
TRTPN*ATPTN Bel300
3
Bel900
3
-2058.84
1850.18 422
-1.11
0.2664 0.05 -5695.55
1577.87
TRTPN*ATPTN Bel300
3
Bel900
4
-1010.35
1850.18 422
-0.55
0.5853 0.05 -4647.06
2626.36
TRTPN*ATPTN Bel300
3
Oxy30
0
-4652.43
1922.13 422
-2.42
0.0159 0.05 -8430.58
-874.28
TRTPN*ATPTN Bel300
3
Oxy30
0.5
-2380.28
1922.13 422
-1.24
0.2163 0.05 -6158.43
1397.86
TRTPN*ATPTN Bel300
3
Oxy30
1
-525.56
1883.53 422
-0.28
0.7804 0.05 -4227.83
3176.71
TRTPN*ATPTN Bel300
3
Oxy30
2
-1380.71
1850.26 422
-0.75
0.4559 0.05 -5017.58
2256.16
TRTPN*ATPTN Bel300
3
Oxy30
3
-2975.55
1850.26 422
-1.61
0.1085 0.05 -6612.42
661.32
TRTPN*ATPTN Bel300
3
Oxy30
4
-3196.30
1850.26 422
-1.73
0.0848 0.05 -6833.17
440.57
TRTPN*ATPTN Bel300
3
Oxy60
0
-3192.32
1886.80 422
-1.69
0.0914 0.05 -6901.02
516.39
TRTPN*ATPTN Bel300
3
Oxy60
0.5
-960.08
1886.80 422
-0.51
0.6111 0.05 -4668.78
2748.62
TRTPN*ATPTN Bel300
3
Oxy60
1
1131.44
1852.83 422
0.61
0.5418 0.05 -2510.49
4773.38
TRTPN*ATPTN Bel300
3
Oxy60
2
2124.00
1822.14 422
1.17
0.2444 0.05 -1457.60
5705.59
TRTPN*ATPTN Bel300
3
Oxy60
3
1457.18
1822.14 422
0.80
0.4243 0.05 -2124.42
5038.78
TRTPN*ATPTN Bel300
3
Oxy60
4
1338.04
1822.14 422
0.73
0.4632 0.05 -2243.56
4919.64
TRTPN*ATPTN Bel300
3
Plac
0
-3060.24
1821.91 422
-1.68
0.0938 0.05 -6641.38
520.90
TRTPN*ATPTN Bel300
3
Plac
0.5
-4585.86
1821.91 422
-2.52
0.0122 0.05 -8167.01 -1004.72
TRTPN*ATPTN Bel300
3
Plac
1
-5537.37
1821.91 422
-3.04
0.0025 0.05 -9118.51 -1956.22
TRTPN*ATPTN Bel300
3
Plac
2
-1471.07
1821.91 422
-0.81
0.4199 0.05 -5052.21
2110.08
TRTPN*ATPTN Bel300
3
Plac
3
-1885.14
1821.91 422
-1.03
0.3014 0.05 -5466.28
1696.01
TRTPN*ATPTN Bel300
3
Plac
4
-3064.37
1821.91 422
-1.68
0.0933 0.05 -6645.51
516.77
TRTPN*ATPTN Bel300
4
Bel600
0
-3555.99
1852.53 422
-1.92
0.0556 0.05 -7197.32
85.3376
TRTPN*ATPTN Bel300
4
Bel600
0.5
-4542.71
1852.53 422
-2.45
0.0146 0.05 -8184.05
-901.38
Page 294 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 12 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
4
Bel600
1
-3158.09
1822.76 422
-1.73
0.0839 0.05 -6740.90
424.72
TRTPN*ATPTN Bel300
4
Bel600
2
-1552.86
1822.76 422
-0.85
0.3947 0.05 -5135.67
2029.95
TRTPN*ATPTN Bel300
4
Bel600
3
-713.22
1822.76 422
-0.39
0.6958 0.05 -4296.03
2869.59
TRTPN*ATPTN Bel300
4
Bel600
4
-896.66
1822.76 422
-0.49
0.6230 0.05 -4479.47
2686.15
TRTPN*ATPTN Bel300
4
Bel900
0
-5326.48
1883.44 422
-2.83
0.0049 0.05 -9028.57 -1624.40
TRTPN*ATPTN Bel300
4
Bel900
0.5
-6761.16
1850.18 422
-3.65
0.0003 0.05
-10398 -3124.45
TRTPN*ATPTN Bel300
4
Bel900
1
-3941.68
1850.18 422
-2.13
0.0337 0.05 -7578.39
-304.97
TRTPN*ATPTN Bel300
4
Bel900
2
-2183.93
1850.18 422
-1.18
0.2385 0.05 -5820.64
1452.78
TRTPN*ATPTN Bel300
4
Bel900
3
-1503.66
1850.18 422
-0.81
0.4168 0.05 -5140.37
2133.04
TRTPN*ATPTN Bel300
4
Bel900
4
-455.17
1850.18 422
-0.25
0.8058 0.05 -4091.88
3181.53
TRTPN*ATPTN Bel300
4
Oxy30
0
-4097.25
1922.13 422
-2.13
0.0336 0.05 -7875.40
-319.11
TRTPN*ATPTN Bel300
4
Oxy30
0.5
-1825.10
1922.13 422
-0.95
0.3429 0.05 -5603.25
1953.04
TRTPN*ATPTN Bel300
4
Oxy30
1
29.6164
1883.53 422
0.02
0.9875 0.05 -3672.65
3731.88
TRTPN*ATPTN Bel300
4
Oxy30
2
-825.53
1850.26 422
-0.45
0.6557 0.05 -4462.40
2811.33
TRTPN*ATPTN Bel300
4
Oxy30
3
-2420.37
1850.26 422
-1.31
0.1915 0.05 -6057.24
1216.50
TRTPN*ATPTN Bel300
4
Oxy30
4
-2641.12
1850.26 422
-1.43
0.1542 0.05 -6277.99
995.74
TRTPN*ATPTN Bel300
4
Oxy60
0
-2637.14
1886.80 422
-1.40
0.1629 0.05 -6345.84
1071.56
TRTPN*ATPTN Bel300
4
Oxy60
0.5
-404.90
1886.80 422
-0.21
0.8302 0.05 -4113.61
3303.80
TRTPN*ATPTN Bel300
4
Oxy60
1
1686.62
1852.83 422
0.91
0.3632 0.05 -1955.31
5328.56
TRTPN*ATPTN Bel300
4
Oxy60
2
2679.17
1822.14 422
1.47
0.1422 0.05
-902.43
6260.77
TRTPN*ATPTN Bel300
4
Oxy60
3
2012.36
1822.14 422
1.10
0.2701 0.05 -1569.24
5593.96
TRTPN*ATPTN Bel300
4
Oxy60
4
1893.22
1822.14 422
1.04
0.2994 0.05 -1688.38
5474.82
TRTPN*ATPTN Bel300
4
Plac
0
-2505.06
1821.91 422
-1.37
0.1699 0.05 -6086.20
1076.08
TRTPN*ATPTN Bel300
4
Plac
0.5
-4030.69
1821.91 422
-2.21
0.0275 0.05 -7611.83
-449.54
TRTPN*ATPTN Bel300
4
Plac
1
-4982.19
1821.91 422
-2.73
0.0065 0.05 -8563.33 -1401.05
Page 295 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 13 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel300
4
Plac
2
-915.89
1821.91 422
-0.50
0.6154 0.05 -4497.03
2665.25
TRTPN*ATPTN Bel300
4
Plac
3
-1329.96
1821.91 422
-0.73
0.4658 0.05 -4911.10
2251.18
TRTPN*ATPTN Bel300
4
Plac
4
-2509.19
1821.91 422
-1.38
0.1692 0.05 -6090.33
1071.95
TRTPN*ATPTN Bel600
0
Bel600
0.5
-986.72
1848.84 422
-0.53
0.5938 0.05 -4620.80
2647.35
TRTPN*ATPTN Bel600
0
Bel600
1
397.90
1820.87 422
0.22
0.8271 0.05 -3181.21
3977.02
TRTPN*ATPTN Bel600
0
Bel600
2
2003.13
1820.87 422
1.10
0.2719 0.05 -1575.98
5582.24
TRTPN*ATPTN Bel600
0
Bel600
3
2842.78
1820.87 422
1.56
0.1192 0.05
-736.34
6421.89
TRTPN*ATPTN Bel600
0
Bel600
4
2659.33
1820.87 422
1.46
0.1449 0.05
-919.78
6238.45
TRTPN*ATPTN Bel600
0
Bel900
0
-1770.49
1886.03 422
-0.94
0.3484 0.05 -5477.67
1936.69
TRTPN*ATPTN Bel600
0
Bel900
0.5
-3205.16
1852.11 422
-1.73
0.0843 0.05 -6845.67
435.35
TRTPN*ATPTN Bel600
0
Bel900
1
-385.69
1852.11 422
-0.21
0.8351 0.05 -4026.20
3254.82
TRTPN*ATPTN Bel600
0
Bel900
2
1372.07
1852.11 422
0.74
0.4592 0.05 -2268.44
5012.57
TRTPN*ATPTN Bel600
0
Bel900
3
2052.33
1852.11 422
1.11
0.2684 0.05 -1588.18
5692.84
TRTPN*ATPTN Bel600
0
Bel900
4
3100.82
1852.11 422
1.67
0.0948 0.05
-539.69
6741.33
TRTPN*ATPTN Bel600
0
Oxy30
0
-541.26
1925.09 422
-0.28
0.7787 0.05 -4325.21
3242.69
TRTPN*ATPTN Bel600
0
Oxy30
0.5
1730.89
