Clinical trial NCT03953820
Conditions: Epilepsy
Sponsor: Aquestive Therapeutics
Start date: 2019-04-13; Completion date: 2019-07-31
Enrollment: 31 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
This was a multiple centers, single-dose, open-label, randomized two-sequence crossover, two-period study to evaluate the pharmacokinetics (PK) of single doses of Diazepam Buccal Film (DBF) compared with Diastat® Rectal Gel (DRG) under fed conditions in adult male and female participants on a stable concomitant regimen of anti-epileptic drugs for the treatment of epilepsy.

Detailed description:
Period 1 was a randomized, 2-sequence, crossover study in which participants received DBF and DRG following a moderate-fat meal in a randomized sequence with a washout period of 28 days between doses. DBF dose was based on body weight according to the currently recommended dose regimen (derived by Aquestive from population PK modeling in healthy volunteers). DRG dose was based on body weight according to the current product labeling for DRG.

Period 2: Participants who completed Period 1 were asked to participate in a second period on a voluntary basis during which volunteers received a second dose of DBF administered at the same dose and in exactly the same manner as the earlier dose of DBF with the exception that DBF was administered following a high-fat meal.

Arms: arm 1: Participants received a single dose of Diazepam Buccal Film following a moderate-fat meal and then received a single dose of Diastat Rectal Gel following a moderate-fat meal with a 28-day washout between doses. arm 2: Participants received a single dose of Diastat Rectal Gel following a moderate-fat meal and then received a single dose of Diazepam Buccal Film following a moderate-fat meal with a 28-day washout between doses. arm 3: Participants who volunteered to participate in the second period received a second dose of Diazepam Buccal Film at the same dose and exactly the same manner as the earlier dose with the exception that the dose was administered following ingestion of a high-fat meal.
Interventions: intervention 1: Diazepam Buccal Film intervention 2: Diastat® Rectal Gel (Valeant Pharmaceuticals USA)
Intervention descriptions: intervention 1: Diazepam Buccal Film administered on inner aspect of the cheek at the recommended dose regimen (10 mg to 17.5 mg according to body weight) following ingestion of a moderate fat meal and following ingestion of a high-fat meal. intervention 2: Diastat Rectal Gel administered rectally according to product label administration and dosing instructions (10 mg to 20 mg according to body weight) following ingestion of a moderate-fat meal.

Protocol documents:
Prot_000.pdf: 
180323 Diazepam Buccal Film DRG Crossover 
Aquestive Therapeutics 
24-MAY-2019 
 
 
 
 
 
PROTOCOL 180323 
AMENDMENT III 
 
IND Number: 129068 
 
A RANDOMIZED, OPEN-LABEL, 2-SEQUENCE, 3-TREATMENT, CROSSOVER 
STUDY TO EVALUATE THE PHARMACOKINETICS OF SINGLE DOSES OF 
DIAZEPAM BUCCAL FILM (DBF) (AQUESTIVE THERAPEUTICS) COMPARED 
WITH DIASTAT® RECTAL GEL (VALEANT PHARMACEUTICALS NORTH 
AMERICA) IN ADULT MALE AND FEMALE SUBJECTS ON A CONCOMITANT 
REGIMEN OF ANTIEPILEPTIC DRUGS (AED) FOR THE TREATMENT OF 
EPILEPSY 
 
 
Contract Research Organization: 
inVentiv Health Clinique inc. 
(« inVentiv »), a Syneos Health 
company 
2500, rue Einstein 
Québec (Québec)  
Canada, G1P 0A2 
Tel.: 1-418-527-4000 
Sponsor: 
Aquestive Therapeutics 
30 Technology Drive 
Warren, NJ 07059 
USA  
Tel.: 908-941-1900 
 
 
 
CONFIDENTIAL 
 
 
This document is strictly confidential. It was developed for Aquestive Therapeutics by inVentiv and must not be 
disclosed to a third party, with the exception of the clinical sites, regulatory agencies and study audit personnel 
without the consent of either inVentiv or the Sponsor. This document is copyrighted in favor of inVentiv and cannot 
be reproduced, modified, or adapted, in part or in total, without prior written approval by inVentiv.  
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Protocol Historical File 
Version 
number 
Brief description/summary of changes 
Date 
Final 
Version submitted to the IEC. 
16-JAN-2019 
Amendment I 
Changes included in Amendment I: 
The following changes were brought to the study protocol as 
required by the Advarra institutional review board (IRB): 
1. Female contraception duration was extended to 51 days 
and male contraception to 111 days following the last 
study drug administration, due to the half-life of the 
study drug. In addition, the sperm donation restriction 
was revised from 105 days to 111 days after the last 
study drug administration. 
2. The exclusion criteria were revised to exclude subjects 
with any clinically significant rectal abnormality or any 
condition for which administration of rectal gel would 
cause a potential risk. 
3. Baseline levels assessment of the concomitant 
antiepileptic drug(s) (AED) was added at screening. The 
AED level(s) must be within an acceptable therapeutic 
range.  
4. The use of any AED of the benzodiazepine class (other 
than diazepam administered as study drug) is prohibited 
during the study.   
For all the pharmacokinetic (PK) blood samples to be 
collected as return visits, it is clarified that subjects may 
have the blood sample collected at home by a home care 
nurse.  
Information was added to section 9.13 Adverse Events in 
order to clarify the adverse events recording, follow up, and 
reporting process. Contact information was added for the 
Sponsor’s safety representative.  
19-FEB-2019 
Amendment II 
Changes included in Amendment II: 
Subjects who complete study periods 1 and 2 may volunteer 
to participate in a third period where they would receive a 
second dose of DBF administered following a high-fat meal.  
Details on clinical sites and biomedical laboratories names 
and locations have been removed from the protocol.  
Any flexibility in the washout duration was excluded since a 
07-MAR-2019 
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washout period of no more than 28 days must be used in this 
study.  
The smoking restriction period of at least 2 hours prior to 
until 4 hours after study drug administration has been 
removed from the protocol. Smoking is allowed on study and 
the restriction period around the dosing procedures will be 
managed by each clinical site.  
In case of a positive result to the urine benzodiazepine (drug) 
screen in periods 2 and 3, continuous subject participation in 
the study will be evaluated by the Principal Investigator.  
In addition, some minor editorial changes and clarifications 
have been made throughout the document, such as sentence 
clarifications, corrections of typographical or punctuation 
errors.  
Amendment III 
See below for a description of changes. 
24-MAY-2019 
Changes included in Amendment III: 
The following changes were brought to the study protocol Amendment II dated 07-MAR-2019: 
The sample size has been increased to a maximum of 32 subjects. Moreover, since only 
exploratory pharmacokinetic data will be gathered from treatment period 3 (DBF administration 
following a high-fat-meal), no more than 50% of the subjects should receive this treatment. This 
involves changes to the following sections: 
• page 9, section 2 Synopsis of Protocol - Study Design and Subjects; 
• 
page 30, section 7 Study Design; 
• 
page 31, section 8.1 Sample Size. 
A discrepancy has been corrected on page 43, under section 9.9.4 DBF Application Site 
Inspection. 
The urobilinogen has been removed from the urinalysis routine tests to be performed at screening 
and at study exit. The change was made on page 43, section 9.9.7.4 Urinalysis.     
 
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Investigator’s Signature Page 
 
I have carefully read this study protocol and agree that it contains all necessary information 
required to conduct this study. I agree to conduct the study according to this protocol (including 
any amendments) and in accordance with ICH Good Clinical Practices (GCP), Good Laboratory 
Practices (GLP), and all other applicable regulations. 
 
 
________________________________________  
______________________ 
Investigator signature 
Date 
 
________________________________________ 
Investigator printed name 
 
________________________________________ 
Name of clinical facility 
 
________________________________________ 
Location of facility 
(City, state, country) 
 
 
 
 
 
 
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1. 
Facilities and Responsible Staff 
1.1 
Clinical Research Organization (CRO)  
inVentiv Health Clinique inc. (« inVentiv »), a Syneos Health company 
2500, rue Einstein 
Québec (Québec)  
Canada, G1P 0A2 
Tel.: 1-418-527-4000 
1.2 
Clinical Research Sites  
This study will be conducted at multiple clinical facilities. Any clinical research sites involved in 
this study will be documented and communicated to the Ethic committee. 
1.3 
Biomedical Laboratory Facilities 
Biomedical laboratories involved in clinical laboratory testing will be documented by the clinical 
research sites. 
1.4 
Clinical Pharmacology 
inVentiv 
2500, rue Einstein 
Québec (Québec), Canada, G1P 0A2 
Tel.: 1-418-527-4000 
Pierre-Olivier Tremblay, M.Sc. 
Vice-President, Clinical Pharmacology & Data Services 
France Nadeau, B.Sc. 
Senior Clinical Research Scientist (Protocol Editing) 
1.5 
Bioanalytical Facility 
inVentiv 
2500, rue Einstein 
Québec (Québec), Canada, G1P 0A2 
Tel.: 1-418-527-4000 
Clark V. Williard, B.S. 
Executive Director, Mass Spectrometry Operations 
1.6 
Medical Monitor   
Dr. Heidi Mitchell, MD 
Syneos Health 
 
 
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Table of Contents 
1. 
FACILITIES AND RESPONSIBLE STAFF ................................................................................. 6 
1.1 
CLINICAL RESEARCH ORGANIZATION (CRO) .............................................................................................................................................. 6 
1.2 
CLINICAL RESEARCH SITES ......................................................................................................................................................................... 6 
1.3 
BIOMEDICAL LABORATORY FACILITIES ....................................................................................................................................................... 6 
1.4 
CLINICAL PHARMACOLOGY ......................................................................................................................................................................... 6 
1.5 
BIOANALYTICAL FACILITY .......................................................................................................................................................................... 6 
1.6 
MEDICAL MONITOR ..................................................................................................................................................................................... 6 
2. 
SYNOPSIS OF PROTOCOL .......................................................................................................... 9 
3. 
LIST OF ABBREVIATIONS ........................................................................................................ 14 
4. 
SCHEDULE OF EVENTS ............................................................................................................. 16 
5. 
INTRODUCTION .......................................................................................................................... 17 
5.1 
BACKGROUND ON TREATMENT AND MANAGEMENT OF INDIVIDUALS WITH REFRACTORY EPILEPSY ....................................................... 17 
5.2 
DIAZEPAM ................................................................................................................................................................................................. 17 
5.3 
DIASTAT® ACUDIALTM .............................................................................................................................................................................. 19 
5.4 
DIAZEPAM BUCCAL FILM (DBF) ............................................................................................................................................................... 19 
5.5 
BACKGROUND ON DIAZEPAM BUCCAL FILM (DBF) .................................................................................................................................. 20 
5.6 
RATIONALE FOR DOSE LEVELS OF DIAZEPAM BUCCAL FILM .................................................................................................................... 26 
5.7 
RATIONALE FOR STUDY DESIGN ................................................................................................................................................................ 27 
5.8 
CLINICAL RISKS/BENEFITS OF STUDY DRUG ............................................................................................................................................. 28 
5.9 
RATIONALE FOR THE STUDY POPULATION ................................................................................................................................................. 29 
6. 
OBJECTIVES ................................................................................................................................. 30 
7. 
STUDY DESIGN ............................................................................................................................ 30 
8. 
STUDY POPULATION ................................................................................................................. 31 
8.1 
SAMPLE SIZE ............................................................................................................................................................................................. 31 
8.2 
INCLUSION CRITERIA ................................................................................................................................................................................. 31 
8.3 
EXCLUSION CRITERIA ................................................................................................................................................................................ 33 
9. 
CLINICAL PROCEDURES .......................................................................................................... 35 
9.1 
SCREENING PROCEDURES .......................................................................................................................................................................... 35 
9.2 
CONFINEMENTS, VISITS, AND WASHOUT ................................................................................................................................................... 36 
9.3 
RANDOMIZATION AND BLINDING .............................................................................................................................................................. 36 
9.4 
STUDY MEDICATION .................................................................................................................................................................................. 37 
9.5 
DRUG SUPPLIES AND ACCOUNTABILITY .................................................................................................................................................... 37 
9.6 
DRUG ADMINISTRATION ............................................................................................................................................................................ 38 
9.7 
STUDY RESTRICTIONS................................................................................................................................................................................ 39 
9.8 
SAMPLE COLLECTION AND PROCESSING .................................................................................................................................................... 41 
9.9 
SUBJECT MONITORING............................................................................................................................................................................... 42 
9.10 
STUDY EXIT PROCEDURES ......................................................................................................................................................................... 44 
9.11 
DATA COLLECTION AND EVALUATION ...................................................................................................................................................... 44 
9.12 
SUBJECT WITHDRAWAL AND REPLACEMENT ............................................................................................................................................ 44 
9.13 
ADVERSE EVENTS ...................................................................................................................................................................................... 45 
9.14 
REPORTABLE DISEASE ............................................................................................................................................................................... 48 
10. 
STUDY TERMINATION .............................................................................................................. 48 
11. 
ANALYTICAL METHODOLOGY ............................................................................................. 48 
12. 
PHARMACOKINETIC AND STATISTICAL ANALYSES ..................................................... 49 
12.1 
PHARMACOKINETICS ................................................................................................................................................................................. 49 
12.2 
ANALYSIS POPULATIONS ........................................................................................................................................................................... 49 
12.3 
STATISTICAL ANALYSES ............................................................................................................................................................................ 50 
12.4 
SAFETY AND TOLERABILITY PARAMETERS AND ANALYSES ...................................................................................................................... 51 
13. 
FINAL REPORT ............................................................................................................................ 51 
14. 
REGULATORY CONSIDERATIONS AND QUALITY ASSURANCE .................................. 51 
14.1 
INDEPENDENT ETHICS COMMITTEE APPROVAL OF PROTOCOL AND OTHER STUDY DOCUMENTS .............................................................. 51 
14.2 
COMPLIANCE ............................................................................................................................................................................................. 52 
14.3 
AUDITS, INSPECTIONS AND MONITORING .................................................................................................................................................. 52 
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15. 
CONFIDENTIALITY .................................................................................................................... 52 
16. 
REFERENCES ............................................................................................................................... 52 
17. 
APPENDIX I – DIAZEPAM PK STUDY PARTICIPANT QUESTIONS ............................... 54 
18. 
APPENDIX II – STUDY RESTRICTIONS ................................................................................. 57 
19. 
APPENDIX III - PLACEMENT DIAGRAM FOR AQUESTIVE THERAPEUTICS 
BUCCAL FILM ........................................................................................................................................ 59 
20. 
APPENDIX IV - PLACEMENT DIAGRAM FOR DIASTAT® ACUDIAL™ RECTAL 
DELIVERY SYSTEM .............................................................................................................................. 60 
 
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2. 
Synopsis of Protocol 
Project No.: 
180323 
Objectives: 
Primary objective: 
• 
Evaluate the pharmacokinetics (PK) of single doses of Diazepam 
Buccal Film (DBF) at the recommended dose regimen (range 10 mg to 
17.5 mg according to body weight) compared with Diastat® (DRG) at 
the labeled dose regimen (range 10 mg to 20 mg according to body 
weight) in adult male and female subjects on a stable concomitant 
regimen of antiepileptic drugs (AED) for the treatment of epilepsy, 
following a moderate-fat meal.  
Secondary objectives: 
• 
Evaluate the PK of single doses of DBF following a high-fat meal 
compared with DRG following a moderate-fat meal at the 
recommended dose regimen in adult male and female subjects on a 
stable concomitant regimen of AED for the treatment of epilepsy. 
• 
Assess the safety-tolerability of single doses of DBF and DRG 
administered to adult male and female subjects on a stable concomitant 
regimen of AEDs under fed conditions. 
Study Design: 
Randomized, multiple centers, single-dose, open-label, three-period, 
three-treatment, two-sequence crossover study under fed conditions.  
Periods 1 and 2: Each subject will receive both DBF and DRG in a randomized 
sequence following a moderate-fat meal administered according to weight 
category. DBF will be administered according to the currently recommended 
dose regimen (derived by Aquestive from population PK modeling in healthy 
volunteers). DRG will be administered depending on weight category according 
to the current product labeling for Diastat®.  
Period 3: Subjects may be asked to participate in period 3. Subjects who 
volunteer to participate in Period 3 will receive a second dose of DBF 
administered in exactly the same manner as the earlier dose of DBF with the 
exception that DBF in Period 3 will be administered following a high-fat meal. 
Subjects: 
No more than 32 male and female volunteers, ≥ 18 and ≤ 65 years of age, 
smoker and/or non-smoker, with body weight between 38 and 134 kg  (83 -294 
lbs.) on a concomitant stable regimen including one or more AED. 
A stable regimen of AED is defined as no change in the prescribed AED regimen 
during the 30-day period prior to the first study drug administration and no 
change anticipated in the prescribed AED regimen over the course of study 
participation until the last PK blood sample collection. 
Eligible subjects will be enrolled in an effort to complete Period 2 with at least 
16 subjects with representation of both genders, representation across the five 
weight categories of subjects taking one or more AED known to induce 
diazepam metabolism, and representation of subjects taking sodium 
divalproex/valproic acid. Subjects who are eligible may be enrolled without 
regard to weight category. Since only exploratory PK data will be gathered 
from treatment period 3, no more than 50% of the subjects who complete 
Period 1 and Period 2 will participate in Period 3.  
Screening Procedures: 
Demographic data, medical and medication histories, physical examination, brief 
neurologic examination, body measurements, oral cavity examination, 
electrocardiogram (ECG), vital signs (blood pressure [BP], heart rate [HR], and 
respiratory rate [RR]), oral temperature, digital oxygen monitoring, hematology, 
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biochemistry, HIV, hepatitis B and C tests, urinalysis, baseline AED levels*, 
alcohol breath test, urine pregnancy test, and urine drug screen.  
*Unless baseline levels of concomitant AED were obtained within one year prior 
to the first dosing and show levels within an acceptable therapeutic range.  
Confinements, Visits, and 
Washout: 
For each period, subjects will be confined from approximately 14 hours before 
dosing until after the 24-hour post-dose blood draw. For subsequent blood draw, 
subjects may come back to the clinical site or have the blood sample collected at 
home by a home care nurse.   
There will be a washout period of 28 days between doses. 
Drug Administration: 
In Period 1 and Period 2, subjects will receive Treatment A and Treatment B 
following a moderate-fat meal, in a randomized sequence. Subjects who 
volunteer to participate in Period 3 will receive DBF following a high-fat meal. 
In each period, subjects will receive a single dose according to body weight, as 
described in the following table: 
Product 
Meal 
Condition 
Weight 
Category 
Weight 
(kg) 
Dose 
Test 
(Treatment A):  
Diazepam 
Buccal Film 
(Aquestive 
Therapeutics, 
USA) 
Moderate-Fat 
Meal 
A1 
38-50 
1 x 10 mg 
A2 
51-62 
1 x 12.5 mg 
A3 
63-75 
1 x 15 mg 
A4 
76-87 
1 x 15 mg 
A5 
88-111* 
1 x 17.5 mg 
Reference 
(Treatment B):  
Diastat® 
AcuDialTM 
rectal gel 
(Valeant 
Pharmaceuticals 
Moderate-Fat 
Meal 
B1 
38-50 
2 mL (10 mg) 
B2 
51-62 
2.5 mL (12.5 
B3 
63-75 
3 mL (15 mg) 
B4 
76-87 
3.5 mL (17.5 
B5 
88-111* 
4 mL (20 mg) 
Test 
(Treatment C):  
Diazepam 
Buccal Film 
(Aquestive 
Therapeutics, 
USA) 
High-Fat 
Meal 
A1 
38-50 
1 x 10 mg 
A2 
51-62 
1 x 12.5 mg 
A3 
63-75 
1 x 15 mg 
A4 
76-87 
1 x 15 mg 
A5 
88-111* 
1 x 17.5 mg 
*Subjects eligible for study with weights in the range of 112 to 134 kg will be 
dosed at the 88-111 kg weight range as shown above. 
After a supervised fast of at least 10 hours, subjects will be served a standardized 
moderate-fat meal (in Periods 1 and 2) or a high-fat high-calorie meal (in 
Period 3). Drug administration will occur approximately 30 minutes after the 
meal has been started.  
No water will be allowed during the DBF administration and for at least 
15 minutes following DBF administration. Water will be allowed ad libitum at 
all other times.  
DBF ease of use will be evaluated by the clinical staff and the subjects following 
the first film administration in Period 1 or Period 2. Questions regarding past 
experience in using DRG or other rescue medication for the treatment of epilepsy 
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will also be asked to subjects, prior to DRG administration. Questions are listed 
in Appendix I – Diazepam PK Study Participant Questions.  
Study Restrictions: 
Subjects will be asked to refrain from using products that may potentially affect 
their safety and/or the pharmacokinetic profile of the study drug. For the 
complete list of restrictions refer to Appendix II – Study Restrictions. Main study 
restrictions include: 
• 
Any benzodiazepines (other than study drug),  phenothiazines, or strong 
inhibitors of cytochrome P450 (CYP) enzymes (e.g. cimetidine, 
fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, 
ketoconazole, itraconazole, diltiazem, and HIV antivirals), from 30 days 
prior to the first dosing until after the last PK blood sample collection of 
the study. Strong inducers of CYP enzymes (e.g. barbiturates, 
carbamazepine, glucocorticoids, phenytoin, phenobarbital, St. John´s 
Wort, rifampicin) and AEDs known to induce CYP enzymes are 
permitted provided that the regimen of such drugs is stable (taken at 
least once a day [q.d]. on a regular basis) within 30 days prior to first 
study drug administration and until at least 10 days after last study drug 
administration; 
• 
Any prescription medication (other than non-systemic topical products) 
within 30 days prior to first study drug administration.  Prescription 
drugs (other than any benzodiazepines, phenothiazines, and strong 
inhibitors of CYP enzymes) that is part of a stable drug regimen (taken 
at least q.d. on a regular basis) are allowed if taken from at least 30 days 
prior to the first study drug administration and if there is no expected 
change in dosage throughout the study.  
• 
Over-the-counter (OTC) medications (other than spermicidal/barrier 
contraceptive products and non-systemic topical products), within 
30 days prior to first study drug administration. OTC drugs that is part 
of a stable drug regimen (taken at least q.d. on a regular basis) is allowed 
if taken from at least 30 days prior to the first study drug administration 
and if there is no expected change in dosage throughout the study. 
• 
Natural health products (including oral multivitamins, herbal and/or 
dietary supplements and/or teas) from 30 days pre-dose until after the 
last PK blood sample collection of each period. 
• 
For females, oral or transdermal hormonal contraceptives within 30 days 
prior to first study drug administration until after the last PK blood 
sample collection of each period. Oral or transdermal hormonal 
contraceptives  with a 28-days treatment cycle taken daily from at least 
30 days prior to the first study drug administration will be allowed if 
there is no expected change in dosage throughout the study; 
• 
For females, implanted, injected, or intravaginal contraceptive within 6 
months prior to first study drug administration until after the last PK 
blood sample collection of each period; 
• 
Monoamine oxidase (MAO) inhibitors from 30 days prior to the first 
dosing until 14 days after the last study drug administration; 
• 
Use of marijuana and THC containing products within 3 months prior to 
screening unless such products are a part of the subject’s stable 
antiepileptic regimen; 
• 
Food containing poppy seeds from 48 hours pre-dose; 
• 
Food or beverages containing caffeine/methylxanthines derivatives or 
energy drinks from 48 hours prior to dosing until after the last PK blood 
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sample collection of each period; 
• 
Food or beverages containing grapefruit, star fruit, and/or pomelo from 
30 days pre-dose until after the last PK blood sample collection of the 
study; 
• 
Alcohol-based products from 48 hours pre-dose until after the last PK 
blood sample collection of each period. 
Diazepam may cause sedation.  Consistent with intended use of DBF and the use 
of DRG subjects should be in a safe comfortable position (sitting or reclining in 
bed) for at least one hour after dosing to allow for an assessment of drug effect 
including sedation. After one hour and depending on the assessment of the 
investigator/clinical staff, the subject may be permitted to ambulate provided that 
ambulation does not interfere with study procedures.  Vital signs should be taken 
in a consistent position (sitting or reclining).  Subject visits to the bathroom or 
washroom will be monitored by clinic staff for 4 hours after each study drug 
administration, and the following information will be recorded: whether the 
subject urinated, defecated, or vomited. Subjects will be instructed not to flush if 
they vomit. Vomitus will be verified and noted in the subject’s file for further 
evaluation if needed.  
Subjects will be advised to avoid performing vigorous physical activities (e.g., 
intense or long-distance running or biking, etc.) at all times during the study 
duration (from at least 5 days prior to admission), including the washout period. 
Sample Collection: 
A total of 19 blood samples will be collected in each period: at pre-dose and 
(± 1 minute) 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, (± 3 minutes) 9, 12, 24, (± 60 minutes) 
48, 72, 96, 120, 144, 192, and 240 hours post-dose. 
Subject Safety: 
Continuous cardiac ECG monitoring: from approximately 1 hour prior to dosing 
until 8 hours post-dose (and beyond if clinically indicated). 
Vital signs and digital oxygen monitoring before dosing and approximately 0.5, 
1, 1.5, 2, 4, and 8 hours post-dose (and beyond if clinically indicated). 
Vital signs will also be recorded at approximately 12 and 24 hours post-dose. 
Serum pregnancy test (for women): before dosing 
Alcohol breath test and urine drug screen: before dosing. 
Medical surveillance: Subjects will be monitored throughout the study by the 
clinical staff for adverse events. In each period, the investigator will be on site 
for drug administration and until 8 hours post-dose, and available on call for the 
remainder of the study. 
DBF Application Site 
Inspection: 
DBF application site will be inspected at screening, prior to DBF administration, 
and approximately 6 and 24 hours after DBF administration to evaluate the oral 
mucosa (normal/abnormal). Assessments will be conducted by the Principal 
Investigator/Sub-Investigator or a trained nurse.  
Study Exit Procedures: 
Physical examination, brief neurologic examination, hematology, biochemistry, 
urinalysis, vital signs (BP, HR, and RR), oral temperature, digital oxygen 
monitoring, ECG, oral temperature, urine pregnancy test, and adverse events 
monitoring. 
Analytical Method: 
The Bioanalytical Division of inVentiv will analyze diazepam and nordiazepam 
in plasma samples using a validated method.   
Pharmacokinetics: 
Parameters: AUC0-t, AUC0-inf, Cmax, Residual area, Tmax, T½ el, Kel, Cl/F, Vd/F, 
Cl/F/kg, and Vd/F/kg. 
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Data from nordiazepam will be reported and presented as supportive data. 
Statistical Analyses: 
Pharmacokinetics: 
For diazepam and nordiazepam, using GLM procedures in SAS, ANOVA will be 
performed on untransformed Tmax, Kel, and T½ el and on ln-transformed AUC0-t, 
AUC0-inf, Cmax, Cl/F, Cl/F/kg, Vd/F, and Vd/F/kg at the alpha level of 0.05. 
Factors incorporated in the model will include: Sequence, Subject(Sequence), 
Period, and Treatment. Tmax will be analyzed using an additional non parametric 
test (Wilcoxon signed-rank test). 
Treatment Comparison Following a Moderate-Fat Meal: 
The ratio of geometric means will be calculated for AUC0-t, AUC0-inf, and Cmax  
for the Test product versus the Reference product (A/B) irrespective of weight 
category. The 90% confidence interval for the ratio of geometric means, based on 
least-squares means from the ANOVA of the ln transformed data will also be 
calculated. Intra and inter-subject coefficient of variation will be estimated.  
Treatment Comparison Following Different Meal Conditions:  
An exploratory pair-wise analysis comparing DBF following a high-fat meal 
(Treatment C) with DRG following a moderate-fat meal (Treatment B) will also 
be conducted and reported. 
Additional analyses may be performed.  
Details of the pharmacokinetic and statistical analyses will be provided in the 
statistical analysis plan (SAP). 
Safety and tolerability: 
Treatment-emergent AEs will be tabulated by treatment. Changes from baseline 
values in vital signs, ECG, and clinical laboratory parameters will be evaluated. 
Safety and tolerability data will be reported using descriptive statistics. Details of 
the safety and tolerability analyses will be provided in the SAP. 
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3. 
List of Abbreviations 
AE 
Adverse Event 
AED 
Antiepileptic drug 
ANOVA 
Analysis of variance 
AUC 
Area Under the Concentration-time Curve 
AUC0-inf 
Area Under the Concentration-time Curve From Time 
Zero to Infinity (extrapolated) 
AUC0-t 
Area Under the Concentration-time Curve From Time 
Zero to the Last Non-zero Concentration 
BA 
Bioavailability 
BP 
Blood Pressure 
CK 
Creatine Kinase 
Cl/F 
Apparent Total Clearance (L/hr) estimated from 
dose/AUC0-inf 
Cl/F/kg 
Apparent Total Clearance/kg (L/hr) estimated from 
dose/kg/AUC0-inf 
Cmax 
Maximum Observed Concentration 
CRO 
Contract Research Organization 
CRF 
Case Report Form 
CYP 
Cytochrome P450 
DBF 
Diazepam Buccal Film 
DRG 
Diastat® rectal gel 
ECG 
Electrocardiogram 
EDC 
Electronic data capture 
FDA 
Food and Drug Administration 
g 
Grams 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HIV 
Human Immunodeficiency Virus 
HR 
Heart Rate 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethic Committee 
IND 
Investigational new drug 
IRB 
Institutional Review Board 
lbs. 
pounds 
Kel 
Elimination Rate Constant 
kg 
Kilogram 
kg/m2 
Kilogram/Meter Squared 
MDMA 
Methylene Di-Methamphetamine (Ecstasy) 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliters  
msec 
Millisecond 
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mmHg 
Millimeter of Mercury 
MAO 
Monoamine oxidase 
N/A or NA 
Not applicable, Not Available 
NDA 
New drug application 
PCP 
Phencyclidine 
PK 
Pharmacokinetic 
PT 
Preferred Term 
QA 
Quality Assurance 
QC 
Quality Control 
QTcF 
Fridericia’s Corrected QT Interval 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System 
SD or STD 
Standard Deviation 
SOC 
System Organ Classification 
SOP 
Standard Operating Procedure 
SARS 
Severe Acute Respiratory Syndrome 
T½ el 
Terminal elimination half-life, estimated as ln(2)/Kel 
THC 
Tetrahydrocannabinol 
Temp 
Temperature 
Tmax 
Time when the maximal plasma concentration is observed 
UBG 
Urobilinogen 
U.S. 
United States 
Vd/F 
Apparent Volume of distribution (L) estimated from 
Cl/Kel (β) 
Vd/F/kg 
Apparent Volume of distribution/kg (L) estimated from 
Cl/Kel (β)/kg 
 
 
 
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4. 
Schedule of Events 
PROCEDURE 
Screening 
Periods 1, 2 & 3 
Study Exit 
D-1 
D1 
D2 
D3-D11 
Demographic Data 
X 
 
 
 
 
 
Medical and Medication Histories 
X 
 
 
 
 
 
Review and Monitoring of AEs 
and Concomitant Medications 
 
X 
X 
X 
X 
X 
Physical Exam and Brief 
Neurologic Exam  
X 
 
 
 
 
X 
Body Measurements 
X 
 
 
 
 
 
Oral Temperature 
X 
 
 
 
 
X 
Vital signs (BP, HR, RR) 
X 
 
X1 
X2 
 
X 
Digital Oxygen Monitoring 
X 
 
X1 
 
 
X 
Continuous Cardiac ECG 
Monitoring 
 
 
X3 
 
 
 
ECG 
X 
 
 
 
 
X 
Hematology 
X 
 
 
 
 
X 
Biochemistry 
X 
 
 
 
 
X 
HIV and Hepatitis 
X 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
X 
Baseline AED Levels Assessment4 
X 
 
 
 
 
 
Urine Drug Screen 
X 
X 
 
 
 
 
Alcohol Breath Test 
X 
X 
 
 
 
 
Serum Pregnancy Test 
 
X 
 
 
 
 
Urine Pregnancy Test 
X 
 
 
 
 
X 
Confinement 
 
X 
X 
 
 
 
Drug Administration5 
 
 
X 
 
 
 
Visual Inspection of DBF 
Application Site 
X 
 
X6 
X6 
 
 
PK Samples7 
 
 
X 
X 
X 
 
1 Vital signs and digital oxygen monitoring before dosing and approximately 0.5, 1, 1.5, 2, 4, and 8 hours post-dose 
(and beyond if clinically indicated). 
2 Vital signs approximately 12 and 24 hours post-dose.  
3 Continuous cardiac ECG monitoring: from approximately 1 hour pre-dose until 8 h after dosing (and beyond if 
clinically indicated).  
4 Unless baseline levels of concomitant AED was obtained within one year prior to the first dosing and show levels 
within an acceptable therapeutic range. 
5 Questions regarding past experience in using DRG or other rescue medication for the treatment of epilepsy will be 
asked to subjects prior to DRG administration. DBF ease of use will be evaluated by the clinical staff and the 
subjects following the first film administration (in Period 1 or Period 2).  
6 A visual inspection of the application site will be conducted prior to DBF administration and approximately 6 and 
24 hours after DBF administration to evaluate the oral mucosa (normal/abnormal).  
7 Blood samples: pre-dose and (± 1 minute) 0.5, 0.75, 1, 1.5, 2, 3, 4, 6, (± 3 minutes) 9, 12, 24, (± 60 minutes) 48, 
72, 96, 120, 144, 192, and 240 hours post-dose.  
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5. 
Introduction 
5.1 
Background on Treatment and Management of Individuals with Refractory Epilepsy 
Acute repetitive seizures, including breakthrough seizures, repetitive seizures, and seizure 
clusters occur in a significant number of epilepsy patients who are on established antiepileptic 
drug treatment. These types of seizures have distinguishable characteristics that are usually 
recognized by patients, caregivers, and physicians. 
Although patients typically recover between seizures, these seizures can last from minutes to 
hours. When these seizures occur outside a hospital, the patient is often transported to an acute 
care facility for treatment to prevent prolonged seizures. If treatment is not prompt and effective 
there is a risk that seizure activity will continue, and may become life threatening, including the 
risk of status epilepticus. In these cases, the primary goals of the treatment are seizure cessation 
and prevention of seizure recurrence. Usually, acute benzodiazepine treatment is effective for 
seizure control and often results in rapid seizure termination. Nevertheless, many treatment 
options rely on appropriate intervention by medical personnel, and treatment may be delayed 
while the patient is transported to a medical facility.1  
Outpatient treatment for these types of seizures may reduce emergency medical intervention, 
decrease seizure duration, prevent general deterioration due to the repeated seizures and improve 
the quality of life of these patients.  
5.2 
Diazepam 
Diazepam is a benzodiazepine that exerts anxiolytic, sedative, muscle-relaxant, anticonvulsant, 
and amnestic effects. Most of these effects are thought to result from a facilitation of the action 
of gamma aminobutyric acid (GABA), an inhibitory neurotransmitter in the central nervous 
system.2 
Diazepam is a Schedule IV controlled substance approved for the treatment of anxiety, acute 
alcohol withdrawal, skeletal muscle spasm, and convulsive disorders. Diazepam is used as 
adjunctive treatment of seizures other than status epilepticus in selected, refractory patients with 
partial seizures or generalized tonic-clonic seizures who require intermittent use of diazepam to 
control bouts of increased seizure activity.2 It is used off-label for numerous other conditions 
including insomnia, restless leg syndrome, and pre-/post-operative sedation. 
Diazepam can be taken by mouth, inserted into the rectum, injected into muscle, or injected 
intravenously. When given intravenously, effects begin in one to five minutes. When diazepam is 
taken orally, effects may be delayed as long as 40 minutes.1  
Intravenous diazepam is a first-line treatment for status epilepticus. Diazepam gel has been 
demonstrated superior to placebo gel in reducing the risk of continuing seizures. Diazepam is 
rarely used for the long-term treatment of epilepsy because tolerance to its anticonvulsant effects 
develops over time with continuous treatment. However, diazepam is effective when used 
intermittently for the prevention of repeated seizures. Like other benzodiazepines, diazepam 
administration may cause sedation, anxiolysis, and amnesia.1  
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5.2.1 
Mechanism of Action 
Diazepam is a benzodiazepine derivative that exhibits anti-anxiety, sedative, hypnotic and 
anticonvulsant properties. Although the precise mechanism by which diazepam exerts its anti-
seizure effects is unknown, animal and in vitro studies suggest that diazepam acts to suppress 
seizures through an interaction with γ-aminobutyric acid (GABA) receptors of the A-type 
(GABAA).3 GABAA receptors mediate the sedative, anterograde amnesic, anticonvulsive, 
anxiolytic, muscle relaxant, and temporal/spatial memory effects of benzodiazepines.1 It is 
believed that diazepam enhances the actions of GABA by causing GABA to more tightly bind to 
the GABAA receptors located within the limbic system, including areas of the thalamus and 
hypothalamus.  
GABA, the major inhibitory neurotransmitter in the central nervous system, acts at these 
receptors to open the membrane channel, and allows chloride ions to flow into neurons. 
Excessive neuronal depolarization is implicated in the generation and spread of seizures.3 Entry 
of chloride ions causes an inhibitory potential that reduces the ability of neurons to depolarize to 
the threshold potential necessary to produce action potentials, ultimately leading to membrane 
hyperpolarization and a decrease in neuronal excitability. 
5.2.2 
Metabolism and Elimination 
Diazepam is extensively metabolized to one major active metabolite (N-desmethyldiazepam 
[nordiazepam]) and two minor active metabolites, 3-hydroxydiazepam (temazepam) and 3-
hydroxy-N-diazepam (oxazepam) in plasma. At therapeutic doses, under steady state conditions, 
desmethyldiazepam is found in plasma at concentrations equivalent to those of diazepam, while 
oxazepam and temazepam are not usually detectable. Both diazepam and desmethyldiazepam 
bind extensively to plasma proteins (95-98%).3 
The volume of distribution of Diastat rectal gel is calculated to be approximately 1 L/kg. 
Following rectal administration of a 15 mg dose of Diastat, the mean elimination half-life was 
reported to be about 46 hours (CV=43%) for diazepam and 71 hours (CV=37%) for 
desmethyldiazepam.3 After oral administration, the initial distribution phase is followed by a 
prolonged terminal elimination phase, with a half-life up to 48 hours, and the terminal 
elimination half-life of the active metabolite N-desmethyldiazepam is up to 100 hours.4 
The metabolism of diazepam is primarily hepatic and involves demethylation (involving 
primarily CYP2C19 and CYP3A4) and 3-hydroxylation (involving primarily CYP3A4), 
followed by glucuronidation. The marked inter-individual variability in the clearance of 
diazepam reported in the literature is probably attributable to variability of CYP2C19 (which is 
known to exhibit genetic polymorphism; about 3-5% of Caucasians have little or no activity and 
are “poor metabolizers”) and CYP3A4. No inhibition was demonstrated in the presence of 
inhibitors selective for CYP2A6, CYP2C9, CYP2D6, CYP2E1, or CYP1A2, indicating that 
these enzymes are not significantly involved in metabolism of diazepam.3 
Diazepam and its metabolites are excreted mainly in the urine, predominantly as their 
glucuronide conjugates.4 
 