1925.09 422
0.90
0.3691 0.05 -2053.06
5514.84
TRTPN*ATPTN Bel600
0
Oxy30
1
3585.61
1886.28 422
1.90
0.0580 0.05
-122.07
7293.29
TRTPN*ATPTN Bel600
0
Oxy30
2
2730.46
1852.82 422
1.47
0.1413 0.05
-911.45
6372.37
TRTPN*ATPTN Bel600
0
Oxy30
3
1135.62
1852.82 422
0.61
0.5403 0.05 -2506.29
4777.53
TRTPN*ATPTN Bel600
0
Oxy30
4
914.87
1852.82 422
0.49
0.6217 0.05 -2727.04
4556.78
TRTPN*ATPTN Bel600
0
Oxy60
0
918.86
1886.96 422
0.49
0.6265 0.05 -2790.16
4627.87
TRTPN*ATPTN Bel600
0
Oxy60
0.5
3151.09
1886.96 422
1.67
0.0957 0.05
-557.92
6860.11
TRTPN*ATPTN Bel600
0
Oxy60
1
5242.62
1853.41 422
2.83
0.0049 0.05
1599.55
8885.68
TRTPN*ATPTN Bel600
0
Oxy60
2
6235.17
1822.19 422
3.42
0.0007 0.05
2653.47
9816.86
TRTPN*ATPTN Bel600
0
Oxy60
3
5568.35
1822.19 422
3.06
0.0024 0.05
1986.66
9150.05
Page 296 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 14 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel600
0
Oxy60
4
5449.21
1822.19 422
2.99
0.0029 0.05
1867.52
9030.91
TRTPN*ATPTN Bel600
0
Plac
0
1050.93
1820.82 422
0.58
0.5641 0.05 -2528.08
4629.94
TRTPN*ATPTN Bel600
0
Plac
0.5
-474.69
1820.82 422
-0.26
0.7944 0.05 -4053.70
3104.32
TRTPN*ATPTN Bel600
0
Plac
1
-1426.19
1820.82 422
-0.78
0.4339 0.05 -5005.20
2152.81
TRTPN*ATPTN Bel600
0
Plac
2
2640.11
1820.82 422
1.45
0.1478 0.05
-938.90
6219.11
TRTPN*ATPTN Bel600
0
Plac
3
2226.04
1820.82 422
1.22
0.2222 0.05 -1352.97
5805.05
TRTPN*ATPTN Bel600
0
Plac
4
1046.80
1820.82 422
0.57
0.5657 0.05 -2532.21
4625.81
TRTPN*ATPTN Bel600
0.5
Bel600
1
1384.63
1820.87 422
0.76
0.4474 0.05 -2194.49
4963.74
TRTPN*ATPTN Bel600
0.5
Bel600
2
2989.85
1820.87 422
1.64
0.1013 0.05
-589.26
6568.97
TRTPN*ATPTN Bel600
0.5
Bel600
3
3829.50
1820.87 422
2.10
0.0360 0.05
250.38
7408.61
TRTPN*ATPTN Bel600
0.5
Bel600
4
3646.05
1820.87 422
2.00
0.0459 0.05
66.9402
7225.17
TRTPN*ATPTN Bel600
0.5
Bel900
0
-783.77
1886.03 422
-0.42
0.6779 0.05 -4490.95
2923.41
TRTPN*ATPTN Bel600
0.5
Bel900
0.5
-2218.44
1852.11 422
-1.20
0.2317 0.05 -5858.95
1422.07
TRTPN*ATPTN Bel600
0.5
Bel900
1
601.03
1852.11 422
0.32
0.7457 0.05 -3039.47
4241.54
TRTPN*ATPTN Bel600
0.5
Bel900
2
2358.79
1852.11 422
1.27
0.2035 0.05 -1281.72
5999.29
TRTPN*ATPTN Bel600
0.5
Bel900
3
3039.05
1852.11 422
1.64
0.1016 0.05
-601.46
6679.56
TRTPN*ATPTN Bel600
0.5
Bel900
4
4087.54
1852.11 422
2.21
0.0279 0.05
447.03
7728.05
TRTPN*ATPTN Bel600
0.5
Oxy30
0
445.46
1925.09 422
0.23
0.8171 0.05 -3338.49
4229.41
TRTPN*ATPTN Bel600
0.5
Oxy30
0.5
2717.61
1925.09 422
1.41
0.1588 0.05 -1066.34
6501.56
TRTPN*ATPTN Bel600
0.5
Oxy30
1
4572.33
1886.28 422
2.42
0.0158 0.05
864.65
8280.01
TRTPN*ATPTN Bel600
0.5
Oxy30
2
3717.18
1852.82 422
2.01
0.0455 0.05
75.2728
7359.09
TRTPN*ATPTN Bel600
0.5
Oxy30
3
2122.34
1852.82 422
1.15
0.2527 0.05 -1519.57
5764.25
TRTPN*ATPTN Bel600
0.5
Oxy30
4
1901.59
1852.82 422
1.03
0.3053 0.05 -1740.32
5543.50
TRTPN*ATPTN Bel600
0.5
Oxy60
0
1905.58
1886.96 422
1.01
0.3131 0.05 -1803.44
5614.59
TRTPN*ATPTN Bel600
0.5
Oxy60
0.5
4137.81
1886.96 422
2.19
0.0289 0.05
428.80
7846.83
Page 297 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 15 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel600
0.5
Oxy60
1
6229.34
1853.41 422
3.36
0.0008 0.05
2586.28
9872.40
TRTPN*ATPTN Bel600
0.5
Oxy60
2
7221.89
1822.19 422
3.96
<.0001 0.05
3640.19
10804
TRTPN*ATPTN Bel600
0.5
Oxy60
3
6555.07
1822.19 422
3.60
0.0004 0.05
2973.38
10137
TRTPN*ATPTN Bel600
0.5
Oxy60
4
6435.93
1822.19 422
3.53
0.0005 0.05
2854.24
10018
TRTPN*ATPTN Bel600
0.5
Plac
0
2037.66
1820.82 422
1.12
0.2637 0.05 -1541.35
5616.67
TRTPN*ATPTN Bel600
0.5
Plac
0.5
512.03
1820.82 422
0.28
0.7787 0.05 -3066.98
4091.04
TRTPN*ATPTN Bel600
0.5
Plac
1
-439.47
1820.82 422
-0.24
0.8094 0.05 -4018.48
3139.54
TRTPN*ATPTN Bel600
0.5
Plac
2
3626.83
1820.82 422
1.99
0.0470 0.05
47.8170
7205.84
TRTPN*ATPTN Bel600
0.5
Plac
3
3212.76
1820.82 422
1.76
0.0784 0.05
-366.25
6791.77
TRTPN*ATPTN Bel600
0.5
Plac
4
2033.52
1820.82 422
1.12
0.2647 0.05 -1545.49
5612.53
TRTPN*ATPTN Bel600
1
Bel600
2
1605.23
1790.13 422
0.90
0.3704 0.05 -1913.45
5123.90
TRTPN*ATPTN Bel600
1
Bel600
3
2444.87
1790.13 422
1.37
0.1727 0.05 -1073.81
5963.55
TRTPN*ATPTN Bel600
1
Bel600
4
2261.43
1790.13 422
1.26
0.2072 0.05 -1257.25
5780.11
TRTPN*ATPTN Bel600
1
Bel900
0
-2168.40
1856.55 422
-1.17
0.2435 0.05 -5817.63
1480.84
TRTPN*ATPTN Bel600
1
Bel900
0.5
-3603.07
1822.36 422
-1.98
0.0487 0.05 -7185.09 -21.0431
TRTPN*ATPTN Bel600
1
Bel900
1
-783.59
1822.36 422
-0.43
0.6674 0.05 -4365.62
2798.43
TRTPN*ATPTN Bel600
1
Bel900
2
974.16
1822.36 422
0.53
0.5932 0.05 -2607.86
4556.18
TRTPN*ATPTN Bel600
1
Bel900
3
1654.43
1822.36 422
0.91
0.3645 0.05 -1927.60
5236.45
TRTPN*ATPTN Bel600
1
Bel900
4
2702.91
1822.36 422
1.48
0.1388 0.05
-879.11
6284.94
TRTPN*ATPTN Bel600
1
Oxy30
0
-939.16
1896.89 422
-0.50
0.6208 0.05 -4667.68
2789.36
TRTPN*ATPTN Bel600
1
Oxy30
0.5
1332.98
1896.89 422
0.70
0.4826 0.05 -2395.54
5061.51
TRTPN*ATPTN Bel600
1
Oxy30
1
3187.71
1856.86 422
1.72
0.0868 0.05
-462.14
6837.55
TRTPN*ATPTN Bel600
1
Oxy30
2
2332.55
1822.29 422
1.28
0.2012 0.05 -1249.33
5914.44
TRTPN*ATPTN Bel600
1
Oxy30
3
737.72
1822.29 422
0.40
0.6858 0.05 -2844.17
4319.60
TRTPN*ATPTN Bel600
1
Oxy30
4
516.96
1822.29 422
0.28
0.7768 0.05 -3064.92
4098.85
Page 298 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 16 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel600
1
Oxy60
0
520.95
1857.43 422
0.28
0.7793 0.05 -3130.02
4171.93
TRTPN*ATPTN Bel600
1
Oxy60
0.5
2753.19
1857.43 422
1.48
0.1390 0.05
-897.79
6404.16
TRTPN*ATPTN Bel600
1
Oxy60
1
4844.71
1822.82 422
2.66
0.0082 0.05
1261.78
8427.64
TRTPN*ATPTN Bel600
1
Oxy60
2
5837.26
1791.36 422
3.26
0.0012 0.05
2316.16
9358.37
TRTPN*ATPTN Bel600
1
Oxy60
3
5170.45
1791.36 422
2.89
0.0041 0.05
1649.34
8691.55
TRTPN*ATPTN Bel600
1
Oxy60
4
5051.31
1791.36 422
2.82
0.0050 0.05
1530.20
8572.41
TRTPN*ATPTN Bel600
1
Plac
0
653.03
1790.78 422
0.36
0.7155 0.05 -2866.93
4172.99
TRTPN*ATPTN Bel600
1
Plac
0.5
-872.60
1790.78 422
-0.49
0.6263 0.05 -4392.55
2647.36
TRTPN*ATPTN Bel600
1
Plac
1
-1824.10
1790.78 422
-1.02
0.3090 0.05 -5344.06
1695.86
TRTPN*ATPTN Bel600
1
Plac
2
2242.20
1790.78 422
1.25
0.2112 0.05 -1277.76
5762.16
TRTPN*ATPTN Bel600
1
Plac
3
1828.13
1790.78 422
1.02
0.3079 0.05 -1691.83
5348.09
TRTPN*ATPTN Bel600
1
Plac
4
648.90
1790.78 422
0.36
0.7173 0.05 -2871.06
4168.85
TRTPN*ATPTN Bel600
2
Bel600
3
839.65
1790.13 422
0.47
0.6393 0.05 -2679.03
4358.33
TRTPN*ATPTN Bel600
2
Bel600
4
656.20
1790.13 422
0.37
0.7141 0.05 -2862.48
4174.88
TRTPN*ATPTN Bel600
2
Bel900
0
-3773.62
1856.55 422
-2.03
0.0427 0.05 -7422.86
-124.39
TRTPN*ATPTN Bel600
2
Bel900
0.5
-5208.29
1822.36 422
-2.86
0.0045 0.05 -8790.32 -1626.27
TRTPN*ATPTN Bel600
2
Bel900
1
-2388.82
1822.36 422
-1.31
0.1906 0.05 -5970.84
1193.20
TRTPN*ATPTN Bel600
2
Bel900
2
-631.06
1822.36 422
-0.35
0.7293 0.05 -4213.09
2950.96
TRTPN*ATPTN Bel600
2
Bel900
3
49.1998
1822.36 422
0.03
0.9785 0.05 -3532.82
3631.22
TRTPN*ATPTN Bel600
2
Bel900
4
1097.69
1822.36 422
0.60
0.5473 0.05 -2484.33
4679.71
TRTPN*ATPTN Bel600
2
Oxy30
0
-2544.39
1896.89 422
-1.34
0.1805 0.05 -6272.91
1184.13
TRTPN*ATPTN Bel600
2
Oxy30
0.5
-272.24
1896.89 422
-0.14
0.8859 0.05 -4000.76
3456.28
TRTPN*ATPTN Bel600
2
Oxy30
1
1582.48
1856.86 422
0.85
0.3946 0.05 -2067.37
5232.33
TRTPN*ATPTN Bel600
2
Oxy30
2
727.33
1822.29 422
0.40
0.6900 0.05 -2854.56
4309.22
TRTPN*ATPTN Bel600
2
Oxy30
3
-867.51
1822.29 422
-0.48
0.6343 0.05 -4449.40
2714.38
Page 299 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 17 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel600
2
Oxy30
4
-1088.26
1822.29 422
-0.60
0.5507 0.05 -4670.15
2493.62
TRTPN*ATPTN Bel600
2
Oxy60
0
-1084.27
1857.43 422
-0.58
0.5597 0.05 -4735.25
2566.70
TRTPN*ATPTN Bel600
2
Oxy60
0.5
1147.96
1857.43 422
0.62
0.5369 0.05 -2503.02
4798.94
TRTPN*ATPTN Bel600
2
Oxy60
1
3239.49
1822.82 422
1.78
0.0763 0.05
-343.45
6822.42
TRTPN*ATPTN Bel600
2
Oxy60
2
4232.04
1791.36 422
2.36
0.0186 0.05
710.93
7753.14
TRTPN*ATPTN Bel600
2
Oxy60
3
3565.22
1791.36 422
1.99
0.0472 0.05
44.1157
7086.33
TRTPN*ATPTN Bel600
2
Oxy60
4
3446.08
1791.36 422
1.92
0.0551 0.05 -75.0234
6967.19
TRTPN*ATPTN Bel600
2
Plac
0
-952.20
1790.78 422
-0.53
0.5952 0.05 -4472.15
2567.76
TRTPN*ATPTN Bel600
2
Plac
0.5
-2477.82
1790.78 422
-1.38
0.1672 0.05 -5997.78
1042.13
TRTPN*ATPTN Bel600
2
Plac
1
-3429.33
1790.78 422
-1.91
0.0562 0.05 -6949.28
90.6325
TRTPN*ATPTN Bel600
2
Plac
2
636.97
1790.78 422
0.36
0.7222 0.05 -2882.98
4156.93
TRTPN*ATPTN Bel600
2
Plac
3
222.91
1790.78 422
0.12
0.9010 0.05 -3297.05
3742.86
TRTPN*ATPTN Bel600
2
Plac
4
-956.33
1790.78 422
-0.53
0.5936 0.05 -4476.29
2563.63
TRTPN*ATPTN Bel600
3
Bel600
4
-183.44
1790.13 422
-0.10
0.9184 0.05 -3702.12
3335.23
TRTPN*ATPTN Bel600
3
Bel900
0
-4613.27
1856.55 422
-2.48
0.0133 0.05 -8262.50
-964.03
TRTPN*ATPTN Bel600
3
Bel900
0.5
-6047.94
1822.36 422
-3.32
0.0010 0.05 -9629.96 -2465.92
TRTPN*ATPTN Bel600
3
Bel900
1
-3228.47
1822.36 422
-1.77
0.0772 0.05 -6810.49
353.56
TRTPN*ATPTN Bel600
3
Bel900
2
-1470.71
1822.36 422
-0.81
0.4201 0.05 -5052.74
2111.31
TRTPN*ATPTN Bel600
3
Bel900
3
-790.45
1822.36 422
-0.43
0.6647 0.05 -4372.47
2791.58
TRTPN*ATPTN Bel600
3
Bel900
4
258.04
1822.36 422
0.14
0.8875 0.05 -3323.98
3840.07
TRTPN*ATPTN Bel600
3
Oxy30
0
-3384.04
1896.89 422
-1.78
0.0751 0.05 -7112.56
344.48
TRTPN*ATPTN Bel600
3
Oxy30
0.5
-1111.89
1896.89 422
-0.59
0.5581 0.05 -4840.41
2616.63
TRTPN*ATPTN Bel600
3
Oxy30
1
742.83
1856.86 422
0.40
0.6893 0.05 -2907.01
4392.68
TRTPN*ATPTN Bel600
3
Oxy30
2
-112.32
1822.29 422
-0.06
0.9509 0.05 -3694.20
3469.57
TRTPN*ATPTN Bel600
3
Oxy30
3
-1707.16
1822.29 422
-0.94
0.3494 0.05 -5289.04
1874.73
Page 300 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 18 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel600
3
Oxy30
4
-1927.91
1822.29 422
-1.06
0.2907 0.05 -5509.80
1653.98
TRTPN*ATPTN Bel600
3
Oxy60
0
-1923.92
1857.43 422
-1.04
0.3009 0.05 -5574.90
1727.05
TRTPN*ATPTN Bel600
3
Oxy60
0.5
308.31
1857.43 422
0.17
0.8682 0.05 -3342.66
3959.29
TRTPN*ATPTN Bel600
3
Oxy60
1
2399.84
1822.82 422
1.32
0.1887 0.05 -1183.09
5982.77
TRTPN*ATPTN Bel600
3
Oxy60
2
3392.39
1791.36 422
1.89
0.0589 0.05
-128.72
6913.49
TRTPN*ATPTN Bel600
3
Oxy60
3
2725.57
1791.36 422
1.52
0.1289 0.05
-795.53
6246.68
TRTPN*ATPTN Bel600
3
Oxy60
4
2606.43
1791.36 422
1.46
0.1464 0.05
-914.67
6127.54
TRTPN*ATPTN Bel600
3
Plac
0
-1791.84
1790.78 422
-1.00
0.3176 0.05 -5311.80
1728.11
TRTPN*ATPTN Bel600
3
Plac
0.5
-3317.47
1790.78 422
-1.85
0.0646 0.05 -6837.43
202.49
TRTPN*ATPTN Bel600
3
Plac
1
-4268.97
1790.78 422
-2.38
0.0176 0.05 -7788.93
-749.01
TRTPN*ATPTN Bel600
3
Plac
2
-202.67
1790.78 422
-0.11
0.9099 0.05 -3722.63
3317.29
TRTPN*ATPTN Bel600
3
Plac
3
-616.74
1790.78 422
-0.34
0.7307 0.05 -4136.70
2903.22
TRTPN*ATPTN Bel600
3
Plac
4
-1795.98
1790.78 422
-1.00
0.3165 0.05 -5315.93
1723.98
TRTPN*ATPTN Bel600
4
Bel900
0
-4429.82
1856.55 422
-2.39
0.0175 0.05 -8079.06
-780.59
TRTPN*ATPTN Bel600
4
Bel900
0.5
-5864.50
1822.36 422
-3.22
0.0014 0.05 -9446.52 -2282.47
TRTPN*ATPTN Bel600