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5.2.3 
Pharmacokinetics 
Following rectal administration, diazepam is well absorbed, reaching peak plasma concentrations 
in 1.5 hours,3 and the absolute bioavailability of Diastat rectal gel relative to Valium injectable is 
90%.  
After Valium oral administration, the average time to achieve peak plasma concentrations is 1–
1.5 hours, with a range of 0.25 to 2.5 hours, and more than 90% of diazepam is absorbed. Valium 
absorption is delayed and decreased when diazepam is administered with a moderate-fat meal. In 
the presence of food, mean lag times are approximately 45 minutes as compared with 15 minutes 
when fasting. There is also an increase in the average time to achieve peak concentrations to 
about 2.5 hours in the presence of food as compared with 1.25 hours when fasting. This results in 
an average decrease in Cmax of 20% in addition to a 27% decrease in area under the plasma 
concentration-time curve (AUC; range 15% to 50%) when administered with food.4 
5.3 
Diastat® AcuDialTM  
Diazepam rectal gel administered after the onset of acute repetitive and prolonged seizures has 
been shown to significantly reduce seizure recurrence and emergency department admissions. 
Nonetheless, social objections to and legal concerns about rectal administration have limited its 
use.1  
The rectal route of administration of diazepam is not ideal. First, it entails the need to expose and 
appropriately position a patient in order to administer drug, both of which can be time 
consuming, with a potential delay of time to treatment. Successful use of a rectal product also is 
dependent upon the competence of the caregiver and requires training in the correct 
administration of the gel. Improper technique could lead to patient injury and leakage of gel from 
the rectum can result in incomplete dosing. Additionally, the attitude of many patients toward a 
rectal route of drug administration is unfavorable, which may impact compliance to treatment. 
Each of these factors has a potential impact on usability and morbidity. Persistent seizure activity 
is associated with worse outcomes across a spectrum of precipitating conditions. In addition, 
experimental models of status epilepticus have demonstrated that the effectiveness of 
anticonvulsant medication to terminate seizures rapidly decreases as the time between the start of 
convulsions and drug administration lengthens. Further, it has been demonstrated that if seizures 
are not terminated quickly, escalating doses of benzodiazepines are required to achieve seizure 
cessation and seizures may become refractory to anticonvulsant therapy.1 
A need for better, more patient-friendly therapies for seizure emergencies such as prolonged 
seizures, acute repetitive seizures, or status epilepticus has resulted in development of innovative 
benzodiazepine formulations using non-rectal routes.1  
5.4 
Diazepam Buccal Film (DBF) 
One new route of diazepam administration is via buccal soluble film. Buccal soluble diazepam 
(DBF) may be particularly well-suited for administration in outpatient settings. The study drug is 
administered by placing the film against the inner aspect of the cheek, where it adheres, and 
allows for transbuccal absorption of diazepam. There is no need to position or disrobe the 
subject. Additionally, there is less potential for delay in initial treatment and greater subject and 
caregiver acceptance with improved compliance may also be expected.  
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The development of DBF will meet the treatment need for a form of diazepam that is effective, 
safe, allows for reliable dose administration, and is easier to administer than the rectal gel in a 
subset of epileptic subjects. Subjects, caregivers, and physicians have indicated that this type of 
product would be desirable for acute, intermittent treatment of breakthrough, repetitive or cluster 
seizures. The clinical trials with DBF have focused on assessing its relative bioavailability to the 
reference therapy, Diastat® AcuDial™ rectal gel, dose proportionality, assessment of food 
effect, and the pharmacokinetics in subjects with epilepsy. Overall safety and tolerability have 
been assessed in clinical trials conducted with DBF.  
Aquestive Therapeutics initiated development of DBF, specifically intended for buccal delivery 
for subjects who require control of intermittent bouts of seizure activity. DBF contains the Food 
and Drug Administration (FDA) approved active ingredient diazepam, a benzodiazepine, as a 
treatment for the management of selected, refractory subjects with epilepsy, on stable regimens 
of antiepileptic drugs who require intermittent use of diazepam to control bouts of increased 
seizure activity. The study drug, with a planned dose range of 5 mg to 17.5 mg, is expected to 
achieve peak plasma concentrations of diazepam equivalent to the reference therapy, Diastat® 
AcuDial™ rectal gel. The DBF product is intended for submission as a 505(b)(2) New Drug 
Application (NDA) using Diastat® AcuDial™ rectal gel as the reference therapy.  
5.5 
Background on Diazepam Buccal Film (DBF) 
Diastat® AcuDial™ rectal gel is prescribed for increased seizure activity as defined by a marked 
increase in seizure activity, sometimes heralded by non-convulsive symptoms that are 
characteristic for each subject and deemed by the prescriber to be the kind of seizure for which a 
benzodiazepine would be administered.3 Diastat® AcuDial™ rectal gel has been marketed in the 
US since 1997 and currently is the only FDA approved drug in the US for this indication.  
Though the Diastat® AcuDial™ rectal gel formulation is considered safe and effective, the route 
of administration is less than ideal. The mechanics of administering a rectal gel can be a difficult, 
time-consuming, and embarrassing experience for both subject and care-givers alike. For 
example, the subject or caregiver must first remove articles of clothing and then place the subject 
in an appropriate position. The Diastat® AcuDial™ rectal gel syringe tip is inserted into the 
rectum to a specific depth and the gel expressed into the rectal vault. However, improper 
technique can lead to subject injury, and leakage of gel from the rectum can result in incomplete 
dosing. Additionally, some subjects have a negative view of the rectal route of administration, 
and this may reduce compliance to treatment. Each of these factors has a potential influence on 
subject morbidity. Persistent seizure activity is associated with less favorable outcomes across a 
spectrum of precipitating conditions. Further, it has been demonstrated that if seizures are not 
terminated quickly, escalating doses of benzodiazepines are required to achieve seizure cessation 
and seizures may become refractory to anticonvulsant therapy.  
The DBF is intended for application to the inner aspect of the cheek where it adheres, dissolves, 
and releases the drug into the buccal mucosa. Though buccal absorption is expected as the 
primary route of absorption of the drug, some absorption through the gastrointestinal (GI) tract 
may be possible due to swallowing of some dissolved drug substance in the saliva. It is expected 
that that timing of use of the buccal film will be similar to the use of Diastat® AcuDial™ rectal 
gel, i.e., the film would be administered after a seizure with characteristics for which the 
Reference Listed Drug (RLD) would be indicated. 
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5.5.1 
Nonclinical Studies 
Mechanism of Action: Diazepam is a benzodiazepine derivative that exhibits anti-anxiety, 
sedative, hypnotic and anticonvulsant properties. Although the precise mechanism by which 
diazepam exerts its anti-seizure effects is unknown, animal and in vitro studies suggest that 
diazepam acts to suppress seizures through an interaction with γ-aminobutyric acid (GABA) 
receptors of the A-type (GABAA).3 GABAA receptors mediate the sedative, anterograde amnesic, 
anticonvulsive, anxiolytic, muscle relaxant, and temporal/spatial memory effects of 
benzodiazepines.1 It is believed that diazepam enhances the actions of GABA by causing GABA 
to more tightly bind to the GABAA receptors located within the limbic system, including areas of 
the thalamus and hypothalamus.  
GABA, the major inhibitory neurotransmitter in the central nervous system, acts at these 
receptors to open the membrane channel, and allows chloride ions to flow into neurons. 
Excessive neuronal depolarization is implicated in the generation and spread of seizures.3 Entry 
of chloride ions causes an inhibitory potential that reduces the ability of neurons to depolarize to 
the threshold potential necessary to produce action potentials, ultimately leading to membrane 
hyperpolarization and a decrease in neuronal excitability. 
Metabolism and Elimination: It has been reported in the literature that diazepam is extensively 
metabolized to one major active metabolite (desmethyldiazepam) and two minor active 
metabolites, 3-hydroxydiazepam (temazepam) and 3-hydroxy-N-diazepam (oxazepam). With 
steady state dosing, desmethyldiazepam is found in plasma at concentrations equivalent to those 
of diazepam while oxazepam and temazepam are not usually detectable. The metabolism of 
diazepam is primarily hepatic and involves demethylation (involving primarily CYP2C19 and 
CYP3A4) and 3-hydroxylation (involving primarily CYP3A4), followed by glucuronidation. The 
marked inter-individual variability in the clearance of diazepam reported in the literature is 
probably attributable to variability of CYP2C19 (which is known to exhibit genetic 
polymorphism; about 3-5% of Caucasians have little or no CYP2C19 activity and are “poor 
metabolizers”) and CYP3A4. No inhibition was demonstrated in the presence of inhibitors 
selective for CYP2A6, CYP2C9, CYP2D6, CYP2E1, or CYP1A2, indicating that these enzymes 
are not significantly involved in metabolism of diazepam.3  
5.5.2 
Clinical Studies 
As of December, 2018, six clinical studies in healthy adult volunteers have been completed with 
the DBF product. These comprise two bioavailability pilot studies in comparison with Diastat 
gel® (1899 and 1900), a dose-proportionality study (162013), a bioavailability study in 
comparison with Diastat® gel (162021), and two food effect studies. A two-arm food effect study 
investigated the effect of a high fat meal (Study 162022). A four-arm food effect study compared 
the pharmacokinetics of diazepam (A) fasting in an upright position after dosing (B) fasting in a 
reclining position after dosing (C) Following a high fat meal in a reclining position after 
dosing (D) Following a moderate fat meal in a reclining position after dosing (Study172018).1 
5.5.2.1 
Safety in Clinical Studies 
It is anticipated that the adverse event (AE) profile from systemic exposure observed with study 
drug will resemble the already well-known profile for diazepam in general and the reference 
therapy, Diastat® AcuDial™ rectal gel, in particular. Diazepam rectal gel AE data were collected 
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from double-blind, placebo-controlled studies and open label studies with 573 subjects exposed 
to diazepam rectal gel. The majority of AEs were mild to moderate in severity and transient. The 
most frequent AE reported with diazepam rectal gel in the two double-blind, placebo-controlled 
studies was somnolence (23%). Less frequent AEs were headache (≤5%), diarrhea (≤4%), ataxia 
(≤3%), dizziness (≤3%), euphoria (≤3%), incoordination (≤3%), rash (≤3%), vasodilatation 
(≤2%), and asthma (≤2%).3  
In the 6 completed DBF studies, there have been a total of 154 subjects enrolled, with 132 
subjects (65.9% male, 34.1% female; age range 19-64) having received at least one dose of study 
drug.  A total of 268 doses of DBF and 119 doses of Diastat® AcuDial™ were administered.1 
Sixty-five percent of all administrations of DBF (n = 175) and 63.9% (n=78) of Diastat 
administrations were followed by one or more Treatment Emergent Adverse Events (TEAE). A 
total of 252 TEAEs were reported following administrations of DBSF; the majority were mild 
(90.9%) or moderate (8.3%) in severity.  80.1% were deemed to be possibly or probably related 
to study drug. Of 103 TEAEs reported following Diastat doses, 98%were mild and 2% were 
moderate. 75.7% were possibly or probably related.1   
There was 1 serious adverse event (SAE) reported and 2 TEAEs leading to discontinuation. 
There were no adverse events resulting in persistent impairment and there were no deaths 
reported.1 
In all studies to date, somnolence followed by dizziness was the most frequently reported TEAE, 
consistent with the known pharmacologic action of diazepam. Somnolence has also been the 
most frequent AE reported for Diastat.1 
The frequency of AEs increased in a dose-related manner with DBSF. An analysis of 
138 administrations of 15 or 20 mg in a fasted state showed no particular pattern of TEAEs 
according to Cmax or increase in frequency with an increase in Cmax.1    
A decreased frequency of AEs following dosing in a fed state was observed in the two food 
effect studies.1  
Overall, the administration of DBF was safe and well tolerated in healthy subjects following a 
single oral dose of 5 mg through 20 mg under both fast and fed conditions. Adverse events were 
primarily mild to moderate in severity, short-lasting and consistent with the known 
pharmacologic effects of diazepam. There were few SAEs reported and no events associated 
with death or lasting impairment were observed.1 
5.5.2.2 
Pharmacokinetics in Clinical Studies 
Pharmacokinetics: A 15 mg dose of Diastat® AcuDial™ rectal gel following rectal 
administration produces peak plasma concentrations in 1.5 hours, with absolute bioavailability of 
90% relative to Valium® injectable. The volume of distribution of diazepam rectal gel is 
calculated to be approximately 1 L/kg. The mean elimination half-life of diazepam and 
desmethyldiazepam following administration of a 15 mg dose of diazepam rectal gel was found 
to be about 46 hours (CV=43%) and 71 hours (CV=37%), respectively. Both diazepam and its 
major active metabolite desmethyldiazepam bind extensively to plasma proteins (95-98%).3 
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5.5.2.2.1 
Pilot Studies 1899 and 1900 
The Sponsor conducted two randomized, open label, single-dose, fasting condition, crossover 
pilot studies in healthy male and female volunteers to assess the bioavailability of study drug in 
comparison to the same nominal dose of Diastat® AcuDial™ rectal gel. The planned enrollment 
was 12 subjects in both studies. 
Study 1899 compared study drug 5 mg to Diastat® AcuDial™ rectal gel 5 mg. Among the 11 
subjects who completed both treatments, DBF 5 mg was bioequivalent to Diastat rectal gel 5 mg 
with respect to area under the curve (AUCt and AUCinf), i.e., the 90% confidence interval (CI) 
for the ratio of geometric means was within the acceptable range of 80%-125%. For Cmax, the 
ratio of geometric means was 1.07 with the 90% CI 87.1-131.5%. The median Tmax was 0.67 
hours for the DBF (range 0.33-1.50 hours) and 0.25 hours for the Diastat rectal gel (range 0.15-
1.00 hours). The difference in Tmax values was not statistically significant.1 
Study 1900 compared DBF 20 mg to Diastat® AcuDial™ rectal gel 20 mg. Evaluable data from 
10 subjects who completed both treatments showed that the extent of the absorption of DBF 
20 mg was comparable to Diastat® AcuDial™ 20 mg rectal gel, with the ratio of geometric 
means for AUCt and AUC∞ within the acceptable range of 80-125%. For Cmax, the ratio of 
geometric means was 158.72% (90% CI 122.81-205.14). The median Tmax was 1.25 hours for the 
DBF (range 0.36-2.05 hours) and 1.00 hours for the Diastat® AcuDial™ rectal gel (range 0.25-
2.00 hours). The difference in Tmax values was not statistically significant. Examination of the 
mean plasma curves for DBF and Diastat® AcuDial™ showed that although the Cmax was higher 
for the DBF relative to Diastat® AcuDial™, the pharmacokinetics were comparable in terms of 
rapid rate of absorption, duration of plateau, and the rate of elimination.1 
5.5.2.2.2 
Study 162013 – Dose-Proportionality 
Study 162013 was a single-dose, randomized, open-label, three-period, six-sequence, crossover 
study conducted to assess dose-proportionality of DBSF at doses of 5, 10, and 15 mg. A total of 
30 subjects were randomized and dosed in the study. Analysis of the pharmacokinetic data 
confirmed that DBSF is dose-proportional over the dose range 5 mg to 15 mg (Table 1). The 
criteria for dose proportionality were met for diazepam since for both comparisons (A/B: DBSF 
5 mg/DBSF 10 mg and C/B: DBSF 15 mg/DBSF 10 mg), the geometric mean 90% CI of the 
ratios of Least-Squares means from the analysis of variance (ANOVA) of the ln-transformed 
AUCt, AUC∞, and Cmax were within the acceptable range 80-125%.1  
 
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Table 1: 
Study 162013 - Dose-Proportionality of DBSF at Doses of 5, 10, and 15 mg 
Parameter1 
Treatment Comparisons 
Geometric Mean 
Ratio2 
90% CI3 
Lower 
Upper 
AUCt 
DBSF 5 mg (A) – DBSF 10 mg (B) 
103.53% 
99.51% 
107.72% 
AUC∞ 
DBSF 5 mg (A) – DBSF 10 mg (B) 
104.08% 
99.43% 
108.96% 
Cmax 
DBSF 5 mg (A) – DBSF 10 mg (B) 
104.57% 
97.92% 
111.67% 
 
 
 
 
 
AUCt 
DBSF 15 mg (C) – DBSF 10 mg (B) 
101.94% 
97.62% 
106.44% 
AUC∞ 
DBSF 15 mg (C) – DBSF 10 mg (B) 
103.64% 
98.52% 
109.02% 
Cmax 
DBSF 15 mg (C) – DBSF 10 mg (B) 
98.84% 
92.36% 
105.78% 
AUC∞ = area under the concentration-time curve from time zero to infinity; AUCt = area under the concentration-
time curve from time zero until the last measurable concentration or last sampling time t; CI = confidence interval; 
Cmax= the maximal observed plasma concentration; DBSF= Diazepam Buccal Soluble Film (equivalent to DBF). 
1 Dose normalized to 10 mg 
2 Calculated using least-squares means according to the formula eDIFFERENCE X 100 
90% Geometric Mean Confidence Interval using ln-transformed data. 
5.5.2.2.3 
Study 162021 – Pivotal Bioavailability Study 
This pivotal relative bioavailability study was a four-period, four-sequence randomized 
crossover in 36 healthy adult males and females. The four treatments were DBSF 15 mg and 
three doses of Diastat® AcuDial™ rectal gel: 5 mg, 12.5 mg, and 20 mg. These Diastat® 
AcuDial™ doses span the approved dose range for the rectal gel. The objective of this study was 
to gain a thorough and precise understanding of the comparative exposure to diazepam and 
nordiazepam (both AUC and Cmax) after administration of DBF or Diastat® AcuDial™. A 
secondary objective was to evaluate the dose proportionality of the three doses of Diastat rectal 
gel.1 
Pharmacokinetic parameters (Cmax, AUCt, and AUC∞) were compared pairwise; DBF 15 mg with 
each of the three doses of the rectal gel (Table 2). Results demonstrate that AUC (both AUCt and 
AUC∞) are dose proportional following single doses for both DBF and for Diastat® AcuDial™ 
gel over the studied dose. These results, normalized for dose in mg, suggest that the relative 
bioavailability of diazepam administered as DMF compared with Diastat® AcuDial™ gel is 
118% to 128%.1  
 
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Table 2: 
Study 162021: Ratios (DBSF 15 mg/Rectal Gel 5, 12.5, 20 mg), 90% 
Geometric Confidence Intervals for Diazepam: AUCt, AUC∞, and Cmax - 
PK Population 
Treatment  
 
 
Geometric 
Geometric 
 
90% Geometric CI2 
Comparison 
N 
Parameter 
LSM A 
LSM B 
Ratio1 
Lower 
Upper 
DBSF 15 mg (A) 
24 
AUCt 
11310.33 
3181.98 
355.45% 
292.89% 
431.37% 
Diastat  
24 
AUC∞ 
13204.10 
3730.87 
353.91% 
295.32% 
424.14% 
rectal gel 5 mg (B) 
24 
Cmax 
461.88 
116.88 
395.18% 
291.06% 
536.54% 
 
 
 
Geometric 
Geometric 
 
 
 
 
 
 
LSM A 
LSM C 
 
 
 
DBSF 15 mg (A) 
23 
AUCt 
11381.05 
7314.63. 
155.59% 
127.26% 
190.24% 
Diastat  
23 
AUC∞ 
12871.61 
8370.26 
153.78% 
126.56% 
186.86% 
rectal gel 12.5 mg (C) 
23 
Cmax 
490.93 
206.30 
237.97% 
176.72% 
320.45% 
 
 
 
Geometric 
Geometric 
 
 
 
 
 
 
LSM A 
LSM D 
 
 
 
DBSF 15 mg (A) 
21 
AUCt 
11186.57 
12392.66 
90.27% 
42.23% 
112.80% 
Diastat  
20 
AUC∞ 
13191.81 
14824.85 
88.98% 
69.28% 
114.29% 
rectal gel 12.5 mg (D) 
21 
Cmax 
458.51 
327.86 
139.85% 
140.92% 
186.42% 
AUC∞ = area under the concentration-time curve from time zero to infinity; AUCt = area under the concentration-
time curve from time zero until the last measurable concentration or last sampling time t; CI = confidence interval; 
Cmax= the maximal observed plasma concentration; DBSF= Diazepam Buccal Soluble Film (equivalent to DBF); 
LSM = Least-Squares Mean 
1 Calculated least-squares means according to the formula: e(Difference) x 100 
2 90% Geometric Mean Confidence Interval using ln-transformed data 
5.5.2.2.4 
Food Effect Studies 
Aquestive Therapeutics conducted two food effect studies (Study 162022 in Section 5.5.2.2.5 
and Study 172018 in Section 5.5.2.2.6 ). Results for a high fat meal were consistent across the 
two studies.1  
The food effect studies indicate that a high fat or moderate fat meal within 30 minutes prior to 
dosing of DBF has no effect on diazepam AUC but reduces diazepam Cmax on average of 45% 
and 33%, respectively. Bimodal peaks were observed under fed conditions due to the 
combination of oral transmucosal absorption and intestinal absorption of DBF. The first peak 
(mean concentration curves) for both high fat and moderate fat meals is observed at 45 minutes 
(mean of 199.04 ng/mL and 222.37 ng/mL, respectively) and the second peak of the mean 
concentration curves is observed at 3 hours (mean of 196.22 ng/mL and 261.79 ng/mL, 
respectively).1 
5.5.2.2.5 
Study 162022 
Study 162022 was a single-dose, open-label, two-period, randomized two-sequence crossover 
study with DBF 15 mg administered under fasted conditions and within 30 minutes following a 
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high-fat meal. The washout period between doses was 28 days. The study was conducted with 
18 healthy male and female subjects aged 18 to 62 years, inclusive. AUCt and AUC∞ were not 
affected by food; however, Cmax after a high fat meal was approximately 55% of the fasting 
value, 90% CI 48.6% – 62.7% (ratio of geometric means). Median Tmax fasting was 
approximately 0.75 hour with range of 0.25 hour to 2 hours whereas median Tmax after a high fat 
meal was 3.0 hours with range 0.5 hour to 6.0 hours, p = 0.0008.1  
5.5.2.2.6 
Study 172018 
Study 172018 was a four-period, randomized four-sequence crossover study in 24 male and 
female adults with four treatments: (A) DBF 15 mg fasted, administered upright; (B) DBF 15 mg 
fasted, administered reclining; DBF 15 mg within 30 minutes following a standardized high-fat 
meal, administered reclining; and DBF 15 mg within 30 minutes of a standardized moderate-fat 
meal, administered reclining.1 
The primary objective was to assess the effect of a moderate-fat meal on the diazepam PK 
profile. A secondary objective was to assess the effect of administration of DBF with the subject 
reclining on his/her side (application site downward) for 15 minutes after application. This was 
based on aligning treatment administration with the typical posture assumed by subjects in a 
postictal state and the Sponsor’s interest in investigating whether position affected diazepam PK 
following administration of DBF.1  
Analysis comprised pairwise comparisons of Treatment C (high-fat meal, reclining) and 
Treatment D (moderate-fat meal, reclining) with Treatment B (fasting, reclining) as well as a 
comparison between Treatment B (fasting, reclining) with Treatment A (fasting, upright).1 
Overall, AUCt and AUC∞ were not affected by either food or position. Cmax after the high fat 
meal (reclining) was approximately 53% of the fasting value (reclining), 90% CI: 41.1% - 59.5% 
(ratio of geometric means). Cmax after the moderate fat meal (reclining) was approximately 67% 
of the fasting value (reclining), 90% CI 59.8% - 74.6% (ratio of geometric means). Comparison 
of Treatment B with Treatment A demonstrated that position in the fasting condition (reclining 
versus upright) had no meaningful effect on either Cmax or AUC. Diazepam profiles (reclining 
versus upright) met bioequivalence criteria for the upright and fasting condition. There was no 
difference in Tmax, p = 0.4979.1 
Median Tmax fasting, upright was 1.00 hour with range 0.28 hour to 2.03 hours. Median Tmax 
fasting, reclining was 0.80 hour with range 0.50 hour to 2.03 hours whereas median Tmax after a 
high fat meal, reclining was 2.01 hours with range 0.50 hour to 4.06 hours (p = 0.0147 versus 
fasting, reclining). and median Tmax after a moderate fat meal, reclining was 3.00 hours with 
range 0.50 hour to 4.02 hours (p = 0.0005 versus fasting, reclining).1  
5.6 
Rationale for Dose Levels of Diazepam Buccal Film 
As described above, the data from Study 162013 and Study 162021 demonstrate that DBF is 
dose-proportional over the studied dose-range, while Diastat rectal gel is less than dose-
proportional with respect to Cmax. Also, as described above, the data from Study 162022 and 
Study 172018 demonstrate that food taken within 30 minutes prior to dosing affects the rate (but 
not the extent) of absorption of diazepam administered as DBF. Accordingly, Aquestive used 
population PK modeling to select a dosing regimen to compensate for the differences in PK 
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between DBF and DRG. The recommendation for adults derived from Population PK modelling 
is a weight-based dosing regimen with doses of 10.0 mg, 12.5 mg, 15.0 mg, 15.0 mg, and 17.5 
mg for the five weight bins (weight range 38 to 111 kg) corresponding to the labeled Diastat 
doses of 10.0 mg, 12.5 mg, 15.0 mg, 17.5 mg, and 20.0 mg (Table 3).1  
Table 3:  
Table 3Calculated Prescribed Dose of Study Drug 
Weight (Kg) 
DRG (mg) 
DBF Weight – Adjusted (mg) 
38 to 50 
10 
10 
51 to 62 
12.5 
12.5 
63 to 75 
15 
15 
76 to 87 
17.5 
15 
88 to 111 
20 
17.5 
 
Using data from Study 162013, Study 162021, and Study 172018, population pharmacokinetic 
modeling was used to model the pharmacokinetic profiles for DBF and Diastat rectal gel under 
fasted and fed conditions. In brief, the recommended DBF dose for each weight class as defined 
in the Diastat rectal gel label was selected (1) to provide a dose sufficiently high to ensure that 
the predicted median of the resulting diazepam Cmax following a moderate fat meal was similar to 
the median Cmax following the labeled dose of Diastat rectal gel, and (2) to provide a dose for 
which the predicted median of the resulting diazepam Cmax under fasting conditions would not 
exceed the median Cmax values observed and demonstrated as safe in Phase 1 studies with DBF. 
It was demonstrated that the predicted median diazepam Cmax values with the proposed regimen 
administered under fasting conditions did not meaningfully exceed the median Cmax values 
observed in the 115 healthy volunteers (adult men and women) who received DBF 15 or 20 mg 
under fasting conditions in Phase 1 studies conducted by Aquestive. The median Cmax among 
these 115 healthy subjects (138 DBF administrations) was 486 ng/mL. Under conditions of a 
moderate fat meal, the proposed DBF dosing regimen produces a Cmax similar to the Cmax 
expected following the labeled dose of Diastat rectal gel.1 
5.7 
Rationale for Study Design 
A prior study to investigate the PK of DBF in patients with epilepsy on a regimen of AEDs 
(Aquestive Study 160326) indicated that diazepam plasma concentrations observed in patients 
were on average lower than the concentrations predicted from healthy volunteer data.  Lower 
diazepam concentrations in patients could result from drug interactions with concomitant AEDs 
by means of induction of enzymes involved in diazepam metabolism and/or displacement of 
diazepam from binding sites on albumin (as described for valproic acid and sodium divalproex).   
If the lower plasma diazepam concentrations observed in patients vs. healthy volunteers 
following DBF is a consequence of enzyme induction and/or protein binding displacement from 
concomitant AEDs, the same effect of concomitant AEDs would be expected following 
administration of DRG, and the relative bioavailability of diazepam administered as DBF 
compared with DRG should be the same in patients as in healthy volunteers.  
In the current study, the PK of diazepam will be compared in patients already receiving a stable 
concomitant AED treatment following single doses of DBF or Diastat® AcuDial™ according to 
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body weight as described in Table 3. Moreover, the DBF regimen was demonstrated in healthy 
male and female volunteer simulations to produce within each weight group a median Cmax value 
following a moderate-fat meal comparable to the median Cmax value following DRG 
administration. Therefore Period 1 and Period 2 of this study will be conducted under fed 
conditions where DBF and Diastat® AcuDial™ will be administered following intake of a 
moderate-fat meal. In addition, subjects who volunteer to participate in a third period will receive 
DBF in Period 3 following a high-fat meal. This third period will allow for the PK evaluation of 
DBF following a single dose administration under conditions of a high-fat meal.  
The study will also aim to obtain PK data for Diastat® AcuDial™ under conditions of use in 
patient population and to address whether lower concentrations observed in patients versus 
healthy volunteers following DBF administration are also observed following Diastat® 
AcuDial™ administration. The study will also determine whether the DBF recommended dose 
regimen (mapping between DBF and Diastat® AcuDial™) developed from healthy volunteer 
data is applicable to patients under conditions of use.  
The weight-based DBF dose regimen was designed to elicit within each weight group a median 
Cmax value following a moderate fat meal comparable to the median Cmax value following DRG 
administered according to the current weight-based product labeling for Diastat® AcuDial™. 
Because of the crossover design, the effect of drug-drug interactions can be expected to be 
similar for both treatments.  Therefore, to the extent that population PK modeling in healthy 
volunteers is predictive for patients under conditions of use, it can be expected that diazepam 
Cmax values observed in this study following a moderate-fat meal will be similar under both 
treatments.  In the event that this is not the case, Aquestive anticipates that results from this study 
will be used to refine the recommended dose regimen in consultation and collaboration with the 
Agency. 
5.8 
Clinical Risks/Benefits of Study Drug 
5.8.1 
Managing Clinical Risks/Benefits in the Current Study 
The available data indicate that study drug is dose proportional over the studied dose-range, 
while Diastat® AcuDial™ is less than dose proportional with respect to Cmax.  
In this study, dose is based on weight category (Table 3). Subjects will be weighed at screening 
visit and dose dispensed will be adjusted depending on weight category at that visit. The 
rationale for the dose regimen for DBF is explained in Section 5.6. Trained study site staff will 
administer the study drug. The study design includes several study site visits in each period to 
monitor safety and tolerability.  
5.8.2 
Overdosage Information Derived from Diastat® AcuDialTM Prescribing 
Information 
According to the prescribing information for Diastat® AcuDial™ rectal gel, previous reports of 
diazepam overdosage have shown that manifestations of diazepam overdosage include 
somnolence, confusion, coma, and diminished reflexes. Respiration, pulse, and blood pressure 
should be monitored, as in all cases of drug overdosage, although, in general, these effects have 
been minimal. General supportive measures should be employed, along with intravenous fluids, 
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and an adequate airway maintained. Hypotension may be combated by the use of levarterenol or 
metaraminol. Dialysis is of limited value.3 
Flumazenil, a specific benzodiazepine-receptor antagonist, is indicated for the complete or 
partial reversal of the sedative effects of benzodiazepines and may be used in situations when an 
overdose with a benzodiazepine is known or suspected. Prior to the administration of flumazenil, 
necessary measures should be instituted to secure airway, ventilation, and intravenous access. 
Flumazenil is intended as an adjunct to, not as a substitute for, proper management of 
benzodiazepine overdose. Patients treated with flumazenil should be monitored for resedation, 
respiratory depression and other residual benzodiazepine effects for an appropriate period after 
treatment. The prescriber should be aware of a risk of seizure in association with flumazenil 
treatment, particularly in long-term benzodiazepine users and in cyclic antidepressant overdose. 
Caution should be observed in use of flumazenil in epileptic patients treated with 
benzodiazepines. The complete flumazenil package insert, including CONTRAINDICATIONS, 
WARNINGS, and PRECAUTIONS, should be consulted prior to use.3 
5.9 
Rationale for the Study Population 
The study employs a 3-period, 2-sequence crossover design enrolling male and female 
volunteers on a concomitant stable regimen including one or more AED for the treatment of 
epilepsy. Eligible subjects will be enrolled in an effort to complete Period 2 with at least 
16 subjects with representation of both genders, representation of subjects taking/not taking one 
or more AED known to induce diazepam metabolism, and representation of subjects taking/not 
taking Sodium divalproex/valproic acid.   
No clinical studies have been conducted with diazepam rectal gel in pregnant women. However, 
an increased risk of congenital malformations associated with the use of benzodiazepine drugs 
has been suggested by several studies. There have been reports of neonatal flaccidity, respiratory 
and feeding difficulties, and hypothermia in children born to mothers who have been receiving 
benzodiazepines late in pregnancy. Children born to mothers receiving benzodiazepines on a 
regular basis late in pregnancy may be at some risk of experiencing withdrawal symptoms during 
the postnatal period. During labor and delivery, measurable amounts of diazepam have been 
found in maternal and cord blood, indicating placental transfer of the drug. Additionally, 
diazepam and its metabolites may be present in human breast milk for prolonged periods of time 
after acute use. A recent study suggested that paternal exposure may be associated with fetal 
abnormalities.1 In humans, measurable amounts of diazepam have been found in maternal and 
cord blood, indicating placental transfer of the drug.3  
Since there have been no studies conducted in pregnant women, it is uncertain whether there is 
human fetal risk associated with the use of diazepam. Therefore, non-pregnant, non-lactating 
females will be included in the study. Any females of childbearing potential will be included if 
they use appropriate methods of contraception. In addition, non-surgically-sterile male subjects 
who are sexually active with non-sterile female partners will be required to use effective 
contraceptive methods for the duration of the study and for 111 days following administration of 
the study medication.  
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6. 
Objectives 
Primary objective: 
• Evaluate the PK of single doses of DBF at the recommended dose regimen (range 10 mg 
to 17.5 mg according to body weight) compared with DRG at the labeled dose regimen 
(range 10 mg to 20 mg according to body weight) in adult male and female subjects on a 
stable concomitant regimen of AED for the treatment of epilepsy, following a 
moderate-fat meal.  
Secondary objectives: 
• Evaluate the PK of single doses of DBF following a high-fat meal compared with DRG 
following a moderate-fat meal at the recommended dose regimen in adult male and 
female subjects on a stable concomitant regimen of AED for the treatment of epilepsy. 
• Assess the safety-tolerability of single doses of DBF and DRG administered to adult male 
and female subjects on a stable concomitant regimen of AEDs under fed conditions. 
7. 
Study Design 
This will be a randomized, multiple centers, single-dose, open-label, three-period, 
three-treatment, two-sequence crossover study under fed conditions.  
The study will evaluate single doses of DBF compared with DRG administered according to 
weight category in adult male and female subjects on a stable concomitant regimen of AED for 
the treatment of epilepsy. A stable regimen of AED is defined as no change in the prescribed 
AED regimen during the 30-day period prior to the first study drug administration and no change 
anticipated in the prescribed AED regimen over the course of study participation until the last 
PK blood sample collection.  
Subjects will receive Treatment A and Treatment B (DBF and DRG following a moderate-fat 
meal) in Period 1 and Period 2 in a randomized sequence, and at a dosage specific to body 
weight, as described in Table 4. DBF will be administered according to the currently 
recommended dose regimen (derived by Aquestive from population PK modeling in healthy 
volunteers). DRG will be administered depending on weight category according to the current 
product labeling for Diastat®. Subjects may be asked to participate in a third period, on a 
voluntary basis. Subjects who volunteer to participate in a third period will receive a second 
dose of DBF administered in exactly the same manner as the earlier dose of DBF with the 
exception that DBF in Period 3 will be administered following a high-fat meal. 
A maximum of 32 eligible subjects will be enrolled in an effort to complete Period 2 with at 
least 16 subjects with representation of both genders, representation across the five weight 
categories of subjects taking one or more AEDs known to induce diazepam metabolism, and 
representation of subjects taking sodium divalproex/valproic acid.  Subjects who are eligible may 
be enrolled without regard to weight category. Since only exploratory PK data will be 
gathered from treatment period 3, no more than 50% of the subjects who complete Period 1 
and Period 2 will participate in Period 3.  
This study is intended for filing under FDA regulations. 
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Table 4: 
Table 4 Study Treatment Administration According to Weight Category 
Product 
Meal 
Condition 
Weight 
Category 
Weight (kg) 
Dose 
Test (Treatment A):  
Diazepam Buccal Film 
(Aquestive Therapeutics, USA) 
Moderate-Fat 
Meal 
A1 
38-50 
1 x 10 mg 
A2 
51-62 
1 x 12.5 mg 
A3 
63-75 
1 x 15 mg 
A4 
76-87 
1 x 15 mg 
A5 
88-111* 
1 x 17.5 mg 
Reference (Treatment B):   
Diastat® AcuDialTM rectal gel 
(Valeant Pharmaceuticals, 
USA) 
Moderate-Fat 
Meal 
B1 
38-50 
2 mL (10 mg) 
B2 
51-62 
2.5 mL (12.5 mg) 
B3 
63-75 
3 mL (15 mg) 
B4 
76-87 
3.5 mL (17.5 mg) 
B5 
88-111* 
4 mL (20 mg) 
Test (Treatment C):  
Diazepam Buccal Film 
(Aquestive Therapeutics, USA) 
High-Fat 
Meal 
A1 
38-50 
1 x 10 mg 
A2 
51-62 
1 x 12.5 mg 
A3 
63-75 
1 x 15 mg 
A4 
76-87 
1 x 15 mg 
A5 
88-111* 
1 x 17.5 mg 
*Subjects eligible for study with weights in the range of 112 to 134 kg will be dosed at the 88-111 kg weight range 
as shown above. 
8. 
Study Population 
8.1 
Sample Size 
Subjects will be enrolled to attain a sample size of no more than 32 subjects (and a minimum of 
16 completed subjects in Period 2). Because this is not a formal hypothesis testing study, the 
sample size is proposed based on the desired level of precision for estimating pharmacokinetic 
parameters and the relationship between pharmacokinetic parameters. In principle, the expected 
precision of the estimates of the ratios of geometric means of interest can be estimated from the 
intra-subject variability observed in Aquestive Study 162021 (pharmacokinetic crossover of DBF 
15 mg with DRG 5, 12.5, and 20 mg in healthy volunteers). Aquestive has not undertaken a 
formal analysis to predict the expected precision. 
8.2 
Inclusion Criteria 
Subjects enrolled in this study will be members of the community at large. The recruitment 
advertisements may use various media types (e.g. radio, newspaper, Web site, volunteer 
database). Subjects must meet all of the following criteria to be included in the study: 
1) Male or female, smoker (no more than 25 cigarettes or equivalent daily) or non-smoker, ≥ 18 
and ≤ 65 years of age, with body weight between 38 and 111 kg, inclusive. Potential subjects 
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with weights in the range of 112 to 134 kg (247 – 249 pounds) may be allowed to participate 
in the study at the discretion of the Principal Investigator. 
 