4
Bel900
1
-3045.02
1822.36 422
-1.67
0.0955 0.05 -6627.05
537.00
TRTPN*ATPTN Bel600
4
Bel900
2
-1287.27
1822.36 422
-0.71
0.4803 0.05 -4869.29
2294.76
TRTPN*ATPTN Bel600
4
Bel900
3
-607.00
1822.36 422
-0.33
0.7392 0.05 -4189.03
2975.02
TRTPN*ATPTN Bel600
4
Bel900
4
441.49
1822.36 422
0.24
0.8087 0.05 -3140.54
4023.51
TRTPN*ATPTN Bel600
4
Oxy30
0
-3200.59
1896.89 422
-1.69
0.0923 0.05 -6929.11
527.93
TRTPN*ATPTN Bel600
4
Oxy30
0.5
-928.44
1896.89 422
-0.49
0.6248 0.05 -4656.96
2800.08
TRTPN*ATPTN Bel600
4
Oxy30
1
926.28
1856.86 422
0.50
0.6182 0.05 -2723.57
4576.12
TRTPN*ATPTN Bel600
4
Oxy30
2
71.1266
1822.29 422
0.04
0.9689 0.05 -3510.76
3653.01
TRTPN*ATPTN Bel600
4
Oxy30
3
-1523.71
1822.29 422
-0.84
0.4035 0.05 -5105.60
2058.17
TRTPN*ATPTN Bel600
4
Oxy30
4
-1744.46
1822.29 422
-0.96
0.3390 0.05 -5326.35
1837.42
Page 301 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 19 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel600
4
Oxy60
0
-1740.48
1857.43 422
-0.94
0.3493 0.05 -5391.45
1910.50
TRTPN*ATPTN Bel600
4
Oxy60
0.5
491.76
1857.43 422
0.26
0.7913 0.05 -3159.22
4142.73
TRTPN*ATPTN Bel600
4
Oxy60
1
2583.28
1822.82 422
1.42
0.1572 0.05
-999.65
6166.21
TRTPN*ATPTN Bel600
4
Oxy60
2
3575.83
1791.36 422
2.00
0.0466 0.05
54.7283
7096.94
TRTPN*ATPTN Bel600
4
Oxy60
3
2909.02
1791.36 422
1.62
0.1051 0.05
-612.09
6430.12
TRTPN*ATPTN Bel600
4
Oxy60
4
2789.88
1791.36 422
1.56
0.1201 0.05
-731.23
6310.98
TRTPN*ATPTN Bel600
4
Plac
0
-1608.40
1790.78 422
-0.90
0.3696 0.05 -5128.36
1911.56
TRTPN*ATPTN Bel600
4
Plac
0.5
-3134.03
1790.78 422
-1.75
0.0808 0.05 -6653.98
385.93
TRTPN*ATPTN Bel600
4
Plac
1
-4085.53
1790.78 422
-2.28
0.0230 0.05 -7605.49
-565.57
TRTPN*ATPTN Bel600
4
Plac
2
-19.2279
1790.78 422
-0.01
0.9914 0.05 -3539.19
3500.73
TRTPN*ATPTN Bel600
4
Plac
3
-433.30
1790.78 422
-0.24
0.8089 0.05 -3953.25
3086.66
TRTPN*ATPTN Bel600
4
Plac
4
-1612.53
1790.78 422
-0.90
0.3684 0.05 -5132.49
1907.43
TRTPN*ATPTN Bel900
0
Bel900
0.5
-1434.67
1882.76 422
-0.76
0.4465 0.05 -5135.43
2266.09
TRTPN*ATPTN Bel900
0
Bel900
1
1384.80
1882.76 422
0.74
0.4624 0.05 -2315.95
5085.56
TRTPN*ATPTN Bel900
0
Bel900
2
3142.56
1882.76 422
1.67
0.0958 0.05
-558.20
6843.31
TRTPN*ATPTN Bel900
0
Bel900
3
3822.82
1882.76 422
2.03
0.0429 0.05
122.06
7523.58
TRTPN*ATPTN Bel900
0
Bel900
4
4871.31
1882.76 422
2.59
0.0100 0.05
1170.55
8572.07
TRTPN*ATPTN Bel900
0
Oxy30
0
1229.23
1955.46 422
0.63
0.5299 0.05 -2614.42
5072.88
TRTPN*ATPTN Bel900
0
Oxy30
0.5
3501.38
1955.46 422
1.79
0.0741 0.05
-342.27
7345.03
TRTPN*ATPTN Bel900
0
Oxy30
1
5356.10
1917.18 422
2.79
0.0054 0.05
1587.70
9124.50
TRTPN*ATPTN Bel900
0
Oxy30
2
4500.95
1884.18 422
2.39
0.0173 0.05
797.40
8204.50
TRTPN*ATPTN Bel900
0
Oxy30
3
2906.11
1884.18 422
1.54
0.1237 0.05
-797.44
6609.66
TRTPN*ATPTN Bel900
0
Oxy30
4
2685.36
1884.18 422
1.43
0.1548 0.05 -1018.19
6388.91
TRTPN*ATPTN Bel900
0
Oxy60
0
2689.35
1919.01 422
1.40
0.1618 0.05 -1082.65
6461.35
TRTPN*ATPTN Bel900
0
Oxy60
0.5
4921.58
1919.01 422
2.56
0.0107 0.05
1149.58
8693.58
Page 302 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 20 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel900
0
Oxy60
1
7013.11
1886.16 422
3.72
0.0002 0.05
3305.67
10721
TRTPN*ATPTN Bel900
0
Oxy60
2
8005.66
1855.83 422
4.31
<.0001 0.05
4357.83
11653
TRTPN*ATPTN Bel900
0
Oxy60
3
7338.84
1855.83 422
3.95
<.0001 0.05
3691.02
10987
TRTPN*ATPTN Bel900
0
Oxy60
4
7219.70
1855.83 422
3.89
0.0001 0.05
3571.88
10868
TRTPN*ATPTN Bel900
0
Plac
0
2821.43
1856.35 422
1.52
0.1293 0.05
-827.42
6470.27
TRTPN*ATPTN Bel900
0
Plac
0.5
1295.80
1856.35 422
0.70
0.4855 0.05 -2353.04
4944.64
TRTPN*ATPTN Bel900
0
Plac
1
344.30
1856.35 422
0.19
0.8529 0.05 -3304.55
3993.14
TRTPN*ATPTN Bel900
0
Plac
2
4410.60
1856.35 422
2.38
0.0179 0.05
761.75
8059.44
TRTPN*ATPTN Bel900
0
Plac
3
3996.53
1856.35 422
2.15
0.0319 0.05
347.69
7645.37
TRTPN*ATPTN Bel900
0
Plac
4
2817.29
1856.35 422
1.52
0.1299 0.05
-831.55
6466.13
TRTPN*ATPTN Bel900
0.5
Bel900
1
2819.47
1848.84 422
1.52
0.1280 0.05
-814.60
6453.55
TRTPN*ATPTN Bel900
0.5
Bel900
2
4577.23
1848.84 422
2.48
0.0137 0.05
943.15
8211.30
TRTPN*ATPTN Bel900
0.5
Bel900
3
5257.49
1848.84 422
2.84
0.0047 0.05
1623.42
8891.57
TRTPN*ATPTN Bel900
0.5
Bel900
4
6305.98
1848.84 422
3.41
0.0007 0.05
2671.91
9940.06
TRTPN*ATPTN Bel900
0.5
Oxy30
0
2663.90
1922.09 422
1.39
0.1665 0.05 -1114.16
6441.96
TRTPN*ATPTN Bel900
0.5
Oxy30
0.5
4936.05
1922.09 422
2.57
0.0106 0.05
1157.99
8714.11
TRTPN*ATPTN Bel900
0.5
Oxy30
1
6790.77
1883.48 422
3.61
0.0003 0.05
3088.59
10493
TRTPN*ATPTN Bel900
0.5
Oxy30
2
5935.62
1850.21 422
3.21
0.0014 0.05
2298.84
9572.40
TRTPN*ATPTN Bel900
0.5
Oxy30
3
4340.78
1850.21 422
2.35
0.0194 0.05
704.00
7977.56
TRTPN*ATPTN Bel900
0.5
Oxy30
4
4120.03
1850.21 422
2.23
0.0265 0.05
483.25
7756.81
TRTPN*ATPTN Bel900
0.5
Oxy60
0
4124.02
1886.21 422
2.19
0.0293 0.05
416.48
7831.56
TRTPN*ATPTN Bel900
0.5
Oxy60
0.5
6356.25
1886.21 422
3.37
0.0008 0.05
2648.71
10064
TRTPN*ATPTN Bel900
0.5
Oxy60
1
8447.78
1853.71 422
4.56
<.0001 0.05
4804.11
12091
TRTPN*ATPTN Bel900
0.5
Oxy60
2
9440.33
1822.31 422
5.18
<.0001 0.05
5858.39
13022
TRTPN*ATPTN Bel900
0.5
Oxy60
3
8773.51
1822.31 422
4.81
<.0001 0.05
5191.57
12355
Page 303 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 21 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel900
0.5
Oxy60
4
8654.37
1822.31 422
4.75
<.0001 0.05
5072.43
12236
TRTPN*ATPTN Bel900
0.5
Plac
0
4256.10
1822.11 422
2.34
0.0200 0.05
674.55
7837.64
TRTPN*ATPTN Bel900
0.5
Plac
0.5
2730.47
1822.11 422
1.50
0.1347 0.05
-851.07
6312.01
TRTPN*ATPTN Bel900
0.5
Plac
1
1778.97
1822.11 422
0.98
0.3295 0.05 -1802.58
5360.51
TRTPN*ATPTN Bel900
0.5
Plac
2
5845.27
1822.11 422
3.21
0.0014 0.05
2263.72
9426.81
TRTPN*ATPTN Bel900
0.5
Plac
3
5431.20
1822.11 422
2.98
0.0030 0.05
1849.65
9012.74
TRTPN*ATPTN Bel900
0.5
Plac
4
4251.96
1822.11 422
2.33
0.0201 0.05
670.42
7833.51
TRTPN*ATPTN Bel900
1
Bel900
2
1757.75
1848.84 422
0.95
0.3423 0.05 -1876.32
5391.83
TRTPN*ATPTN Bel900
1
Bel900
3
2438.02
1848.84 422
1.32
0.1880 0.05 -1196.06
6072.09
TRTPN*ATPTN Bel900
1
Bel900
4
3486.51
1848.84 422
1.89
0.0600 0.05
-147.57
7120.58
TRTPN*ATPTN Bel900
1
Oxy30
0
-155.57
1922.09 422
-0.08
0.9355 0.05 -3933.63
3622.49
TRTPN*ATPTN Bel900
1
Oxy30
0.5
2116.58
1922.09 422
1.10
0.2714 0.05 -1661.48
5894.64
TRTPN*ATPTN Bel900
1
Oxy30
1
3971.30
1883.48 422
2.11
0.0356 0.05
269.12
7673.48
TRTPN*ATPTN Bel900
1
Oxy30
2
3116.15
1850.21 422
1.68
0.0929 0.05
-520.63
6752.93
TRTPN*ATPTN Bel900
1
Oxy30
3
1521.31
1850.21 422
0.82
0.4114 0.05 -2115.47
5158.09
TRTPN*ATPTN Bel900
1
Oxy30
4
1300.56
1850.21 422
0.70
0.4825 0.05 -2336.22
4937.34
TRTPN*ATPTN Bel900
1
Oxy60
0
1304.54
1886.21 422
0.69
0.4896 0.05 -2403.00
5012.08
TRTPN*ATPTN Bel900
1
Oxy60
0.5
3536.78
1886.21 422
1.88
0.0615 0.05
-170.76
7244.32
TRTPN*ATPTN Bel900
1
Oxy60
1
5628.30
1853.71 422
3.04
0.0025 0.05
1984.64
9271.97
TRTPN*ATPTN Bel900
1
Oxy60
2
6620.86
1822.31 422
3.63
0.0003 0.05
3038.91
10203
TRTPN*ATPTN Bel900
1
Oxy60
3
5954.04
1822.31 422
3.27
0.0012 0.05
2372.10
9535.98
TRTPN*ATPTN Bel900
1
Oxy60
4
5834.90
1822.31 422
3.20
0.0015 0.05
2252.96
9416.84
TRTPN*ATPTN Bel900
1
Plac
0
1436.62
1822.11 422
0.79
0.4309 0.05 -2144.92
5018.17
TRTPN*ATPTN Bel900
1
Plac
0.5
-89.0037
1822.11 422
-0.05
0.9611 0.05 -3670.55
3492.54
TRTPN*ATPTN Bel900
1
Plac
1
-1040.51
1822.11 422
-0.57
0.5683 0.05 -4622.05
2541.04
Page 304 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 22 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel900
1
Plac
2
3025.79
1822.11 422
1.66
0.0975 0.05
-555.75
6607.34
TRTPN*ATPTN Bel900
1
Plac
3
2611.72
1822.11 422
1.43
0.1525 0.05
-969.82
6193.27
TRTPN*ATPTN Bel900
1
Plac
4
1432.49
1822.11 422
0.79
0.4322 0.05 -2149.05
5014.03
TRTPN*ATPTN Bel900
2
Bel900
3
680.26
1848.84 422
0.37
0.7131 0.05 -2953.81
4314.34
TRTPN*ATPTN Bel900
2
Bel900
4
1728.75
1848.84 422
0.94
0.3503 0.05 -1905.32
5362.83
TRTPN*ATPTN Bel900
2
Oxy30
0
-1913.32
1922.09 422
-1.00
0.3201 0.05 -5691.38
1864.73
TRTPN*ATPTN Bel900
2
Oxy30
0.5
358.82
1922.09 422
0.19
0.8520 0.05 -3419.24
4136.88
TRTPN*ATPTN Bel900
2
Oxy30
1
2213.54
1883.48 422
1.18
0.2406 0.05 -1488.64
5915.72
TRTPN*ATPTN Bel900
2
Oxy30
2
1358.39
1850.21 422
0.73
0.4632 0.05 -2278.39
4995.17
TRTPN*ATPTN Bel900
2
Oxy30
3
-236.44
1850.21 422
-0.13
0.8984 0.05 -3873.23
3400.34
TRTPN*ATPTN Bel900
2
Oxy30
4
-457.20
1850.21 422
-0.25
0.8049 0.05 -4093.98
3179.58
TRTPN*ATPTN Bel900
2
Oxy60
0
-453.21
1886.21 422
-0.24
0.8102 0.05 -4160.75
3254.33
TRTPN*ATPTN Bel900
2
Oxy60
0.5
1779.02
1886.21 422
0.94
0.3461 0.05 -1928.51
5486.56
TRTPN*ATPTN Bel900
2
Oxy60
1
3870.55
1853.71 422
2.09
0.0374 0.05
226.89
7514.21
TRTPN*ATPTN Bel900
2
Oxy60
2
4863.10
1822.31 422
2.67
0.0079 0.05
1281.16
8445.04
TRTPN*ATPTN Bel900
2
Oxy60
3
4196.29
1822.31 422
2.30
0.0218 0.05
614.34
7778.23
TRTPN*ATPTN Bel900
2
Oxy60
4
4077.15
1822.31 422
2.24
0.0258 0.05
495.20
7659.09
TRTPN*ATPTN Bel900
2
Plac
0
-321.13
1822.11 422
-0.18
0.8602 0.05 -3902.68
3260.41
TRTPN*ATPTN Bel900
2
Plac
0.5
-1846.76
1822.11 422
-1.01
0.3114 0.05 -5428.30
1734.79
TRTPN*ATPTN Bel900
2
Plac
1
-2798.26
1822.11 422
-1.54
0.1254 0.05 -6379.80
783.28
TRTPN*ATPTN Bel900
2
Plac
2
1268.04
1822.11 422
0.70
0.4869 0.05 -2313.50
4849.58
TRTPN*ATPTN Bel900
2
Plac
3
853.97
1822.11 422
0.47
0.6395 0.05 -2727.57
4435.51
TRTPN*ATPTN Bel900
2
Plac
4
-325.26
1822.11 422
-0.18
0.8584 0.05 -3906.81
3256.28
TRTPN*ATPTN Bel900
3
Bel900
4
1048.49
1848.84 422
0.57
0.5709 0.05 -2585.59
4682.56
TRTPN*ATPTN Bel900
3
Oxy30
0
-2593.59
1922.09 422
-1.35
0.1779 0.05 -6371.65
1184.47
Page 305 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 23 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel900
3
Oxy30
0.5
-321.44
1922.09 422
-0.17
0.8673 0.05 -4099.50
3456.62
TRTPN*ATPTN Bel900
3
Oxy30
1
1533.28
1883.48 422
0.81
0.4161 0.05 -2168.90
5235.46
TRTPN*ATPTN Bel900
3
Oxy30
2
678.13
1850.21 422
0.37
0.7142 0.05 -2958.65
4314.91
TRTPN*ATPTN Bel900
3
Oxy30
3
-916.71
1850.21 422
-0.50
0.6205 0.05 -4553.49
2720.07
TRTPN*ATPTN Bel900
3
Oxy30
4
-1137.46
1850.21 422
-0.61
0.5390 0.05 -4774.24
2499.32
TRTPN*ATPTN Bel900
3
Oxy60
0
-1133.47
1886.21 422
-0.60
0.5482 0.05 -4841.01
2574.06
TRTPN*ATPTN Bel900
3
Oxy60
0.5
1098.76
1886.21 422
0.58
0.5605 0.05 -2608.78
4806.30
TRTPN*ATPTN Bel900
3
Oxy60
1
3190.29
1853.71 422
1.72
0.0860 0.05
-453.38
6833.95
TRTPN*ATPTN Bel900
3
Oxy60
2
4182.84
1822.31 422
2.30
0.0222 0.05
600.89
7764.78
TRTPN*ATPTN Bel900
3
Oxy60
3
3516.02
1822.31 422
1.93
0.0543 0.05 -65.9217
7097.96
TRTPN*ATPTN Bel900
3
Oxy60
4
3396.88
1822.31 422
1.86
0.0630 0.05
-185.06
6978.83
TRTPN*ATPTN Bel900
3
Plac
0
-1001.40
1822.11 422
-0.55
0.5829 0.05 -4582.94
2580.15
TRTPN*ATPTN Bel900
3
Plac
0.5
-2527.02
1822.11 422
-1.39
0.1662 0.05 -6108.57
1054.52
TRTPN*ATPTN Bel900
3
Plac
1
-3478.52
1822.11 422
-1.91
0.0569 0.05 -7060.07
103.02
TRTPN*ATPTN Bel900
3
Plac
2
587.78
1822.11 422
0.32
0.7472 0.05 -2993.77
4169.32
TRTPN*ATPTN Bel900
3
Plac
3
173.71
1822.11 422
0.10
0.9241 0.05 -3407.84
3755.25