2) On a stable and ongoing regimen of at least one AED for treatment of epilepsy.  Stable 
regimen is defined as no change in AED regimen for at least 30 days before the first study 
drug administration and no change anticipated in the prescribed AED regimen over the 
course of study participation. 
3) Subjects must have a diagnosis of seizure disorder (any seizure type or frequency) under 
treatment with at least one AED.  
4) Healthy (except for seizure disorder), according to the medical history, ECG, vital signs, 
laboratory results and physical examination as determined by the Principal Investigator/Sub-
Investigator. 
5) Clinical laboratory values within local laboratories acceptable ranges, unless values are 
deemed by the Principal Investigator/Sub-Investigator as “Not Clinically Significant”. 
6) Ability to comprehend and be informed of the nature of the study, as assessed by clinic staff.  
7) Availability to volunteer for the entire study duration and willing to adhere to all protocol 
requirements. 
8) Agree not to have a tattoo or tongue or body piercing until the end of the study. 
9) Agree not to drive or operate heavy machinery if feeling dizzy or drowsy following drug 
administration until full mental alertness is regained. 
10) Subjects must be able and willing to remove denture or bracing at the time of dosing. 
11) Non-vasectomized male subjects must use two forms of medically accepted method of 
contraception with all sexual partners of childbearing potential during the study and for 
111 days following the last dose of study drug. Medically accepted effective forms of 
contraception include:  
a) simultaneous use of a male condom and  
b) for the female partner, hormonal contraceptives (used since at least 4 weeks) or intra-
uterine contraceptive device (placed since at least 4 weeks) or diaphragm or cervical cap 
with intravaginally applied spermicide. 
12) Male subjects must be willing not to donate sperm until 111 days following the last study 
drug administration. 
13) Female subjects who are sexually active with a non-sterile male partner (sterile male partners 
are defined as men vasectomized since at least 6 months) must fulfill at least one of the 
following: 
a) Be surgically sterile for a minimum of 6 months; 
b) Post-menopausal for a minimum of 1 year; 
c) Agree to avoid pregnancy and use medically acceptable method of contraception as 
described below until at least 51 days after the last PK blood sample collection of the 
study. Medically acceptable methods of contraception include: 
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• Intrauterine device (hormonal and non-hormonal) placed at least 4 weeks prior to 
first study drug administration,  
• Oral or transdermal hormonal contraceptives with a 28-days treatment cycle taken 
daily from at least 30 days prior to first study drug administration and with no 
expected change in dosage throughout the study, or  
• Double barrier method (male condom and intravaginally applied spermicide used 
simultaneously with diaphragm or cervical cap) starting at least 21 days prior to 
first study drug administration;  
d) agree to complete abstinence. 
8.3 
Exclusion Criteria 
Subjects to whom any of the following applies will be excluded from the study: 
1) Clinically significant abnormal laboratory test results found during medical screening.  
2) Positive pregnancy test at screening. 
3) Known presence of any clinically significant: hepatic (e.g. hepatic impairment), 
renal/genitourinary (renal impairment, kidney stones), gastrointestinal (e.g. ulcerative colitis, 
ileus, partial or complete intestinal blockage, appendicitis), cardiovascular (e.g. uncontrolled 
hypertension), cerebrovascular, pulmonary, endocrine (controlled diabetes is acceptable), 
immunological, musculoskeletal, neurological (other than known seizure disorder), 
psychiatric, dermatological or hematological disease or condition unless determined as not 
clinically significant by the Principal Investigator/Sub-Investigator and confirmed by 
Sponsor via written communication prior to subject enrollment. 
4) Presence of any clinically significant gastrointestinal pathology (e.g. chronic diarrhea, 
inflammatory bowel disease), unresolved gastrointestinal symptoms (e.g. diarrhea, vomiting), 
or other conditions known to interfere with the absorption, distribution, metabolism or 
excretion of the study drug experienced within 7 days prior to first study drug administration, 
as determined by the Principal Investigator/Sub-Investigator.  
5) Any clinically significant rectal abnormality suspected by medical history or general physical 
examination, or any condition, for which, in the judgment of the Principal Investigator/Sub-
Investigator, administration of rectal gel would cause a potential risk to the subject. 
6) Baseline levels of concomitant AED outside of an acceptable therapeutic range at screening. 
7) Presence of any clinically significant illness within 30 days prior to first study drug 
administration, as determined by the Principal Investigator/Sub-Investigator. 
8) Presence of any clinically significant physical or organ abnormality as determined by the 
Principal Investigator/Sub-Investigator. 
9) Presence of any clinically significant lesion of the oral cavity. 
10) Clinically significant ECG abnormalities (QTcF interval > 450 msec for males or QTcF 
interval > 470 msec for females) or vital sign abnormalities (systolic blood pressure lower 
than 90 or over 160 mmHg, diastolic blood pressure lower than 50 or over 100 mmHg, or 
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heart rate less than 50 or over 100 bpm) at screening, unless deemed otherwise by the 
Principal Investigator/Sub-Investigator. 
11) A positive test result for HIV, Hepatitis B surface antigen, Hepatitis C.  
12) A positive test result for any of the following: drugs of abuse (amphetamines, 
methamphetamines, barbiturates, cocaine, opiates, phencyclidine, tetrahydrocannabinol, 
MDMA, methadone, and benzodiazepines, except where a positive test is consistent with a 
stable regimen of a prescribed medication) and alcohol breath test. 
13) Known history or presence of: 
a) Alcohol abuse or dependence within one year prior to screening; 
b) Drug abuse or dependence; 
c) Hypersensitivity or idiosyncratic reaction to diazepam, DBF excipients, DRG excipients; 
d) Glaucoma (open or acute narrow angle); 
e) Food allergies and/or presence of any dietary restrictions that, in the judgment of the 
investigator or the Sponsor, would interfere with study procedures or the subject’s safe 
participation in the study. 
f) Severe allergic reactions (e.g. anaphylactic reactions, angioedema). 
14) Intolerance to and/or difficulty with blood sampling through venipuncture. 
15) Individuals who have donated, in the days prior to first study drug administration: 
• 50-499 mL of blood in the previous 30 days; 
• 500 mL or more in the previous 56 days. 
16) Donation of plasma by plasmapheresis within 7 days prior to first study drug administration. 
17) Individuals who have participated in another clinical research study involving the 
administration of an investigational or marketed drug or device within 30 days prior to the 
first dosing, administration of a biological product in the context of a clinical research study 
within 90 days prior to the first dosing, or concomitant participation in an investigational 
study including an investigational study involving no drug or device administration.  
18) Use of diazepam within 30 days prior to first study drug administration.   
19) Use of strong inhibitors of CYP enzymes (e.g. cimetidine, fluoxetine, quinidine, 
erythromycin, ciprofloxacin, fluconazole, ketoconazole, diltiazem and HIV antivirals) in the 
previous 30 days before first study drug administration. Use of strong inducers of CYP 
enzymes (e.g. barbiturates, carbamazepine, glucocorticoids, phenytoin, St. John´s Wort, and 
rifampicin) and AEDs known to induce CYP enzymes are permitted provided that the 
regimen of such drugs is stable (taken at least q.d. on a regular basis) within 30 days prior to 
first study drug administration and until 10 days after last study drug administration.        
20) Use of any prescription medication (other than non-systemic topical products) within 30 days 
prior to first study drug administration. A prescription drug (other than any benzodiazepines, 
phenothiazines, and strong inhibitors of CYP enzymes) that is part of a stable drug regimen 
(taken at least q.d. on a regular basis) is allowed if taken from at least 30 days prior to the 
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first study drug administration and if there is no expected change in dosage throughout the 
study.  
21) Use of any OTC medications (other than spermicidal/barrier contraceptive products and non-
systemic topical products), within 30 days prior to first study drug administration. OTC drugs 
that is part of a stable drug regimen (taken at least q.d. on a regular basis) is allowed if taken 
from at least 30 days prior to the first study drug administration and if there is no expected 
change in dosage throughout the study. 
22) Natural health products (including oral multivitamins, herbal and/or dietary supplements 
and/or teas) from 30 days pre-dose until after the last PK blood sample collection of each 
period. 
23) Use of marijuana and THC containing products within 3 months prior to screening unless 
such products are a part of the subject’s stable antiepileptic regimen.  
24) Use of any monoamine oxidase (MAO) inhibitors (e.g. phenelzine, tranylcypromine), 
phenothiazines (e.g. chlorpromazine) within 30 days prior to first study drug administration. 
25) Female subjects who have taken oral or transdermal hormonal contraceptives (other than 
28-days treatment cycle contraceptive products) within 30 days prior to first drug 
administration, or have used an implanted, injected, or intravaginal contraceptive within 6 
months prior to first drug administration. 
26) Individuals having undergone any major surgery within 6 months prior to the start of the 
study, unless deemed otherwise by Principal Investigator/Sub-Investigator. 
27) Presence of mouth jewellery, dentures, braces, or piercings in the mouth or tongue that, in the 
opinion of the Principal Investigator, would be likely to interfere with successful completion 
of the dosing procedure 
28) Dental procedures performed within 14 days of dosing or dental procedures scheduled to 
occur during study duration. 
29) Unable or unwilling to provide informed consent. 
30) Have had a tattoo or body/mouth piercing within 30 days prior to first study drug 
administration. 
31) Employee or immediate relative of an employee of Aquestive Therapeutics, any of its 
affiliates or partners, of the CRO, or the clinical site. 
32) Breast-feeding subject. 
9. 
Clinical Procedures 
The clinical portion of the study will be conducted at multiple clinical research facilities, as listed 
in Section 1.2. Unless otherwise specified, procedures, data collection and evaluation will be 
conducted as per involved clinical facilities SOPs. Subjects' personal information will be stored 
in electronic data capture (EDC) system or raw data sheets. 
9.1 
Screening Procedures 
Subject screening procedures will be performed within 30 days preceding administration of study 
medication. Subjects must provide written informed consent prior to initiation of any screening 
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procedures. The consent to perform some general screening procedures may be obtained on a 
consent document other than the Informed Consent Form (ICF) specific to this study, and 
therefore, some screening test results could be obtained before signature of the ICF specific to 
this study. The study-specific ICF must be signed and dated by the subject before participation to 
study-specific procedures. 
Screening procedures will include: demographic data, medical and medication histories, physical 
examination, brief neurologic examination, visual inspection of DBF application site, body 
measurements, ECG (12-lead), vital signs (BP, HR, and RR), oral temperature, digital oxygen 
monitoring, hematology, biochemistry, HIV, hepatitis B and C tests, urinalysis, baseline AED 
levels if applicable*, alcohol breath test, urine pregnancy test, and urine drug screen.     
* The Investigator should confirm and document, for those AEDs medications that the patient is 
receiving at baseline screening, that AED drug level testing has been conducted within one year 
prior to the first dosing, and determine, in consultation with patient’s referring neurologist (if not 
the study Investigator), that AEDs are at acceptable therapeutic levels.  
For any AED medication where testing was not conducted within one year before the first dosing 
or was determined in the past not to be therapeutic, the Investigator should obtain and confirm a 
blood test result demonstrating a current therapeutic level for that AED medication.  If the 
Investigator determines that a dose adjustment for that AED medication is needed, then the 
patient will be considered not to be stable on their AED medication regimen, and ineligible for 
study enrollment.  
For eligibility purposes, abnormal laboratory or vital signs results may be repeated once if 
abnormal result is observed at the initial reading. Moreover, abnormalities found in the ECG may 
need to be confirmed by repeated measurements. In the event that the participation of a subject in 
the study is delayed and some screening procedures had been performed outside the prescribed 
screening window, outdated screening procedures can be repeated. 
9.2 
Confinements, Visits, and Washout 
For each period, subjects will be confined from approximately 14 hours before dosing until after 
the 24-hour post-dose blood draw. For subsequent blood draw, subjects may come back to the 
clinical site or have the blood sample collected at home by a home care nurse. 
There will be a washout of 28 days between doses. Participation of each subject in this study 
should last approximately 10 weeks (6 weeks for subjects participating in Period 1 and Period 2 
only), excluding the 30 days screening window. 
9.3 
Randomization and Blinding 
Subjects will be administered each treatment according to the 3-period, 2-sequence, block 
randomization scheme produced by inVentiv. At admission to the clinic, subjects who meet the 
inclusion/exclusion criteria will be assigned between the 2-sequence arms (ABC or BAC) 
according to the randomization schedule. inVentiv will inform the site about the medication to be 
dispensed to each particular subject at the time of subject’s randomization and at the prospective 
protocol visits. The clinic will administer the study treatment as described in Table 4, according 
to the subject’s weight obtained at screening visit.  
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The randomization code will not be available to the Bioanalytical Division until the clinical and 
analytical phases of the study have been completed.  
9.4 
Study Medication 
Test product 
(Treatment A): 
Diazepam Buccal Film (DBF) (Aquestive Therapeutics, USA), under 
fed conditions (breakfast with moderate fat content) 
Strengths: 
10 mg, 12.5 mg, 15 mg, and 17.5 mg 
Doses: 
1 x 10 mg, 1 x 12.5 mg, 1 x 15 mg, or 1 x 17.5 mg 
Reference product 
(Treatment B): 
Diastat® AcuDialTM  rectal gel (Valeant Pharmaceuticals, USA), 
under fed conditions (breakfast with moderate fat content) 
Strengths: 
10 mg/2 mL (5 mg/mL), 20 mg/4 mL (5 mg/mL) 
Doses: 
2 mL (10 mg), 2.5 mL (12.5 mg), 3 mL (15 mg), or 3.5 mL (17.5 mg) 
Test product 
(Treatment C,     
Period 3): 
Diazepam Buccal Film (DBF) (Aquestive Therapeutics, USA), under 
fed conditions (breakfast with high fat content) 
Strengths: 
10 mg, 12.5 mg, 15 mg, and 17.5 mg 
Doses: 
1 x 10 mg, 1 x 12.5 mg, 1 x 15 mg, or 1 x 17.5 mg 
 
9.5 
Drug Supplies and Accountability 
It is the responsibility of the Sponsor to ensure that study medication provided for this study are 
manufactured under Good Manufacturing Practices (GMP) and are suitable for human use. It is 
the responsibility of the Sponsor to ship a sufficient amount of dosage units to allow the clinical 
sites to maintain an appropriate sampling for the study. Study medication will be stored by the 
clinical sites as per applicable requirements. 
The medications will be stored in a locked, environmentally-controlled medication room with 
restricted access. Container(s) will bear a label containing at least the name of the study drug, lot 
and/or batch number, and manufacturing and/or expiry/retest date. Individual subject doses will 
be dispensed according to the randomization schedule. The medications will be dispensed 
according to study specific procedure. 
All study drug received at each site will be inventoried and accounted for throughout the study 
by the pharmacy staff.   
Further details regarding the proper shipment, storage conditions, dispensing, or responsibilities 
will be provided by inVentiv in the pharmacy manual. 
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9.6 
Drug Administration 
In each period, subjects will undergo a 10-hour overnight fast before the dosing procedure. 
Subjects will receive a single dose according to their body weight (as described in Table 4). The 
body weight of each subject will be measured at screening and this value will be used to 
calculate the exact individual dose of diazepam required. 
Following each study drug administration, subjects will remain in a safe comfortable position 
(sitting or reclining in bed) for at least one hour after dosing to allow for an assessment of drug 
effect including sedation. After one hour and depending on the assessment of the 
investigator/clinical staff, the subject may be permitted to ambulate provided that ambulation 
does not interfere with study procedures.   
DBF ease of use will be evaluated by the clinical staff and by the subjects following the first film 
administration in Period 1 or Period 2. Questions regarding past experience in using DRG or 
other rescue medication for the treatment of epilepsy will also be asked to subjects prior to DRG 
administration. Questions are listed in Appendix I – Diazepam PK Study Participant Questions. 
Test (Treatment A and Treatment C): 
After the overnight fast, subjects will be served a standardized moderate-fat meal (Treatment A, 
Period 1 or Period 2) or a high-fat, high-calorie meal (Treatment C, Period 3). Subjects will have 
20 ± 1 minutes to finish the meal. The study drug will be administered 30 ± 1 minutes after the 
start of the meal. A single dose of DBF will be administered by placement of the film against the 
buccal mucosa.   
When opening the foil pouch containing the study drug film, the clinical staff will use scissors to 
carefully cut along the wide edge of the pouch and use gloves when handling and administering 
the study drug to the subject. 
Prior to dosing, the subject will be asked to move his/her tongue around the mouth (front and 
back part of gums, teeth and palate) two times to note any signs of oral irritation and/or any 
mouth, tongue or gum ulcer(s). Study staff will check the subjects’ mouth to ensure the mouth is 
clean and free of food before study drug administration. Subsequently, staff will center the DBF 
against the inner aspect of the right or left buccal mucosa (inside the cheek) and ask the subject 
to close his/her mouth in a natural way, without swallowing, chewing, biting or breaking the 
DBF (refer to Appendix III - Placement Diagram for Aquestive Therapeutics Buccal Film). If the 
subject chews, talks, or moves the study drug within 10 minutes of administration, it is to be 
noted. Dosing time will be set to the time the film is placed on the buccal mucosa.  
The study staff will record the actual time of film placement. Subjects will be instructed to notify 
study staff if the DBF is accidentally swallowed within 5 minutes of dosing. Study staff will 
record the time the film was swallowed.  
Following the administration of the DBF, hands and mouth will be checked in order to confirm 
the consumption. 
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Reference (Treatment B): 
Subjects will consume a standardized moderate-fat meal after the overnight fast. Subjects will 
have 20 ± 1 minutes to finish the meal. The study drug will be administered 30 ± 1 minutes after 
the start of the meal.  
A single dose of DIASTAT® rectal gel will be administered, with subjects lying down on their 
right side. The tip of the syringe containing the DIASTAT® gel will be inserted gently in the 
rectum and the gel will be inserted inside the rectum according to the dosing procedure (refer to 
Appendix IV - Placement Diagram for DIASTAT® AcuDial™ Rectal Delivery System).  
9.7 
Study Restrictions 
If any subject does not comply with the study restrictions, at any time prior to or during the 
study, continued participation will be re-assessed by the Principal Investigator/Sub-Investigator, 
CRO PK Scientist and the Sponsor. 
If drug therapy other than that specified in the protocol, including any change in the subject’s 
stable AED regimen, is required during the study, the decision whether to continue or 
discontinue the subject’s participation in the study will be made by the Principal 
Investigator/Sub-Investigator and/or by the CRO PK Scientist in consultation with the Sponsor.   
Concomitant drug or non-drug treatment (e.g. prune juice, ginger ale) administered to subjects as 
per instructions from clinical sites physicians for treatment of any Adverse Events [AEs] (as 
required) will be permitted. Clinic staff will provide the subjects with the treatment (e.g. 
medication, fluids) and will document all substances given outside of the protocol specified 
requirements. All cases of concomitant medication or herbal/dietary supplement administration 
will be reported as soon as possible to the CRO PK Scientist and/or the Sponsor and will be 
reviewed on a case by case basis to determine the subject’s further participation in the study. 
9.7.1 
Food and Fluids 
After a supervised fast of at least 10 hours, subjects will be served either a standardized 
moderate-fat meal or a high-fat, high-calorie meal. The standardized moderate-fat meal will 
contain approximately 625 calories. Approximately 14% of total calories will be derived from 
protein, 54% from carbohydrates, and 32% from fat.5 The high-fat, high-calorie meal will 
contain approximately 800 to 1000 calories (approximately 50% of total caloric content of the 
meal will be derived from fat). This meal should derive approximately 150, 250, and 500-600 
calories from protein, carbohydrate, and fat, respectively.7 Subjects will be required to start their 
meal as soon as it is served and to complete it within 20 ± 1 minutes. Drug administration will 
occur 30 ± 1 minutes after the meal has been started. Subjects will fast for not less than 4 hours 
after drug administration. Meals will be standardized and similar in composition between 
periods. 
No water will be allowed during the DBF administration and for at least 15 minutes following 
DBF administration. Water will be allowed ad libitum at all other times.  
In addition, subjects will be required to abstain from (refer to Appendix II – Study Restrictions 
for detailed study restrictions): 
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• food containing poppy seeds within 48 hours prior to dosing in each period; 
• food or beverages containing caffeine/methylxanthines derivatives or energy drinks 
from 48 hours prior to dosing until after the last PK blood sample collection of each 
period; 
• natural health products (dietary and/or herbal supplements and/or teas) from 30 days 
pre-dose until after the last PK blood sample collection of each period; 
• Food or beverages containing grapefruit, star fruit, and/or pomelo from 30 days prior 
to the first dosing until the last PK blood sample collection of the study. 
9.7.2 
Tobacco, Alcohol, and Illicit Drugs 
Subjects will be required to abstain from using soft or hard drugs from screening and throughout 
the study. Subjects will not be allowed to smoke more than 25 cigarettes or equivalent per day. 
Marijuana and THC containing products may be allowed if prescribed and part of the subject’s 
stable antiepileptic regimen.  
Consumption of alcohol-based products will be prohibited from 48 hours prior to dosing until 
after the last PK blood sample collection of each period. 
9.7.3 
Medications 
Prescription and OTC medications will be prohibited throughout the study except for 
prescription and OTC drugs that are administered as a stable regimen (taken at least q.d. on a 
regular basis). Any stable prescription drug and OTC treatment (except any benzodiazepines, 
phenothiazines, and strong inhibitors of CYP enzymes) will be allowed if taken from at least 
30 days prior to the first study drug administration and with no changes expected in dosage 
regimen through the study (until the last PK sample).  
No other concomitant drug therapy will be allowed during the study except one(s) required for 
the medical management of an AE. In this case, any concomitant medication use will be 
evaluated on a case-by-case basis by the Principal Investigator or a physician. Concomitant drug 
or non-drug treatment (e.g. acetaminophen, ibuprofen (or other NSAIDs), prune juice, ginger 
ale) for the treatment of an AE will be administered as per instructions from clinic physicians. 
Clinic staff will provide the subjects with the treatment (e.g. medication, fluids) and will 
document all substances given outside of the protocol specified requirements. All cases of 
concomitant medication or herbal/dietary supplement administration will be reported as soon as 
possible to the Sponsor and will be reviewed on a case by case basis to determine the subject’s 
further participation in the study. 
Any benzodiazepines (other than study drug), phenothiazines, and strong inhibitors of CYP 
enzymes (e.g. cimetidine, fluoxetine, quinidine, erythromycin, ciprofloxacin, fluconazole, 
ketoconazole, itraconazole, diltiazem, and HIV antivirals) will be prohibited from 30 days prior 
to the first dosing until after the last PK blood sample collection of the study. Strong inducers of 
CYP enzymes (e.g. barbiturates, carbamazepine, glucocorticoids, phenytoin, phenobarbital, St. 
John´s Wort, rifampicin) and AEDs known to induce CYP enzymes are permitted provided that 
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the regimen of such drugs is stable (taken at least q.d. on a regular basis) within 30 days prior to 
first study drug administration and until at least 10 days after last study drug administration.     
Subjects will be advised that they are not allowed to take MAO inhibitors for 30 days before 
dosing and until 14 days after the last study drug administration. 
For females, oral or transdermal hormonal contraceptives other than 28-days treatment cycle 
contraceptives are prohibited within 30 days prior to first study drug administration and 
implanted, injected, or intravaginal hormonal contraceptive are prohibited within 6 months prior 
to first study drug administration and through the study. 
9.7.4 
Posture and Physical Activity 
Diazepam may cause sedation.  Consistent with intended use of DBF and the use of DRG 
subjects should be in a safe comfortable position (sitting or reclining in bed) for at least one hour 
after dosing to allow for an assessment of drug effect including sedation. After one hour and 
depending on the assessment of the investigator/clinical staff, the subject may be permitted to 
ambulate provided that ambulation does not interfere with study procedures.  Vital signs should 
be taken in a consistent position (sitting or reclining).  Subject visits to the bathroom or 
washroom will be monitored by clinic staff for 4 hours after each study drug administration, and 
the following information will be recorded: whether the subject urinated, defecated, or vomited. 
Subjects will be instructed not to flush if they vomit. Vomitus will be verified and noted in the 
subject’s file for further evaluation if needed.  
Because excessive physical activity may increase the level of CK above the upper normal limit 
value, subjects will be advised to avoid performing vigorous physical activities (e.g., intense or 
long-distance running or biking, etc.) at all times during the study duration (from at least 5 days 
prior to admission), including the washout period.  
9.8 
Sample Collection and Processing 
In each period, a total of 19 blood samples will be drawn from each subject for pharmacokinetic 
analyses. Blood samples will be collected prior to study drug administration and 0.5, 0.75, 1, 1.5, 
2, 3, 4, 6, 9, 12, 24, 48, 72, 96, 120, 144, 192, and 240 hours post-dose (3 mL for each sampling 
time). The time tolerance window for blood samples collected during the confinement period 
will be ±1 minute for all samples collected before 8 hours post-dose and ±3 minutes for 
subsequent samples. The time tolerance window for return visit samples will be ±60 minutes. 
Blood samples will be collected as close as possible to nominal times; exact sample collection 
times will be recorded on the appropriate source documents and reported for each subject. The 
actual time of blood sample collection will be used for PK and statistical analysis. Unless 
otherwise specified or for subject safety, when blood draws and other procedures coincide, blood 
draws will have precedence. A saline intravenous catheter will be used for blood collection to 
avoid multiple skin punctures, when appropriate. Otherwise, blood samples will be collected by 
direct venipuncture. 
The total volume of blood including that collected for eligibility and safety purposes should not 
exceed 313 mL for the whole study.  
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Further details regarding the proper collection, preparation, labeling, storage, and shipment of 
plasma samples for PK analysis will be provided by inVentiv in the lab manual. 
9.9 
Subject Monitoring 
Subjects will be monitored throughout the study by the clinical staff for adverse events. In each 
period, the Principal Investigator or Sub-Investigator will be on site for drug administration and 
until 8 hours after administration of the study medication to the last subject. A Principal 
Investigator or Sub-Investigator will also be on call for the remainder of the study. If necessary, a 
physician, either at the clinic or in a nearby hospital will administer treatment for any AEs. A 
crash cart or emergency bag containing the necessary rescue material and appropriate 
medications will be available in the clinic to allow for rapid intervention in case of emergency. 
Safety parameters, including laboratory results and ECG, will be assessed by the Principal 
Investigator or delegate, using local laboratories acceptance ranges criteria for biomedical 
laboratory as suggested guidelines in making the medical assessment. 
Scheduled safety measurements will be repeated according to appropriate ranges or upon request 
from a physician. Any abnormal repeated measurement will be evaluated by a physician and 
repeated if judged necessary. Further action may be taken upon physician's request. 
Subjects will be advised to notify their health care professional(s) (e.g., physician, dentist, and/or 
pharmacist) that they are participating in a clinical research study on a new formulation of 
diazepam before taking any medicines or undergoing any medical procedure. 
9.9.1 
Vital Signs 
Vital signs (BP, RR, HR ) and digital oxygen monitoring will be measured in a sitting position 
(except for safety reasons) at screening and at study exit. Oral temperature will be measured at 
screening and at study exit. 
Vital signs and digital oxygen monitoring will be measured before dosing and approximately 0.5, 
1, 1.5, 2, 4, and 8 hours post-dose (and beyond if clinically indicated). 
Vital signs will also be measured approximately 12 and 24 hours post-dose.  
When vital signs measurements coincide with a blood draw, they should preferably be performed 
a few minutes before the blood collection whenever possible. 
9.9.2 
ECG 
Supine ECG will be performed at screening and study exit. Continuous ECG monitoring will be 
performed from approximately 1 hour prior to dosing until 8 hours post-dose (and extended if 
clinically indicated). 
9.9.3 
Physical Examination 
A physical examination will be performed at screening and study exit. The physical examination 
includes at least the following components: HEENT (head, eyes, ears, nose, and throat), neck, 
chest and lungs, cardiovascular, abdomen, skin, and musculoskeletal evaluation.   
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A brief neurologic examination will be performed at screening and study exit. The neurologic 
assessment involves at least the following evaluation: mental status, cranial nerves, motor 
system, sensory system, cerebellar disorder, gait, and reflexes. 
9.9.4 
DBF Application Site Inspection 
The Investigator or designee will make a visual inspection of the oral mucosa at screening. The 
application site will also be inspected prior to DBF administration and approximately 6 and 
24 hours after administration. Assessments of the oral mucosa (normal/abnormal) will be 
conducted by the Principal Investigator/Sub-Investigator or a trained nurse.  
Abnormalities observed before dosing will be recorded and evaluated regarding exclusion 
criteria but will not be considered AEs. Any post-dose abnormalities will be reported as AEs and 
followed until resolution. 
9.9.5 
Drug and Alcohol Screen 
A urine drug screen (amphetamines, methamphetamines, barbiturates, benzodiazepines, 
tetrahydrocannabinol, cocaine, opiates, PCP, MDMA, methadone) and an alcohol breath test will 
be performed at screening and before dosing of each period. 
9.9.6 
Pregnancy Test 
A urine pregnancy test will be performed at screening and at study exit, and a serum pregnancy 
test will be performed at check-in of each period. 
9.9.7 
Laboratory Assessments 
9.9.7.1 
Hematology 
Hematology will be performed at screening and at study exit. The following will be assessed: 
complete blood count with differential, hemoglobin, hematocrit and platelet count. 
9.9.7.2 
Biochemistry 
Biochemistry will be performed at screening and at study exit. The following will be assessed: 
albumin, alkaline phosphatase, AST, ALT, urea, calcium, chloride, glucose, phosphorus, 
potassium, creatinine, sodium, total bilirubin, CK, lactate dehydrogenase, uric acid, total protein, 
magnesium, bicarbonates, and ammonia. 
9.9.7.3 
Serology 
Hepatitis B (HBs Ag), Hepatitis C (HCV) antibody, and HIV antigen and antibody detection will 
be performed at screening. 
9.9.7.4 
Urinalysis 
Urinalysis will be performed at screening and at study exit. The following will be assessed: 
macroscopic examination, pH, specific gravity, protein, glucose, ketones, bilirubin, occult blood, 
nitrite, and leukocytes. Unless otherwise specified, microscopic examination will be performed 
on abnormal findings. 
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9.10 Study Exit Procedures 
Physical examination, brief neurologic examination, hematology, biochemistry, urinalysis, vital 
signs (blood pressure, heart rate, respiratory rate), oral temperature, digital oxygen monitoring, 
ECG, urine pregnancy test, and AE monitoring will be performed on the last study day. If not 
possible, all efforts will be made to complete study exit procedures within 14 days after the last 
participation of the subject in the study. 
9.11 Data Collection and Evaluation 
All clinical raw data will be recorded promptly, accurately, and legibly as e-source data or 
indelibly on paper (e.g. ECG readings). A detailed list of the type (electronic or paper) and 
location for all source data will be included in the Trial Master File. All raw data will be 
conserved in order to maintain data integrity. A physician and/or the clinical staff will assume 
the responsibility of ensuring the completeness and accuracy of the clinical data. 
9.12 Subject Withdrawal and Replacement 
Subjects will be advised that they are free to withdraw from the study at any time. Over the 
course of the study, the Sponsor and the Investigator or a delegate may withdraw any subject 
from the study for one of the reasons described below: 
• 
safety reason; 
• 
non-compliance with protocol requirements; 
• 
significant protocol deviation; 
• 
positive alcohol breath test;  
• 
positive drug screen (except for subjects using prescribed marijuana and THC containing 
products as AED treatment);  
• 
positive pregnancy test. 
Positive result to the urine benzodiazepine screen (urine drug screen) in Period 2 and Period 3 
may derive from residual concentrations from study drug administered in the previous period(s). 
Therefore, it is not required that subjects with a positive result to that test in Period 2 and Period 
3 be withdrawn from the study. Continued subject participation in the study will be evaluated by 
the Principal Investigator. 
Subjects experiencing emesis within 4 hours following DBF adminsitration will be evaluated on 
a case-by-case basis by the Principal Investigator/Sub-Investigator, the CRO PK Scientist, and 
the Sponsor, and a decision on their continued participation will be made.  Subjects experiencing 
a bowel movement within 4 hours following DRG administration or clinically significant leakage 
of the rectal gel within 4 hours post-dose will be evaluated on a case-by-case basis by the 
Principal Investigator/Sub-Investigator, the CRO PK Scientist, and the Sponsor, and a decision 
on their continued participation will be made.  All decisions will be made prior to the 
bioanalytical laboratory commencing bioanalysis. 
Subjects who withdraw or are withdrawn from the study after dosing will not be replaced. 
However, in the event that the number of drop-outs exceeds initial expectations, subjects who 
withdraw or are withdrawn might be replaced at the discretion of the Sponsor. Such replacement 
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resulting in dosing of more subjects than planned in this protocol would be documented in a 
protocol amendment. 
Subjects who withdraw or are withdrawn will be asked to remain at the clinic until the 
Investigator or a delegate agrees that the subject is fine and can be discharged. As soon as subject 
withdrawal is confirmed, blood sampling will be stopped.  Study exit procedures will be 
performed at the time of withdrawal from the study or as soon as possible thereafter.  
9.13 Adverse Events 
9.13.1 Adverse Event Recording and Follow-up 
Subjects will be instructed to inform clinical personnel of any untoward medical symptoms 
and/or events that may arise during the course of the study. AEs/SAEs will be collected and 
documented from the signing of the ICF until at least 10 days following the last study drug 
administration, and as observed or reported spontaneously by study participants.  
Prior to subsequent dosing, subjects will be questioned concerning symptoms that may have 
occurred after the previous administration of the study drug. The incidence, seriousness, severity, 
duration, and relation to study drug of all AEs will be recorded. 
9.13.1.1 
Serious Adverse Events 
An SAE is an AE that meets one or more of the following criteria: 
• Results in death 
• Is life-threatening (places the subject at immediate risk of death from the event as it 
occurred; this does not include an event that, had it occurred in a more severe form or 
was allowed to continue, might have caused death) 
• Results in inpatient hospitalization or prolongation of existing hospitalization 
• Results in a persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
• Is a congenital anomaly or birth defect (in the child of a subject who was exposed to the 
study drug) 
An important medical event that may not result in death, be life threatening, or require 
hospitalization may be considered an SAE when, based upon appropriate medical judgment, the 
event may jeopardize the subject and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Medical and scientific judgment should be exercised in 
deciding whether expedited reporting is appropriate in such situations. 
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9.13.1.2 
Evaluation of Severity of AEs 
Severity will be evaluated according to the following scale: 
Mild 
Adverse event resulting in discomfort, but not sufficient to cause interference in 
normal daily activities. 
Moderate 
Adverse event resulting in discomfort that is sufficient to cause interference in 
daily activities.  
Severe 
Adverse event resulting in discomfort causing an inability to carry out normal 
daily activities.  
 
Adverse Event monitoring and reporting will be followed-up until resolution or for up to 2 weeks 
following completion of the study, after which the Investigator will decide the course of action. 
9.13.1.3 
Assessing Relationship to Study Drug 
The Investigator will assess the relationship of all AEs to the drug, using the following scale: 
Probable 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to drug administration, unlikely to be attributed to concurrent disease or 
other drugs or chemicals, and which follows a clinically reasonable response on 
withdrawal. 
Possible 
A clinical event, including laboratory test abnormality, with a reasonable time 
sequence to drug administration, but which could also be explained by concurrent 
disease or other drugs or chemicals. Information on drug withdrawal may be lacking 
or unclear. 
Unlikely 
A clinical event, including laboratory test abnormality, with a temporal relationship 
to drug administration which makes a causal relationship improbable, and which 
other drugs, chemicals or underlying disease provide plausible explanation. 
Unrelated 
This category is applicable to AEs which are judged to be clearly and 
incontrovertibly due to extraneous causes (diseases, environment, etc.) and do not 
meet the criteria for drug relationship listed for the above-mentioned conditions. 
All AEs will be evaluated by the Investigator, who must approve the subject for subsequent 
dosing. 
The Investigator or designee will be present from approximately 30 minutes prior to each dosing 
until at least 8 hours post-dose for each subject. The Investigator or designee will remain on-call 
throughout the duration of each study subject’s visit. 
9.13.1.4 
Follow-up of AEs 
Any AEs, whether serious or non-serious, will be monitored throughout the study and followed 
to resolution or for up to 2 weeks after the last PK blood draw, after which the Investigator will 
decide the course of action. 
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9.13.2 Procedures for Reporting Adverse Events 
Subjects will be instructed to inform clinical personnel of AEs that may arise during the course 
of the study. Treatment of any AEs will be administered under the direction of the Investigator. 
All symptoms will be recorded by clinical staff and will be reviewed by the Investigator prior to 
any subsequent dosing. 
When appropriate, medical tests and examinations will be performed to document resolution of 
the event(s). 
Adverse events will be coded into the Preferred Term (PT), classified according to the current 
version of Medical Dictionary for Regulatory Activities (MedDRA) with System Organ 
Classification (SOC) and reported with severity, duration, onset time and relationship to study 
drug and action taken. 
Female subjects of child-bearing potential must have a negative serum pregnancy test at all 
treatment visits. Following administration of study drug, any known cases of pregnancy in 
female subjects will be reported until the subject completes or withdraws from the study. The 
pregnancy will be reported immediately by faxing/emailing a completed Pregnancy Report to the 
Sponsor’s safety representative, Syneos Health Safety & Pharmacovigilance within 24 hours of 
knowledge of the event. The pregnancy will not be processed as an SAE; however, the 
Investigator will follow the subject until completion of the pregnancy and must assess the 
outcome in the shortest possible time but not more than 30 days after completion of the 
pregnancy. The Investigator should notify the Sponsor’s safety representative, Syneos Health 
Safety & Pharmacovigilance of the pregnancy outcome by submitting a follow-up Pregnancy 
Report. If the outcome of the pregnancy meets the criteria for immediate classification of an SAE 
(e.g., spontaneous or therapeutic abortion [any congenital anomaly detected in an aborted fetus is 
to be documented], stillbirth, neonatal death, or congenital anomaly), the Investigator will report 
the event by emailing/faxing a completed SAE form to the Sponsor’s safety representative, 
Syneos Health Safety & Pharmacovigilance within 24 hours of knowledge of the event.  
SAEs will also be reported to the Sponsor’s safety representative, Syneos Health Safety and 
Pharmacovigilance via e-mail (preferred) or fax within 24 hours of first knowledge by the 
Investigator. The notification must be directed to: 
Syneos Health Safety and Pharmacovigilance  
Fax Number: +1 866 856 1649  
Email: SafetyPV@syneoshealth.com 
 
The following Sponsor personnel are to be contacted on the occurrence of a SAE: 
Allen H. Heller, MD, MPH  
Pharma Study Design LLC  
Office phone: 203-389-2324 
24-hour phone: 908 300 7986 
 
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9.14 Reportable Disease 
In the case a subject has or manifested any clinical signs characteristic of a reportable disease or 
condition (e.g., HIV, Hepatitis B or C), it is the responsibility of the Principal Investigator to 
notify the public health department of the State of Florida by telephone or fax, as soon as 
possible and within the appropriate timelines. 
10. Study Termination 
The study may be terminated by the Principal Investigator following consultation with the 
Sponsor, by the Sponsor or by the regulatory authorities. Following a decision to discontinue the 
trial, the Principal Investigator will immediately inform the active study subjects and the 
IRB/IEC responsible for this trial, stating the reasons for discontinuation of the study and, 
furthermore, advise them in writing of any potential risks to the health of study subjects or other 
persons. It is the Sponsor’s responsibility to report the premature termination of the study to the 
regulatory authority(ies), when required by the applicable regulatory requirement(s).  
11. Analytical Methodology 
Each plasma sample for PK analysis will be aliquoted in 2 samples. One set of aliquots from all 
subjects will be delivered to the analytical facility packed on a sufficient amount of dry ice so 
that the samples remain frozen for at least 72 hours. Once the initial set has been confirmed to 
have been received by the analytical facility, the second set of aliquots will then be delivered, if 
requested. 
All shipments will be accompanied by an inventory list and delivered to the following address:  
 
inVentiv 
2500, rue Einstein 
Québec (Québec), Canada, G1P 0A2 
Attn: Sample Management 
Tel.: 1-418-527-4000 
Fax: 1-418-527-3456  
E-mail: DL-SamplesControllerQuebec@syneoshealth.com 
 
Clinical personnel will notify the analytical laboratory prior to shipment by phone, fax or e-mail. 
The Bioanalytical Division of inVentiv will analyze diazepam and nordiazepam in plasma 
samples using a validated method.  
Analyst and Watson LIMS (Laboratory Information Management System) will be used at 
different steps of the analysis. 
Samples from subjects included in the pharmacokinetic population (see section 12.2.2) and from 
subjects who were withdrawn from the study due to adverse events or vomiting episodes will be 
analyzed. 
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12. Pharmacokinetic and Statistical Analyses 
Pharmacokinetic analysis will be performed using Phoenix® WinNonlin®, which is validated for 
bioequivalence/bioavailability studies by inVentiv. Inferential statistical analyses will be 
performed using SAS® according to FDA guidelines. 
12.1 Pharmacokinetics 
The following pharmacokinetic parameters will be calculated by standard non-compartmental 
methods for diazepam and nordiazepam:  
1) AUC0-t: area under the concentration-time curve from time zero to the last non-zero 
concentration 
2) AUC0-inf: area under the concentration-time curve from time zero to infinity 
(extrapolated) 
3) Cmax: maximum observed concentration  
4) Residual area: calculated as 100*(1- AUC0-t /AUC0-inf) 
5) Tmax: time of observed Cmax 
6) T½ el: elimination half-life 
7) Kel: elimination rate constant  
8) Cl/F: Apparent Total Clearance (L/hr) estimated from dose/AUC0-inf 
9) Vd/F: Apparent Volume of distribution (L) estimated from Cl/Kel (β) 
10) Cl/F/kg: Apparent Total Clearance/kg (L/hr) estimated from dose/kg/AUC0-inf 
11) Vd/F/kg: Apparent Volume of distribution/kg (L) estimated from Cl/Kel (β)/kg 
12.2 Analysis Populations 
12.2.1 Safety Population 
The safety population is defined as all subjects who received at least one dose of the study 
medication. 
12.2.2 Pharmacokinetic Population 
The pharmacokinetic population will include all subjects completing at least Period 1 and 
Period 2 with no significant violation of study restrictions, and for whom the pharmacokinetic 
profile can be adequately characterized. Any subject who completes only one period will be 
presented in the concentrations and pharmacokinetic tables but excluded from descriptive 
statistics and ANOVA. 
A violation of the requirement to maintain a stable regimen of AEDs or a stable regimen of other 
concomitant drugs with the potential to influence diazepam pharmacokinetics will be considered 
a significant violation of study restrictions.  A change of drug in the prescribed AED regimen 
and/or change in the dose of a prescribed AED will be considered a departure from a stable 
regimen.  Any subject who does not maintain a stable AED regimen in the course of the study 
will be presented in the concentrations and pharmacokinetic tables but excluded from descriptive 
statistics and ANOVA.  For cases in which a departure from a stable AED regimen is a matter of 
judgment, the decision will be made by the Principal Investigator/Sub-Investigator and/or by the 
CRO PK Scientist in consultation with the Sponsor prior to bioanalysis.   
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Any subject with diazepam or nordiazepam pre-dose concentrations will be presented in the 
concentrations and pharmacokinetic tables but excluded from descriptive statistics and ANOVA 
if the pre-dose concentration is greater than 5% of the Cmax value for that analyte of that period 
for that subject. 
Subjects withdrawn due to vomiting episodes as per criterion established under section 9.12 or 
due to adverse events will be presented but excluded from the statistical analyses (i.e., 
descriptive statistics and ANOVA). 
Data from subjects who experienced emesis during the sampling interval and who were not 
withdrawn as per criterion established under section 9.12 may be evaluated after completion of 
the pharmacokinetic analysis. Any subject who experienced emesis within 2 times median Tmax 
of the current study (based on the reference product) will be excluded from the statistical 
analysis (i.e., descriptive statistics and ANOVA). 
12.3 Statistical Analyses 
Demographic parameters will be summarized descriptively. Treatment-emergent adverse events 
will be summarized descriptively by treatment for all subjects who were dosed (safety 
population). No inferential statistical analysis of safety data is planned. 
Individual and mean plasma concentration versus time curves will be presented for both linear 
and semi-log scales. Descriptive statistics (arithmetic and geometric means, standard deviation 
[SD], coefficient of variation [CV%], minimum [Min], maximum [Max], and median) of the 
plasma concentrations versus time and the pharmacokinetic parameters will be presented for the 
Test and the Reference products for each weight category as well as irrespective of weight 
category. 
For diazepam and nordiazepam, using GLM procedures in SAS, ANOVA will be performed on 
untransformed Tmax, Kel, and T½ el and on ln-transformed AUC0-t, AUC0-inf, Cmax, Cl/F, Cl/F/kg, 
Vd/F, and Vd/F/kg at the alpha level of 0.05. Factors incorporated in the model will include: 
Sequence, Subject(Sequence), Period, and Treatment. Tmax will be analyzed using an additional 
non-parametric test (Wilcoxon signed-rank test). 
12.3.1 Treatment Comparison DBF (Test) versus DRG (Reference) Following a 
Moderate-Fat Meal 
The ratio of geometric means will be calculated for AUC0-t, AUC0-inf, and Cmax  for the Test 
product versus the Reference product (Treatment A/Treatment B) irrespective of weight 
category. The 90% confidence interval for the ratio of geometric means, based on least-squares 
means from the ANOVA of the ln-transformed data will also be calculated. Intra and inter-
subject coefficient of variation will be estimated.  
12.3.2 Treatment Comparison DBF (Test) versus DRG (Reference) Following Different 
Meal Conditions 
An exploratory pair-wise analysis comparing DBF following a high-fat meal (Treatment C) with 
DRG following a moderate-fat meal (Treatment B) will be conducted and reported. 
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The ratio of geometric means will be calculated for AUC0-t, AUC0-inf, and Cmax for Treatment C 
versus Treatment B, irrespective of weight category. The 90% confidence interval for the ratio of 
geometric means, based on least-squares means from the ANOVA of the ln-transformed data 
will also be calculated. Intra and inter-subject coefficient of variation will be estimated.  
Additional analyses may be performed.  
Details of the pharmacokinetic and statistical analyses will be provided in the SAP. 
12.4 Safety and Tolerability Parameters and Analyses 
Demographic parameters will be summarized descriptively. 
Safety and tolerability to DBF will be evaluated through the assessment of AEs (i.e., seriousness, 
severity, relationship to the study drug, outcome, duration, and management), vital signs, clinical 
laboratory parameters and physical examination. Treatment-emergent AEs will be summarized 
descriptively by treatment for all subjects who were dosed (safety population). Changes from 
baseline values in vital signs, ECG, and clinical laboratory parameters will be evaluated. Safety 
and tolerability data will be reported using descriptive statistics. No inferential statistical analysis 
of safety data is planned. 
Details of the safety and tolerability analyses will be provided in the SAP. 
13. Final Report 
A final report including clinical, bioanalytical, and statistical sections will be the responsibility 
of inVentiv. 
In the event that the study is prematurely terminated, inVentiv will produce an abbreviated safety 
report. In such an event, raw data will not be submitted with the abbreviated report but will be 
archived at inVentiv, unless requested by the Sponsor. 
14. Regulatory Considerations and Quality Assurance 
14.1 Independent Ethics Committee Approval of Protocol and Other Study Documents 
The Investigator(s) agree to provide the IRB/IEC with all appropriate documents, including a 
copy of the protocol/amendments, ICFs, advertising text (if any), Investigator’s Brochure (if any) 
and any other written information provided to study subjects. The trial will not begin until the 
Investigators have obtained the IEC favourable written approvals for the above-mentioned study 
documents. A properly executed written ICF shall be read, signed, and dated by each subject 
prior to entering the trial or prior to performing any study procedure. The original signed and 
dated ICF will be kept by the Investigator and a copy will be given to the subject.  
In the event that the protocol is amended, the revised protocol must be approved by the IEC prior 
to its implementation, unless the changes involve only logistical or administrative aspects of the 
trial. If a revised ICF is introduced during the study, each subject’s further consent must be 
obtained. The new version of the ICF must be approved by the IEC, prior to subsequently 
obtaining each subject’s consent. 
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The Investigators and the Sponsor’s representative must sign the protocol and its amendments (if 
any) before initiating the study. 
It is the Sponsor’s responsibility to submit the protocol and its amendments (if any), and the 
ICFs to regulatory authorities when necessary. 
14.2 Compliance 
This study will be conducted in compliance with the protocol, GCP, GLP, and all applicable 
regulations, including the Federal Food, Drug and Cosmetic Act, U.S. applicable Code of 
Federal Regulations (title 21), and any IEC requirements relative to clinical studies. The study 
will also be conducted in compliance with the recommendations laid down in the most recent 
version of the Declaration of Helsinki, with the exception that registration of such Phase 1 trials 
in a publicly accessible database is not mandatory.    
14.3 Audits, Inspections and Monitoring 
All source documents and laboratory reports will be Quality Control reviewed to ensure accuracy 
and completeness. Adverse events will be reviewed and assessed for severity and causality by 
the Principal Investigator/Sub-Investigator.  
In accordance with the principles of GCP and GLP, the study may be inspected by regulatory 
authorities, the Sponsor, and the CRO. The Sponsor is entitled to access information about the 
status of the study and to review the original documents of the study. 
15. Confidentiality 
This document contains trade secrets and commercial information that is confidential and may 
not be disclosed to third parties. Persons to whom this study protocol is disclosed must be 
informed that all the information herein is confidential and may not be further divulged. These 
restrictions will apply as well to all future communications if deemed privileged or confidential. 
Publication of the study results may only be allowed with written permission from the Sponsor. 
All information on a subject obtained during the conduct of the study will be kept confidential. 
Subjects will be identified by an anonymized identifier on all samples and study records 
provided to the Sponsor or designee. In compliance with ICH GCP, the Sponsor’s authorized 
representatives, monitor(s), auditor(s), IEC, and regulatory authority(ies) will be granted direct 
access to the subject’s original trial-related records for verification of clinical trial procedures 
and/or data, without violating the confidentiality of the subject, to the extent permitted by the 
applicable laws and regulations. Consent from the subject for disclosure of such information will 
be obtained in writing in the ICF. In addition, should a subject requires medical care or 
hospitalization during the course of the study, the clinical site’s representatives may contact the 
treating physician with the subject’s consent, except that consent may not be requested if there is 
an emergency situation. If the results of the study are published, the subject’s identity will 
remain confidential. 
16. References 
1 Diazepam Buccal Film (DBF) Investigator's Brochure_4.0_XX Dec 2018 
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2 Physician’s Desk Reference (PDR). Diazepam – drug summary. http://www.pdr.net/drug-
summary/Valium-diazepam-2100. Accessed 01 October 2018. 
3 Diastat® AcuDial™ C-IV label, FDA revision date 12/2016, available at: 
www.accessdata.fda.gov/drugsatfda_docs/label/2013/013263s092lbl.pdf.  
4 Valium® (diazepam) label, FDA revision date 12/16/2016, available at: 
www.accessdata.fda.gov/drugsatfda_docs/label/2013/013263s092lbl.pdf. 
5 Bonate PL, Howard D. Pharmacokinetics in drug development: Problems and Challenges 
in Oncology. Switzerland: Springer; 2016. 
6 Bonate PL, Howard D. Pharmacokinetics in drug development: Problems and Challenges 
in Oncology. Switzerland: Springer; 2016. 
7 FDA Guidance for Industry – Food-Effect Bioavailability and Fed Bioequivlence 
Studies, 2002. 
 
 
 
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17. Appendix I – Diazepam PK Study Participant Questions  
 
SECTION 1 
 
Audience: 
 
Study Participants – Subjects Enrolled in Study 180323 
 
Timeframe:  
Prior to Dosing 
 
Areas of Interest: 
Current rescue medication, previous experience with Diastat (if any), 
preferred route of administration 
 
Questions: 
 
1) What is your current rescue medication treatment? 
 
A) Diastat 
B) Extra dose of usual maintenance medication 
C) Oral diazepam 
D) ER visit/call 911 
E) No treatment 
 
2) If you have used Diastat (diazepam rectal gel) in the past, how 
would you rate the experience in terms of ease of use for your 
caregiver? 
 
 
1  
very easy 
to use 
2  
easy, but with 
some 
limitations 
3  
neutral 
4  
somewhat 
difficult to 
use 
5  
very difficult 
to use 
 
 
 
 
3) How would your ideal rescue medication be taken? 
 
 
 
 
A) orally – via the mouth 
 
 
 
B) rectally 
 
 
 
C) nasally – as a nasal spray 
 
 
 
SECTION 2 
 
Audience: 
 
Study Participants – Subjects Enrolled in Study 180323 
 
Timeframe:  
Post Diazepam Buccal Film (DBF) Dosing 
 
Areas of Interest: 
Experience with DBF, perceptions of ease of use, comparison to Diastat 
experience, ability to self-administer 
 
 
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Questions: 
 
1) How would you rate the experience of taking DBF? 
 
 
1  
very easy  
2  
somewhat 
easy 
3  
neutral 
4  
somewhat 
difficult  
5  
very difficult  
 
 
 
 
2) Do you prefer DBF over DRG? 
 
A) yes 
B) no 
 
3) How willing would you be to use DBF in public following a seizure 
(at work, in a public setting, etc.)? 
 
 
1  
very willing 
2  
neutral 
3  
not willing 
 
4) Do you prefer DBF vs a medication that requires a device to use? 
 
A) yes 
B) no 
 
 
SECTION 3 
 
Audience: 
 
Study Administrators  
 
Timeframe:  
Post DBF Dosing 
 
Areas of Interest: 
Experience with DBF, ease of administration 
 
Questions: 
 
1) How would you rate the experience of administering DBF? 
 
 
1  
very easy  
2  
somewhat 
easy 
3  
neutral 
4  
somewhat 
difficult  
5  
very difficult  
 
 
 
 
2) Do you prefer to administer DBF over Diastat? 
 
A) yes 
B) no 
 
 
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3) How clear were the administration instructions for DBF? 
 
 
1  
very clear  
2  
somewhat 
clear 
3  
neutral 
4  
somewhat 
unclear  
5  
very unclear  
 
 
 
 
 
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18. Appendix II – Study Restrictions 
 
Restriction Period 
Item Restricted 
Examples 
6 months prior to first 
study drug administration 
until the last blood draw 
in the final study period 
Females: implanted, injected, or 
intravaginal hormonal contraceptive 
 
 
3 months prior to 
screening until the last 
blood draw in the final 
study period 
Marijuana and THC containing products 
other than as a prescribed AED 
 
30 days prior to first drug 
administration until the 
last blood draw in the 
final study period 
 
Enzyme-modifying drugs 
(Strong Inhibitors)  
Strong inhibitors of CYP 
enzymes (e.g. Cimetidine, 
fluoxetine, quinidine, 
erythromycin, ciprofloxacin, 
fluconazole, ketoconazole, 
diltiazem and HIV antivirals); 
Females: oral or transdermal hormonal 
contraceptives other than a continuous 
28-days treatment cycle  
 
Monoamine oxidase (MAO) inhibitors  
Note: until 14 days after the last study 
drug administration 
Phenelzine, tranylcypromine 
Phenothiazines 
Chlorpromazine 
Diazepam  and any benzodiazepines 
  
Prescription medication other than a 
prescribed drug that is part of a stable 
drug regimen* 
Prescription pills, topical 
systemic creams, inhalants, 
sprays. 
OTC medication other than an OTC drug 
that is part of a stable drug regimen* 
 
Note: Spermicidal/barrier contraceptive 
products may be permitted 
 
dietary and/or herbal supplements and/or 
teas 
Ricola, oral multivitamins 
Foods and/or beverages containing 
grapefruit, star fruit and/or pomelo 
Grapefruit, grapefruit juice, 
grapefruit candies, pomelo, 
star fruit, etc. 
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Restriction Period 
Item Restricted 
Examples 
48 hours prior to drug 
administration until after 
the last blood draw in 
each study period. 
Products containing 
caffeine/methylxanthines 
Coffee, tea, chocolate, caffeine-
containing soft drinks (e.g. 
Coke, Pepsi, Red Bull) 
Alcohol of any kind 
Wine, beer, liquor, cocktails 
Poppy seeds  
Note: 48 hours prior to drug 
administration in each period only 
Poppy seed cake, cookies, 
bagels 
*A stable drug regiment is defined as at least once a day administration from at least 30 days prior to the 
first study drug administration and with no changes expected in dosage regimen through the study (until 
the last PK sample). 
 
 
 
 
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19. Appendix III - Placement Diagram for Aquestive Therapeutics Buccal Film 
Test Drug: Placement against the buccal mucosa (either side of film can be placed against the 
buccal mucosa): 
Aquestive Therapeutics film is to be centered against the inner aspect of the right or left cheek, 
as illustrated by the Figure below. The film may be placed without regard to the location of the 
parotid duct. 
Ensure film is completely adhered to the mucosal surface. 
Note: Figure is for illustrative purposes and not drawn to scale. 
 
 
 
 
 
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20. Appendix IV - Placement Diagram for DIASTAT® AcuDial™ Rectal Delivery System 
 
 
 
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SAP_001.pdf: 
 
Statistical Analysis Plan 
Aquestive Therapeutics 
Project No. 180323 
28-JUN-2019 (Final 1.0) 
Page 1 of 29 
 
 
 
 
Statistical Analysis Plan 
 
 
A RANDOMIZED, OPEN-LABEL, 2-SEQUENCE, 3-TREATMENT, CROSSOVER 
STUDY TO EVALUATE THE PHARMACOKINETICS OF SINGLE DOSES OF 
DIAZEPAM BUCCAL FILM (DBF) (AQUESTIVE THERAPEUTICS) COMPARED 
WITH DIASTAT® RECTAL GEL (VALEANT PHARMACEUTICALS NORTH 
AMERICA) IN ADULT MALE AND FEMALE SUBJECTS ON A CONCOMITANT 
REGIMEN OF ANTIEPILEPTIC DRUGS (AED) FOR THE TREATMENT OF 
EPILEPSY 
 
 
Sponsor Protocol No. 180323 
inVentiv Health Clinique inc. Project No. 180323 
 
 
Final Version: 1.0 
Date: 28-JUN-2019 
 
 
 
 
Contract Research Organization: 
inVentiv Health Clinique Inc. (“inVentiv”),  
a Syneos Health company 
2500, rue Einstein Québec (Québec)  
Canada, G1P 0A2 
Sponsor: 
Aquestive Therapeutics 
30 Technology Drive 
Warren, NJ 07059 
USA 
 
 
 
 
CONFIDENTIAL 
 
 


Statistical Analysis Plan 
ProJ<:et No. 180323 
SIGNATURES 
Sponsor Protocol No. 180323 
inVentiv Project No.: 180323 
os. 
Aquc;;tive Therapeuücs 
Study Title: A Randomized, Open-Label, 2-Sequence, J-Treatment, Crossover Study to 
Evaluate the Pharmacokinetics of Single Doses of J)iazepam Buccal Film 
(DBF) (Aquestive Therapeutics) Compared with Diastat\8: Rectal Gel (VaJeant 
Phannaceuticals Nqrth Am 
in Adult Male and Female Subjects on a 
Concomitant Regimen of Antiepileptic .Drugs (A ED) for the Treatment of 
Epilepsy 
Author: 
Sponsor's 
Claude Lapoï:nte, M. Sc. 
Principal Statistician 
inVentiv 
Representa.tive: 
Allen H Helier, 
MPH 
Founder and CEO, Pharma Study 
Design LLC (Consultant to Aquesti.ve 
Therapeuti cs) 
28-JUN-20 1 Y (Final 1.0) 
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Statistical Analysis Plan 
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Project No. 180323 
28-JUN-2019 (Final 1.0) 
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TABLE OF CONTENTS 
 
SIGNATURES ....................................................................................................................... 2 
LIST OF ABBREVIATIONS ................................................................................................ 5 
1. 
Introduction ................................................................................................................. 7 
2. 
Study Objectives .......................................................................................................... 8 
2.1 
Primary Objective .................................................................................................... 8 
2.2 
Secondary Objectives .............................................................................................. 8 
3. 
Study Design ............................................................................................................... 9 
3.1 
General Design ........................................................................................................ 9 
3.2 
Study Procedures ..................................................................................................... 9 
3.3 
Treatment Description ............................................................................................. 9 
3.4 
Sample Size ........................................................................................................... 10 
3.5 
Subject Withdrawal and Replacement ................................................................... 11 
4. 
Change From the Protocol ......................................................................................... 12 
5. 
Primary and Secondary Parameters ........................................................................... 13 
6. 
Analysis Populations ................................................................................................. 14 
6.1 
Safety Population ................................................................................................... 14 
6.2 
Pharmacokinetic Population and Pharmacokinetic Analysis Data Set .................. 14 
7. 
Interim Analyses ........................................................................................................ 15 
8. 
Study Population and Exposure ................................................................................ 16 
8.1 
Subject Disposition ................................................................................................ 16 
8.2 
Protocol Deviations ............................................................................................... 16 
8.3 
Demographics and Baseline Characteristics .......................................................... 16 
8.4 
Medical History ..................................................................................................... 16 
8.5 
Prior and Concomitant Medications ...................................................................... 16 
8.6 
Study Drug Administration ................................................................................... 16 
9. 
Safety Analyses ......................................................................................................... 17 
9.1 
Physical Examination Findings ............................................................................. 17 
9.2 
Adverse Events ...................................................................................................... 17 
9.3 
Laboratory Parameters ........................................................................................... 19 
9.4 
Vital Signs ............................................................................................................. 20 
9.5 
Electrocardiogram.................................................................................................. 21 
9.6 
DBF Application Site Inspection ........................................................................... 21 
10. 
Pharmacokinetic Analyses......................................................................................... 22 
10.1 Handling of the Below the Lower Limit of Quantitation (BLQ) and the No 
Reportable Concentration Values .......................................................................... 22 


 
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10.2 Handling of the Difference Between the Scheduled and the Actual Sampling 
Times ..................................................................................................................... 22 
10.3 Pharmacokinetic Parameters .................................................................................. 22 
10.4 Statistical Analyses ................................................................................................ 23 
10.4.1 
Treatment Comparison DBF (Test) versus DRG (Reference) Following a 
Moderate-Fat Meal ........................................................................................ 24 
10.4.2 
Treatment Comparison DBF (Test) versus DRG (Reference) Following 
Different Meal Conditions ............................................................................. 24 
11. 
Percentages and Decimal Places ............................................................................... 25 
12. 
Data Handling ............................................................................................................ 26 
13. 
Handling of Missing Data ......................................................................................... 27 
14. 
Software to be Used .................................................................................................. 28 
15. 
Reference List ............................................................................................................ 29 
 


 
Statistical Analysis Plan 
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LIST OF ABBREVIATIONS 
A 
Abnormal 
AE 
Adverse event 
AED 
Antiepileptic drug 
ALP 
Alkaline phosphatase 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of variance 
AST 
Aspartate aminotransferase 
AUC 
Area under the concentration-time curve  
AUC0-inf 
Area under the concentration-time curve from time 0 to infinity (extrapolated) 
AUC0-t 
Area under the concentration-time curve from time 0 to the last non-zero 
concentration 
BLQ 
Below the lower limit of quantitation 
BMI 
Body mass index 
BP 
Blood Pressure 
CK 
Creatine Kinase 
Cl/F 
Apparent total clearance 
Cl/F/kg 
Apparent total clearance normalized for the subject body weight in kg  
Clast 
The last observed non-zero concentration 
Cmax 
Maximal observed plasma concentration 
CSR 
Clinical study report 
CV 
Coefficient of variation (equivalent to C.V.) 
DBF 
Diazepam Buccal Film 
DRG 
Diastat® Rectal Gel 
ECG 
Electrocardiogram 
FDA 
Food and Drug Administration 
H 
Above normal range 
HBsAg 
Surface Antigen of the Hepatitis B Virus 
HCV 
Human Hepatitis C Virus 
HEENT 
Head, eyes, ears, nose and throat 
HIV 
Human immunodeficiency virus 
HR 
Heart rate 
Kel  
Terminal elimination rate constant 
Kel Lower 
The actual sampling time where Kel calculation begins 
Kel Upper 
The actual sampling time of the last measurable concentration used to estimate Kel 
kg 
Kilogram 


 
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L 
Below normal range (conflicting with Liter) 
Max 
Maximum (equivalent to max.) 
MDMA 
3,4-methylenedioxy-N-methylamphetamine 
MedDRA® Medical Dictionary for Regulatory Activities 
mg 
Milligram 
Min 
Minimum (equivalent to min.) 
mL 
Milliliter 
N 
Number of observations 
PCP 
Phencyclidine 
PK 
Pharmacokinetic 
PT 
MedDRA® Preferred Term 
QI 
Qualified Investigator 
QRS 
The QRS complex is a structure on the ECG that corresponds to the depolarization 
of the ventricles 
QT 
Time from electrocardiogram Q wave to the end of the T wave corresponding to 
electrical systole 
QTcB 
QT Corrected with Bazett formula 
QTcF 
QT Corrected with Fridericia’s formula 
RR 
Respiratory Rate 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS® 
Statistical Analysis System 
SD 
Standard Deviation 
SOC 
MedDRA® System Organ Class 
SOP 
Standard Operating Procedure 
TEAE 
Treatment-Emergent Adverse Event 
T½ el 
Elimination half-life 
THC 
Tetrahydrocannabinol 
Tmax 
Time of maximal observed plasma concentration 
vs 
Versus 
Vd/F 
Apparent volume of distribution 
Vd/F/kg 
Apparent volume of distribution normalized for the subject body weight in kg 
WHO DD 
World Health Organization Drug Dictionary 


 
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1. 
Introduction 
This statistical analysis plan (SAP) is intended to give a detailed description of the summaries 
and the analyses that will be generated for the present study by inVentiv. Analyses specified in 
this plan are based on Aquestive Therapeutics study Protocol No. 180323 Amendment III, dated 
24 May 2019 (inVentiv Project No. 180323). Safety, tolerability and pharmacokinetic (PK) 
analyses will all be described.  
The plan may change due to unforeseen circumstances and any changes made after the plan has 
been finalized will be documented. If additional analyses are required to supplement the planned 
analyses described in the SAP, the changes and justification for the changes will be outlined in 
the clinical study report (CSR). No change will be made without prior approval of the study 
sponsor. No revision to the SAP is required for changes which do not affect the statistical 
analysis methods, definitions, or rules defined in this document.  
When applicable, all methodology and related processes will be conducted according to 
inVentiv’s Standard Operating Procedures (SOPs). Protocol deviations occurring during the 
study will be listed. 
Shells for all statistical tables, figures and listings referred to in this SAP will be displayed in a 
separate document.  


 
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2. 
Study Objectives 
2.1 
Primary Objective 
• Evaluate the pharmacokinetics (PK) of single doses of Diazepam Buccal Film (DBF) at 
the recommended dose regimen (range 10 mg to 17.5 mg according to body weight) 
compared with Diastat® Rectal Gel (DRG) at the labeled dose regimen (range 10 mg to 
20 mg according to body weight) in adult male and female subjects on a stable 
concomitant regimen of antiepileptic drugs (AED) for the treatment of epilepsy, 
following a moderate-fat meal. 
2.2 
Secondary Objectives 
• Evaluate the PK of single doses of DBF following a high-fat meal compared with DRG 
following a moderate-fat meal at the recommended dose regimen in adult male and 
female subjects on a stable concomitant regimen of AED for the treatment of epilepsy. 
• Assess the safety-tolerability of single doses of DBF and DRG administered to adult male 
and female subjects on a stable concomitant regimen of AEDs under fed conditions. 
 


 
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3. 
Study Design 
3.1 
General Design 
This will be a randomized, multiple centers, single-dose, open-label, three-period, three 
treatment, two-sequence crossover study under fed conditions. 
The study will evaluate single doses of DBF compared with DRG administered according to 
weight category in adult male and female subjects on a stable concomitant regimen of AED for 
the treatment of epilepsy. A stable regimen of AED is defined as no change in the prescribed 
AED regimen during the 30 day period prior to the first study drug administration and no change 
anticipated in the prescribed AED regimen over the course of study participation until the last 
PK blood sample collection. 
Subjects will receive Treatment A and Treatment B (DBF and DRG following a moderate-fat 
meal) in Period 1 and Period 2 in a randomized sequence, and at a dosage specific to body 
weight. DBF will be administered according to the currently recommended dose regimen 
(derived by Aquestive from population PK modeling in healthy volunteers). DRG will be 
administered depending on weight category according to the current product labeling for 
Diastat®. Subjects may be asked to participate in a third period, on a voluntary basis. Subjects 
who volunteer to participate in a third period will receive a second dose of DBF administered in 
exactly the same manner as the earlier dose of DBF with the exception that DBF in Period 3 will 
be administered following a high-fat meal. There will be a washout of 28 days between doses. 
A maximum of 32 eligible subjects will be enrolled in an effort to complete Period 2 with at least 
16 subjects with representation of both genders, representation across the five weight categories 
of subjects taking one or more AEDs known to induce diazepam metabolism, and representation 
of subjects taking sodium divalproex/valproic acid.  Subjects who are eligible may be enrolled 
without regard to weight category. Since only exploratory PK data will be gathered from 
treatment period 3, no more than 50% of the subjects who complete Period 1 and Period 2 will 
participate in Period 3.  
This study is intended for filing under FDA regulations. 
3.2 
Study Procedures 
The overall schedule of procedures and assessments is provided in the protocol. 
3.3 
Treatment Description 
Subjects will be administered each treatment according to the 3-period, 2-sequence, block 
randomization scheme produced by inVentiv. At admission to the clinic, subjects who meet the 
inclusion/exclusion criteria will be assigned between the 2-sequence arms (ABC or BAC) 
according to the randomization schedule. inVentiv will inform the site about the medication to be 
dispensed to each particular subject at the time of subject’s randomization and at the prospective 


 
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protocol visits. The clinic will administer the study treatment as described in Table 3-1, 
according to the subject’s weight obtained at screening visit. 
The randomization code will not be available to the Bioanalytical Division until the clinical and 
analytical phases of the study have been completed. 
Table 3-1 Study Treatment Administration According to Weight Category 
Product 
Meal 
Condition 
Weight 
Category 
Weight (kg) 
Dose 
Test (Treatment A):  
Diazepam Buccal Film 
(Aquestive Therapeutics, USA) 
Moderate-Fat 
Meal 
A1 
38-50 
1 x 10 mg 
A2 
51-62 
1 x 12.5 mg 
A3 
63-75 
1 x 15 mg 
A4 
76-87 
1 x 15 mg 
A5 
88-111* 
1 x 17.5 mg 
Reference (Treatment B):   
Diastat® AcuDialTM rectal gel 
(Valeant Pharmaceuticals, 
USA) 
Moderate-Fat 
Meal 
B1 
38-50 
2 mL (10 mg) 
B2 
51-62 
2.5 mL (12.5 mg) 
B3 
63-75 
3 mL (15 mg) 
B4 
76-87 
3.5 mL (17.5 mg) 
B5 
88-111* 
4 mL (20 mg) 
Test (Treatment C):  
Diazepam Buccal Film 
(Aquestive Therapeutics, USA) 
High-Fat 
Meal 
A1 
38-50 
1 x 10 mg 
A2 
51-62 
1 x 12.5 mg 
A3 
63-75 
1 x 15 mg 
A4 
76-87 
1 x 15 mg 
A5 
88-111* 
1 x 17.5 mg 
*Subjects eligible for study with weights in the range of 112 to 134 kg will be dosed at the 88-111 kg weight range 
as shown above. 
3.4 
Sample Size 
Subjects will be enrolled to attain a sample size of no more than 32 subjects (and a minimum of 
16 completed subjects in Period 2). Because this is not a formal hypothesis testing study, the 
sample size is proposed based on the desired level of precision for estimating pharmacokinetic 
parameters and the relationship between pharmacokinetic parameters. In principle, the expected 
precision of the estimates of the ratios of geometric means of interest can be estimated from the 
intra-subject variability observed in Aquestive Study 162021 (pharmacokinetic crossover of DBF 
15 mg with DRG 5, 12.5, and 20 mg in healthy volunteers). Aquestive has not undertaken a 
formal analysis to predict the expected precision. 


 
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3.5 
Subject Withdrawal and Replacement 
Subjects will be advised that they are free to withdraw from the study at any time. Over the 
course of the study, the Sponsor and the Investigator or a delegate may withdraw any subject 
from the study for one of the reasons described below: 
• safety reason; 
• non-compliance with protocol requirements; 
• significant protocol deviation; 
• positive alcohol breath test;  
• positive drug screen (except for subjects using prescribed marijuana and THC containing 
products as AED treatment);  
• positive pregnancy test. 
Positive result to the urine benzodiazepine screen (urine drug screen) in Period 2 and Period 3 
may derive from residual concentrations from study drug administered in the previous period(s). 
Therefore, it is not required that subjects with a positive result to that test in Period 2 and Period 
3 be withdrawn from the study. Continued subject participation in the study will be evaluated by 
the Principal Investigator. 
Subjects experiencing emesis within 4 hours following DBF administration will be evaluated on 
a case-by-case basis by the Principal Investigator/Sub-Investigator, the CRO PK Scientist, and 
the Sponsor, and a decision on their continued participation will be made.  Subjects experiencing 
a bowel movement within 4 hours following DRG administration or clinically significant leakage 
of the rectal gel within 4 hours post-dose will be evaluated on a case-by-case basis by the 
Principal Investigator/Sub-Investigator, the CRO PK Scientist, and the Sponsor, and a decision 
on their continued participation will be made.  All decisions will be made prior to the 
bioanalytical laboratory commencing bioanalysis. 
Subjects who withdraw or are withdrawn from the study after dosing will not be replaced. 
However, in the event that the number of drop-outs exceeds initial expectations, subjects who 
withdraw or are withdrawn might be replaced at the discretion of the Sponsor. Such replacement 
resulting in dosing of more subjects than planned in this protocol would be documented in a 
protocol amendment. 
Subjects who withdraw or are withdrawn will be asked to remain at the clinic until the 
Investigator or a delegate agrees that the subject is fine and can be discharged. As soon as subject 
withdrawal is confirmed, blood sampling will be stopped.  Study exit procedures will be 
performed at the time of withdrawal from the study or as soon as possible thereafter. 


 
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4. 
Change From the Protocol 
No changes in planned analyses were done compared to the protocol. However, for B vs C 
comparison, the period will not be included in the ANOVA since Treatment C is confounded 
with Period 3.  


 
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5. 
Primary and Secondary Parameters 
For PK analyses (A vs B comparison), AUC0-t, AUC0-inf, and Cmax calculated using diazepam 
plasma concentrations will be regarded as the primary endpoints. All other PK parameters 
(including those calculated using nordiazepam) will be regarded as secondary endpoints (refer to 
Section 10.3). 
The safety and tolerability parameters will be regarded as secondary endpoints (refer to 
Section 9). 


 
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6. 
Analysis Populations 
The analysis of safety and tolerability parameters will be based on the safety population detailed 
in Section 6.1 below. The analysis of PK parameters will be based on the PK population detailed 
in Section 6.2 below. Treatment assignment will be according to the actual treatment received. 
6.1 
Safety Population 
The safety population is defined as all subjects who received at least one dose of the study 
medication. 
6.2 
Pharmacokinetic Population and Pharmacokinetic Analysis Data Set 
The pharmacokinetic population will include all subjects completing at least Period 1 and Period 
2 with no significant violation of study restrictions, and for whom the pharmacokinetic profile 
can be adequately characterized. Any subject who completes only one period will be presented in 
the concentrations and pharmacokinetic tables but excluded from descriptive statistics and 
ANOVA. 
A violation of the requirement to maintain a stable regimen of AEDs or a stable regimen of other 
concomitant drugs with the potential to influence diazepam pharmacokinetics will be considered 
a significant violation of study restrictions. A change of drug in the prescribed AED regimen 
and/or change in the dose of a prescribed AED will be considered a departure from a stable 
regimen. Any subject who does not maintain a stable AED regimen in the course of the study 
will be presented in the concentrations and pharmacokinetic tables but excluded from descriptive 
statistics and ANOVA.  For cases in which a departure from a stable AED regimen is a matter of 
judgment, the decision will be made by the Principal Investigator/Sub-Investigator and/or by the 
CRO PK Scientist in consultation with the Sponsor prior to bioanalysis.   
Any subject with diazepam or nordiazepam pre-dose concentrations will be presented in the 
concentrations and pharmacokinetic tables but excluded from descriptive statistics and ANOVA 
if the pre-dose concentration is greater than 5% of the Cmax value for that analyte of that period 
for that subject. 
Subjects withdrawn due to vomiting episodes as per criterion established under section 3.5 or 
due to adverse events will be presented but excluded from the statistical analyses (i.e., 
descriptive statistics and ANOVA). 
Data from subjects who experienced emesis during the sampling interval and who were not 
withdrawn as per criterion established under section 3.5 may be evaluated after completion of the 
pharmacokinetic analysis. Any subject who experienced emesis within 2 times median Tmax of 
the current study (based on the reference product) will be excluded from the statistical analysis 
(i.e., descriptive statistics and ANOVA). 
 


 
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7. 
Interim Analyses 
No interim analysis will be performed.  


 
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8. 
Study Population and Exposure 
No inferential analysis will be done. Only observed data will be used. 
8.1 
Subject Disposition 
Subject disposition will be summarized for the number of subjects who were screened, enrolled, 
randomized and dosed, completed the study, and who were withdrawn from the study and the 
reason. The data will be presented by treatment and overall (frequency and the percentage of 
subjects) and listed. 
8.2 
Protocol Deviations 
The protocol deviations will be categorized and listed by subject. 
8.3 
Demographics and Baseline Characteristics 
The descriptive statistics (mean, median, standard deviation [SD], minimum [Min], maximum 
[Max], and sample size) will be calculated for continuous variables (age, body mass index 
[BMI], height, and weight) considering last results (scheduled or unscheduled) obtained at 
screening. Frequency counts and percentages will be tabulated for categorical variables (age 
group, gender, ethnicity, and race). Results will be presented overall and by treatment group for 
each study population (only if populations are different). All demographic characteristics will be 
listed by subject. 
8.4 
Medical History 
Medical history at screening will be listed by subject. The Medical Dictionary for Regulatory 
Activities (MedDRA®) Version 21.1 will be used to classify all medical history findings by 
System Organ Class (SOC) and Preferred Term (PT). 
8.5 
Prior and Concomitant Medications 
The use of prior and/or concomitant medications will be monitored throughout the study and 
listed by subject. The World Health Organization Drug Dictionary (WHO DD) Version Sep2018, 
format B3 will be used to classify all medication reported during the study.  
8.6 
Study Drug Administration 
The study drug administration details (including treatment received, start and end date and time 
of administration) will be listed by subject. The time of dosing will be set as the time the film is 
placed against the buccal mucosa. 


 
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9. 
Safety Analyses 
Safety and tolerability data will be evaluated through the assessment of AEs, clinical laboratory 
parameters (biochemistry, hematology, and urinalysis), 12-lead electrocardiogram (ECG), vital 
sign (blood pressure, heart rate, respiratory rate, pulse oximetry, and oral temperature), 
continuous cardiac ECG monitoring, physical examination, and visual oral inspection. 
Laboratory parameters, vital signs, and ECG parameters will be listed and summarized using 
descriptive statistics. All AEs will be listed and summarized using descriptive methodology. The 
incidence of AEs for each treatment will be presented by severity and association with the study 
drug. 
Safety data will be summarized but will not be subjected to inferential analysis. The analysis of 
the safety variables will be based on safety population. 
9.1 
Physical Examination Findings 
A physical examination will be performed at screening and study exit. The physical examination 
includes at least the following components: HEENT (head, eyes, ears, nose, and throat), neck, 
chest and lungs, cardiovascular, abdomen, skin, and musculoskeletal evaluation.   
A brief neurologic examination will be performed at screening and study exit. The neurologic 
assessment involves at least the following evaluation: mental status, cranial nerves, motor 
system, sensory system, cerebellar disorder, gait, and reflexes. 
Any abnormal findings judged to be clinically significant will be documented as medical history 
or as an AE, depending upon whether noted at screening, prior to dosing or after dosing, as 
appropriate. Any physical examination findings documented as AEs will be included in the AE 
summaries. 
9.2 
Adverse Events 
Treatment-emergent AEs (TEAEs) and non-TEAEs (those occurring prior to administration of 
study medication or that first occurred prior to study drug administration and did not worsen in 
frequency or severity) will be listed. TEAEs will be defined as AEs that occur on or after the 
date and time of study drug administration, or those that first occur pre-dose but worsen in 
frequency or severity after study drug administration. AEs will be collected and documented 
from the signing of the ICF until at least 10 days following the last study drug administration, 
and as observed or reported spontaneously by study participants. TEAEs will be attributed to the 
most recent study drug taken. A TEAE with a start date and time during the wash-out period 
(ending at the time of study drug administration) will be attributed to the study drug taken during 
the previous treatment period. Any AEs, whether serious or non-serious, will be monitored 
throughout the study and followed to resolution or for up to 2 weeks after the last PK blood 
draw, after which the Investigator will decide the course of action. 


 
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The incidence of TEAEs will be summarized using the safety population. The MedDRA® 
dictionary Version 21.1 will be used to classify all AEs reported during the study by SOC and 
PT. 
Incidence of subjects who experienced TEAEs (as well as number of events) will be presented 
by treatment and overall, by SOC, and PT, investigator-assessed relationship and also by 
severity. Each subject may only contribute once to each of the incidence rates, for a TEAE 
following a given treatment, regardless of the number of occurrences; the highest severity or 
highest relationship will be presented, as appropriate. In each table, SOC will be presented in 
descending order of overall incidence rate in terms of frequency of subjects and then in 
frequency of events (alphabetical order will be used in case of equal rates). For each SOC, PT 
will be presented the same way.  
The relationship of an AE to the study drug will be assessed according to the study protocol as:  
Probable: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to drug administration, unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and which follows a 
clinically reasonable response on withdrawal. 
Possible: 
A clinical event, including laboratory test abnormality, with a reasonable 
time sequence to drug administration, but which could also be explained by 
concurrent disease or other drugs or chemicals. Information on drug 
withdrawal may be lacking or unclear. 
Unlikely: 
A clinical event, including laboratory test abnormality, with a temporal 
relationship to drug administration which makes a causal relationship 
improbable, and which other drugs, chemicals or underlying disease 
provide plausible explanation. 
Unrelated: 
This category is applicable to AEs which are judged to be clearly and 
incontrovertibly due to extraneous causes (diseases, environment, etc.) and 
do not meet the criteria for drug relationship listed for the above-mentioned 
conditions. 
 