TRTPN*ATPTN Bel900
3
Plac
4
-1005.53
1822.11 422
-0.55
0.5813 0.05 -4587.07
2576.02
TRTPN*ATPTN Bel900
4
Oxy30
0
-3642.08
1922.09 422
-1.89
0.0588 0.05 -7420.14
135.98
TRTPN*ATPTN Bel900
4
Oxy30
0.5
-1369.93
1922.09 422
-0.71
0.4764 0.05 -5147.99
2408.13
TRTPN*ATPTN Bel900
4
Oxy30
1
484.79
1883.48 422
0.26
0.7970 0.05 -3217.39
4186.97
TRTPN*ATPTN Bel900
4
Oxy30
2
-370.36
1850.21 422
-0.20
0.8414 0.05 -4007.14
3266.42
TRTPN*ATPTN Bel900
4
Oxy30
3
-1965.20
1850.21 422
-1.06
0.2888 0.05 -5601.98
1671.58
TRTPN*ATPTN Bel900
4
Oxy30
4
-2185.95
1850.21 422
-1.18
0.2381 0.05 -5822.73
1450.83
TRTPN*ATPTN Bel900
4
Oxy60
0
-2181.96
1886.21 422
-1.16
0.2480 0.05 -5889.50
1525.58
TRTPN*ATPTN Bel900
4
Oxy60
0.5
50.2714
1886.21 422
0.03
0.9787 0.05 -3657.27
3757.81
Page 306 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 24 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Bel900
4
Oxy60
1
2141.80
1853.71 422
1.16
0.2486 0.05 -1501.87
5785.46
TRTPN*ATPTN Bel900
4
Oxy60
2
3134.35
1822.31 422
1.72
0.0862 0.05
-447.60
6716.29
TRTPN*ATPTN Bel900
4
Oxy60
3
2467.53
1822.31 422
1.35
0.1764 0.05 -1114.41
6049.48
TRTPN*ATPTN Bel900
4
Oxy60
4
2348.39
1822.31 422
1.29
0.1982 0.05 -1233.55
5930.34
TRTPN*ATPTN Bel900
4
Plac
0
-2049.89
1822.11 422
-1.13
0.2612 0.05 -5631.43
1531.66
TRTPN*ATPTN Bel900
4
Plac
0.5
-3575.51
1822.11 422
-1.96
0.0504 0.05 -7157.06
6.0322
TRTPN*ATPTN Bel900
4
Plac
1
-4527.01
1822.11 422
-2.48
0.0134 0.05 -8108.56
-945.47
TRTPN*ATPTN Bel900
4
Plac
2
-460.71
1822.11 422
-0.25
0.8005 0.05 -4042.26
3120.83
TRTPN*ATPTN Bel900
4
Plac
3
-874.78
1822.11 422
-0.48
0.6314 0.05 -4456.33
2706.76
TRTPN*ATPTN Bel900
4
Plac
4
-2054.02
1822.11 422
-1.13
0.2603 0.05 -5635.56
1527.53
TRTPN*ATPTN Oxy30
0
Oxy30
0.5
2272.15
1985.97 422
1.14
0.2532 0.05 -1631.47
6175.77
TRTPN*ATPTN Oxy30
0
Oxy30
1
4126.87
1951.67 422
2.11
0.0351 0.05
290.66
7963.08
TRTPN*ATPTN Oxy30
0
Oxy30
2
3271.72
1922.33 422
1.70
0.0895 0.05
-506.82
7050.26
TRTPN*ATPTN Oxy30
0
Oxy30
3
1676.88
1922.33 422
0.87
0.3835 0.05 -2101.66
5455.42
TRTPN*ATPTN Oxy30
0
Oxy30
4
1456.13
1922.33 422
0.76
0.4492 0.05 -2322.41
5234.66
TRTPN*ATPTN Oxy30
0
Oxy60
0
1460.11
1958.61 422
0.75
0.4564 0.05 -2389.73
5309.95
TRTPN*ATPTN Oxy30
0
Oxy60
0.5
3692.35
1958.61 422
1.89
0.0601 0.05
-157.49
7542.19
TRTPN*ATPTN Oxy30
0
Oxy60
1
5783.87
1927.80 422
3.00
0.0029 0.05
1994.59
9573.16
TRTPN*ATPTN Oxy30
0
Oxy60
2
6776.43
1896.92 422
3.57
0.0004 0.05
3047.84
10505
TRTPN*ATPTN Oxy30
0
Oxy60
3
6109.61
1896.92 422
3.22
0.0014 0.05
2381.03
9838.19
TRTPN*ATPTN Oxy30
0
Oxy60
4
5990.47
1896.92 422
3.16
0.0017 0.05
2261.89
9719.05
TRTPN*ATPTN Oxy30
0
Plac
0
1592.19
1895.07 422
0.84
0.4013 0.05 -2132.76
5317.15
TRTPN*ATPTN Oxy30
0
Plac
0.5
66.5664
1895.07 422
0.04
0.9720 0.05 -3658.39
3791.52
TRTPN*ATPTN Oxy30
0
Plac
1
-884.94
1895.07 422
-0.47
0.6408 0.05 -4609.89
2840.02
TRTPN*ATPTN Oxy30
0
Plac
2
3181.36
1895.07 422
1.68
0.0939 0.05
-543.59
6906.32
Page 307 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 25 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Oxy30
0
Plac
3
2767.29
1895.07 422
1.46
0.1450 0.05
-957.66
6492.25
TRTPN*ATPTN Oxy30
0
Plac
4
1588.06
1895.07 422
0.84
0.4025 0.05 -2136.89
5313.01
TRTPN*ATPTN Oxy30
0.5
Oxy30
1
1854.72
1951.67 422
0.95
0.3425 0.05 -1981.49
5690.93
TRTPN*ATPTN Oxy30
0.5
Oxy30
2
999.57
1922.33 422
0.52
0.6034 0.05 -2778.97
4778.11
TRTPN*ATPTN Oxy30
0.5
Oxy30
3
-595.27
1922.33 422
-0.31
0.7570 0.05 -4373.81
3183.27
TRTPN*ATPTN Oxy30
0.5
Oxy30
4
-816.02
1922.33 422
-0.42
0.6714 0.05 -4594.56
2962.52
TRTPN*ATPTN Oxy30
0.5
Oxy60
0
-812.03
1958.61 422
-0.41
0.6786 0.05 -4661.87
3037.81
TRTPN*ATPTN Oxy30
0.5
Oxy60
0.5
1420.20
1958.61 422
0.73
0.4688 0.05 -2429.64
5270.04
TRTPN*ATPTN Oxy30
0.5
Oxy60
1
3511.73
1927.80 422
1.82
0.0692 0.05
-277.56
7301.02
TRTPN*ATPTN Oxy30
0.5
Oxy60
2
4504.28
1896.92 422
2.37
0.0180 0.05
775.69
8232.86
TRTPN*ATPTN Oxy30
0.5
Oxy60
3
3837.46
1896.92 422
2.02
0.0437 0.05
108.88
7566.04
TRTPN*ATPTN Oxy30
0.5
Oxy60
4
3718.32
1896.92 422
1.96
0.0506 0.05 -10.2601
7446.91
TRTPN*ATPTN Oxy30
0.5
Plac
0
-679.96
1895.07 422
-0.36
0.7199 0.05 -4404.91
3045.00
TRTPN*ATPTN Oxy30
0.5
Plac
0.5
-2205.58
1895.07 422
-1.16
0.2451 0.05 -5930.54
1519.37
TRTPN*ATPTN Oxy30
0.5
Plac
1
-3157.08
1895.07 422
-1.67
0.0965 0.05 -6882.04
567.87
TRTPN*ATPTN Oxy30
0.5
Plac
2
909.22
1895.07 422
0.48
0.6316 0.05 -2815.74
4634.17
TRTPN*ATPTN Oxy30
0.5
Plac
3
495.15
1895.07 422
0.26
0.7940 0.05 -3229.81
4220.10
TRTPN*ATPTN Oxy30
0.5
Plac
4
-684.09
1895.07 422
-0.36
0.7183 0.05 -4409.04
3040.87
TRTPN*ATPTN Oxy30
1
Oxy30
2
-855.15
1882.89 422
-0.45
0.6499 0.05 -4556.16
2845.86
TRTPN*ATPTN Oxy30
1
Oxy30
3
-2449.99
1882.89 422
-1.30
0.1939 0.05 -6150.99
1251.02
TRTPN*ATPTN Oxy30
1
Oxy30
4
-2670.74
1882.89 422
-1.42
0.1568 0.05 -6371.75
1030.26
TRTPN*ATPTN Oxy30
1
Oxy60
0
-2666.75
1920.15 422
-1.39
0.1656 0.05 -6441.00
1107.49
TRTPN*ATPTN Oxy30
1
Oxy60
0.5
-434.52
1920.15 422
-0.23
0.8211 0.05 -4208.76
3339.72
TRTPN*ATPTN Oxy30
1
Oxy60
1
1657.01
1888.02 422
0.88
0.3806 0.05 -2054.09
5368.10
TRTPN*ATPTN Oxy30
1
Oxy60
2
2649.56
1856.88 422
1.43
0.1544 0.05 -1000.32
6299.43
Page 308 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 26 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Oxy30
1
Oxy60
3
1982.74
1856.88 422
1.07
0.2862 0.05 -1667.14
5632.62
TRTPN*ATPTN Oxy30
1
Oxy60
4
1863.60
1856.88 422
1.00
0.3161 0.05 -1786.27
5513.48
TRTPN*ATPTN Oxy30
1
Plac
0
-2534.68
1855.92 422
-1.37
0.1728 0.05 -6182.68
1113.32
TRTPN*ATPTN Oxy30
1
Plac
0.5
-4060.30
1855.92 422
-2.19
0.0292 0.05 -7708.30
-412.30
TRTPN*ATPTN Oxy30
1
Plac
1
-5011.80
1855.92 422
-2.70
0.0072 0.05 -8659.81 -1363.80
TRTPN*ATPTN Oxy30
1
Plac
2
-945.50
1855.92 422
-0.51
0.6107 0.05 -4593.51
2702.50
TRTPN*ATPTN Oxy30
1
Plac
3
-1359.57
1855.92 422
-0.73
0.4642 0.05 -5007.57
2288.43
TRTPN*ATPTN Oxy30
1
Plac
4
-2538.81
1855.92 422
-1.37
0.1721 0.05 -6186.81
1109.19
TRTPN*ATPTN Oxy30
2
Oxy30
3
-1594.84
1848.84 422
-0.86
0.3888 0.05 -5228.91
2039.24
TRTPN*ATPTN Oxy30
2
Oxy30
4
-1815.59
1848.84 422
-0.98
0.3267 0.05 -5449.67
1818.48
TRTPN*ATPTN Oxy30
2
Oxy60
0
-1811.60
1886.98 422
-0.96
0.3376 0.05 -5520.66
1897.45
TRTPN*ATPTN Oxy30
2
Oxy60
0.5
420.63
1886.98 422
0.22
0.8237 0.05 -3288.43
4129.69
TRTPN*ATPTN Oxy30
2
Oxy60
1
2512.16
1853.66 422
1.36
0.1761 0.05 -1131.39
6155.71
TRTPN*ATPTN Oxy30
2
Oxy60
2
3504.71
1822.29 422
1.92
0.0551 0.05 -77.1821
7086.60
TRTPN*ATPTN Oxy30
2
Oxy60
3
2837.89
1822.29 422
1.56
0.1201 0.05
-744.00
6419.78
TRTPN*ATPTN Oxy30
2
Oxy60
4
2718.75
1822.29 422
1.49
0.1365 0.05
-863.14
6300.64
TRTPN*ATPTN Oxy30
2
Plac
0
-1679.53
1822.16 422
-0.92
0.3572 0.05 -5261.16
1902.11
TRTPN*ATPTN Oxy30
2
Plac
0.5
-3205.15
1822.16 422
-1.76
0.0793 0.05 -6786.79
376.49
TRTPN*ATPTN Oxy30
2
Plac
1
-4156.65
1822.16 422
-2.28
0.0230 0.05 -7738.29
-575.02
TRTPN*ATPTN Oxy30
2
Plac
2
-90.3546
1822.16 422
-0.05
0.9605 0.05 -3671.99
3491.28
TRTPN*ATPTN Oxy30
2
Plac
3
-504.42
1822.16 422
-0.28
0.7820 0.05 -4086.06
3077.21
TRTPN*ATPTN Oxy30
2
Plac
4
-1683.66
1822.16 422
-0.92
0.3560 0.05 -5265.30
1897.98
TRTPN*ATPTN Oxy30
3
Oxy30
4
-220.75
1848.84 422
-0.12
0.9050 0.05 -3854.83
3413.32
TRTPN*ATPTN Oxy30
3
Oxy60
0
-216.77
1886.98 422
-0.11
0.9086 0.05 -3925.82
3492.29
TRTPN*ATPTN Oxy30
3
Oxy60
0.5
2015.47
1886.98 422
1.07
0.2861 0.05 -1693.59
5724.53
Page 309 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 27 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Oxy30
3
Oxy60
1
4106.99
1853.66 422
2.22
0.0273 0.05
463.44
7750.55
TRTPN*ATPTN Oxy30
3
Oxy60
2
5099.55
1822.29 422
2.80
0.0054 0.05
1517.66
8681.43
TRTPN*ATPTN Oxy30
3
Oxy60
3
4432.73
1822.29 422
2.43
0.0154 0.05
850.84
8014.62
TRTPN*ATPTN Oxy30
3
Oxy60
4
4313.59
1822.29 422
2.37
0.0184 0.05
731.70
7895.48
TRTPN*ATPTN Oxy30
3
Plac
0
-84.6873
1822.16 422
-0.05
0.9630 0.05 -3666.33
3496.95
TRTPN*ATPTN Oxy30
3
Plac
0.5
-1610.31
1822.16 422
-0.88
0.3773 0.05 -5191.95
1971.32
TRTPN*ATPTN Oxy30
3
Plac
1
-2561.82
1822.16 422
-1.41
0.1605 0.05 -6143.45
1019.82
TRTPN*ATPTN Oxy30
3
Plac
2
1504.48
1822.16 422
0.83
0.4095 0.05 -2077.15
5086.12
TRTPN*ATPTN Oxy30
3
Plac
3
1090.41
1822.16 422
0.60
0.5499 0.05 -2491.22
4672.05
TRTPN*ATPTN Oxy30
3
Plac
4
-88.8197
1822.16 422
-0.05
0.9611 0.05 -3670.46
3492.82
TRTPN*ATPTN Oxy30
4
Oxy60
0
3.9867
1886.98 422
0.00
0.9983 0.05 -3705.07
3713.04
TRTPN*ATPTN Oxy30
4
Oxy60
0.5
2236.22
1886.98 422
1.19
0.2367 0.05 -1472.83
5945.28
TRTPN*ATPTN Oxy30
4
Oxy60
1
4327.75
1853.66 422
2.33
0.0200 0.05
684.20
7971.30
TRTPN*ATPTN Oxy30
4
Oxy60
2
5320.30
1822.29 422
2.92
0.0037 0.05
1738.41
8902.19
TRTPN*ATPTN Oxy30
4
Oxy60
3
4653.48
1822.29 422
2.55
0.0110 0.05
1071.59
8235.37
TRTPN*ATPTN Oxy30
4
Oxy60
4
4534.34
1822.29 422
2.49
0.0132 0.05
952.45
8116.23
TRTPN*ATPTN Oxy30
4
Plac
0
136.07
1822.16 422
0.07
0.9405 0.05 -3445.57
3717.70
TRTPN*ATPTN Oxy30
4
Plac
0.5
-1389.56
1822.16 422
-0.76
0.4461 0.05 -4971.20
2192.08
TRTPN*ATPTN Oxy30
4
Plac
1
-2341.06
1822.16 422
-1.28
0.1996 0.05 -5922.70
1240.57
TRTPN*ATPTN Oxy30
4
Plac
2
1725.24
1822.16 422
0.95
0.3443 0.05 -1856.40
5306.87
TRTPN*ATPTN Oxy30
4
Plac
3
1311.17
1822.16 422
0.72
0.4722 0.05 -2270.47
4892.81
TRTPN*ATPTN Oxy30
4
Plac
4
131.93
1822.16 422
0.07
0.9423 0.05 -3449.71
3713.57
TRTPN*ATPTN Oxy60
0
Oxy60
0.5
2232.24
1913.73 422
1.17
0.2441 0.05 -1529.39
5993.86
TRTPN*ATPTN Oxy60
0
Oxy60
1
4323.76
1885.44 422
2.29
0.0223 0.05
617.73
8029.79
TRTPN*ATPTN Oxy60
0
Oxy60
2
5316.31
1855.33 422
2.87
0.0044 0.05
1669.47
8963.15
Page 310 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 28 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Oxy60
0
Oxy60
3
4649.50
1855.33 422
2.51
0.0126 0.05
1002.66
8296.33
TRTPN*ATPTN Oxy60
0
Oxy60
4
4530.36
1855.33 422
2.44
0.0150 0.05
883.52
8177.20
TRTPN*ATPTN Oxy60
0
Plac
0
132.08
1856.77 422
0.07
0.9433 0.05 -3517.59
3781.75
TRTPN*ATPTN Oxy60
0
Plac
0.5
-1393.55
1856.77 422
-0.75
0.4534 0.05 -5043.22
2256.12
TRTPN*ATPTN Oxy60
0
Plac
1
-2345.05
1856.77 422
-1.26
0.2073 0.05 -5994.72
1304.62
TRTPN*ATPTN Oxy60
0
Plac
2
1721.25
1856.77 422
0.93
0.3544 0.05 -1928.42
5370.92
TRTPN*ATPTN Oxy60
0
Plac
3
1307.18
1856.77 422
0.70
0.4818 0.05 -2342.49
4956.85
TRTPN*ATPTN Oxy60
0
Plac
4
127.95
1856.77 422
0.07
0.9451 0.05 -3521.72
3777.62
TRTPN*ATPTN Oxy60
0.5
Oxy60
1
2091.53
1885.44 422
1.11
0.2679 0.05 -1614.50
5797.55
TRTPN*ATPTN Oxy60
0.5
Oxy60
2
3084.08
1855.33 422
1.66
0.0972 0.05
-562.76
6730.91
TRTPN*ATPTN Oxy60
0.5
Oxy60
3
2417.26
1855.33 422
1.30
0.1933 0.05 -1229.58
6064.10
TRTPN*ATPTN Oxy60
0.5
Oxy60
4
2298.12
1855.33 422
1.24
0.2162 0.05 -1348.72
5944.96
TRTPN*ATPTN Oxy60
0.5
Plac
0
-2100.16
1856.77 422
-1.13
0.2587 0.05 -5749.83
1549.51
TRTPN*ATPTN Oxy60
0.5
Plac
0.5
-3625.78
1856.77 422
-1.95
0.0515 0.05 -7275.45
23.8874
TRTPN*ATPTN Oxy60
0.5
Plac
1
-4577.29
1856.77 422
-2.47
0.0141 0.05 -8226.96
-927.62
TRTPN*ATPTN Oxy60
0.5
Plac
2
-510.99
1856.77 422
-0.28
0.7833 0.05 -4160.66
3138.68
TRTPN*ATPTN Oxy60
0.5
Plac
3
-925.05
1856.77 422
-0.50
0.6186 0.05 -4574.72
2724.62
TRTPN*ATPTN Oxy60
0.5
Plac
4
-2104.29