The Severity of AEs will be rated as according to the study protocol as: 
 
Mild: 
AE resulting in discomfort, but not sufficient to cause interference in 
normal daily activities. 
Moderate: 
AE resulting in discomfort that is sufficient to cause interference in daily 
activities. 
Severe: 
AE resulting in discomfort causing an inability to carry out normal daily 
activities. 


 
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A significant AE will be defined as any event (other than those reported as serious) that led to an 
intervention, including withdrawal of treatment, or significant additional concomitant therapy. 
Serious and significant AEs will be listed separately. 
9.3 
Laboratory Parameters 
Clinical laboratory (biochemistry, hematology, and urinalysis) results will be obtained at 
screening, and at study exit or early termination.  
Biochemistry parameters include the following: albumin, alkaline phosphatase (ALP), aspartate 
aminotransferase (AST), alanine aminotransferase (ALT), urea, calcium, chloride, glucose, 
phosphorus, potassium, creatinine, sodium, total bilirubin, CK, lactate dehydrogenase, uric acid, 
total protein, magnesium, bicarbonates, and ammonia. 
Hematology parameters include the following: complete blood count with differential, 
hemoglobin, hematocrit and platelet count. 
Urinalysis parameters include the following: macroscopic examination, pH, specific gravity, 
protein, glucose, ketones, bilirubin, occult blood, nitrite, and leukocytes. Unless otherwise 
specified, microscopic examination will be performed on abnormal findings and results will be 
listed. 
Hepatitis B (HBs Ag), Hepatitis C (HCV) antibody, and HIV antigen and antibody detection will 
be performed at screening. 
A urine drug screen (amphetamines, methamphetamines, barbiturates, benzodiazepines, 
tetrahydrocannabinol, cocaine, opiates, Phencyclidine (PCP), 3, 4-methylenedioxy-N-
methylamphetamine (MDMA), methadone), and an alcohol breath test will be performed at 
screening and before dosing of each period. 
A urine pregnancy test will be performed at screening and at study exit, and a serum pregnancy 
test will be performed at check-in of each period. 
Listings of all clinical laboratory (biochemistry, hematology, and urinalysis) results will be 
provided with the abnormal values flagged with "L" (low) and "H" (high) for continuous 
parameters, and "A" (abnormal) for categorical parameters. 
Descriptive statistics (mean, median, SD, Min, Max, and sample size) for each clinical laboratory 
test (continuous variables) will be presented overall for screening and study exit visit. 
Descriptive statistics for change from screening will also be presented for study exit. Screening 
includes the last screening results (scheduled or unscheduled). For categorical variable 
(urinalysis test), the number of subjects (frequency and percentage) will be tabulated by results 
(e.g. negative, positive, trace…). A summary table of shifts from screening to study exit visit will 
be provided. Results from repeat or unscheduled tests will not be included in the summary 
statistics unless the repeat was required (and documented as such) due to technical reasons or an 


 
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invalid initial result, or for screening determination, if applicable. Early termination results (if 
any) will be included with the study exit visit for the summary statistics. 
 
If more than one clinical laboratory is used for the study, a formula that takes into consideration 
the relative normal ranges of each test of laboratories used will be applied in order to normalize 
these data. The conversion formula used will depend on the typical distribution of the normal 
range for each laboratory test; the two formulae used are presented below: 
Hemoglobin, hematocrit, and platelet count test results are considered to have a normal 
distribution (Chuang-Stein, 1992) and the following formula will be used (Karvanen J., 2003): 
s= Ls + (x-Lx) Us-Ls
Ux-Lx 
Where U= Upper limit; L= Lower limit; s= Primary facility result; and x= Secondary facility 
results. 
The remaining hematology, serum chemistry, and urinalysis test results are considered to have a 
non-normal distribution (Chuang-Stein, 1992) and the following formula will be used (Karvanen 
J., 2003):  
s= x Us
Ux
 
Prior to applying these formulae, if required, units will be adjusted.  
9.4 
Vital Signs 
Vital signs measurements (blood pressure (BP), heart rate (HR), respiratory rate (RR)) and 
digital oxygen monitoring will be measured in a sitting position (except for safety reasons) at 
screening, and at study exit or early termination. Oral temperature will be measured at screening, 
and at study exit or early termination. 
Vital signs and digital oxygen monitoring will be measured before dosing and approximately 0.5, 
1, 1.5, 2, 4, and 8 hours post-dose (and beyond if clinically indicated). Vital signs will also be 
measured approximately 12 and 24 hours post-dose. 
Descriptive statistics (mean, median, SD, Min, Max, and sample size) will be presented overall 
for screening and study exit, and by associated current treatment for on-study measurements for 
each parameter where applicable. Descriptive statistics for change from screening to study exit, 
and for change from baseline for on-study measurements will also be presented. Screening 
includes the last screening results (scheduled or unscheduled). Baseline will be defined as the 
last results (scheduled or unscheduled) obtained prior to drug administration in each period. 
Results from repeat or unscheduled tests will not be included in the summary statistics unless the 
repeat was required (and documented as such) due to technical reasons or an invalid initial result, 


 
Statistical Analysis Plan 
Aquestive Therapeutics 
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28-JUN-2019 (Final 1.0) 
Page 21 of 29 
 
or for screening or baseline determination, if applicable. Early termination results (if any) will be 
included with the study exit visit for the summary statistics. 
A listing of all vital signs results will be provided. 
9.5 
Electrocardiogram 
Supine ECG will be performed at screening and study exit. Continuous ECG monitoring will be 
performed from approximately 1 hour prior to dosing until 8 hours post-dose (and extended if 
clinically indicated). 
For supine ECG, descriptive statistics (mean, median, SD, Min, Max, and sample size), for each 
ECG parameter (heart rate, PR interval, QRS interval, QT interval, and QTcF interval) will be 
presented overall for screening and study exit visit. Descriptive statistics for change from 
screening will also be presented for study exit. Screening includes the last screening results 
(scheduled or unscheduled). Results from repeat or unscheduled tests will not be included in the 
summary statistics unless the repeat was required (and documented as such) due to technical 
reasons or an invalid initial result, or for screening determination, if applicable. Early termination 
results (if any) will be included with the study exit visit for the summary statistics. 
A listing of all supine ECG results will be provided. 
9.6 
DBF Application Site Inspection 
The Investigator or designee will make a visual inspection of the oral mucosa at screening. The 
application site will also be inspected prior to DBF administration and approximately 6 and 24 
hours after administration. Assessments of the oral mucosa (normal/abnormal) will be conducted 
by the Principal Investigator/Sub-Investigator or a trained nurse. A listing will be provided.  
Abnormalities observed before dosing will be recorded and evaluated regarding exclusion 
criteria but will not be considered AEs. Any post-dose abnormalities will be reported as AEs and 
followed until resolution. 
 


 
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Aquestive Therapeutics 
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28-JUN-2019 (Final 1.0) 
Page 22 of 29 
 
10. Pharmacokinetic Analyses 
10.1 Handling of the Below the Lower Limit of Quantitation (BLQ) and the No 
Reportable Concentration Values 
All concentration values BLQ will be set to zero, except when they occur between two 
non-BLQ concentrations where they will be considered as missing for pharmacokinetic 
calculations. Samples with no reportable value occurring prior to dosing for a given period will 
be replaced by “0.00”, otherwise they will be set to missing for tabulation, graphical 
representation and calculation purposes. All samples with no reportable value observed after 
dosing will be set to missing.  
10.2 Handling of the Difference Between the Scheduled and the Actual Sampling Times 
The actual clock time for dosing and the actual clock time for each collection time for the PK 
samples will be recorded using the electronic data capture. For all sampling times, the actual 
sampling times will be calculated as the difference between the sample collection actual clock 
time and the actual clock time of dosing. The actual post-dose sampling times expressed in hours 
and rounded off to three decimal digits will be used to calculate the PK parameters, except for 
pre-dose samples occurring prior to dosing, which will always be reported as zero (0.000), 
regardless of the time difference. In the PK section of the report, scheduled sampling times will 
be presented in concentration tables and mean graphs while actual times are presented for the 
individual graphs. A listing of the actual times for PKs will be provided for PK samples. 
10.3 Pharmacokinetic Parameters  
In each period, a total of 19 blood samples will be drawn from each subject for pharmacokinetic 
analyses. Blood samples will be collected prior to study drug administration (0.00 hour) and 
0.500, 0.750, 1.00, 1.50, 2.00, 3.00, 4.00, 6.00, 9.00, 12.0, 24.0, 48.0, 72.0, 96.0, 120, 144, 192, 
and 240 hours post-dose (3 mL for each sampling time). The time tolerance window for blood 
samples collected during the confinement period will be ±1 minute for all samples collected 
before 8 hours post-dose and ±3 minutes for subsequent samples. The time tolerance window for 
return visit samples will be ±60 minutes. Blood samples will be collected as close as possible to 
nominal times; exact sample collection times will be recorded on the appropriate source 
documents and reported for each subject. The actual time of blood sample collection will be used 
for PK and statistical analysis. 
Plasma concentrations from diazepam and nordiazepam will be used to calculate the following 
PK parameters by standard non-compartmental methods: 
AUC0-t 
Area under the concentration-time curve from time zero to the last non-zero 
concentration and it is calculated using the linear trapezoidal method. 
AUC0-inf 
Area under the concentration-time curve from time zero to infinity 
(extrapolated), calculated as AUC0-t + Clast / Kel, where Clast is the last 
observed non-zero concentration. 


 
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28-JUN-2019 (Final 1.0) 
Page 23 of 29 
 
Cmax 
Maximal observed plasma concentration. 
Residual Area 
Residual area, calculated as 100*(1- AUC0-t / AUC0-inf).  
Tmax 
Time when the maximal plasma concentration is observed. 
Kel 
Elimination rate constant. This parameter will be the negative of the 
estimated slope of the linear regression of the ln-transformed concentration 
versus time profile in the elimination phase. Four non-zero observations 
during the elimination phase (excluding the Cmax) will be used to calculate 
Kel, or a minimum of 3 concentration points will be used if fewer than four 
observations are available. The time point where ln-linear Kel calculation 
begins (Kel Lower), and the actual sampling time of the last quantifiable 
concentration used to estimate the Kel (Kel Upper) will be reported with the 
correlation coefficient from the linear regression to calculate Kel 
(Correlation). 
T½ el 
Elimination half-life, calculated as ln(2) / Kel. 
Cl/F 
Apparent total clearance, calculated as Dose / AUC0-inf. 
Cl/F/kg 
Apparent total clearance normalized for the subject body weight in kg, 
calculated as (Cl/F) / weight. 
Vd/F 
Apparent volume of distribution, calculated as Dose/(Kel x AUC0-inf) 
Vd/F/kg 
Apparent volume of distribution normalized for the subject body weight in 
kg, calculated as (Vd/F) / weight. 
 
For subjects with missing or non-reportable concentrations for three or more of the last samples 
(e.g. timepoints pass Tmax), the data will be reviewed on a case-by-case basis by inVentiv 
pharmacokinetic scientist and/or sponsor to determine if the data are reliable for Cmax and Tmax. If 
so, only the Cmax and Tmax will be presented and included in the statistical analysis. Other PK 
parameters will not be reported. Explanations for PK parameters that could not be estimated will 
be provided in the CSR. 
Additional PK analysis may be performed.  
10.4 Statistical Analyses  
Individual and mean plasma concentration versus time curves will be presented for both linear 
and semi-log scales for diazepam and nordiazepam. Descriptive statistics (arithmetic and 
geometric means, SD, coefficient of variation [CV (%)], Min, Max, and median) of the plasma 
concentrations versus time will be presented as well for the PK parameters for diazepam and 
nordiazepam.  


 
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28-JUN-2019 (Final 1.0) 
Page 24 of 29 
 
10.4.1 Treatment Comparison DBF (Test) versus DRG (Reference) Following a 
Moderate-Fat Meal 
The statistical analyses below will include only data from subjects completing both Treatments 
A and B. 
For diazepam and nordiazepam, using GLM procedures in SAS, ANOVA will be performed on 
untransformed Tmax, Kel, and T½ el and on ln-transformed AUC0-t, AUC0-inf, Cmax, Cl/F, Cl/F/kg, 
Vd/F, and Vd/F/kg at the alpha level of 0.05. Factors incorporated in the model will include: 
Sequence, Subject(Sequence), Period, and Treatment. Tmax will be analyzed using an additional 
non-parametric test (Wilcoxon signed-rank test).  
The ratio of geometric means will be calculated for AUC0-t, AUC0-inf, and Cmax  for the Test 
product versus the Reference product (Treatment A/Treatment B) irrespective of weight 
category. The 90% confidence interval for the ratio of geometric means, based on least-squares 
means from the ANOVA of the ln-transformed data will also be calculated. Intra and inter-
subject coefficient of variation will be estimated. 
10.4.2 Treatment Comparison DBF (Test) versus DRG (Reference) Following Different 
Meal Conditions 
An exploratory pair-wise analysis comparing DBF following a high-fat meal (Treatment C) with 
DRG following a moderate-fat meal (Treatment B) will be conducted and reported. The 
statistical analyses below will include only data from subjects completing both Treatments B and 
C. 
For diazepam and nordiazepam, using GLM procedures in SAS, ANOVA will be performed on 
untransformed Tmax, Kel, and T½ el and on ln-transformed AUC0-t, AUC0-inf, Cmax, Cl/F, Cl/F/kg, 
Vd/F, and Vd/F/kg at the alpha level of 0.05. Factors incorporated in the model will include: 
Sequence, Subject(Sequence), and Treatment. Tmax will be analyzed using an additional 
non-parametric test (Wilcoxon signed-rank test).  
The ratio of geometric means will be calculated for AUC0-t, AUC0-inf, and Cmax for Treatment C 
versus Treatment B, irrespective of weight category. The 90% confidence interval for the ratio of 
geometric means, based on least-squares means from the ANOVA of the ln-transformed data 
will also be calculated. Intra and inter-subject coefficient of variation will be estimated. 
Additional analyses may be performed.  
 
 


 
Statistical Analysis Plan 
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28-JUN-2019 (Final 1.0) 
Page 25 of 29 
 
11. Percentages and Decimal Places 
If not otherwise specified, the following rules will be applied, with the exception of PK tables 
and listings described below: 
• Percentages will be presented to one decimal point. 
• Percentages equal to 0 or 100 will be presented as such without a decimal point. 
• Minimum and maximum will be presented with the same precision as the original values 
and, mean, standard deviation, and median will be presented with one more decimal place 
than the original values. 
All digits will be used for pharmacokinetic and statistical PK calculations. For PK tables and 
listings, the final reportable results or data will be presented by rounding off to two decimal 
digits, except for the following situations (this applies to individual data and descriptive 
statistics): 
• Kel data: rounded off to four decimal digits. 
• Pharmacokinetic parameters related to time such as Tmax must be reported with the same 
precision as the actual sampling time: rounded off to 3 decimal digits. 
• Concentration versus time data, as well as Cmax: reported as they appear in corresponding 
dataset. 
• Ratios and 90% confidence intervals, CV (%), Inter-CV%, Intra-CV% will be presented 
to two decimal places. 


 
Statistical Analysis Plan 
Aquestive Therapeutics 
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28-JUN-2019 (Final 1.0) 
Page 26 of 29 
 
12. Data Handling 
The PK plasma concentrations, safety and tolerability data will be received as SAS® datasets 
from the inVentiv data management facility. Screening failures and ineligible volunteer’s data 
(subject disposition) will be received from the clinical site as source data. 
 


 
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28-JUN-2019 (Final 1.0) 
Page 27 of 29 
 
13. Handling of Missing Data  
For PK, only observed data will be used in the data analysis except for concentration values BLQ 
and samples with no reportable value occurring prior to dosing as described in Section 10.1. No 
attempt will be made to extrapolate or interpolate estimates for missing data. 
For safety,  
• If an AE is recorded with an onset date corresponding to a dosing day, but the time is 
missing, then the AE will be assigned to the treatment. 
• If an AE is recorded with an onset date that does not correspond to the dosing day, but the 
time is missing, then the AE will be assigned to the treatment if AE onset date is after 
dosing date. 
• If an AE is recorded with an onset date where day and time are both missing, then the AE 
allocation to the treatment will be done on a case by case basis considering available 
information (e.g., AE onset date, AE end date, AE comments, subject disposition). 
 


 
Statistical Analysis Plan 
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28-JUN-2019 (Final 1.0) 
Page 28 of 29 
 
14. Software to be Used 
PK analysis will be performed using Phoenix WinNonlin® version 8.0 or higher, which is 
validated for bioequivalence/bioavailability studies by inVentiv. Inferential statistical analyses 
will be performed using SAS® according to FDA guidelines. The safety data tables and listings, 
as well as PK tables and listings will be created using SAS®, release 9.2 or a higher version. PK 
figures will be created using R version 3.5. The report text will be created using Microsoft® 
Office Word 2010, or a higher version.  


 
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28-JUN-2019 (Final 1.0) 
Page 29 of 29 
 
15. Reference List 
• 
Chuang-Stein C. Summarizing laboratory data with different reference ranges in 
multi-center clinical trials. Drug Information Journal. 1992; 26:77-84. 
• Karvanen J. The statistical basis of laboratory data normalization. Drug 
Information Journal. 2003; 37:101-107. 


180323 Diazepam Buccal Film DRG Crossover 
Aquestive Therapeutics 
16.1.9 Documentation of Statistical Methods 
 
Confidential 
Page 3 of 11 
Final 1.0 
Table/Figure/Listing Shells


Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 1 of 62 
Table/Figure/Listing Shells 
A RANDOMIZED, OPEN-LABEL, 2-SEQUENCE, 3-TREATMENT, CROSSOVER 
STUDY TO EVALUATE THE PHARMACOKINETICS OF SINGLE DOSES OF 
DIAZEPAM BUCCAL FILM (DBF) (AQUESTIVE THERAPEUTICS) COMPARED 
WITH DIASTAT® RECTAL GEL (VALEANT PHARMACEUTICALS NORTH 
AMERICA) IN ADULT MALE AND FEMALE SUBJECTS ON A CONCOMITANT 
REGIMEN OF ANTIEPILEPTIC DRUGS (AED) FOR THE TREATMENT OF 
EPILEPSY 
Sponsor Protocol No. 180323 
inVentiv Health Clinical Inc. Project No. 180323 
Final Version: 1.0 
Date: 28-JUN-2019 
Contract Research Organization: 
inVentiv Health Clinique Inc. (“inVentiv”), 
a Syneos Health company 
2500, rue Einstein 
Québec (Québec) 
Canada, G1P 0A2 
Sponsor: 
Aquestive Therapeutics 
30 Technology Drive 
Warren, NJ 07059 
USA 
CONFIDENTIAL 




Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 3 of 62 
TABLE OF CONTENTS 
SIGNATURES ....................................................................................................................... 2 
TABLE OF CONTENTS ....................................................................................................... 3 
1.
Tables, Figures and Data Listings Formatting ............................................................ 4
Table 1-1 Layout Specifications ................................................................................. 4 
2.
Summary TFLs ............................................................................................................ 5
Table 2-1 List of Table Shells ..................................................................................... 5 
Table 2-2 List of Figures Shells .................................................................................. 7 
Table 2-3 List of Data Listings Shells ........................................................................ 8 
3.
CSR In-text Tables ...................................................................................................... 9
4.
Summary Tables ........................................................................................................ 14
5.
Figures ....................................................................................................................... 36
6.
Listings ...................................................................................................................... 43


Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 4 of 62 
1.
Tables, Figures and Data Listings Formatting
The table, figure, and data listing (TFL) shells are presented in order to provide a framework for 
displaying the study data. The shells may change due to unforeseen circumstances. The shells 
may not be truly representative of every aspect of the study (e.g., sampling time points, assessed 
laboratory parameters, calculated parameters, units), but are intended to illustrate the general 
layout of the tables, figures, and data listings that will be included in the final report. 
The default tables, listings, and figures layout will be as presented in Table 1-1: 
Table 1-1 Layout Specifications 
Orientation 
Portrait 
Landscape 
Paper Size 
Letter 
Letter 
Margins 
Top: 3.05 cm 
Bottom: 2.54 cm 
Left: 2.54 cm 
Right: 2.54 cm 
Top: 3.05 cm 
Bottom: 2.2 cm 
Left: 1.9 cm 
Right: 1.9 cm 
Font 
Table text: Times new Roman 9 or 10 pts 
Table title: Times new Roman 12 pts 
Table legend: Times new Roman 10 pts 
The font size may be reduced as necessary to allow additional columns to be presented, but not at 
the expense of clarity. Also the orientation may be changed to portrait if appropriate. 
Except for pharmacokinetic (PK) tables, descriptive statistics for minimum and maximum will 
be presented with the same decimal digits as the original values, and with one more decimal 
place than the original data for mean, standard Deviation, and median. For PK tables, the data 
presentation will be as per the appropriate inVentiv SOP.  


 
 
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Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 5 of 62 
2. 
Summary TFLs 
Table 2-1 List of Table Shells 
Table 
Number 
Title 
 
In-Text Table 
10.1-1 
Subject Disposition 
11.4.2.3-1  
Summary of Pharmacokinetic Parameters of Diazepam– PK Population 
11.4.2.3-2 
Ratios (A/B), 90% Geometric Confidence Intervals, Intra-Subjects CV (%), Inter-Subjects CV 
(%) and P-values  for Plasma Pharmacokinetic Parameters of  Diazepam – PK Population 
11.4.2.3-3 
Ratios (C/B), 90% Geometric Confidence Intervals, Intra-Subjects CV (%), Inter-Subjects CV 
(%) and P-values  for Plasma Pharmacokinetic Parameters of  Diazepam – PK Population 
11.4.2.3-4  
Summary of Pharmacokinetic Parameters Nordiazepam – PK Population 
11.4.2.3-5 
Ratios (A/B), 90% Geometric Confidence Intervals, Intra-Subjects CV (%), Inter-Subjects CV 
(%) and P-values  for Plasma Pharmacokinetic Parameters of   Nordiazepam – PK Population 
11.4.2.3-6 
Ratios (C/B), 90% Geometric Confidence Intervals, Intra-Subjects CV (%), Inter-Subjects CV 
(%) and P-values  for Plasma Pharmacokinetic Parameters of   Nordiazepam – PK Population 
 
 
 
Demographic Data Summary Tables 
14.1-1 
Summary of Demographic Characteristics of Subjects Included in the Safety Population 
14.1-2 
Summary of Demographic Characteristics of Subjects Included in the Pharmacokinetic 
Population 
 
 
 
Pharmacokinetic Tables 
14.2.1-1  
Descriptive Statistics for Plasma Concentration over Nominal Time by Treatment– PK 
Population 
14.2.1-2 
Descriptive Statistics of Plasma Pharmacokinetic Parameters by Treatment - PK Population 
14.2.1-3 
Descriptive Statistics of Individual Ratios or Individual Differences between Treatments for 
Pharmacokinetic Parameters - PK Population 
14.2.1-4 
Ratios (A/B), 90% Geometric Confidence Intervals, Intra-Subjects CV (%) and P-values for 
Diazepam – PK Population 
14.2.1-5 
Ratios (C/B), 90% Geometric Confidence Intervals, Intra-Subjects CV (%) and P-values for 
Diazepam – PK Population 
14.2.1-6 
Ratios (A/B), 90% Geometric Confidence Intervals, Intra-Subjects CV (%) and P-values for  
Nordiazepam – PK Population 
14.2.1-7 
Ratios (C/B), 90% Geometric Confidence Intervals, Intra-Subjects CV (%) and P-values for  
Nordiazepam – PK Population 
 
 
 
Safety Data Summary Tables 
14.3.1-1 
Frequency of Subjects Experiencing Treatment-Emergent Adverse Events and Number of 
Events Summarized per Treatment – Safety Population 
14.3.1-2 
Frequency of Subjects Experiencing Treatment-Emergent Adverse Events Summarized per 
Treatment and Severity – Safety Population 
14.3.1-3 
Number of Treatment-Emergent Adverse Events Summarized per Treatment and Severity – 
Safety Population 


 
 
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Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 6 of 62 
 
 
 
14.3.1-4 
Frequency of Subjects Experiencing Treatment-Emergent Adverse Events Summarized per 
Treatment and Relationship – Safety Population 
14.3.1-5 
Number of Treatment-Emergent Adverse Events Summarized per Treatment and Relationship 
– Safety Population 
14.3.4-1 
Biochemistry Summary Descriptive Statistics and Change from Screening to Study Exit – 
Safety Population 
14.3.4-2 
Frequency of Subjects – Biochemistry Shifts from Screening to Study Exit – Safety Population 
14.3.4-3 
Hematology Summary Descriptive Statistics and Change from Screening to Study Exit – Safety 
Population 
14.3.4-4 
Frequency of Subjects - Hematology Shifts from Screening to Study Exit – Safety Population 
14.3.4-5 
Urinalysis Summary Descriptive Statistics and Change from Screening to Study Exit – Safety 
Population 
14.3.4-6 
Frequency of Subjects - Urinalysis Shifts from Screening to Study Exit, pH and Specific 
Gravity – Safety Population 
14.3.4-7 
Urinalysis Frequency Summary: Categorical Results – Safety Population 
14.3.4-8 
Frequency of Subjects - Urinalysis Shifts from Screening to Study Exit : Categorical Results – 
Safety Population   
14.3.4-9 
Vital Signs Summary Descriptive Statistics – Safety Population 
14.3.4-10 
Electrocardiogram Summary Descriptive Statistics – Safety Population 


 
 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 7 of 62 
Table 2-2 List of Figures Shells 
* Depending on the number of subjects included in the PK population, the figure numbering presented here may 
change in the report. 
** Similar figures will be presented for each subject who received study medication 
 
 
Figure 
Number* 
Title 
14.2.2-1a to 
14.2.2-32a** 
Plasma Concentrations of Diazepam for Subject XX - Linear Scale 
14.2.2-1b to 
14.2.2-32b** 
Plasma Concentrations of Diazepam for Subject XX - Semi-Log Scale 
14.2.2-33a 
Mean (± SD) Plasma Concentrations of Diazepam - Linear Scale 
14.2.2-33b 
Mean (± SD) Plasma Concentrations of Diazepam - Semi-Log Scale 
14.2.2-34a 
Overlay of Individual and Mean Plasma Concentrations of Diazepam by Treatment - Linear Scale 
14.2.2-34b 
Overlay of Individual and Mean Plasma Concentrations of Diazepam by Treatment - Semi-Log 
Scale 
14.2.2-35a to 
14.2.2-66a** 
Plasma Concentrations of Nordiazepam for Subject XX - Linear Scale 
14.2.2-35b to 
14.2.2-66b** 
Plasma Concentrations of Nordiazepam for Subject XX -  Semi-Log Scale 
14.2.2-67a 
Mean (± SD) Plasma Concentrations of Nordiazepam - Linear Scale 
14.2.2-67b 
Mean (± SD) Plasma Concentrations of Nordiazepam - Semi-Log Scale 
14.2.2-68a 
Overlay of Individual and Mean Plasma Concentrations of Nordiazepam by Treatment - Linear 
Scale 
14.2.2-68b 
Overlay of Individual and Mean Plasma Concentrations of Nordiazepam by Treatment - Semi-
Log Scale 


 
 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 8 of 62 
Table 2-3 List of Data Listings Shells 
 
 
 
Listing 
Number 
Title 
 
Documentation of Statistical Methods  
16.1.9-1  
ANOVA for Treatment Comparison of Diazepam – PK Population  
16.1.9-2  
ANOVA for Treatment Comparison of Nordiazepam – PK Population  
16.1.9-3 
Wilcoxon Signed-Rank Test for Tmax for Treatment Comparison of Diazepam – PK 
Population  
16.1.9-4 
Wilcoxon Signed-Rank Test for Tmax for Treatment Comparison of Nordiazepam – PK 
Population  
 
 
 
Subject Characteristics Listings 
16.2.1-1 
Subjects Completion and Discontinuation Information 
16.2.2-1 
Protocol Deviations 
16.2.4-1 
Demographics 
16.2.4-2 
Medical History Findings at Screening 
16.2.4-3 
Prior and Concomitant Medications  
16.2.4-4 
Study Drug Administration 
16.2.4-5 
Assignment to Analysis Populations 
 
 
 
PK Data Listings 
16.2.6-1 
Listing of Individual Actual Sampling Times and Pharmacokinetic Concentrations  
16.2.6-2 
Listing of Individual Pharmacokinetic Parameters 
16.2.6-3 
Listing of Individual Ratios or Differences between Treatment for Pharmacokinetic 
Parameters 
 
 
 
Safety Data Listings 
16.2.7-1 
Non-Treatment-Emergent Adverse Events  
16.2.7-2 
Treatment-Emergent Adverse Events 
16.2.7-3 
Serious Adverse Events 
16.2.7-4 
Significant Adverse Events 
16.2.8-1 
Clinical Laboratory – Biochemistry 
16.2.8-2 
Clinical Laboratory – Hematology 
16.2.8-3 
Clinical Laboratory – Urinalysis 
16.2.8-4 
Vital Signs Result 
16.2.8-5 
Electrocardiogram Result 
16.2.8-6 
DBF Application Site Visual Inspection 


 
 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 9 of 62 
3. 
CSR In-text Tables 


 
 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                              Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 10 of 62 
Table 10.1-1 Subject Disposition 
Category 
Treatment A 
Treatment B 
Treatment C 
Overall 
 
 
 
 
 
Screened  
- 
- 
- 
xx 
Screening Failures1,2  
- 
- 
- 
x ( xx.x) 
Not Enrolled1,3 
- 
- 
- 
x ( xx.x) 
Enrolled1,4 
- 
- 
- 
x ( xx.x) 
 
 
 
 
 
Dosed 
 
 
xx 
xx 
xx 
xx 
Not Dosed 
xx 
xx 
xx 
xx 
 Completed5 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
- 
 Completed All Treatment Periods6 
- 
- 
- 
x ( xx.x) 
 
 
 
 
 
Number of Subjects Discontinued7, 8 
xx 
xx 
xx 
xx 
 Primary Reason for Discontinuation7, 8, 9 
 
 
 
 
 Adverse Event 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 Lost to Follow-up 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 Non-Compliance with Protocol 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 Requirements 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 Positive Alcohol Breath Test 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 Positive Drug Screen 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 Positive Pregnancy Test 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 Safety Reason 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 Significant Protocol Deviation 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 Study Terminated by Sponsor 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 Other 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 Informed Consent Withdrawn 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 Investigator's decision 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 
 
 
 
 
Programming Note: 
if a subject was withdrawn from one period or more but he is included in next period(s) please add a footnote 10 to clarify, e.g.  
“10 Subject No. XX completed Period 1 (Treatment A) but was discontinued before dosing in Period 2 (Treatment B) and was dosed in Periods 3 (Treatment C).” 
1 Percentage based on the number of screened subjects. 


 
 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                              Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 11 of 62 
2 Screening failures include volunteers who did not meet project criteria. 
3 Not enrolled include volunteers who were judged eligible but decided not to participate on study or who were not selected to participate in the study since there was 
already a sufficient number of subjects. 
4 Enrolled include volunteers who were judged eligible and accepted to participate in the trial after having signed the approved final version of the study informed consent 
form and also those identified as standby who may replace subjects who withdraw from the study before dosing. 
5 Percentage based on the number of dosed subjects for a given treatment. 
6 Percentage based on the overall number of subjects dosed (safety population). 
7 Includes subjects who discontinued during the washout period or during the baseline assessment; these subjects are included under the last treatment received prior to 
discontinuation. 
8 Overall, each subject could only contribute once to each reason for discontinuation, regardless of the number of occurrences. 
9 Percentage based on the number of discontinued subjects per treatment group or overall, as appropriate. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content), 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
Data source: Listings 16.2.1-1 and 16.2.4-4. 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                              Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 12 of 62 
Table 11.4.2.3-1 Summary of Plasma Pharmacokinetic Parameters of Diazepam – PK Population 
Parameter(unit) 
Treatment A 
 
Treatment B 
 
Treatment C 
N 
Mean 
SD 
CV% 
 
N 
Mean 
SD 
CV% 
 
N 
Mean 
SD 
CV% 
AUC0-t (h*ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AUC0-inf (h*ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Residual area (%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cmax (ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
T½ el (h) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Kel (/h) 
Cl/F  
Vd/F  
Cl/F/kg  
Vd/F/kg  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Parameter (unit) 
Treatment A  
 
Treatment B 
 
Treatment C  
N 
Median 
Min 
Max 
 
N 
Median 
Min 
Max 
 
N 
Median 
Min 
Max 
Tmax (h) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N: Number of observations; SD: Standard Deviation; CV = Coefficient of Variation; Min = Minimum, Max = Maximum; ‘.’ : Not calculated. 
Residual area (%) = 100*(1- AUC0-t / AUC0-inf). 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content); 
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 
Note: Similar layout will be used for Tables 11.4.2.3-4. Please adapt title and footnotes accordingly.  
 


 
 
 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                   Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 13 of 62 
Table 11.4.2.3-2 Ratios (A/B), 90% Geometric Confidence Intervals, Intra-Subjects CV (%), Inter-Subjects CV (%) and p-values 
for Plasma Pharmacokinetic Parameters of  Diazepam – PK Population 
Parameter (unit) 
Geometric LSM 
 
90% Geometric 
C.I.2 
 
p-values 
Treatment A 
Treatment B 
Ratio1  
 (%) 
Lower  
 (%) 
Upper  
 (%) 
Intra-Subject 
   CV (%)3 
Inter-Subject 
   CV (%)4 
Sequence 
Period 
Treatment 
AUC0-t (h*ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AUC0-inf (h*ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cmax (ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Calculated using least-squares means according to the formula: exp (DIFFERENCE) * 100. 
2 90% Geometric Confidence Interval calculated according to the formula: exp (DIFFERENCE ± t(dfResidual)* SEDIFFERENCE) 
3 Calculated according to formula: SQRT (exp (MSE) – 1) * 100 
4 Calculated according to formula: SQRT (exp ((MSSUBJECT(SEQ) - MSE)/2) – 1) * 100 
LSM: Least Square Mean. 
Probability (p) values are derived from Type III sums of squares. p-value for the Sequence effect is tested using the Subject(Sequence) effect as the error term. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content). 
 
 
 
 
Note: Similar layout will be used for Tables 11.4.2.3-3, 11.4.2.3-5 and 11.4.2.3-6. Please adapt title and footnotes accordingly. 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                              Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                           Page 14 of 62 
4. 
Summary Tables 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                                                                                                           Page 15 of 62 
Table 14.1-1 Summary of Demographic Characteristics of Subjects Included in the Safety Population 
Category 
Statistic 
Treatment A  
Treatment B  
Treatment C 
Overall 
Age (years) 
N 
xx 
xx 
xx 
xx 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
 
SD.  
xx.x 
xx.x 
xx.x 
xx.x 
 
Median  
xx.x 
xx.x 
xx.x 
xx.x 
 
Min, Max  
xx-xx 
xx-xx 
xx-xx 
xx-xx 
Age Groups 
 
 
 
 
 
<18 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
18-40 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
> 40 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
Sex 
 
 
 
 
 
Female 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
Male 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
Ethnicity 
 
 
 
 
 
Hispanic or Latino 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
Not Hispanic or Latino 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
Not Reported 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
Unknown 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
Race 
 
 
 
 
 
Am Indian 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
Asian 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
Black 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
Hawaiian 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
Islander 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
White 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
Other 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
Height (cm) 
N 
xx 
xx 
xx 
xx 
 
Mean  
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
SD  
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Median  
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Min, Max  
xx.x-xx.x 
xx.x-xx.x 
xx.x-xx.x 
xx.x-xx.x 
Weight (kg) 
N 
xx 
xx 
xx 
xx 
 
Mean  
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
SD  
xx.xx 
xx.xx 
xx.xx 
xx.xx 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                                                                                                           Page 16 of 62 
 
Median  
xx.xx 
xx.xx 
xx.xx 
xx.xx 
 
Min, Max 
xx.x-xx.x 
xx.x-xx.x 
xx.x-xx.x 
xx.x-xx.x 
 
 
 
 
 
 
BMI (kg/m2) 
N 
xx 
xx 
xx 
xx 
 
Mean  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
 
SD  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
 
Median  
xx.xxx 
xx.xxx 
xx.xxx 
xx.xxx 
 
Min, Max  
xx.xx-xx.xx 
xx.xx-xx.xx 
xx.xx-xx.xx 
xx.xx-xx.xx 
 
 
 
 
 
 
Programming Note: 
 
1) 
Refer to the note below for additional instructions 
 
N: Number of subjects dosed; n (%): Number and percent of subjects; SD: Standard Deviation. 
Am Indian: American Indian or Alaskan Native; Black: Black or African American; Hawaiian: Native Hawaiian or Pacific Islander;  
BMI: body mass index. 
Last results (scheduled or unscheduled) obtained at screening were used to generate this table. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
Data source: Listing 16.2.4-1 
 
Note: This table will be repeated for Table 14.1-2 only if PK Population is not the same as Safety Population. Otherwise, the title will be updated accordingly.  
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                                                                                                           Page 17 of 62 
Table 14.2.1-1 Descriptive Statistics for Plasma Concentration over Nominal Time by Treatment– PK Population 
Analyte 
Treatment 
Nominal Time Time Unit 
N 
Mean 
SD 
CV% 
Min 
Median 
Max 
Geometric Mean Concentration Unit  
Diazepam 
A 
0.000 
h 
0.500 
h 
0.750 
h 
1.00 
h 
1.50 
h 
2.00 
h 
3.00 
h 
4.00 
h 
6.00 
h 
9.00 
h 
12.0 
h 
24.0 
h 
48.0 
h 
72.0 
h 
96.0 
h 
 
 
120 
h 
 
 
 
 
 
 
 
 
 
144 
h 
192 
h 
240 
h 
… 
… 
N: Number of observations; SD: Standard Deviation; CV: Coefficient of Variation; Min: Minimum, Max: Maximum. 
 Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content); 
 Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
 Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
Data source: Listing 16.2.6-1 
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                                                                                                           Page 18 of 62 
Table 14.2.1-2  Descriptive Statistics of Plasma Pharmacokinetic Parameters by Treatment - PK Population 
Analyte 
Treatment 
Parameter(unit) 
N 
Mean 
SD 
CV% 
Min 
Median 
Max 
Geometric Mean 
Diazepam 
A 
AUC0-t (ng*h/mL) 
 
 
 
 
 
 
 
 
 
 
AUC0-inf (ng*h/mL) 
 
 
 
 
 
 
 
 
 
 
Residual Area (%) 
 
 
 
 
 
 
 
 
 
 
Cmax  (ng/mL) 
 
 
 
 
 
 
 
 
 
 
Tmax  (h) 
 
 
 
 
 
 
 
 
 
 
T1/2 el (h) 
 
 
 
 
 
 
 
 
 
 
Kel (/h) 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
Cl/F(h) 
Vd/F(h)  
Cl/F/kg  
Vd/F/kg  
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
N: Number of observations; SD: Standard Deviation; CV = Coefficient of Variation; Min = Minimum, Max = Maximum; ‘.’ : Not calculated. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content); 
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
Data source: Listing 16.2.6-2 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                                                                                                           Page 19 of 62 
Table 14.2.1-3 Descriptive Statistics of Individual Ratios or Individual Differences between Treatments for Pharmacokinetic 
Parameters - PK Population 
Analyte 
Comparison  
Parameter 
Ratio/Difference  (unit)      N  Mean SD CV% Min Median Max Geometric Mean 
Diazepam 
A vs B 
AUC0-t 
A/B (%) 
AUC0-inf 
A/B (%) 
Residual Area 
A - B (%) 
Cmax 
A/B (%) 
Tmax 
A - B (h) 
T½ el 
A/B (%) 
Kel 
A/B (%) 
… 
N: Number of observations; SD: Standard Deviation; CV = Coefficient of Variation; Min = Minimum, Max = Maximum; ‘.’: Not calculated. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
Data source: Listing 16.2.6-3 
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                                                                                                           Page 20 of 62 
Table 14.2.1-4 Ratios (A/B), 90% Geometric Confidence Intervals, Intra-Subjects CV (%) and P-values for Diazepam – PK 
Population 
Comparison 
(Test vs. Ref.) 
Parameter(unit) 
Geometric LSM 
 
90% Geometric 
C.I.2 
 
p-values 
Test 
Ref. 
Ratio1  
 (%) 
Lower  
 (%) 
Upper  
 (%) 
Intra-Subject 
   CV (%)3 
Inter-Subject 
   CV (%)4 
Sequence 
Period 
Treatment 
A vs B 
AUC0-t (h*ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
AUC0-inf (h*ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Cmax (ng/mL) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1 Calculated using least-squares means according to the formula: exp (DIFFERENCE) * 100. 
2 90% Geometric Confidence Interval calculated according to the formula: exp (DIFFERENCE ± t(dfResidual)* SEDIFFERENCE) 
3 Calculated according to formula: SQRT (exp (MSE) – 1) * 100 
4 Calculated according to formula: SQRT (exp ((MSSUBJECT (SEQ) - MSE)/2) – 1) * 100 
LSM: Least Square Mean; Ref.: Reference. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content). 
Data Source: Listing 16.1.9-1 
 
 
Note: Similar layout will be used for Table 14.2.1-5, 14.2.1-6 and 14.2.1-7. Please adapt title and footnotes accordingly.  
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                                                                                                           Page 21 of 62 
Table 14.3.1-1 Frequency of Subjects Experiencing Treatment-Emergent Adverse Events and Number of Events Summarized per 
Treatment – Safety Population 
MedDRA® System Organ Class 
 MedDRA® Preferred Term 
Statistic 
Treatment A  
(N=XX) 
Treatment B  
(N=XX) 
Treatment C  
(N=XX) 
Overall 
(N=XX) 
Number of TEAEs 
E 
xx 
xx 
xx 
xx 
Number of Subjects with TEAEs 
n (%) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 
MedDRA® System Organ Class 1 
n(%) E  
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
MedDRA® Preferred Term 1 
n(%) E  
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
MedDRA® Preferred Term 2 
n(%) E  
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
 
 
 
 
MedDRA® System Organ Class 2 
n(%) E  
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
MedDRA® Preferred Term 1 
n(%) E  
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
MedDRA® Preferred Term 2 
n(%) E  
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
 
 
 
 
MedDRA® System Organ Class 3 
n(%) E  
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
MedDRA® Preferred Term 1 
n(%) E  
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
MedDRA® Preferred Term 2 
n(%) E  
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
x ( xx.x) x 
 
 
 
 
Programming Notes: 
 
 
 
 
1) SOC will be presented in descending order of overall incidence rate in terms of frequency of subjects and then in frequency of events (alphabetical order will be used in case of equal 
rates). For each SOC, PT will be presented the same way. 
2) Refer to footnotes for additional instructions. 
E: Number of TEAEs; N: Number of subjects dosed; n (%): Number and percent of subjects with TEAE; MedDRA®: Medical Dictionary for Regulatory Activities, 
version 21.1; TEAEs: Treatment-Emergent Adverse Events. 
Each subject could only contribute once to each of the incidence rates, regardless of the number of occurrences. 
Overall: Included results from all treatment groups. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
Data source: Listing 16.2.7-2  
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                                                                                                           Page 22 of 62 
Table 14.3.1-2 Frequency of Subjects Experiencing Treatment-Emergent Adverse Events Summarized per Treatment and Severity 
– Safety Population 
MedDRA® System Organ Class  
 MedDRA® Preferred Term 
Treatment A  
(N=XX) 
Treatment B  
(N=XX) 
n (%) 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Severe 
 
 
 
 
 
 
 
MedDRA® System Organ Class 1 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 MedDRA® Preferred Term 1 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 MedDRA® Preferred Term 2 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 
 
 
 
 
 
 
MedDRA® System Organ Class 2 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 MedDRA® Preferred Term 1 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 MedDRA® Preferred Term 2 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 
 
 
 
 
 
 
Programming Notes: 
1) 
SOC will be presented in descending order of overall incidence rate in terms of frequency of subjects and then in frequency of events (alphabetical order will be used in case of 
equal rates). For each SOC, PT will be presented the same way. 
2) 
If the distribution of treatments is presented on more than one page, preserve the order of the SOC and PT as defined in the generation of the global table without severity. 
3) 
Refer to footnotes for additional instructions. 
 
 
N: Number of subjects dosed; n (%): Number and percent of subjects with treatment-emergent adverse events; MedDRA®: Medical Dictionary for Regulatory Activities, 
version 21.1. 
Each subject could only contribute once to each of the incidence rates, regardless of the number of occurrence; the highest severity is presented. 
Overall: Included results from all treatment groups. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
Data source: Listing 16.2.7-2 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                                                                                                           Page 23 of 62 
Table 14.3.1-2 Frequency of Subjects Experiencing Treatment-Emergent Adverse Events Summarized per Treatment and Severity 
– Safety Population 
MedDRA® System Organ Class  
 MedDRA® Preferred Term 
Treatment C  
(N=XX) 
Overall 
(N=XX) 
n (%) 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Severe 
 
 
 
 
 
 
 
MedDRA® System Organ Class 1 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 MedDRA® Preferred Term 1 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 MedDRA® Preferred Term 2 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 
 
 
 
 
 
 
MedDRA® System Organ Class 2 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 MedDRA® Preferred Term 1 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 MedDRA® Preferred Term 2 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 
 
 
 
 
 
 
Programming Notes: 
1) 
SOC will be presented in descending order of overall incidence rate in terms of frequency of subjects and then in frequency of events (alphabetical order will be used in case of 
equal rates). For each SOC, PT will be presented the same way. 
2) 
If the distribution of treatments is presented on more than one page, preserve the order of the SOC and PT as defined in the generation of the global table without severity. 
3) 
Refer to footnotes for additional instructions. 
 
 
N: Number of subjects dosed; n (%): Number and percent of subjects with treatment-emergent adverse events; MedDRA®: Medical Dictionary for Regulatory Activities, 
version 21.1. 
Each subject could only contribute once to each of the incidence rates, regardless of the number of occurrence; the highest severity is presented. 
Overall: Included results from all treatment groups. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
Data source: Listing 16.2.7-2 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                                                                                                           Page 24 of 62 
Table 14.3.1-3 Number of Treatment-Emergent Adverse Events Summarized per Treatment and Severity – Safety Population 
MedDRA® System Organ Class  
 MedDRA® Preferred Term 
Treatment A  
(N=XX) 
Treatment B  
(N=XX) 
E 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Severe 
 
 
 
 
 
 
 
MedDRA® System Organ Class 1 
x 
x 
x 
x 
x 
x 
 MedDRA® Preferred Term 1 
x 
x 
x 
x 
x 
x 
 MedDRA® Preferred Term 2 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
MedDRA® System Organ Class 2 
x 
x 
x 
x 
x 
x 
 MedDRA® Preferred Term 1 
x 
x 
x 
x 
x 
x 
 MedDRA® Preferred Term 2 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
Programming Notes: 
1) 
SOC will be presented in descending order of overall incidence rate in terms of frequency of subjects and then in frequency of events (alphabetical order will be used in case of 
equal rates). For each SOC, PT will be presented the same way. 
2) 
If the distribution of treatments is presented on more than one page, preserve the order of the SOC and PT as defined in the generation of the global table without severity. 
 
 
E: Number of treatment-emergent adverse event; N: Number of subjects dosed; MedDRA®: Medical Dictionary for Regulatory Activities, version 21.1. 
Overall: Included results from all treatment groups. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
Data source: Listing 16.2.7-2 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                                                                                                           Page 25 of 62 
Table 14.3.1-3 Number of Treatment-Emergent Adverse Events Summarized per Treatment and Severity – Safety Population 
MedDRA® System Organ Class  
 MedDRA® Preferred Term 
Treatment C  
(N=XX) 
Overall 
(N=XX) 
E 
Mild 
Moderate 
Severe 
Mild 
Moderate 
Severe 
 
 
 
 
 
 
 
MedDRA® System Organ Class 1 
x 
x 
x 
x 
x 
x 
 MedDRA® Preferred Term 1 
x 
x 
x 
x 
x 
x 
 MedDRA® Preferred Term 2 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
MedDRA® System Organ Class 2 
x 
x 
x 
x 
x 
x 
 MedDRA® Preferred Term 1 
x 
x 
x 
x 
x 
x 
 MedDRA® Preferred Term 2 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
Programming Notes: 
1) 
SOC will be presented in descending order of overall incidence rate in terms of frequency of subjects and then in frequency of events (alphabetical order will be used in case of 
equal rates). For each SOC, PT will be presented the same way. 
2) 
If the distribution of treatments is presented on more than one page, preserve the order of the SOC and PT as defined in the generation of the global table without severity. 
 
 
E: Number of treatment-emergent adverse event; N: Number of subjects dosed; MedDRA®: Medical Dictionary for Regulatory Activities, version 21.1. 
Overall: Included results from all treatment groups. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
Data source: Listing 16.2.7-2 
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                                                                                                           Page 26 of 62 
Table 14.3.1-4 Frequency of Subjects Experiencing Treatment-Emergent Adverse Events Summarized per Treatment and 
Relationship – Safety Population 
MedDRA® System Organ Class 
   MedDRA® Preferred Term 
Treatment A  
 (N=XX) 
Treatment B  
 (N=XX) 
n (%) 
Unrelated 
Unlikely 
Possible  
Probable 
Unrelated 
Unlikely 
Possible  
Probable 
 
MedDRA® System Organ Class 1 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 MedDRA® Preferred Term 1 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 MedDRA® Preferred Term 2 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 
MedDRA® System Organ Class 2 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 MedDRA® Preferred Term 1 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 MedDRA® Preferred Term 2 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 
 
 
 
 
 
 
 
 
Programming Notes: 
1) 
SOC will be presented in descending order of overall incidence rate in terms of frequency of subjects and then in frequency of events (alphabetical order will be used in case of 
equal rates). For each SOC, PT will be presented the same way. 
2) 
If the distribution of treatments is presented on more than one page, preserve the order of the SOC and PT as defined in the generation of the global table without relationship. 
3) 
Refer to footnotes for additional instructions. 
N: Number of subjects dosed; n (%): Number and percent of subjects with treatment-emergent adverse event; MedDRA®: Medical Dictionary for Regulatory Activities, 
version 21.1. 
Each subject could only contribute once to each of the incidence rates, regardless of the number of occurrence; the highest relationship is presented. 
Overall: Included results from all treatment groups. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
Data source: Listing 16.2.7-2 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                                                                                                           Page 27 of 62 
Table 14.3.1-4 Frequency of Subjects Experiencing Treatment-Emergent Adverse Events Summarized per Treatment and 
Relationship – Safety Population 
MedDRA® System Organ Class 
   MedDRA® Preferred Term 
Treatment C  
 (N=XX) 
Overall 
(N=XX) 
n (%) 
Unrelated 
Unlikely 
Possible  
Probable 
Unrelated 
Unlikely 
Possible  
Probable 
 
MedDRA® System Organ Class 1 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 MedDRA® Preferred Term 1 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 MedDRA® Preferred Term 2 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 
MedDRA® System Organ Class 2 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 MedDRA® Preferred Term 1 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 MedDRA® Preferred Term 2 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 
 
 
 
 
 
 
 
 
Programming Notes: 
1) 
SOC will be presented in descending order of overall incidence rate in terms of frequency of subjects and then in frequency of events (alphabetical order will be used in case of 
equal rates). For each SOC, PT will be presented the same way. 
2) 
If the distribution of treatments is presented on more than one page, preserve the order of the SOC and PT as defined in the generation of the global table without relationship. 
3) 
Refer to footnotes for additional instructions. 
N: Number of subjects dosed; n (%): Number and percent of subjects with treatment-emergent adverse event; MedDRA®: Medical Dictionary for Regulatory Activities, 
version 21.1. 
Each subject could only contribute once to each of the incidence rates, regardless of the number of occurrence; the highest relationship is presented. 
Overall: Included results from all treatment groups. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
Data source: Listing 16.2.7-2 
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                                                                                                           Page 28 of 62 
Table 14.3.1-5 Number of Treatment-Emergent Adverse Events Summarized per Treatment and Relationship – Safety Population 
MedDRA® System Organ Class 
   MedDRA® Preferred Term 
Treatment A  
(N=XX) 
Treatment B 
(N=XX) 
E 
Unrelated 
Unlikely 
Possible  
Probable 
Unrelated 
Unlikely 
Possible  
Probable 
 
MedDRA® System Organ Class 1 
x 
x 
x 
x 
x 
x 
x 
x 
 MedDRA® Preferred Term 1 
x 
x 
x 
x 
x 
x 
x 
x 
 MedDRA® Preferred Term 2 
x 
x 
x 
x 
x 
x 
x 
x 
 
MedDRA® System Organ Class 2 
x 
x 
x 
x 
x 
x 
x 
x 
 MedDRA® Preferred Term 1 
x 
x 
x 
x 
x 
x 
x 
x 
 MedDRA® Preferred Term 2 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
Programming Notes: 
4) 
SOC will be presented in descending order of overall incidence rate in terms of frequency of subjects and then in frequency of events (alphabetical order will be used in case of 
equal rates). For each SOC, PT will be presented the same way. 
5) 
If the distribution of treatments is presented on more than one page, preserve the order of the SOC and PT as defined in the generation of the global table without relationship. 
 
E: Number of treatment-emergent adverse event; N: Number of subjects dosed; MedDRA®: Medical Dictionary for Regulatory Activities, version 21.1. 
Overall: Included results from all treatment groups. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
Data source: Listing 16.2.7-2 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                                                                                                           Page 29 of 62 
Table 14.3.1-5 Number of Treatment-Emergent Adverse Events Summarized per Treatment and Relationship – Safety Population 
MedDRA® System Organ Class 
   MedDRA® Preferred Term 
Treatment C   
(N=XX) 
Overall 
(N=XX) 
E 
Unrelated 
Unlikely 
Possible  
Probable 
Unrelated 
Unlikely 
Possible  
Probable 
 
MedDRA® System Organ Class 1 
x 
x 
x 
x 
x 
x 
x 
x 
 MedDRA® Preferred Term 1 
x 
x 
x 
x 
x 
x 
x 
x 
 MedDRA® Preferred Term 2 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
MedDRA® System Organ Class 2 
x 
x 
x 
x 
x 
x 
x 
x 
 MedDRA® Preferred Term 1 
x 
x 
x 
x 
x 
x 
x 
x 
 MedDRA® Preferred Term 2 
x 
x 
x 
x 
x 
x 
x 
x 
 
 
 
 
 
 
 
 
 
Programming Notes: 
1) 
SOC will be presented in descending order of overall incidence rate in terms of frequency of subjects and then in frequency of events (alphabetical order will be used in case of 
equal rates). For each SOC, PT will be presented the same way. 
2) 
If the distribution of treatments is presented on more than one page, preserve the order of the SOC and PT as defined in the generation of the global table without relationship. 
 
E: Number of treatment-emergent adverse event; N: Number of subjects dosed; MedDRA®: Medical Dictionary for Regulatory Activities, version 21.1. 
Overall: Included results from all treatment groups. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
Data source: Listing 16.2.7-2 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                          Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                  Page 30 of 62 
Table 14.3.4-1 Biochemistry Summary Descriptive Statistics and Change from Screening 
to Study Exit – Safety Population 
Parameter (unit) 
Normal Range 
 
Visit 
Statistic 
Overall 
(N=XX) 
 
 
 
 
Parameter 1 (xxx)  
Screening 
n  
xx 
XX-XX  
 
Mean  
xx.x 
 
 
SD  
xx.x 
 
 
Median  
xx.x 
 
 
Min, Max  
xx, xx 
 
 
 
 
 
Study Exit 
n  
xx 
 
 
Mean  
xx.x 
 
 
SD 
xx.x 
 
 
Median  
xx.x 
 
 
Min, Max  
xx, xx 
 
 
 
 
 
Study Exit - CFS 
n  
xx 
 
 
Mean  
xx.x 
 
 
SD 
xx.x 
 
 
Median  
xx.x 
 
 
Min, Max  
xx, xx 
… 
 
 
 
Programming Notes: 
1) 
Refer to study protocol for laboratory tests to be presented. 
2) 
Urinalysis parameters (quantitative results) expected and sorted as: pH (PH) and Specific Gravity(SPGRAV). 
3) 
For each parameter provide normal range of primary facility and, for gender specific parameters, use the same sorting of sex from 
demographic table. 
4) 
If multiple laboratories involved, refer to the SAP instructions for results normalization. 
5) 
Evaluate individually for each table if some standard results were not quantifiable and, if applicable, add footnote: Not quantifiable 
values outside of limit of quantitation (<x or >y) will be set to missing for calculation of summary statistics. 
6) 
Refer to footnotes for additional instructions. 
7) 
 Adapt Data Source to the appropriate laboratory category listing. 
 
 
 
CFS: Change from screening; N: Number of subjects dossed; n: number of subjects; SD: Standard Deviation. 
Screening is defined as the last screening results (scheduled or unscheduled).  
Data source: Listing 16.2.8-1 
 
Note:  This table will be repeated for Tables 14.3.4-3, 14.3.4-5 and Table 14.3.4-10. Please adapt title 
and data source footnote accordingly.


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                          Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                  Page 31 of 62 
Table 14.3.4-2 Frequency of Subjects – Biochemistry Shifts from Screening to Study Exit - 
– Safety Population 
 
 
Study Exit 
Parameter (unit) 
Screening 
Low 
Normal 
High 
 
 
n (%) 
n (%) 
n (%) 
 
 
 
 
 
Parameter 1 (xxx) 
Low 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 
Normal 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 
High 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 
 
 
 
 
Parameter 2 (xxx) 
Low 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 
Normal 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 
High 
x ( xx.x) 
x ( xx.x) 
x ( xx.x) 
 
 
 
 
 
Programming Notes: 
 
 
 
 
1) 
Refer to study protocol for parameters to be presented. 
2) 
Preserve parameters and sorting defined in Summary Descriptive Statistics Table 
3) 
Refer to footnotes for additional instructions. 
4) 
Adapt Data Source to the appropriate laboratory category listing. 
 
 
 
 
 
n (%): Number and percentage of subjects. 
Percentage based on the number of subjects having available results at screening and at study exit. 
Screening is defined as the last screening results (scheduled or unscheduled). 
Data source: Listing 16.2.8-1 
 
 
Note: This table will be repeated for Tables 14.3.4-4, and 14.3.4-6. Please adapt title and data source accordingly.


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                          Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0)                                                                                                                  Page 32 of 62 
 
n (%): Number and percentage of subjects. 
Percentage based on the number of subjects having available results at screening and at study exit. 
Data source: Listing 16.2.8-3 
 
 
Table 14.3.4-7 Urinalysis Frequency Summary: Categorical Results – Safety Population 
Parameter (unit) 
Normal range 
Visit 
Result 
Overall  
n (%) 
Parameter 1 (xxx) 
Screening  
Clear 
x ( xx.x) 
[Normal range] 
 
Cloudy 
x ( xx.x) 
Turbid 
x ( xx.x) 
 
Study Exit 
Clear 
x ( xx.x) 
Cloudy 
x ( xx.x) 
 
 
Turbid 
x ( xx.x) 
 
Parameter 2 (xxx) 
Screening  
+ 
x ( xx.x) 
[Normal range] 
Negative 
x ( xx.x) 
  
Study Exit 
Negative 
x ( xx.x) 
 
Parameter 3 (xxx)) 
Screening  
+ 
x ( xx.x) 
[Normal range] 
Negative 
x ( xx.x) 
 
  
Trace 
x ( xx.x) 
Study Exit 
+ 
x ( xx.x) 
  
 
Negative 
x ( xx.x) 
 
 
Trace 
x ( xx.x) 
Programming Notes: 
 
 
1) 
Refer to study protocol for parameters to be presented. 
2) 
Urine Microscopy parameters will not presented in this table. 
3) 
Evaluate if the units must be added to parameter name if a numeric result was observed. Remove (Units) from column header if no 
numeric results were observed. 
4) 
For each parameter provide normal range of primary facility and, for gender specific parameters, use the same sorting of sex from 
demographic table. 
5) 
Independently for each parameter test, sort results by gradation. 
6) 
Refer to footnotes for additional instructions. 
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
                                                                                                                                                                                                           Page 33 of 62 
Table 14.3.4-8 Frequency of Subjects - Urinalysis Shifts from Screening to Study Exit: Categorical Results – Safety Population 
 
 
Study Exit 
Parameter  
Screening 
Normal 
Abnormal 
 
 
n (%) 
n (%) 
Parameter 1  
 
 
 
 
 
Normal 
x (xx.x) 
x (xx.x) 
 
Abnormal 
x (xx.x) 
x (xx.x) 
 
 
 
 
Parameter 2  
 
 
 
 
 
Normal 
x (xx.x) 
x (xx.x) 
 
Abnormal 
x (xx.x) 
x (xx.x) 
 
 
 
 
Parameter 3  
 
 
 
 
 
Normal 
x (xx.x) 
x (xx.x) 
 
Abnormal 
x (xx.x) 
x (xx.x) 
 
 
 
 
Programming Notes: 
 
 
 
1) 
Refer to study protocol for parameters to be presented. 
2) 
Preserve parameters and sorting defined in Summary Descriptive Statistics Table 
3) 
Refer to footnotes for additional instructions. 
 
 
 
 
n (%): Number and percentage of subjects. 
Percentage based on the number of subjects having available results at screening and at study exit. 
Screening is defined as the last screening results (scheduled or unscheduled). 
Data source: Listing 16.2.8-3 
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
                                                                                                                                                                                                           Page 34 of 62 
Table 14.3.4-9 Vital Signs Summary Descriptive Statistics - Safety Population 
Parameter (unit) 
  Normal Range 
Timepoint 
Statistic 
Treatment A  
(N=XX) 
Treatment B  
(N=XX) 
Treatment C  
(N=XX) 
Overall 
(N=XX) 
 
 
 
 
Parameter 1 (xxx) 
Screening 
n  
- 
- 
- 
xx 
  XX-XX 
Mean  
- 
- 
- 
xx.x 
SD  
- 
- 
- 
xx.x 
Median  
- 
- 
- 
xx.x 
 
 
Min, Max  
- 
- 
- 
xx, xx 
 
 
 
 
Pre-dose 
n  
xx 
xx 
xx 
- 
Mean  
xx.x 
xx.x 
xx.x 
- 
SD  
xx.x 
xx.x 
xx.x 
- 
Median  
xx.x 
xx.x 
xx.x 
- 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
- 
 
 
 
 
 
Baseline 
n  
xx 
xx 
xx 
- 
Mean  
xx.x 
xx.x 
xx.x 
- 
 
 
SD  
xx.x 
xx.x 
xx.x 
- 
Median  
xx.x 
xx.x 
xx.x 
- 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
- 
 
 
 
 
 
0.5H Post-Dose 
n 
xx 
xx 
xx 
- 
Mean  
xx.x 
xx.x 
xx.x 
- 
 
 
SD 
xx.x 
xx.x 
xx.x 
- 
Median  
xx.x 
xx.x 
xx.x 
- 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
- 
 
 
 
 
 
0.5H Post-Dose – CFB 
n 
xx 
xx 
xx 
- 
Mean  
xx 
xx 
xx 
- 
 
 
SD 
xx 
xx 
xx 
- 
Median  
xx 
xx 
xx 
- 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
- 
 
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
                                                                                                                                                                                                           Page 35 of 62 
 
1.00H Post-Dose 
n 
xx 
xx 
xx 
- 
Mean  
xx.x 
xx.x 
xx.x 
- 
 
 
SD 
xx.x 
xx.x 
xx.x 
- 
Median  
xx.x 
xx.x 
xx.x 
- 
 
 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
- 
 
 
 
 
 
1.00H Post-Dose – CFB 
N 
xx 
xx 
xx 
- 
Mean  
xx 
xx 
xx 
- 
 
 
SD 
xx 
xx 
xx 
- 
Median  
xx 
xx 
xx 
- 
Min, Max 
xx, xx 
xx, xx 
xx, xx 
- 
 
 
 
 
 
 
 
 
…. 
 
 
 
 
 
 
 
 
 
 
Study Exit 
n  
- 
- 
- 
xx 
Mean  
- 
- 
- 
xx.x 
 
 
SD  
- 
- 
- 
xx.x 
Median  
- 
- 
- 
xx.x 
 
 
Min, Max  
- 
- 
- 
xx, xx 
 
 
 
 
 
Study Exit - CFS 
n  
- 
- 
- 
xx 
Mean  
- 
- 
- 
xx.x 
 
 
SD  
- 
- 
- 
xx.x 
Median  
- 
- 
- 
xx.x 
 
 
Min, Max  
- 
- 
- 
xx, xx 
Programming Notes: 
 
 
 
 
1) 
Preserve parameters and sorting defined in Summary Descriptive Statistics Table 
2) 
Independently for each parameter, if Baseline assessment is composed by the same visit and timepoint for all subjects, identify this timepoint with Baseline between parentheses. ex. Day 1 Pre-Dose 
(Baseline) 
3) 
Refer to footnotes for additional instructions. 
 
 
 
 
 
 
 
CFB: Change from Baseline; CFS: Change from Screening; N: Number of subjects dosed; n: Number of subjects; SD: Standard Deviation. 
Screening is defined as the last screening results (scheduled or unscheduled).  
Baseline is defined as the last results (scheduled or unscheduled) obtained prior to drug administration in each period.  
Data source: Listing 16.2.8-4 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 36 of 62 
5. 
Figures 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 37 of 62 
Figure 14.2.2-1a: Plasma Concentrations of Diazepam for Subject XX - Linear Scale 
 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 
 
Note: This figure will be repeated for each subject included in the PK population, and for nordiazepam.  
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 38 of 62 
Figure 14.2.2-1b: Plasma Concentrations of Diazepam for Subject XX – Semi-Log Scale 
 
 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 
 
Note: This figure will be repeated for each subject included in the PK population, and for nordiazepam.  
 
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 39 of 62 
Figure 14.2.2-33a: Mean (± SD) Plasma Concentrations of Diazepam - Linear Scale 
 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 
 
Note: This figure will be repeated for nordiazepam. 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 40 of 62 
Figure 14.2.2-33b: Mean (± SD) Plasma Concentrations of Diazepam - Semi-Log Scale 
 
 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 
 
Note: This figure will be repeated for nordiazepam. 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 41 of 62 
Figure 14.2.2-34a: Overlay of Individual and Mean Plasma Concentrations of Diazepam 
by Treatment - Linear Scale 
 
 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 
 
Note: This figure will be repeated for nordiazepam. 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 42 of 62 
Figure 14.2.2-34b: Overlay of Individual and Mean Plasma Concentrations of Diazepam 
by Treatment - Semi-Log Scale 
  
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 
 
Note: This figure will be repeated for nordiazepam. 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 43 of 62 
6. 
Listings 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 44 of 62 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam – PK Population 
Comparison: A vs B 
Dependent Variable: xxx 
 
Source 
DF Sum of Squares Mean Square 
F Value 
Pr > F 
Model 
 
 
 
 
 
Error 
 
 
 
 
 
Corrected Total 
 
 
 
 
 
 
R-Square 
Coeff Var 
Root MSE 
VAR Mean 
 
 
 
 
 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
SEQ 
 
 
 
 
 
PERIOD 
 
 
 
 
 
TRT 
 
 
 
 
 
SUBJECT (SEQ) 
 
 
 
 
 
 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F 
SEQ 
 
 
 
 
 
PERIOD 
 
 
 
 
 
TRT 
 
 
 
 
 
SUBJECT (SEQ) 
 
 
 
 
 
 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
SEQ 
 
 
 
 
 
PERIOD 
 
 
 
 
 
TRT 
 
 
 
 
 
SUBJECT (SEQ) 
 
 
 
 
 
 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F 
SEQ 
 
 
 
 
 
PERIOD 
 
 
 
 
 
TRT 
 
 
 
 
 
SUBJECT (SEQ) 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 45 of 62 
Tests of Hypotheses Using the Type III MS for SUBJECT(SEQ) as an Error Term 
Source  
DF  
Type III SS  
Mean Square  
F Value  
Pr > F  
SEQ 
 
 
 
 
 
 
 
 
 
 
 
 
Level of 
TRT 
N 
 
Mean 
Std Dev 
A 
 
 
 
B 
 
 
 
 
TRT VAR LSMEAN Standard Error Pr > |t| 
A 
 
 
 
B 
 
 
 
 
 
Parameter 
Estimate 
Standard Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
 
 
 
 
 
 
 
 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content)  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content) 
 
 
Note 1: For each comparison, all ANOVA results for ln-transformed AUC0-t, AUC0-inf, Cmax, Cl/F, Cl/F/kg, Vd/F, 
Vd/F/kg and untransformed, Kel, and T½ el for plasma concentration will be presented in this listing.  
 
Note 2: For B vs C comparison, PERIOD will not be included in the model. 
 
Note: Similar layout will be used for listing 16.1.9-2. Please adapt title and footnotes accordingly.  
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 46 of 62 
Listing 16.1.9-3 Wilcoxon Signed-Rank Test for Tmax for Treatment Comparison of 
Diazepam – PK Population 
Comparison: A vs B 
Difference 
Statistic 
Value 
A – B  
n 
 
 
Mean 
 
 
Median 
 
 
SD 
 
 
 
 
Wilcoxon 
S 
 
Signed-rank Test 
p-value 
 
 
 
 
n: Number of subjects; SD: Standard Deviation. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content)  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content) 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content) 
 
Note 1: For each comparison Wilcoxon Signed-Rank Test for Tmax will be presented in this listing. 
Note2: Similar layout will be used for listing 16.1.9-4. Please adapt title and footnotes accordingly.  
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 47 of 62 
Listing 16.2.1-1 Subjects Completion and Discontinuation Information 
Subject 
Number 
Treatment 
Sequence 
Period 
Last Treatment Received 
Prior to Discontinuation 
Last Period Prior to 
Discontinuation 
Completion/ Discontinuation 
Date and Time 
Primary Reason for 
Discontinuation 
Comment 
 
ABC 
1 
A 
2 
DD-MM-YYYY/HH:MM 
XXX 
XXX 
 
 
2 
B 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 48 of 62 
 
Listing 16.2.2-1 Protocol Deviations 
Subject 
Treatment Sequence 
Period 
Category 
Deviation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 49 of 62 
Listing 16.2.4-1 Demographics  
Subject 
Treatment Sequence 
Age (years) 
Gender 
Race 
Ethnicity 
BMI (kg/m2) 
Height (cm) 
Weight (kg) 
 
ABC 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
BMI: Body Mass Index. 
Last results (scheduled or unscheduled) obtained at screening were used to generate this table.  
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 50 of 62 
Listing 16.2.4-2 Medical History Findings at Screening 
Subject 
Treatment 
Sequence 
Finding 
MedDRA® Preferred Term 
MedDRA® System Organ Class 
Onset Date 
Resolution Date 
(or Ongoing) 
 
 
FINDING 1 
Preferred Term 1 
SOC 1 
YYYY-MM-DDTHH:MM  
YYYY-MM-DDTHH:MM 
 
 
 
 
 
 
 
 
 
FINDING 2 
Preferred Term 2 
SOC 2 
YYYY-MM-DDTHH:MM  
ONGOING 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Notes: 
1) SOC and Finding will be presented in uppercase. The Preferred Term will be presented in “propcase”. The SAS coding “/~n” between terms will generate the break line. 
2) The SAS coding “/~n” between dates will generate the break line. 
3) If finding is ongoing, replace missing resolution date per ONGOING. 
4) Sort events per Subject, Start Date, Stop Date, SOC and PT. 
5) For incomplete date display, refer to CDISC SDTM Implementation Guide according to ISO 8601 format. 
MedDRA®: Medical Dictionary for Regulatory Activities; MedDRA® Version 21.1. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 51 of 62 
Listing 16.2.4-3 Prior and Concomitant Medications  
Subject 
Treatment Sequence/ 
Treatment 
Prior/ 
Concomitant 
WHO DDE ATC / 
WHO DDE  Preferred Term / 
Medication 
Dose (unit)/ 
Frequency 
Route 
Onset Date and Time/ 
Resolution Date and Time 
(or Ongoing) 
Indication  
(Condition or AE No.) 
 
ABC 
 
Prior 
ATC 1/ 
Preferred Term 1/ 
MEDICATION 1/ 
20 (mg) 
QID 
ORAL 
YYYY-MM-DDTHH:MM/ 
YYYY-MM-DDTHH:MM 
 
 
 
 
 
 
 
 
 
 
BAC/ 
B 
Concomitant 
ATC 2/ 
Preferred Term 2/ 
MEDICATION 2/ 
 
 
YYYY-MM-DDTHH:MM/ 
ONGOING 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Notes: 
1) ATC and Medication will be presented in uppercase. The Preferred Term will be presented in “propcase”. The SAS coding “/~n” between terms will generate the break line. 
2) The SAS coding “/~n” will generate the break line between treatment sequence and treatment, dose with units and frequency. In the same way apply a break line between dates. 
3) If medication is ongoing, replace missing resolution date per ONGOING. 
4) Sort events per Subject, Onset Date, Resolution Date, ATC and PT. 
5) For incomplete date display, refer to CDISC SDTM Implementation Guide according to ISO 8601 format. 
ATC: Anatomic Therapeutic Chemical; WHO DDE: World Health Organization Drug Dictionary Enhanced Version Sep2018, format B. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 52 of 62 
Listing 16.2.4-4 Study Drug Administration  
Subject 
Treatment 
Sequence 
Period 
Treatment 
Total Dose 
Units 
Start Date and Time 
End Date and Time 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
YYYY-MM-DDTHH:MM:SS 
YYYY-MM-DDTHH:MM:SS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 53 of 62 
Listing 16.2.4-5 Assignment to Analysis Populations 
 
Included in 
Subject 
Safety Population 
Pharmacokinetic Population 
 
 
 
101 
Y 
N 
 
 
 
 
 
 
 
 
 
Y: Yes; N: No 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 54 of 62 
Listing 16.2.6-1 Listing of Individual Actual Sampling Times and Pharmacokinetic Concentrations  
Analyte 
Subject Period Treatment 
Nominal 
Time 
Time 
Unit 
Actual 
Time 
Concentration Concentration Unit Excluded flag  Reason 
Dose Date and 
Time 
PK Sampling Date and 
Time 
Diazepam 
001 
01 
A 
0.500 
h 
0.450 
 
ng/mL 
N 
 
DDMMMYYYY/ 
HH:MM:SS 
DDMMMYYYY/ 
HH:MM:SS 
 
 
 
 
1.00 
h 
1.00 
 
ng /mL 
N 
 
 
 
 
 
 
2.00 
h 
2.01 
 
ng /mL 
Y 
inconclusive 
 
 
 
… 
… 
 
 
 
 
001 
02 
B 
0.500 
h 
0.450 
 
ng /mL 
N 
 
 
 
 
 
 
1.00 
h 
1.00 
 
ng /mL 
N 
 
 
 
2.00 
h 
2.01 
 
ng /mL 
Y 
inconclusive 
 
 
 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
002 
02 
B 
0.500 
h 
0.450 
 
ng /mL 
 
 
 
 
 
 
 
1.00 
h 
1.00 
 
ng /mL 
 
 
 
 
2.00 
h 
2.01 
 
ng /mL 
 
 
 
 
… 
… 
 
 
 
 
 
 
 
 
 
 
 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
  
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 55 of 62 
Listing 16.2.6-2 Listing of Individual Pharmacokinetic Parameters  
Analyte 
Subject 
Period 
Treatment 
Parameter 
Results 
Unit 
Excluding flag  
Reason 
Diazepam 001 
01 
A 
AUC0-t 
 
 
N 
 
 
 
AUC0-inf 
 
 
N 
 
 
 
Cmax 
 
 
Y 
Not Estimable 
 
 
 
Residual area 
 
 
Y 
Not Estimable 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
02 
B 
AUC0-t 
 
 
N 
 
 
 
 
AUC0-inf 
 
 
N 
 
 
 
Cmax 
 
 
Y 
Not Estimable 
 
 
 
Residual area 
 
 
Y 
Not Estimable 
 
 
 
 
… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
… 
 
 
 
 
 
 
 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 56 of 62 
Listing 16.2.6-3 Listing of Individual Ratios or Differences between Treatment for Pharmacokinetic Parameters  
            
Analyte 
Subject  
Parameter (unit) 
Treatment A 
Treatment B 
Treatment C 
A/B 
       C/B 
 
Unit  
Diazepam 
001 
AUC0-t (h*ng/mL) 
 
 
 
 
 
 % 
 
 
AUC0-inf (h*ng/mL) 
 
 
 
 
 
 % 
 
 
Residual Area(%) 
 
 
 
 
 
 % 
 
 
Cmax(ng/mL) 
 
 
 
 
 
 % 
 
 
Tmax (h) 
 
 
 
 
 
 h 
 
 
T½ el (h) 
 
 
 
 
 
 % 
 
 
Kel (/h) 
 
 
 
 
 
 % 
 
… 
 
 
 
 
 
 
 
 
Differences are presented for Residual area and Tmax. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 57 of 62 
Listing 16.2.7-1 Non-Treatment-Emergent Adverse Events  
Subject 
AE 
Number 
MedDRA® System Organ Class/ 
MedDRA® Preferred Term/ 
Adverse Event Description 
Onset Date and Time/ 
Resolution Date and Time 
(or Ongoing) 
Severity/ 
Relationship 
Serious 
(Yes/No) 
Action taken 
Outcome 
Study Drug 
Other 
 
 
 
 
 
 
 
 
 
 
 
SOC 1/ 
Preferred Term 1/ 
DESCRIPTION 1 
YYYY-MM-DDTHH:MM/ 
YYYY-MM-DDTHH:MM 
Severe/ 
Unrelated 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOC 2/ 
Preferred Term 2/ 
DESCRIPTION 2 
YYYY-MM-DDTHH:MM/ 
ONGOING 
Mild/ 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Notes: 
1) SOC and AE Description will be presented in uppercase. The Preferred Term will be presented in “propcase”. The SAS coding “/~n” between terms will generate the break line. 
2) The SAS coding “/~n” will generate the break line between dates and between Severity and Relationship. 
3) If needed, hardcode OUTCOME and ACTIONS in order to introduce break line (~n) between answer elements. 
4) If medication is ongoing, replace missing resolution date per ONGOING. 
5) Sort events per Subject, Onset Date/time, Resolution Date/time, SOC and PT. 
6) For incomplete date display, refer to CDISC SDTM Implementation Guide according to ISO 8601 format. 
7) Please update’ MedDRA® System Organ Class’ footnote by keeping only those SOC terms referred in table. 
MedDRA®: Medical Dictionary for Regulatory Activities (MedDRA®); MedDRA® Version 21.1. 
MedDRA® System Organ Class (SOC): Cardiac disorders (Card); Eye disorders (Eye); Gastrointestinal disorders (Gastr); General disorders and administration site conditions (Genrl); 
Infections and infestations (Infec); Injury, poisoning and procedural complications (Inj&P); Investigations (Inv); Musculoskeletal and connective tissue disorders (Musc); Nervous system 
disorders (Nerv); Psychiatric disorders (Psych); Respiratory, thoracic and mediastinal disorders (Resp); Skin and subcutaneous tissue disorders (Skin) Vascular disorders (Vasc). 
 