1856.77 422
-1.13
0.2577 0.05 -5753.96
1545.38
TRTPN*ATPTN Oxy60
1
Oxy60
2
992.55
1820.88 422
0.55
0.5860 0.05 -2586.57
4571.67
TRTPN*ATPTN Oxy60
1
Oxy60
3
325.74
1820.88 422
0.18
0.8581 0.05 -3253.39
3904.86
TRTPN*ATPTN Oxy60
1
Oxy60
4
206.60
1820.88 422
0.11
0.9097 0.05 -3372.52
3785.72
TRTPN*ATPTN Oxy60
1
Plac
0
-4191.68
1822.94 422
-2.30
0.0220 0.05 -7774.85
-608.51
TRTPN*ATPTN Oxy60
1
Plac
0.5
-5717.31
1822.94 422
-3.14
0.0018 0.05 -9300.48 -2134.14
TRTPN*ATPTN Oxy60
1
Plac
1
-6668.81
1822.94 422
-3.66
0.0003 0.05
-10252 -3085.64
TRTPN*ATPTN Oxy60
1
Plac
2
-2602.51
1822.94 422
-1.43
0.1541 0.05 -6185.68
980.66
Page 311 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 29 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Oxy60
1
Plac
3
-3016.58
1822.94 422
-1.65
0.0987 0.05 -6599.75
566.59
TRTPN*ATPTN Oxy60
1
Plac
4
-4195.81
1822.94 422
-2.30
0.0218 0.05 -7778.98
-612.64
TRTPN*ATPTN Oxy60
2
Oxy60
3
-666.82
1790.13 422
-0.37
0.7097 0.05 -4185.49
2851.86
TRTPN*ATPTN Oxy60
2
Oxy60
4
-785.95
1790.13 422
-0.44
0.6609 0.05 -4304.63
2732.72
TRTPN*ATPTN Oxy60
2
Plac
0
-5184.23
1791.43 422
-2.89
0.0040 0.05 -8705.46 -1663.00
TRTPN*ATPTN Oxy60
2
Plac
0.5
-6709.86
1791.43 422
-3.75
0.0002 0.05
-10231 -3188.63
TRTPN*ATPTN Oxy60
2
Plac
1
-7661.36
1791.43 422
-4.28
<.0001 0.05
-11183 -4140.13
TRTPN*ATPTN Oxy60
2
Plac
2
-3595.06
1791.43 422
-2.01
0.0454 0.05 -7116.29 -73.8314
TRTPN*ATPTN Oxy60
2
Plac
3
-4009.13
1791.43 422
-2.24
0.0257 0.05 -7530.36
-487.90
TRTPN*ATPTN Oxy60
2
Plac
4
-5188.37
1791.43 422
-2.90
0.0040 0.05 -8709.60 -1667.13
TRTPN*ATPTN Oxy60
3
Oxy60
4
-119.14
1790.13 422
-0.07
0.9470 0.05 -3637.82
3399.54
TRTPN*ATPTN Oxy60
3
Plac
0
-4517.42
1791.43 422
-2.52
0.0120 0.05 -8038.65
-996.19
TRTPN*ATPTN Oxy60
3
Plac
0.5
-6043.04
1791.43 422
-3.37
0.0008 0.05 -9564.27 -2521.81
TRTPN*ATPTN Oxy60
3
Plac
1
-6994.55
1791.43 422
-3.90
0.0001 0.05
-10516 -3473.32
TRTPN*ATPTN Oxy60
3
Plac
2
-2928.25
1791.43 422
-1.63
0.1029 0.05 -6449.48
592.98
TRTPN*ATPTN Oxy60
3
Plac
3
-3342.32
1791.43 422
-1.87
0.0628 0.05 -6863.55
178.91
TRTPN*ATPTN Oxy60
3
Plac
4
-4521.55
1791.43 422
-2.52
0.0120 0.05 -8042.78 -1000.32
TRTPN*ATPTN Oxy60
4
Plac
0
-4398.28
1791.43 422
-2.46
0.0145 0.05 -7919.51
-877.05
TRTPN*ATPTN Oxy60
4
Plac
0.5
-5923.90
1791.43 422
-3.31
0.0010 0.05 -9445.13 -2402.67
TRTPN*ATPTN Oxy60
4
Plac
1
-6875.41
1791.43 422
-3.84
0.0001 0.05
-10397 -3354.18
TRTPN*ATPTN Oxy60
4
Plac
2
-2809.11
1791.43 422
-1.57
0.1176 0.05 -6330.34
712.12
TRTPN*ATPTN Oxy60
4
Plac
3
-3223.18
1791.43 422
-1.80
0.0727 0.05 -6744.41
298.05
TRTPN*ATPTN Oxy60
4
Plac
4
-4402.41
1791.43 422
-2.46
0.0144 0.05 -7923.64
-881.18
TRTPN*ATPTN Plac
0
Plac
0.5
-1525.63
1790.13 422
-0.85
0.3946 0.05 -5044.30
1993.05
TRTPN*ATPTN Plac
0
Plac
1
-2477.13
1790.13 422
-1.38
0.1672 0.05 -5995.81
1041.55
Page 312 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 30 of 31
Differences of Least Squares Means
Effect
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Planned 
Treatment 
(N)
Analysis 
Timepoint 
(N)
Estimate
Standard
Error DF t Value Pr > |t| Alpha
Lower
Upper
TRTPN*ATPTN Plac
0
Plac
2
1589.17
1790.13 422
0.89
0.3752 0.05 -1929.51
5107.85
TRTPN*ATPTN Plac
0
Plac
3
1175.10
1790.13 422
0.66
0.5119 0.05 -2343.58
4693.78
TRTPN*ATPTN Plac
0
Plac
4
-4.1324
1790.13 422
-0.00
0.9982 0.05 -3522.81
3514.55
TRTPN*ATPTN Plac
0.5
Plac
1
-951.50
1790.13 422
-0.53
0.5953 0.05 -4470.18
2567.18
TRTPN*ATPTN Plac
0.5
Plac
2
3114.80
1790.13 422
1.74
0.0826 0.05
-403.88
6633.48
TRTPN*ATPTN Plac
0.5
Plac
3
2700.73
1790.13 422
1.51
0.1321 0.05
-817.95
6219.41
TRTPN*ATPTN Plac
0.5
Plac
4
1521.49
1790.13 422
0.85
0.3958 0.05 -1997.18
5040.17
TRTPN*ATPTN Plac
1
Plac
2
4066.30
1790.13 422
2.27
0.0236 0.05
547.62
7584.98
TRTPN*ATPTN Plac
1
Plac
3
3652.23
1790.13 422
2.04
0.0420 0.05
133.55
7170.91
TRTPN*ATPTN Plac
1
Plac
4
2473.00
1790.13 422
1.38
0.1679 0.05 -1045.68
5991.68
TRTPN*ATPTN Plac
2
Plac
3
-414.07
1790.13 422
-0.23
0.8172 0.05 -3932.75
3104.61
TRTPN*ATPTN Plac
2
Plac
4
-1593.30
1790.13 422
-0.89
0.3739 0.05 -5111.98
1925.38
TRTPN*ATPTN Plac
3
Plac
4
-1179.23
1790.13 422
-0.66
0.5104 0.05 -4697.91
2339.44
Tests of Effect Slices
Effect
Analysis 
Timepoint 
(N)
Num 
DF
Den 
DF F Value Pr > F
TRTPN*ATPTN 0
5422
0.61 0.6906
TRTPN*ATPTN 0.5
5422
3.11 0.0090
TRTPN*ATPTN 1
5422
3.97 0.0016
TRTPN*ATPTN 2
5422
2.84 0.0155
TRTPN*ATPTN 3
5422
1.55 0.1719
TRTPN*ATPTN 4
5422
1.75 0.1215
Page 313 of 314


BioDelivery Sciences, Inc.                                                                                                           
Protocol: BUP-401                                                                                                                    
                                                                   
Appendix 16.1.9.2.4                                                          
Statistical Methods and Analysis Output Supporting Table 14.2.5                                    
Supporting Table 14.2.4                                                        
                                                                   
_____________________________________________________________________________________________________________________________________
The Mixed Procedure
Parameter Code=MVMIPM
____________________________________________________________________________________________________________________________________
Program: A_Bio4.sas  Created: 02APR2020  7:36 POSTLOCK             
Page 31 of 31
Page 314 of 314