 
Note: The list of MedDRA® SOC will be updated according to the AEs observed for the study. 
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 58 of 62 
Listing 16.2.7-2 Treatment-Emergent Adverse Events  
Subject 
Treatment 
AE 
Number 
MedDRA® System Organ Class/ 
MedDRA® Preferred Term/ 
Adverse Event Description 
Onset Date and Time/ 
Resolution Date and Time 
(or Ongoing) 
Severity/ 
Relationship 
Serious 
(Yes/No) 
Action taken 
Outcome 
Study Drug 
Other 
 
 
 
 
 
 
 
 
 
 
001 
 
 
SOC 1/ 
Preferred Term 1/ 
DESCRIPTION 1 
YYYY-MM-DDTHH:MM/ 
YYYY-MM-DDTHH:MM 
Severe/ 
Unrelated 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SOC 2/ 
Preferred Term 2/ 
DESCRIPTION 2 
YYYY-MM-DDTHH:MM/ 
ONGOING 
Mild/ 
 
No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Notes: 
1) SOC and AE Description will be presented in uppercase. The Preferred Term will be presented in “propcase”. The SAS coding “/~n” between terms will generate the break line. 
2) The SAS coding “/~n” will generate the break line between dates and between Severity and Relationship. 
3) If needed, hardcode OUTCOME and ACTIONS in order to introduce break line (~n) between answer elements. 
4) If medication is ongoing, replace missing resolution date per ONGOING. 
5) Sort events per Subject, Onset Date/time, Resolution Date/time, SOC and PT. 
6) For incomplete date display, refer to CDISC SDTM Implementation Guide according to ISO 8601 format. 
7) Please update’ MedDRA® System Organ Class’ footnote by keeping only those SOC terms referred in table. 
MedDRA®: Medical Dictionary for Regulatory Activities (MedDRA®); MedDRA® Version 21.1. 
MedDRA® System Organ Class (SOC): Cardiac disorders (Card); Eye disorders (Eye); Gastrointestinal disorders (Gastr); General disorders and administration site conditions (Genrl); 
Infections and infestations (Infec); Injury, poisoning and procedural complications (Inj&P); Investigations (Inv); Musculoskeletal and connective tissue disorders (Musc); Nervous system 
disorders (Nerv); Psychiatric disorders (Psych); Respiratory, thoracic and mediastinal disorders (Resp); Skin and subcutaneous tissue disorders (Skin) Vascular disorders (Vasc). 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 
 
Note: The list of MedDRA® SOC will be updated according to the AEs observed for the study. 
 
Note: Similar layout will be used for Listings 16.2.7-3 and 16.2.7-4, please adapt title and footnotes accordingly.  
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 59 of 62 
Listing 16.2.8-1 Clinical Laboratory - Biochemistry 
Subject 
Period 
Treatment 
Laboratory 
Visit 
Collection Date and Time  
Parameter(unit) 
Result 
Flag 
Normal Range 
 
 
 
 
 
 
 
 
 
 
001 
 
 
 
 
YYYY-MM-DDTHH:MM 
 
 
H 
XX.X-XX.X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Notes: 
1) 
Sort assessments per Subject, Timepoint/Date and parameters. Sorting for parameter should be as defined in Summary Descriptive Statistics Table. 
2) 
For each parameter provide normal range of primary facility and, for gender specific parameters, use the same sorting of gender from demographic table. 
3) 
If multiple laboratories involved, display standard and normalised results.  Display the ranges in the same way.  The SAS coding “/~n” between results or ranges will generate the 
break line. 
Take care to use the same precision of both, standard and normalised results/ranges. 
4) 
Adapt flag footnote for Urinalysis listing per 
N: Normal result; A: Abnormal result; H: Above normal range; L: Below normal range. 
5) 
Laboratory facilities could be abbreviated with appropriation description on footnote (iHC: inVentiv Health Clinical Laboratory; BML: Biron Medical Laboratory). 
H: Above normal range; L: Below normal range; N: Normal Range. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 
Note: Similar layout will be used for Listing 16.2.8-2 and 16.2.8-3. Please adapt title and footnotes accordingly.  
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells) 
Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 60 of 62 
Listing 16.2.8-4 Vital Signs Result 
Subject 
Period 
Treatment 
Time point 
Measurement Date and Time 
Parameter(unit) 
Result 
 
 
 
 
 
 
 
 
 
 
 
YYYY-MM-DDTHH:MM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Notes: 
1) 
Sort assessments per Subject, Timepoint/Date and parameter. Parameters for each subject to be sorted as defined in Summary Descriptive Statistics Table. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 61 of 62 
 
Listing 16.2.8-5 Electrocardiogram Result 
Subject 
Period 
Treatment 
Visit 
Measurement Date and Time 
Parameter(unit) 
Result/ Interpretation* 
 
 
 
 
 
 
 
 
 
 
 
 
 
YYYY-MM-DDTHH:MM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Notes: 
1) 
Sort assessments per Subject, timepoint/Date and parameter. Parameters for each subject to be sorted as defined in Summary Descriptive Statistics Table. 
*The medical judgement for abnormal ECG interpretation is also presented in this column as CS: Clinically significant or NCS: Not clinically significant. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content);  
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
Statistical Analysis Plan (Table/Figure/Listing Shells)                                                                                                                                                 Aquestive Therapeutics 
Project 180323 
28-Jun-2019 (Final 1.0) 
Page 62 of 62 
Listing 16.2.8-6 DBF Application Site Visual Inspection 
Subject 
Time point 
Inspection Date and Time 
Result 
    Abnormality 
 
 
 
 
 
 
 
 
 
 
 
YYYY-MM-DDTHH:MM 
Normal 
 
 
 
 
 
 
Abnormal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
DBF: Diazepam Buccal Film 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


180323 Diazepam Buccal Film DRG Crossover 
Aquestive Therapeutics 
16.1.9 Documentation of Statistical Methods 
 
Confidential 
Page 4 of 11 
Final 1.0 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam – PK Population


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 27 
101 201 202 203 204 205 301 302 303 304 402 404 406 407 408 409 
410 411 412 413 414 501 502 503 505 507 508 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
54 
Number of Observations Used 
54 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) 
The GLM Procedure 
Dependent Variable: LN_AUCLST 
R-Square 
Coeff Var 
Root MSE 
LN_AUCLST Mean
0.695214 
7.128689 
0.625101 
8.768809 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.03076554 
0.03076554 
0.08 
0.7813
period 
1 
0.00220583 
0.00220583 
0.01 
0.9407
trt 
1 
0.83747933 
0.83747933 
2.14 
0.1557
subject(sequence) 
25 21.41205990 
0.85648240 
2.19 
0.0275
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.03076554 
0.03076554 
0.08 
0.7813
period 
1 
0.00653318 
0.00653318 
0.02 
0.8982
trt 
1 
0.83747933 
0.83747933 
2.14 
0.1557
subject(sequence) 
25 21.41205990 
0.85648240 
2.19 
0.0275
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.03076554 
0.03076554 
0.08 
0.7813
period 
1 
0.00653318 
0.00653318 
0.02 
0.8982
trt 
1 
0.83747933 
0.83747933 
2.14 
0.1557
subject(sequence) 
25 21.41205990 
0.85648240 
2.19 
0.0275
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.03076554 
0.03076554 
0.08 
0.7813
period 
1 
0.00653318 
0.00653318 
0.02 
0.8982
trt 
1 
0.83747933 
0.83747933 
2.14 
0.1557
subject(sequence) 
25 21.41205990 
0.85648240 
2.19 
0.0275
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.030766 
0.030766 
0.04 
0.8512
Error 
25 
21.412060 
0.856482 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F 
* period 
1 
0.002206 
0.002206 
0.01 
0.9407 
 trt 
1 
0.837479 
0.837479 
2.14 
0.1557 
 subject(sequence) 25 
21.412060 0.856482 
2.19 
0.0275 
 Error: MS(Error) 
25 
9.768787 
0.390751 
 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.030766 
0.030766 
0.04 
0.8512
Error 
25 
21.412060 
0.856482 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.006533 
0.006533 
0.02 
0.8982
trt 
1 
0.837479 
0.837479 
2.14 
0.1557
subject(sequence) 
25 21.412060 
0.856482 
2.19 
0.0275
Error: MS(Error) 
25 9.768787 
0.390751 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.030766 
0.030766 
0.04 
0.8512 
Error 
25 
21.412060 
0.856482 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.006533 
0.006533 
0.02 
0.8982
trt 
1 
0.837479 
0.837479 
2.14 
0.1557
subject(sequence) 
25 21.412060 
0.856482 
2.19 
0.0275
Error: MS(Error) 
25 9.768787 
0.390751 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.030766 
0.030766 
0.04 
0.8512
Error 
25 
21.412060 
0.856482 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.006533 
0.006533 
0.02 
0.8982
trt 
1 
0.837479 
0.837479 
2.14 
0.1557
subject(sequence) 
25 21.412060 
0.856482 
2.19 
0.0275
Error: MS(Error) 
25 9.768787 
0.390751 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) 
Least Squares Means 
trt LN_AUCLST LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
8.89431407 
0.1557
B 
8.64507378 
trt 
LN_AUCLST LSMEAN 
90% Confidence Limits 
A 
8.894314 
8.688682 
9.099946 
B 
8.645074 
8.439442 
8.850706 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.249240 
-0.041567 
0.540047 
 
Dependent Variable: LN_AUCLST 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.24924028 0.17024780 1.46 
0.1557 -0.04156692 0.54004749 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 27 
101 201 202 203 204 205 301 302 303 304 402 404 406 407 408 409 
410 411 412 413 414 501 502 503 505 507 508 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
54 
Number of Observations Used 
54 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) 
The GLM Procedure 
Dependent Variable: LN_AUCIFO 
R-Square 
Coeff Var 
Root MSE 
LN_AUCIFO Mean
0.845550 
4.690616 
0.419817 
8.950149 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.16367800 
0.16367800 
0.93 
0.3444
period 
1 
0.11005743 
0.11005743 
0.62 
0.4368
trt 
1 
0.72158060 
0.72158060 
4.09 
0.0538
subject(sequence) 
25 23.12666887 
0.92506675 
5.25 
<.0001
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.16367800 
0.16367800 
0.93 
0.3444
period 
1 
0.09003600 
0.09003600 
0.51 
0.4814
trt 
1 
0.72158060 
0.72158060 
4.09 
0.0538
subject(sequence) 
25 23.12666887 
0.92506675 
5.25 
<.0001
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.16367800 
0.16367800 
0.93 
0.3444
period 
1 
0.09003600 
0.09003600 
0.51 
0.4814
trt 
1 
0.72158060 
0.72158060 
4.09 
0.0538
subject(sequence) 
25 23.12666887 
0.92506675 
5.25 
<.0001
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.16367800 
0.16367800 
0.93 
0.3444
period 
1 
0.09003600 
0.09003600 
0.51 
0.4814
trt 
1 
0.72158060 
0.72158060 
4.09 
0.0538
subject(sequence) 
25 23.12666887 
0.92506675 
5.25 
<.0001
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.163678 
0.163678 
0.18 
0.6776
Error 
25 
23.126669 
0.925067 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F 
* period 
1 
0.110057 
0.110057 
0.62 
0.4368 
 trt 
1 
0.721581 
0.721581 
4.09 
0.0538 
 subject(sequence) 25 
23.126669 0.925067 
5.25 
<.0001 
 Error: MS(Error) 
25 
4.406161 
0.176246 
 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.163678 
0.163678 
0.18 
0.6776
Error 
25 
23.126669 
0.925067 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.090036 
0.090036 
0.51 
0.4814
trt 
1 
0.721581 
0.721581 
4.09 
0.0538
subject(sequence) 
25 23.126669 
0.925067 
5.25 
<.0001
Error: MS(Error) 
25 4.406161 
0.176246 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.163678 
0.163678 
0.18 
0.6776 
Error 
25 
23.126669 
0.925067 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.090036 
0.090036 
0.51 
0.4814
trt 
1 
0.721581 
0.721581 
4.09 
0.0538
subject(sequence) 
25 23.126669 
0.925067 
5.25 
<.0001
Error: MS(Error) 
25 4.406161 
0.176246 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.163678 
0.163678 
0.18 
0.6776
Error 
25 
23.126669 
0.925067 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.090036 
0.090036 
0.51 
0.4814
trt 
1 
0.721581 
0.721581 
4.09 
0.0538
subject(sequence) 
25 23.126669 
0.925067 
5.25 
<.0001
Error: MS(Error) 
25 4.406161 
0.176246 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) 
Least Squares Means 
trt LN_AUCIFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
9.06786545 
0.0538
B 
8.83651326 
trt 
LN_AUCIFO LSMEAN 
90% Confidence Limits 
A 
9.067865 
8.929763 
9.205967 
B 
8.836513 
8.698411 
8.974615 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.231352 
0.036046 
0.426658 
 
Dependent Variable: LN_AUCIFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 90% Confidence Limits 
A - B 
0.23135219 0.11433820 2.02 
0.0538 0.03604644 0.42665794 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 28 
101 201 202 203 204 205 301 302 303 304 402 404 406 407 408 409 
410 411 412 413 414 501 502 503 505 506 507 508 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
56 
Number of Observations Used 
56 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) 
The GLM Procedure 
Dependent Variable: LN_CMAX 
R-Square 
Coeff Var 
Root MSE 
LN_CMAX Mean
0.507826 
12.97276 
0.692244 
5.336136 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04753083 
0.04753083 
0.10 
0.7553
period 
1 
0.03349429 
0.03349429 
0.07 
0.7936
trt 
1 
0.01574029 
0.01574029 
0.03 
0.8576
subject(sequence) 
26 12.75869056 
0.49071887 
1.02 
0.4761
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04753083 
0.04753083 
0.10 
0.7553
period 
1 
0.03349429 
0.03349429 
0.07 
0.7936
trt 
1 
0.01574029 
0.01574029 
0.03 
0.8576
subject(sequence) 
26 12.75869056 
0.49071887 
1.02 
0.4761
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04753083 
0.04753083 
0.10 
0.7553
period 
1 
0.03349429 
0.03349429 
0.07 
0.7936
trt 
1 
0.01574029 
0.01574029 
0.03 
0.8576
subject(sequence) 
26 12.75869056 
0.49071887 
1.02 
0.4761
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04753083 
0.04753083 
0.10 
0.7553
period 
1 
0.03349429 
0.03349429 
0.07 
0.7936
trt 
1 
0.01574029 
0.01574029 
0.03 
0.8576
subject(sequence) 
26 12.75869056 
0.49071887 
1.02 
0.4761
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.047531 
0.047531 
0.10 
0.7581
Error 
26 
12.758691 
0.490719 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.033494 
0.033494 
0.07 
0.7936
trt 
1 
0.015740 
0.015740 
0.03 
0.8576
subject(sequence) 
26 12.758691 
0.490719 
1.02 
0.4761
Error: MS(Error) 
26 12.459242 
0.479202 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.047531 
0.047531 
0.10 
0.7581
Error 
26 
12.758691 
0.490719 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.033494 
0.033494 
0.07 
0.7936
trt 
1 
0.015740 
0.015740 
0.03 
0.8576
subject(sequence) 
26 12.758691 
0.490719 
1.02 
0.4761
Error: MS(Error) 
26 12.459242 
0.479202 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.047531 
0.047531 
0.10 
0.7581 
Error 
26 
12.758691 
0.490719 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.033494 
0.033494 
0.07 
0.7936
trt 
1 
0.015740 
0.015740 
0.03 
0.8576
subject(sequence) 
26 12.758691 
0.490719 
1.02 
0.4761
Error: MS(Error) 
26 12.459242 
0.479202 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.047531 
0.047531 
0.10 
0.7581
Error 
26 
12.758691 
0.490719 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.033494 
0.033494 
0.07 
0.7936
trt 
1 
0.015740 
0.015740 
0.03 
0.8576
subject(sequence) 
26 12.758691 
0.490719 
1.02 
0.4761
Error: MS(Error) 
26 12.459242 
0.479202 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) 
Least Squares Means 
trt 
LN_CMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
5.31937021 
0.8576
B 
5.35290089 
trt 
LN_CMAX LSMEAN 
90% Confidence Limits 
A 
5.319370 
5.096238 
5.542502 
B 
5.352901 
5.129769 
5.576033 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 
-0.033531 
-0.349087 
0.282026 
 
Dependent Variable: LN_CMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.03353068 0.18500996 -0.18 
0.8576 -0.34908699 0.28202562 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 28 
101 201 202 203 204 205 301 302 303 304 402 404 406 407 408 409 
410 411 412 413 414 501 502 503 505 506 507 508 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
55 
Number of Observations Used 
55 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
The GLM Procedure 
Dependent Variable: LN_CLFOW 
R-Square 
Coeff Var 
Root MSE 
LN_CLFOW Mean
0.855739 
-11.79232 
0.435284 
-3.691249 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.40957690 
0.40957690 
2.16 
0.1540
period 
1 
0.04998166 
0.04998166 
0.26 
0.6120
trt 
1 
1.58691124 
1.58691124 
8.38 
0.0078
subject(sequence) 
26 26.05157410 
1.00198362 
5.29 
<.0001
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.38456027 
0.38456027 
2.03 
0.1666
period 
1 
0.07279375 
0.07279375 
0.38 
0.5410
trt 
1 
1.38322100 
1.38322100 
7.30 
0.0122
subject(sequence) 
26 26.05157410 
1.00198362 
5.29 
<.0001
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.47095872 
0.47095872 
2.49 
0.1275
period 
1 
0.07279375 
0.07279375 
0.38 
0.5410
trt 
1 
1.38322100 
1.38322100 
7.30 
0.0122
subject(sequence) 
26 26.05157410 
1.00198362 
5.29 
<.0001
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.47095872 
0.47095872 
2.49 
0.1275
period 
1 
0.07279375 
0.07279375 
0.38 
0.5410
trt 
1 
1.38322100 
1.38322100 
7.30 
0.0122
subject(sequence) 
26 26.05157410 
1.00198362 
5.29 
<.0001
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.409577 
0.409577 
0.41 
0.5299
Error 
25.903 
26.164431 
1.010105 
Error: 1.01*MS(subject(sequence)) - 0.01*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
0.049982 
0.049982 
0.25 
0.6185
Error 
27.469 
5.411267 
0.196998 
Error: 0.0093*MS(subject(sequence)) + 0.9907*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
1.586911 
1.586911 
8.04 
0.0085
Error 
27.564 
5.438057 
0.197288 
Error: 0.0096*MS(subject(sequence)) + 0.9904*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
26 26.051574 
1.001984 
5.29 
<.0001
Error: MS(Error) 
25 4.736800 
0.189472 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.384560 
0.384560 
0.38 
0.5426 
Error 
25.903 
26.164357 
1.010100 
 
Error: 1.01*MS(subject(sequence)) - 0.01*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.072794 
0.072794 
0.38 
0.5410
trt 
1 
1.383221 
1.383221 
7.30 
0.0122
subject(sequence) 
26 26.051574 
1.001984 
5.29 
<.0001
Error: MS(Error) 
25 4.736800 
0.189472 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.470959 
0.470959 
0.48 
0.4958
Error 
26.182 
25.847523 
0.987232 
Error: 0.9818*MS(subject(sequence)) + 0.0182*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.072794 
0.072794 
0.38 
0.5410
trt 
1 
1.383221 
1.383221 
7.30 
0.0122
subject(sequence) 
26 26.051574 
1.001984 
5.29 
<.0001
Error: MS(Error) 
25 4.736800 
0.189472 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.470959 
0.470959 
0.48 
0.4958 
Error 
26.182 
25.847523 
0.987232 
 
Error: 0.9818*MS(subject(sequence)) + 0.0182*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.072794 
0.072794 
0.38 
0.5410
trt 
1 
1.383221 
1.383221 
7.30 
0.0122
subject(sequence) 
26 26.051574 
1.001984 
5.29 
<.0001
Error: MS(Error) 
25 4.736800 
0.189472 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
Least Squares Means 
trt 
LN_CLFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
-3.86011863 
0.0122
B 
-3.53980386 
trt 
LN_CLFOW LSMEAN 
90% Confidence Limits 
A 
-3.860119 
-4.000632 
-3.719605 
B 
-3.539804 
-3.685621 
-3.393986 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.320315 
-0.522816 
-0.117814 
 
Dependent Variable: LN_CLFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.32031478 0.11855059 -2.70 
0.0122 -0.52281587 -0.11781369 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 28 
101 201 202 203 204 205 301 302 303 304 402 404 406 407 408 409 
410 411 412 413 414 501 502 503 505 506 507 508 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
55 
Number of Observations Used 
55 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) 
The GLM Procedure 
Dependent Variable: LN_CLFO 
R-Square 
Coeff Var 
Root MSE 
LN_CLFO Mean
0.853402 
60.55102 
0.435284 
0.718871 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.10625215 
0.10625215 
0.56 
0.4609
period 
1 
0.04807082 
0.04807082 
0.25 
0.6189
trt 
1 
1.59800963 
1.59800963 
8.43 
0.0076
subject(sequence) 
26 25.82232211 
0.99316624 
5.24 
<.0001
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.09367124 
0.09367124 
0.49 
0.4885
period 
1 
0.07279375 
0.07279375 
0.38 
0.5410
trt 
1 
1.38322100 
1.38322100 
7.30 
0.0122
subject(sequence) 
26 25.82232211 
0.99316624 
5.24 
<.0001
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.14399810 
0.14399810 
0.76 
0.3916
period 
1 
0.07279375 
0.07279375 
0.38 
0.5410
trt 
1 
1.38322100 
1.38322100 
7.30 
0.0122
subject(sequence) 
26 25.82232211 
0.99316624 
5.24 
<.0001
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.14399810 
0.14399810 
0.76 
0.3916
period 
1 
0.07279375 
0.07279375 
0.38 
0.5410
trt 
1 
1.38322100 
1.38322100 
7.30 
0.0122
subject(sequence) 
26 25.82232211 
0.99316624 
5.24 
<.0001
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.106252 
0.106252 
0.11 
0.7472
Error 
25.902 
25.932889 
1.001199 
Error: 1.01*MS(subject(sequence)) - 0.01*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
0.048071 
0.048071 
0.24 
0.6252
Error 
27.447 
5.404762 
0.196916 
Error: 0.0093*MS(subject(sequence)) + 0.9907*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
1.598010 
1.598010 
8.10 
0.0083
Error 
27.542 
5.431288 
0.197203 
Error: 0.0096*MS(subject(sequence)) + 0.9904*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
26 25.822322 
0.993166 
5.24 
<.0001
Error: MS(Error) 
25 4.736800 
0.189472 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.093671 
0.093671 
0.09 
0.7621 
Error 
25.902 
25.932817 
1.001194 
 
Error: 1.01*MS(subject(sequence)) - 0.01*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.072794 
0.072794 
0.38 
0.5410
trt 
1 
1.383221 
1.383221 
7.30 
0.0122
subject(sequence) 
26 25.822322 
0.993166 
5.24 
<.0001
Error: MS(Error) 
25 4.736800 
0.189472 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.143998 
0.143998 
0.15 
0.7044
Error 
26.183 
25.622439 
0.978575 
Error: 0.9818*MS(subject(sequence)) + 0.0182*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.072794 
0.072794 
0.38 
0.5410
trt 
1 
1.383221 
1.383221 
7.30 
0.0122
subject(sequence) 
26 25.822322 
0.993166 
5.24 
<.0001
Error: MS(Error) 
25 4.736800 
0.189472 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.143998 
0.143998 
0.15 
0.7044 
Error 
26.183 
25.622439 
0.978575 
 
Error: 0.9818*MS(subject(sequence)) + 0.0182*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.072794 
0.072794 
0.38 
0.5410
trt 
1 
1.383221 
1.383221 
7.30 
0.0122
subject(sequence) 
26 25.822322 
0.993166 
5.24 
<.0001
Error: MS(Error) 
25 4.736800 
0.189472 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) 
Least Squares Means 
trt 
LN_CLFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
0.55019981 
0.0122
B 
0.87051459 
trt 
LN_CLFO LSMEAN 
90% Confidence Limits 
A 
0.550200 
0.409687 
0.690713 
B 
0.870515 
0.724697 
1.016332 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.320315 
-0.522816 
-0.117814 
 
Dependent Variable: LN_CLFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.32031478 0.11855059 -2.70 
0.0122 -0.52281587 -0.11781369 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 28 
101 201 202 203 204 205 301 302 303 304 402 404 406 407 408 409 
410 411 412 413 414 501 502 503 505 506 507 508 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
55 
Number of Observations Used 
55 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) 
The GLM Procedure 
Dependent Variable: LN_VZFOW 
R-Square 
Coeff Var 
Root MSE 
LN_VZFOW Mean
0.632660 
86.92906 
0.774751 
0.891245 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.47432211 
0.47432211 
0.79 
0.3825
period 
1 
0.06567700 
0.06567700 
0.11 
0.7436
trt 
1 
1.61360452 
1.61360452 
2.69 
0.1136
subject(sequence) 
26 23.69080306 
0.91118473 
1.52 
0.1502
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.51435042 
0.51435042 
0.86 
0.3635
period 
1 
0.03845720 
0.03845720 
0.06 
0.8022
trt 
1 
1.38527031 
1.38527031 
2.31 
0.1413
subject(sequence) 
26 23.69080306 
0.91118473 
1.52 
0.1502
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.39567269 
0.39567269 
0.66 
0.4245
period 
1 
0.03845720 
0.03845720 
0.06 
0.8022
trt 
1 
1.38527031 
1.38527031 
2.31 
0.1413
subject(sequence) 
26 23.69080306 
0.91118473 
1.52 
0.1502
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.39567269 
0.39567269 
0.66 
0.4245
period 
1 
0.03845720 
0.03845720 
0.06 
0.8022
trt 
1 
1.38527031 
1.38527031 
2.31 
0.1413
subject(sequence) 
26 23.69080306 
0.91118473 
1.52 
0.1502
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.474322 
0.474322 
0.52 
0.4779
Error 
25.661 
23.461639 
0.914293 
Error: 1.01*MS(subject(sequence)) - 0.01*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
0.065677 
0.065677 
0.11 
0.7441
Error 
25.71 
15.505995 
0.603119 
Error: 0.0093*MS(subject(sequence)) + 0.9907*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
1.613605 
1.613605 
2.67 
0.1141
Error 
25.737 
15.525466 
0.603230 
Error: 0.0096*MS(subject(sequence)) + 0.9904*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
26 23.690803 
0.911185 
1.52 
0.1502
Error: MS(Error) 
25 15.005966 
0.600239 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.514350 
0.514350 
0.56 
0.4600 
Error 
25.661 
23.461786 
0.914291 
 
Error: 1.01*MS(subject(sequence)) - 0.01*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.038457 
0.038457 
0.06 
0.8022
trt 
1 
1.385270 
1.385270 
2.31 
0.1413
subject(sequence) 
26 23.690803 
0.911185 
1.52 
0.1502
Error: MS(Error) 
25 15.005966 
0.600239 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.395673 
0.395673 
0.44 
0.5143
Error 
26.633 
24.117372 
0.905539 
Error: 0.9818*MS(subject(sequence)) + 0.0182*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.038457 
0.038457 
0.06 
0.8022
trt 
1 
1.385270 
1.385270 
2.31 
0.1413
subject(sequence) 
26 23.690803 
0.911185 
1.52 
0.1502
Error: MS(Error) 
25 15.005966 
0.600239 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.395673 
0.395673 
0.44 
0.5143
Error 
26.633 
24.117372 
0.905539 
Error: 0.9818*MS(subject(sequence)) + 0.0182*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.038457 
0.038457 
0.06 
0.8022
trt 
1 
1.385270 
1.385270 
2.31 
0.1413
subject(sequence) 
26 23.690803 
0.911185 
1.52 
0.1502
Error: MS(Error) 
25 15.005966 
0.600239 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) 
Least Squares Means 
trt 
LN_VZFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
0.72543476 
0.1413
B 
1.04598673 
trt 
LN_VZFOW LSMEAN 
90% Confidence Limits 
A 
0.725435 
0.475339 
0.975531 
B 
1.045987 
0.786450 
1.305524 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.320552 
-0.680979 
0.039875 
 
Dependent Variable: LN_VZFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.32055197 0.21100520 -1.52 
0.1413 -0.68097856 0.03987461 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 28 
101 201 202 203 204 205 301 302 303 304 402 404 406 407 408 409 
410 411 412 413 414 501 502 503 505 506 507 508 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
55 
Number of Observations Used 
55 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) 
The GLM Procedure 
Dependent Variable: LN_VZFO 
R-Square 
Coeff Var 
Root MSE 
LN_VZFO Mean
0.717804 
14.61417 
0.774751 
5.301365 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.00546546 
1.00546546 
1.68 
0.2074
period 
1 
0.06790738 
0.06790738 
0.11 
0.7394
trt 
1 
1.62479570 
1.62479570 
2.71 
0.1124
subject(sequence) 
26 35.47146425 
1.36428709 
2.27 
0.0218
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.06348469 
1.06348469 
1.77 
0.1952
period 
1 
0.03845720 
0.03845720 
0.06 
0.8022
trt 
1 
1.38527031 
1.38527031 
2.31 
0.1413
subject(sequence) 
26 35.47146425 
1.36428709 
2.27 
0.0218
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.87575663 
0.87575663 
1.46 
0.2384
period 
1 
0.03845720 
0.03845720 
0.06 
0.8022
trt 
1 
1.38527031 
1.38527031 
2.31 
0.1413
subject(sequence) 
26 35.47146425 
1.36428709 
2.27 
0.0218
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.87575663 
0.87575663 
1.46 
0.2384
period 
1 
0.03845720 
0.03845720 
0.06 
0.8022
trt 
1 
1.38527031 
1.38527031 
2.31 
0.1413
subject(sequence) 
26 35.47146425 
1.36428709 
2.27 
0.0218
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
1.005465 
1.005465 
0.73 
0.3998
Error 
25.774 
35.359383 
1.371924 
Error: 1.01*MS(subject(sequence)) - 0.01*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
0.067907 
0.067907 
0.11 
0.7408
Error 
26.062 
15.828153 
0.607316 
Error: 0.0093*MS(subject(sequence)) + 0.9907*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
1.624796 
1.624796 
2.67 
0.1140
Error 
26.104 
15.860304 
0.607588 
Error: 0.0096*MS(subject(sequence)) + 0.9904*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
26 35.471464 
1.364287 
2.27 
0.0218
Error: MS(Error) 
25 15.005966 
0.600239 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
1.063485 
1.063485 
0.78 
0.3868 
Error 
25.774 
35.359454 
1.371919 
 
Error: 1.01*MS(subject(sequence)) - 0.01*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.038457 
0.038457 
0.06 
0.8022
trt 
1 
1.385270 
1.385270 
2.31 
0.1413
subject(sequence) 
26 35.471464 
1.364287 
2.27 
0.0218
Error: MS(Error) 
25 15.005966 
0.600239 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.875757 
0.875757 
0.65 
0.4278
Error 
26.423 
35.681954 
1.350415 
Error: 0.9818*MS(subject(sequence)) + 0.0182*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.038457 
0.038457 
0.06 
0.8022
trt 
1 
1.385270 
1.385270 
2.31 
0.1413
subject(sequence) 
26 35.471464 
1.364287 
2.27 
0.0218
Error: MS(Error) 
25 15.005966 
0.600239 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.875757 
0.875757 
0.65 
0.4278
Error 
26.423 
35.681954 
1.350415 
Error: 0.9818*MS(subject(sequence)) + 0.0182*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.038457 
0.038457 
0.06 
0.8022
trt 
1 
1.385270 
1.385270 
2.31 
0.1413
subject(sequence) 
26 35.471464 
1.364287 
2.27 
0.0218
Error: MS(Error) 
25 15.005966 
0.600239 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) 
Least Squares Means 
trt 
LN_VZFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
5.13575320 
0.1413
B 
5.45630517 
trt 
LN_VZFO LSMEAN 
90% Confidence Limits 
A 
5.135753 
4.885657 
5.385849 
B 
5.456305 
5.196768 
5.715842 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.320552 
-0.680979 
0.039875 
 
Dependent Variable: LN_VZFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.32055197 0.21100520 -1.52 
0.1413 -0.68097856 0.03987461 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 28 
101 201 202 203 204 205 301 302 303 304 402 404 406 407 408 409 
410 411 412 413 414 501 502 503 505 506 507 508 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
56 
Number of Observations Used 
56 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) 
The GLM Procedure 
Dependent Variable: TMAX 
R-Square 
Coeff Var 
Root MSE 
TMAX Mean
0.501084 
86.12793 
0.961541 
1.116411 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04855716 
0.04855716 
0.05 
0.8205
period 
1 
0.16973016 
0.16973016 
0.18 
0.6718
trt 
1 
7.32326787 
7.32326787 
7.92 
0.0092
subject(sequence) 
26 16.60152389 
0.63852015 
0.69 
0.8244
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04855716 
0.04855716 
0.05 
0.8205
period 
1 
0.16973016 
0.16973016 
0.18 
0.6718
trt 
1 
7.32326787 
7.32326787 
7.92 
0.0092
subject(sequence) 
26 16.60152389 
0.63852015 
0.69 
0.8244
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04855716 
0.04855716 
0.05 
0.8205
period 
1 
0.16973016 
0.16973016 
0.18 
0.6718
trt 
1 
7.32326787 
7.32326787 
7.92 
0.0092
subject(sequence) 
26 16.60152389 
0.63852015 
0.69 
0.8244
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04855716 
0.04855716 
0.05 
0.8205
period 
1 
0.16973016 
0.16973016 
0.18 
0.6718
trt 
1 
7.32326787 
7.32326787 
7.92 
0.0092
subject(sequence) 
26 16.60152389 
0.63852015 
0.69 
0.8244
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.048557 
0.048557 
0.08 
0.7849
Error 
26 
16.601524 
0.638520 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.169730 
0.169730 
0.18 
0.6718
trt 
1 
7.323268 
7.323268 
7.92 
0.0092
subject(sequence) 
26 16.601524 
0.638520 
0.69 
0.8244
Error: MS(Error) 
26 24.038608 
0.924562 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.048557 
0.048557 
0.08 
0.7849
Error 
26 
16.601524 
0.638520 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.169730 
0.169730 
0.18 
0.6718
trt 
1 
7.323268 
7.323268 
7.92 
0.0092
subject(sequence) 
26 16.601524 
0.638520 
0.69 
0.8244
Error: MS(Error) 
26 24.038608 
0.924562 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.048557 
0.048557 
0.08 
0.7849 
Error 
26 
16.601524 
0.638520 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.169730 
0.169730 
0.18 
0.6718
trt 
1 
7.323268 
7.323268 
7.92 
0.0092
subject(sequence) 
26 16.601524 
0.638520 
0.69 
0.8244
Error: MS(Error) 
26 24.038608 
0.924562 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.048557 
0.048557 
0.08 
0.7849
Error 
26 
16.601524 
0.638520 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.169730 
0.169730 
0.18 
0.6718
trt 
1 
7.323268 
7.323268 
7.92 
0.0092
subject(sequence) 
26 16.601524 
0.638520 
0.69 
0.8244
Error: MS(Error) 
26 24.038608 
0.924562 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) 
Least Squares Means 
trt TMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 1.47803571 
0.0092
B 
0.75478571 
trt 
TMAX LSMEAN 
90% Confidence Limits 
A 
1.478036 
1.168101 
1.787971 
B 
0.754786 
0.444851 
1.064721 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.723250 
0.284936 
1.161564 
 
Dependent Variable: TMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 90% Confidence Limits 
A - B 
0.72325000 0.25698275 2.81 
0.0092 0.28493562 1.16156438 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 28 
101 201 202 203 204 205 301 302 303 304 402 404 406 407 408 409 
410 411 412 413 414 501 502 503 505 506 507 508 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
55 
Number of Observations Used 
55 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) 
The GLM Procedure 
Dependent Variable: LAMZ 
R-Square 
Coeff Var 
Root MSE 
LAMZ Mean
0.946551 
25.74042 
0.003426 
0.013309 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00056954 
0.00056954 
48.53 
<.0001
period 
1 
0.00000351 
0.00000351 
0.30 
0.5896
trt 
1 
0.00000846 
0.00000846 
0.72 
0.4039
subject(sequence) 
26 0.00461412 
0.00017747 
15.12 
<.0001
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00057011 
0.00057011 
48.58 
<.0001
period 
1 
0.00000301 
0.00000301 
0.26 
0.6167
trt 
1 
0.00000867 
0.00000867 
0.74 
0.3981
subject(sequence) 
26 0.00461412 
0.00017747 
15.12 
<.0001
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00056257 
0.00056257 
47.94 
<.0001
period 
1 
0.00000301 
0.00000301 
0.26 
0.6167
trt 
1 
0.00000867 
0.00000867 
0.74 
0.3981
subject(sequence) 
26 0.00461412 
0.00017747 
15.12 
<.0001
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00056257 
0.00056257 
47.94 
<.0001
period 
1 
0.00000301 
0.00000301 
0.26 
0.6167
trt 
1 
0.00000867 
0.00000867 
0.74 
0.3981
subject(sequence) 
26 0.00461412 
0.00017747 
15.12 
<.0001
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.000570 
0.000570 
3.18 
0.0863
Error 
25.966 
0.004651 
0.000179 
Error: 1.01*MS(subject(sequence)) - 0.01*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
0.000003505 
0.000003505 
0.26 
0.6108
Error 
31.955 
0.000424 
0.000013270 
Error: 0.0093*MS(subject(sequence)) + 0.9907*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000008459 
0.000008459 
0.63 
0.4315
Error 
32.215 
0.000429 
0.000013329 
Error: 0.0096*MS(subject(sequence)) + 0.9904*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
26 0.004614 
0.000177 
15.12 
<.0001
Error: MS(Error) 
25 0.000293 
0.000011735 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.000570 
0.000570 
3.18 
0.0861 
Error 
25.966 
0.004651 
0.000179 
 
Error: 1.01*MS(subject(sequence)) - 0.01*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000003015 
0.000003015 
0.26 
0.6167
trt 
1 
0.000008674 
0.000008674 
0.74 
0.3981
subject(sequence) 
26 0.004614 
0.000177 
15.12 
<.0001
Error: MS(Error) 
25 0.000293 
0.000011735 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000563 
0.000563 
3.22 
0.0841
Error 
26.064 
0.004547 
0.000174 
Error: 0.9818*MS(subject(sequence)) + 0.0182*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000003015 
0.000003015 
0.26 
0.6167
trt 
1 
0.000008674 
0.000008674 
0.74 
0.3981
subject(sequence) 
26 0.004614 
0.000177 
15.12 
<.0001
Error: MS(Error) 
25 0.000293 
0.000011735 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000563 
0.000563 
3.22 
0.0841
Error 
26.064 
0.004547 
0.000174 
Error: 0.9818*MS(subject(sequence)) + 0.0182*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000003015 
0.000003015 
0.26 
0.6167
trt 
1 
0.000008674 
0.000008674 
0.74 
0.3981
subject(sequence) 
26 0.004614 
0.000177 
15.12 
<.0001
Error: MS(Error) 
25 0.000293 
0.000011735 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) 
Least Squares Means 
trt LAMZ LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t| 
A 
0.01363966 
0.3981 
B 
0.01283753 
 
trt 
LAMZ LSMEAN 
90% Confidence Limits 
A 
0.013640 
0.012534 
0.014745 
B 
0.012838 
0.011690 
0.013985 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.000802 
-0.000792 
0.002396 
 
Dependent Variable: LAMZ 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.00080213 0.00093299 0.86 
0.3981 -0.00079154 0.00239581 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 28 
101 201 202 203 204 205 301 302 303 304 402 404 406 407 408 409 
410 411 412 413 414 501 502 503 505 506 507 508 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
55 
Number of Observations Used 
55 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) 
The GLM Procedure 
Dependent Variable: LAMZHL 
R-Square 
Coeff Var 
Root MSE 
LAMZHL Mean
0.606732 
108.1335 
103.9234 
96.10660 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
4800.1835 
4800.1835 
0.44 
0.5111
period 
1 
25036.9728 
25036.9728 
2.32 
0.1404
trt 
1 
15.8745 
15.8745 
0.00 
0.9697
subject(sequence) 
26 386704.1776 
14873.2376 
1.38 
0.2134
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
5200.3781 
5200.3781 
0.48 
0.4941
period 
1 
23912.6921 
23912.6921 
2.21 
0.1493
trt 
1 
35.5975 
35.5975 
0.00 
0.9547
subject(sequence) 
26 386704.1776 
14873.2376 
1.38 
0.2134
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
4819.6458 
4819.6458 
0.45 
0.5102
period 
1 
23912.6921 
23912.6921 
2.21 
0.1493
trt 
1 
35.5975 
35.5975 
0.00 
0.9547
subject(sequence) 
26 386704.1776 
14873.2376 
1.38 
0.2134
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
4819.6458 
4819.6458 
0.45 
0.5102
period 
1 
23912.6921 
23912.6921 
2.21 
0.1493
trt 
1 
35.5975 
35.5975 
0.00 
0.9547
subject(sequence) 
26 386704.1776 
14873.2376 
1.38 
0.2134
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 1 
4800.183539 
4800.183539 
0.32 
0.5754
Error 
25.626 
382189 
14914 
Error: 1.01*MS(subject(sequence)) - 0.01*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
25037 
25037 
2.31 
0.1408
Error 
25.644 
277923 
10838 
Error: 0.0093*MS(subject(sequence)) + 0.9907*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
15.874529 
15.874529 
0.00 
0.9698
Error 
25.669 
278231 
10839 
Error: 0.0096*MS(subject(sequence)) + 0.9904*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
26 386704 
14873 
1.38 
0.2134
Error: MS(Error) 
25 270002 
10800 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
5200.378088 
5200.378088 
0.35 
0.5600
Error 
25.627 
382192 
14914 
Error: 1.01*MS(subject(sequence)) - 0.01*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
23913 
23913 
2.21 
0.1493
trt 
1 
35.597453 
35.597453 
0.00 
0.9547
subject(sequence) 
26 386704 
14873 
1.38 
0.2134
Error: MS(Error) 
25 270002 
10800 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
4819.645818 
4819.645818 
0.33 
0.5730
Error 
26.698 
395110 
14799 
Error: 0.9818*MS(subject(sequence)) + 0.0182*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F 
period 
1 
23913 
23913 
2.21 
0.1493 
trt 
1 
35.597453 
35.597453 
0.00 
0.9547 
subject(sequence) 
26 386704 
14873 
1.38 
0.2134 
Error: MS(Error) 
25 270002 
10800 
 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
4819.645818 
4819.645818 
0.33 
0.5730
Error 
26.698 
395110 
14799 
Error: 0.9818*MS(subject(sequence)) + 0.0182*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
23913 
23913 
2.21 
0.1493
trt 
1 
35.597453 
35.597453 
0.00 
0.9547
subject(sequence) 
26 386704 
14873 
1.38 
0.2134
Error: MS(Error) 
25 270002 
10800 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) 
Least Squares Means 
trt 
LAMZHL LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
97.1991044 
0.9547
B 
95.5741519 
trt 
LAMZHL LSMEAN 
90% Confidence Limits 
A 
97.199104 
63.651764 
130.746444 
B 
95.574152 
60.760432 
130.387872 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 1.624952 
-46.721910 
49.971815 
 
Dependent Variable: LAMZHL 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
1.62495244 28.3037931 0.06 
0.9547 -46.72191032 49.97181521 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
9 
101 201 202 203 204 301 402 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
18 
Number of Observations Used 
18 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) 
The GLM Procedure 
Dependent Variable: LN_AUCLST 
R-Square 
Coeff Var 
Root MSE 
LN_AUCLST Mean
0.756552 
3.539328 
0.317973 
8.983989 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00053007 
0.00053007 
0.01 
0.9441
trt 
1 
0.02765765 
0.02765765 
0.27 
0.6151
subject(sequence) 
7 
2.48544900 
0.35506414 
3.51 
0.0496
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00053007 
0.00053007 
0.01 
0.9441
trt 
1 
0.02765765 
0.02765765 
0.27 
0.6151
subject(sequence) 
7 
2.48544900 
0.35506414 
3.51 
0.0496
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00053007 
0.00053007 
0.01 
0.9441
trt 
1 
0.02765765 
0.02765765 
0.27 
0.6151
subject(sequence) 
7 
2.48544900 
0.35506414 
3.51 
0.0496
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00053007 
0.00053007 
0.01 
0.9441
trt 
1 
0.02765765 
0.02765765 
0.27 
0.6151
subject(sequence) 
7 
2.48544900 
0.35506414 
3.51 
0.0496
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.000530 
0.000530 
0.00 
0.9703 
Error 
7 
2.485449 
0.355064 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.027658 
0.027658 
0.27 
0.6151
subject(sequence) 
7 
2.485449 
0.355064 
3.51 
0.0496
Error: MS(Error) 
8 
0.808854 
0.101107 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000530 
0.000530 
0.00 
0.9703
Error 
7 
2.485449 
0.355064 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.027658 
0.027658 
0.27 
0.6151
subject(sequence) 
7 
2.485449 
0.355064 
3.51 
0.0496
Error: MS(Error) 
8 
0.808854 
0.101107 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.000530 
0.000530 
0.00 
0.9703 
Error 
7 
2.485449 
0.355064 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.027658 
0.027658 
0.27 
0.6151
subject(sequence) 
7 
2.485449 
0.355064 
3.51 
0.0496
Error: MS(Error) 
8 
0.808854 
0.101107 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000530 
0.000530 
0.00 
0.9703
Error 
7 
2.485449 
0.355064 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.027658 
0.027658 
0.27 
0.6151
subject(sequence) 
7 
2.485449 
0.355064 
3.51 
0.0496
Error: MS(Error) 
8 
0.808854 
0.101107 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) 
Least Squares Means 
trt LN_AUCLST LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
8.94418393 
0.6151
C 
9.02258127 
trt 
LN_AUCLST LSMEAN 
90% Confidence Limits 
B 
8.944184 
8.746474 
9.141894 
C 
9.022581 
8.824871 
9.220291 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.078397 
-0.357132 
0.200337 
 
Dependent Variable: LN_AUCLST 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.07839735 0.14989384 0.52 
0.6151 -0.20033744 0.35713214 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
9 
101 201 202 203 204 301 402 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
18 
Number of Observations Used 
18 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) 
The GLM Procedure 
Dependent Variable: LN_AUCIFO 
R-Square 
Coeff Var 
Root MSE 
LN_AUCIFO Mean
0.808882 
3.355740 
0.305435 
9.101874 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.01021615 
0.01021615 
0.11 
0.7492
trt 
1 
0.06391088 
0.06391088 
0.69 
0.4318
subject(sequence) 
7 
3.08458984 
0.44065569 
4.72 
0.0222
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.01021615 
0.01021615 
0.11 
0.7492
trt 
1 
0.06391088 
0.06391088 
0.69 
0.4318
subject(sequence) 
7 
3.08458984 
0.44065569 
4.72 
0.0222
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.01021615 
0.01021615 
0.11 
0.7492
trt 
1 
0.06391088 
0.06391088 
0.69 
0.4318
subject(sequence) 
7 
3.08458984 
0.44065569 
4.72 
0.0222
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.01021615 
0.01021615 
0.11 
0.7492
trt 
1 
0.06391088 
0.06391088 
0.69 
0.4318
subject(sequence) 
7 
3.08458984 
0.44065569 
4.72 
0.0222
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.010216 
0.010216 
0.02 
0.8833 
Error 
7 
3.084590 
0.440656 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.063911 
0.063911 
0.69 
0.4318
subject(sequence) 
7 
3.084590 
0.440656 
4.72 
0.0222
Error: MS(Error) 
8 
0.746325 
0.093291 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.010216 
0.010216 
0.02 
0.8833
Error 
7 
3.084590 
0.440656 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.063911 
0.063911 
0.69 
0.4318
subject(sequence) 
7 
3.084590 
0.440656 
4.72 
0.0222
Error: MS(Error) 
8 
0.746325 
0.093291 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.010216 
0.010216 
0.02 
0.8833 
Error 
7 
3.084590 
0.440656 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.063911 
0.063911 
0.69 
0.4318
subject(sequence) 
7 
3.084590 
0.440656 
4.72 
0.0222
Error: MS(Error) 
8 
0.746325 
0.093291 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.010216 
0.010216 
0.02 
0.8833
Error 
7 
3.084590 
0.440656 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.063911 
0.063911 
0.69 
0.4318
subject(sequence) 
7 
3.084590 
0.440656 
4.72 
0.0222
Error: MS(Error) 
8 
0.746325 
0.093291 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) 
Least Squares Means 
trt LN_AUCIFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
9.03962326 
0.4318
C 
9.15879716 
trt 
LN_AUCIFO LSMEAN 
90% Confidence Limits 
B 
9.039623 
8.849709 
9.229538 
C 
9.158797 
8.968883 
9.348712 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.119174 
-0.386918 
0.148570 
 
Dependent Variable: LN_AUCIFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.11917390 0.14398354 0.83 
0.4318 -0.14857041 0.38691820 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
9 
101 201 202 203 204 301 402 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
18 
Number of Observations Used 
18 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) 
The GLM Procedure 
Dependent Variable: LN_CMAX 
R-Square 
Coeff Var 
Root MSE 
LN_CMAX Mean
0.611429 
8.546452 
0.452382 
5.293215 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.02048684 
0.02048684 
0.10 
0.7598
trt 
1 
0.16288431 
0.16288431 
0.80 
0.3984
subject(sequence) 
7 
2.39281131 
0.34183019 
1.67 
0.2436
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.02048684 
0.02048684 
0.10 
0.7598
trt 
1 
0.16288431 
0.16288431 
0.80 
0.3984
subject(sequence) 
7 
2.39281131 
0.34183019 
1.67 
0.2436
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.02048684 
0.02048684 
0.10 
0.7598
trt 
1 
0.16288431 
0.16288431 
0.80 
0.3984
subject(sequence) 
7 
2.39281131 
0.34183019 
1.67 
0.2436
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.02048684 
0.02048684 
0.10 
0.7598
trt 
1 
0.16288431 
0.16288431 
0.80 
0.3984
subject(sequence) 
7 
2.39281131 
0.34183019 
1.67 
0.2436
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.020487 
0.020487 
0.06 
0.8136 
Error 
7 
2.392811 
0.341830 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.162884 
0.162884 
0.80 
0.3984
subject(sequence) 
7 
2.392811 
0.341830 
1.67 
0.2436
Error: MS(Error) 
8 
1.637197 
0.204650 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.020487 
0.020487 
0.06 
0.8136
Error 
7 
2.392811 
0.341830 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.162884 
0.162884 
0.80 
0.3984
subject(sequence) 
7 
2.392811 
0.341830 
1.67 
0.2436
Error: MS(Error) 
8 
1.637197 
0.204650 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.020487 
0.020487 
0.06 
0.8136 
Error 
7 
2.392811 
0.341830 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.162884 
0.162884 
0.80 
0.3984
subject(sequence) 
7 
2.392811 
0.341830 
1.67 
0.2436
Error: MS(Error) 
8 
1.637197 
0.204650 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.020487 
0.020487 
0.06 
0.8136
Error 
7 
2.392811 
0.341830 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.162884 
0.162884 
0.80 
0.3984
subject(sequence) 
7 
2.392811 
0.341830 
1.67 
0.2436
Error: MS(Error) 
8 
1.637197 
0.204650 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) 
Least Squares Means 
trt 
LN_CMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
5.39211392 
0.3984
C 
5.20186011 
trt 
LN_CMAX LSMEAN 
90% Confidence Limits 
B 
5.392114 
5.110830 
5.673398 
C 
5.201860 
4.920576 
5.483144 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 
0.190254 
-0.206304 
0.586812 
 
Dependent Variable: LN_CMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.19025381 0.21325497 -0.89 
0.3984 -0.58681167 0.20630405 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
9 
101 201 202 203 204 301 402 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
18 
Number of Observations Used 
18 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
The GLM Procedure 
Dependent Variable: LN_CLFOW 
R-Square 
Coeff Var 
Root MSE 
LN_CLFOW Mean
0.830934 
-8.026668 
0.309145 
-3.851478 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.10324202 
0.10324202 
1.08 
0.3290
trt 
1 
0.20373302 
0.20373302 
2.13 
0.1824
subject(sequence) 
7 
3.45075985 
0.49296569 
5.16 
0.0172
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.10324202 
0.10324202 
1.08 
0.3290
trt 
1 
0.20373302 
0.20373302 
2.13 
0.1824
subject(sequence) 
7 
3.45075985 
0.49296569 
5.16 
0.0172
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.10324202 
0.10324202 
1.08 
0.3290
trt 
1 
0.20373302 
0.20373302 
2.13 
0.1824
subject(sequence) 
7 
3.45075985 
0.49296569 
5.16 
0.0172
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.10324202 
0.10324202 
1.08 
0.3290
trt 
1 
0.20373302 
0.20373302 
2.13 
0.1824
subject(sequence) 
7 
3.45075985 
0.49296569 
5.16 
0.0172
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.103242 
0.103242 
0.21 
0.6611 
Error 
7 
3.450760 
0.492966 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.203733 
0.203733 
2.13 
0.1824
subject(sequence) 
7 
3.450760 
0.492966 
5.16 
0.0172
Error: MS(Error) 
8 
0.764567 
0.095571 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.103242 
0.103242 
0.21 
0.6611
Error 
7 
3.450760 
0.492966 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.203733 
0.203733 
2.13 
0.1824
subject(sequence) 
7 
3.450760 
0.492966 
5.16 
0.0172
Error: MS(Error) 
8 
0.764567 
0.095571 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.103242 
0.103242 
0.21 
0.6611 
Error 
7 
3.450760 
0.492966 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.203733 
0.203733 
2.13 
0.1824
subject(sequence) 
7 
3.450760 
0.492966 
5.16 
0.0172
Error: MS(Error) 
8 
0.764567 
0.095571 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.103242 
0.103242 
0.21 
0.6611
Error 
7 
3.450760 
0.492966 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.203733 
0.203733 
2.13 
0.1824
subject(sequence) 
7 
3.450760 
0.492966 
5.16 
0.0172
Error: MS(Error) 
8 
0.764567 
0.095571 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
Least Squares Means 
trt 
LN_CLFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
-3.73662235 
0.1824
C 
-3.94939924 
trt 
LN_CLFOW LSMEAN 
90% Confidence Limits 
B 
-3.736622 
-3.928844 
-3.544401 
C 
-3.949399 
-4.141621 
-3.757178 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.212777 
-0.058220 
0.483774 
 
Dependent Variable: LN_CLFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.21277689 0.14573253 -1.46 
0.1824 -0.48377353 0.05821975 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
9 
101 201 202 203 204 301 402 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
18 
Number of Observations Used 
18 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) 
The GLM Procedure 
Dependent Variable: LN_CLFO 
R-Square 
Coeff Var 
Root MSE 
LN_CLFO Mean
0.836327 
52.51067 
0.309145 
0.588729 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.06051145 
0.06051145 
0.63 
0.4492
trt 
1 
0.20373302 
0.20373302 
2.13 
0.1824
subject(sequence) 
7 
3.64249195 
0.52035599 
5.44 
0.0147
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.06051145 
0.06051145 
0.63 
0.4492
trt 
1 
0.20373302 
0.20373302 
2.13 
0.1824
subject(sequence) 
7 
3.64249195 
0.52035599 
5.44 
0.0147
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.06051145 
0.06051145 
0.63 
0.4492
trt 
1 
0.20373302 
0.20373302 
2.13 
0.1824
subject(sequence) 
7 
3.64249195 
0.52035599 
5.44 
0.0147
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.06051145 
0.06051145 
0.63 
0.4492
trt 
1 
0.20373302 
0.20373302 
2.13 
0.1824
subject(sequence) 
7 
3.64249195 
0.52035599 
5.44 
0.0147
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.060511 
0.060511 
0.12 
0.7431 
Error 
7 
3.642492 
0.520356 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.203733 
0.203733 
2.13 
0.1824
subject(sequence) 
7 
3.642492 
0.520356 
5.44 
0.0147
Error: MS(Error) 
8 
0.764567 
0.095571 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.060511 
0.060511 
0.12 
0.7431
Error 
7 
3.642492 
0.520356 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.203733 
0.203733 
2.13 
0.1824
subject(sequence) 
7 
3.642492 
0.520356 
5.44 
0.0147
Error: MS(Error) 
8 
0.764567 
0.095571 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.060511 
0.060511 
0.12 
0.7431 
Error 
7 
3.642492 
0.520356 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.203733 
0.203733 
2.13 
0.1824
subject(sequence) 
7 
3.642492 
0.520356 
5.44 
0.0147
Error: MS(Error) 
8 
0.764567 
0.095571 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.060511 
0.060511 
0.12 
0.7431
Error 
7 
3.642492 
0.520356 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.203733 
0.203733 
2.13 
0.1824
subject(sequence) 
7 
3.642492 
0.520356 
5.44 
0.0147
Error: MS(Error) 
8 
0.764567 
0.095571 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) 
Least Squares Means 
trt 
LN_CLFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
0.68863474 
0.1824
C 
0.47585785 
trt 
LN_CLFO LSMEAN 
90% Confidence Limits 
B 
0.688635 
0.496413 
0.880856 
C 
0.475858 
0.283636 
0.668079 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.212777 
-0.058220 
0.483774 
 
Dependent Variable: LN_CLFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.21277689 0.14573253 -1.46 
0.1824 -0.48377353 0.05821975 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
9 
101 201 202 203 204 301 402 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
18 
Number of Observations Used 
18 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) 
The GLM Procedure 
Dependent Variable: LN_VZFOW 
R-Square 
Coeff Var 
Root MSE 
LN_VZFOW Mean
0.476731 
65.76292 
0.488595 
0.742964 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.29614945 
0.29614945 
1.24 
0.2977
trt 
1 
0.00000581 
0.00000581 
0.00 
0.9962
subject(sequence) 
7 
1.44379145 
0.20625592 
0.86 
0.5700
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.29614945 
0.29614945 
1.24 
0.2977
trt 
1 
0.00000581 
0.00000581 
0.00 
0.9962
subject(sequence) 
7 
1.44379145 
0.20625592 
0.86 
0.5700
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.29614945 
0.29614945 
1.24 
0.2977
trt 
1 
0.00000581 
0.00000581 
0.00 
0.9962
subject(sequence) 
7 
1.44379145 
0.20625592 
0.86 
0.5700
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.29614945 
0.29614945 
1.24 
0.2977
trt 
1 
0.00000581 
0.00000581 
0.00 
0.9962
subject(sequence) 
7 
1.44379145 
0.20625592 
0.86 
0.5700
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.296149 
0.296149 
1.44 
0.2698 
Error 
7 
1.443791 
0.206256 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000005808 
0.000005808 
0.00 
0.9962
subject(sequence) 
7 
1.443791 
0.206256 
0.86 
0.5700
Error: MS(Error) 
8 
1.909799 
0.238725 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.296149 
0.296149 
1.44 
0.2698
Error 
7 
1.443791 
0.206256 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000005808 
0.000005808 
0.00 
0.9962
subject(sequence) 
7 
1.443791 
0.206256 
0.86 
0.5700
Error: MS(Error) 
8 
1.909799 
0.238725 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.296149 
0.296149 
1.44 
0.2698 
Error 
7 
1.443791 
0.206256 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000005808 
0.000005808 
0.00 
0.9962
subject(sequence) 
7 
1.443791 
0.206256 
0.86 
0.5700
Error: MS(Error) 
8 
1.909799 
0.238725 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.296149 
0.296149 
1.44 
0.2698
Error 
7 
1.443791 
0.206256 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000005808 
0.000005808 
0.00 
0.9962
subject(sequence) 
7 
1.443791 
0.206256 
0.86 
0.5700
Error: MS(Error) 
8 
1.909799 
0.238725 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) 
Least Squares Means 
trt 
LN_VZFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
0.72919115 
0.9962
C 
0.72805507 
trt 
LN_VZFOW LSMEAN 
90% Confidence Limits 
B 
0.729191 
0.425391 
1.032991 
C 
0.728055 
0.424255 
1.031855 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.001136 
-0.427166 
0.429438 
 
Dependent Variable: LN_VZFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.00113608 0.23032577 -0.00 
0.9962 -0.42943792 0.42716576 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
9 
101 201 202 203 204 301 402 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
18 
Number of Observations Used 
18 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) 
The GLM Procedure 
Dependent Variable: LN_VZFO 
R-Square 
Coeff Var 
Root MSE 
LN_VZFO Mean
0.671281 
9.426561 
0.488595 
5.183171 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.23543199 
1.23543199 
5.18 
0.0525
trt 
1 
0.00000581 
0.00000581 
0.00 
0.9962
subject(sequence) 
7 
2.66458657 
0.38065522 
1.59 
0.2632
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.23543199 
1.23543199 
5.18 
0.0525
trt 
1 
0.00000581 
0.00000581 
0.00 
0.9962
subject(sequence) 
7 
2.66458657 
0.38065522 
1.59 
0.2632
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.23543199 
1.23543199 
5.18 
0.0525
trt 
1 
0.00000581 
0.00000581 
0.00 
0.9962
subject(sequence) 
7 
2.66458657 
0.38065522 
1.59 
0.2632
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.23543199 
1.23543199 
5.18 
0.0525
trt 
1 
0.00000581 
0.00000581 
0.00 
0.9962
subject(sequence) 
7 
2.66458657 
0.38065522 
1.59 
0.2632
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
1.235432 
1.235432 
3.25 
0.1146 
Error 
7 
2.664587 
0.380655 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000005808 
0.000005808 
0.00 
0.9962
subject(sequence) 
7 
2.664587 
0.380655 
1.59 
0.2632
Error: MS(Error) 
8 
1.909799 
0.238725 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.235432 
1.235432 
3.25 
0.1146
Error 
7 
2.664587 
0.380655 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000005808 
0.000005808 
0.00 
0.9962
subject(sequence) 
7 
2.664587 
0.380655 
1.59 
0.2632
Error: MS(Error) 
8 
1.909799 
0.238725 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
1.235432 
1.235432 
3.25 
0.1146 
Error 
7 
2.664587 
0.380655 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000005808 
0.000005808 
0.00 
0.9962
subject(sequence) 
7 
2.664587 
0.380655 
1.59 
0.2632
Error: MS(Error) 
8 
1.909799 
0.238725 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.235432 
1.235432 
3.25 
0.1146
Error 
7 
2.664587 
0.380655 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000005808 
0.000005808 
0.00 
0.9962
subject(sequence) 
7 
2.664587 
0.380655 
1.59 
0.2632
Error: MS(Error) 
8 
1.909799 
0.238725 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) 
Least Squares Means 
trt 
LN_VZFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
5.15444823 
0.9962
C 
5.15331216 
trt 
LN_VZFO LSMEAN 
90% Confidence Limits 
B 
5.154448 
4.850648 
5.458248 
C 
5.153312 
4.849512 
5.457112 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.001136 
-0.427166 
0.429438 
 
Dependent Variable: LN_VZFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.00113608 0.23032577 -0.00 
0.9962 -0.42943792 0.42716576 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
9 
101 201 202 203 204 301 402 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
18 
Number of Observations Used 
18 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) 
The GLM Procedure 
Dependent Variable: TMAX 
R-Square 
Coeff Var 
Root MSE 
TMAX Mean
0.631705 
72.78556 
0.933434 
1.282444 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.35576247 
0.35576247 
0.41 
0.5407
trt 
1 
7.32679200 
7.32679200 
8.41 
0.0199
subject(sequence) 
7 
4.27317898 
0.61045414 
0.70 
0.6739
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.35576247 
0.35576247 
0.41 
0.5407
trt 
1 
7.32679200 
7.32679200 
8.41 
0.0199
subject(sequence) 
7 
4.27317898 
0.61045414 
0.70 
0.6739
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.35576247 
0.35576247 
0.41 
0.5407
trt 
1 
7.32679200 
7.32679200 
8.41 
0.0199
subject(sequence) 
7 
4.27317898 
0.61045414 
0.70 
0.6739
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.35576247 
0.35576247 
0.41 
0.5407
trt 
1 
7.32679200 
7.32679200 
8.41 
0.0199
subject(sequence) 
7 
4.27317898 
0.61045414 
0.70 
0.6739
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.355762 
0.355762 
0.58 
0.4702 
Error 
7 
4.273179 
0.610454 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
7.326792 
7.326792 
8.41 
0.0199
subject(sequence) 
7 
4.273179 
0.610454 
0.70 
0.6739
Error: MS(Error) 
8 
6.970397 
0.871300 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.355762 
0.355762 
0.58 
0.4702
Error 
7 
4.273179 
0.610454 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
7.326792 
7.326792 
8.41 
0.0199
subject(sequence) 
7 
4.273179 
0.610454 
0.70 
0.6739
Error: MS(Error) 
8 
6.970397 
0.871300 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.355762 
0.355762 
0.58 
0.4702 
Error 
7 
4.273179 
0.610454 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
7.326792 
7.326792 
8.41 
0.0199
subject(sequence) 
7 
4.273179 
0.610454 
0.70 
0.6739
Error: MS(Error) 
8 
6.970397 
0.871300 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.355762 
0.355762 
0.58 
0.4702
Error 
7 
4.273179 
0.610454 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
7.326792 
7.326792 
8.41 
0.0199
subject(sequence) 
7 
4.273179 
0.610454 
0.70 
0.6739
Error: MS(Error) 
8 
6.970397 
0.871300 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) 
Least Squares Means 
trt TMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
0.66016250 
0.0199
C 
1.93616250 
trt 
TMAX LSMEAN 
90% Confidence Limits 
B 
0.660162 
0.079769 
1.240556 
C 
1.936163 
1.355769 
2.516556 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -1.276000 
-2.094248 
-0.457752 
 
Dependent Variable: TMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 90% Confidence Limits 
C - B 
1.27600000 0.44002516 2.90 
0.0199 0.45775208 2.09424792 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
9 
101 201 202 203 204 301 402 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
18 
Number of Observations Used 
18 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) 
The GLM Procedure 
Dependent Variable: LAMZ 
R-Square 
Coeff Var 
Root MSE 
LAMZ Mean
0.964128 
21.79042 
0.002662 
0.012217 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00024799 
0.00024799 
34.99 
0.0004
trt 
1 
0.00001316 
0.00001316 
1.86 
0.2100
subject(sequence) 
7 
0.00126274 
0.00018039 
25.45 
<.0001
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00024799 
0.00024799 
34.99 
0.0004
trt 
1 
0.00001316 
0.00001316 
1.86 
0.2100
subject(sequence) 
7 
0.00126274 
0.00018039 
25.45 
<.0001
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00024799 
0.00024799 
34.99 
0.0004
trt 
1 
0.00001316 
0.00001316 
1.86 
0.2100
subject(sequence) 
7 
0.00126274 
0.00018039 
25.45 
<.0001
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00024799 
0.00024799 
34.99 
0.0004
trt 
1 
0.00001316 
0.00001316 
1.86 
0.2100
subject(sequence) 
7 
0.00126274 
0.00018039 
25.45 
<.0001
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.000248 
0.000248 
1.37 
0.2793 
Error 
7 
0.001263 
0.000180 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000013165 
0.000013165 
1.86 
0.2100
subject(sequence) 
7 
0.001263 
0.000180 
25.45 
<.0001
Error: MS(Error) 
8 
0.000056699 
0.000007087 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000248 
0.000248 
1.37 
0.2793
Error 
7 
0.001263 
0.000180 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000013165 
0.000013165 
1.86 
0.2100
subject(sequence) 
7 
0.001263 
0.000180 
25.45 
<.0001
Error: MS(Error) 
8 
0.000056699 
0.000007087 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.000248 
0.000248 
1.37 
0.2793 
Error 
7 
0.001263 
0.000180 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000013165 
0.000013165 
1.86 
0.2100
subject(sequence) 
7 
0.001263 
0.000180 
25.45 
<.0001
Error: MS(Error) 
8 
0.000056699 
0.000007087 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000248 
0.000248 
1.37 
0.2793
Error 
7 
0.001263 
0.000180 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000013165 
0.000013165 
1.86 
0.2100
subject(sequence) 
7 
0.001263 
0.000180 
25.45 
<.0001
Error: MS(Error) 
8 
0.000056699 
0.000007087 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) 
Least Squares Means 
trt LAMZ LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t| 
B 
0.01348751 
0.2100 
C 
0.01177711 
 
trt 
LAMZ LSMEAN 
90% Confidence Limits 
B 
0.013488 
0.011832 
0.015143 
C 
0.011777 
0.010122 
0.013432 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.001710 
-0.000623 
0.004044 
 
Dependent Variable: LAMZ 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.00171041 0.00125498 -1.36 
0.2100 -0.00404409 0.00062328 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
9 
101 201 202 203 204 301 402 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
18 
Number of Observations Used 
18 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) 
The GLM Procedure 
Dependent Variable: LAMZHL 
R-Square 
Coeff Var 
Root MSE 
LAMZHL Mean
0.678170 
39.06391 
30.52961 
78.15299 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1843.72360 
1843.72360 
1.98 
0.1972
trt 
1 
1955.28434 
1955.28434 
2.10 
0.1855
subject(sequence) 
7 
11913.47712 
1701.92530 
1.83 
0.2085
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1843.72360 
1843.72360 
1.98 
0.1972
trt 
1 
1955.28434 
1955.28434 
2.10 
0.1855
subject(sequence) 
7 
11913.47712 
1701.92530 
1.83 
0.2085
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1843.72360 
1843.72360 
1.98 
0.1972
trt 
1 
1955.28434 
1955.28434 
2.10 
0.1855
subject(sequence) 
7 
11913.47712 
1701.92530 
1.83 
0.2085
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1843.72360 
1843.72360 
1.98 
0.1972
trt 
1 
1955.28434 
1955.28434 
2.10 
0.1855
subject(sequence) 
7 
11913.47712 
1701.92530 
1.83 
0.2085
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1843.723597 
1843.723597 
1.08 
0.3326
Error 
7 
11913 
1701.925303 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
1955.284335 
1955.284335 
2.10 
0.1855
subject(sequence) 
7 
11913 
1701.925303 
1.83 
0.2085
Error: MS(Error) 
8 
7456.458594 
932.057324 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1843.723597 
1843.723597 
1.08 
0.3326
Error 
7 
11913 
1701.925303 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
1955.284335 
1955.284335 
2.10 
0.1855
subject(sequence) 
7 
11913 
1701.925303 
1.83 
0.2085
Error: MS(Error) 
8 
7456.458594 
932.057324 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1843.723597 
1843.723597 
1.08 
0.3326
Error 
7 
11913 
1701.925303 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
1955.284335 
1955.284335 
2.10 
0.1855
subject(sequence) 
7 
11913 
1701.925303 
1.83 
0.2085
Error: MS(Error) 
8 
7456.458594 
932.057324 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1843.723597 
1843.723597 
1.08 
0.3326
Error 
7 
11913 
1701.925303 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
1955.284335 
1955.284335 
2.10 
0.1855
subject(sequence) 
7 
11913 
1701.925303 
1.83 
0.2085
Error: MS(Error) 
8 
7456.458594 
932.057324 
 


 
 
Listing 16.1.9-1 ANOVA for Treatment Comparison of Diazepam - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) 
Least Squares Means 
trt 
LAMZHL LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
66.5990342 
0.1855
C 
87.4438808 
trt 
LAMZHL LSMEAN 
90% Confidence Limits 
B 
66.599034 
47.616228 
85.581840 
C 
87.443881 
68.461075 
106.426687 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -20.844847 
-47.607086 
5.917393 
 
Dependent Variable: LAMZHL 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t|
90% Confidence Limits 
C - B 
20.8448466 
14.3917980 1.45 
0.1855-5.9173931 47.6070863 
 
 


180323 Diazepam Buccal Film DRG Crossover 
Aquestive Therapeutics 
16.1.9 Documentation of Statistical Methods 
 
Confidential 
Page 5 of 11 
Final 1.0 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam – PK Population


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*pg/mL) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 27 
101 201 202 203 204 205 301 302 303 304 402 404 406 407 408 409 
410 411 412 413 414 501 502 503 505 507 508 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
54 
Number of Observations Used 
54 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*pg/mL) 
The GLM Procedure 
Dependent Variable: LN_AUCLST 
R-Square 
Coeff Var 
Root MSE 
LN_AUCLST Mean
0.598953 
3.509791 
0.548042 
15.61468 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.19341151 
0.19341151 
0.64 
0.4298
period 
1 
0.10547371 
0.10547371 
0.35 
0.5588
trt 
1 
0.58421444 
0.58421444 
1.95 
0.1754
subject(sequence) 
25 10.33106002 
0.41324240 
1.38 
0.2153
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.19341151 
0.19341151 
0.64 
0.4298
period 
1 
0.12450538 
0.12450538 
0.41 
0.5255
trt 
1 
0.58421444 
0.58421444 
1.95 
0.1754
subject(sequence) 
25 10.33106002 
0.41324240 
1.38 
0.2153
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.19341151 
0.19341151 
0.64 
0.4298
period 
1 
0.12450538 
0.12450538 
0.41 
0.5255
trt 
1 
0.58421444 
0.58421444 
1.95 
0.1754
subject(sequence) 
25 10.33106002 
0.41324240 
1.38 
0.2153
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.19341151 
0.19341151 
0.64 
0.4298
period 
1 
0.12450538 
0.12450538 
0.41 
0.5255
trt 
1 
0.58421444 
0.58421444 
1.95 
0.1754
subject(sequence) 
25 10.33106002 
0.41324240 
1.38 
0.2153
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*pg/mL) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.193412 
0.193412 
0.47 
0.5002
Error 
25 
10.331060 
0.413242 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F 
* period 
1 
0.105474 
0.105474 
0.35 
0.5588 
 trt 
1 
0.584214 
0.584214 
1.95 
0.1754 
 subject(sequence) 25 
10.331060 0.413242 
1.38 
0.2153 
 Error: MS(Error) 
25 
7.508763 
0.300351 
 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.193412 
0.193412 
0.47 
0.5002
Error 
25 
10.331060 
0.413242 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.124505 
0.124505 
0.41 
0.5255
trt 
1 
0.584214 
0.584214 
1.95 
0.1754
subject(sequence) 
25 10.331060 
0.413242 
1.38 
0.2153
Error: MS(Error) 
25 7.508763 
0.300351 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*pg/mL) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.193412 
0.193412 
0.47 
0.5002 
Error 
25 
10.331060 
0.413242 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.124505 
0.124505 
0.41 
0.5255
trt 
1 
0.584214 
0.584214 
1.95 
0.1754
subject(sequence) 
25 10.331060 
0.413242 
1.38 
0.2153
Error: MS(Error) 
25 7.508763 
0.300351 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.193412 
0.193412 
0.47 
0.5002
Error 
25 
10.331060 
0.413242 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.124505 
0.124505 
0.41 
0.5255
trt 
1 
0.584214 
0.584214 
1.95 
0.1754
subject(sequence) 
25 10.331060 
0.413242 
1.38 
0.2153
Error: MS(Error) 
25 7.508763 
0.300351 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*pg/mL) 
Least Squares Means 
trt LN_AUCLST LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
15.7165433 
0.1754
B 
15.5083737 
trt 
LN_AUCLST LSMEAN 
90% Confidence Limits 
A 
15.716543 
15.536261 
15.896826 
B 
15.508374 
15.328091 
15.688656 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.208170 
-0.046789 
0.463128 
 
Dependent Variable: LN_AUCLST 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.20816961 0.14926067 1.39 
0.1754 -0.04678862 0.46312785 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*pg/mL) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 23 
101 201 202 203 204 205 301 302 303 304 404 407 408 410 411 412 
413 414 501 502 503 505 507 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
38 
Number of Observations Used 
38 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*pg/mL) 
The GLM Procedure 
Dependent Variable: LN_AUCIFO 
R-Square 
Coeff Var 
Root MSE 
LN_AUCIFO Mean
0.798291 
2.274302 
0.367814 
16.17260 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.03357891 
0.03357891 
0.25 
0.6267
period 
1 
0.07277073 
0.07277073 
0.54 
0.4763
trt 
1 
0.27876163 
0.27876163 
2.06 
0.1748
subject(sequence) 
21 6.57528343 
0.31310873 
2.31 
0.0612
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.01837981 
0.01837981 
0.14 
0.7184
period 
1 
0.18098559 
0.18098559 
1.34 
0.2682
trt 
1 
0.14121341 
0.14121341 
1.04 
0.3256
subject(sequence) 
21 6.57528343 
0.31310873 
2.31 
0.0612
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.02101493 
0.02101493 
0.16 
0.6999
period 
1 
0.18098559 
0.18098559 
1.34 
0.2682
trt 
1 
0.14121341 
0.14121341 
1.04 
0.3256
subject(sequence) 
21 6.57528343 
0.31310873 
2.31 
0.0612
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.02101493 
0.02101493 
0.16 
0.6999
period 
1 
0.18098559 
0.18098559 
1.34 
0.2682
trt 
1 
0.14121341 
0.14121341 
1.04 
0.3256
subject(sequence) 
21 6.57528343 
0.31310873 
2.31 
0.0612
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*pg/mL) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.033579 
0.033579 
0.10 
0.7532
Error 
19.404 
6.404979 
0.330078 
Error: 1.0954*MS(subject(sequence)) - 0.0954*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
0.072771 
0.072771 
0.46 
0.5049
Error 
21.876 
3.462747 
0.158289 
Error: 0.1294*MS(subject(sequence)) + 0.8706*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.278762 
0.278762 
1.74 
0.2004
Error 
22.69 
3.636742 
0.160278 
Error: 0.1405*MS(subject(sequence)) + 0.8595*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
21 6.575283 
0.313109 
2.31 
0.0612
Error: MS(Error) 
13 1.758730 
0.135287 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*pg/mL) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.018380 
0.018380 
0.06 
0.8159
Error 
19.415 
6.406079 
0.329958 
Error: 1.0948*MS(subject(sequence)) - 0.0948*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.180986 
0.180986 
1.34 
0.2682
trt 
1 
0.141213 
0.141213 
1.04 
0.3256
subject(sequence) 
21 6.575283 
0.313109 
2.31 
0.0612
Error: MS(Error) 
13 1.758730 
0.135287 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.021015 
0.021015 
0.07 
0.7896
Error 
23.811 
6.873102 
0.288651 
Error: 0.8625*MS(subject(sequence)) + 0.1375*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.180986 
0.180986 
1.34 
0.2682
trt 
1 
0.141213 
0.141213 
1.04 
0.3256
subject(sequence) 
21 6.575283 
0.313109 
2.31 
0.0612
Error: MS(Error) 
13 1.758730 
0.135287 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*pg/mL) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.021015 
0.021015 
0.07 
0.7896
Error 
23.811 
6.873102 
0.288651 
Error: 0.8625*MS(subject(sequence)) + 0.1375*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.180986 
0.180986 
1.34 
0.2682
trt 
1 
0.141213 
0.141213 
1.04 
0.3256
subject(sequence) 
21 6.575283 
0.313109 
2.31 
0.0612
Error: MS(Error) 
13 1.758730 
0.135287 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*pg/mL) 
Least Squares Means 
trt LN_AUCIFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
16.3376718 
0.3256
B 
16.1976255 
trt 
LN_AUCIFO LSMEAN 
90% Confidence Limits 
A 
16.337672 
16.182337 
16.493007 
B 
16.197625 
16.019279 
16.375972 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.140046 
-0.102706 
0.382799 
 
Dependent Variable: LN_AUCIFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.14004633 0.13707607 1.02 
0.3256 -0.10270627 0.38279892 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (pg/mL) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 28 
101 201 202 203 204 205 301 302 303 304 402 404 406 407 408 409 
410 411 412 413 414 501 502 503 505 506 507 508 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
56 
Number of Observations Used 
56 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (pg/mL) 
The GLM Procedure 
Dependent Variable: LN_CMAX 
R-Square 
Coeff Var 
Root MSE 
LN_CMAX Mean
0.652247 
5.248044 
0.551299 
10.50485 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.00601538 
1.00601538 
3.31 
0.0804
period 
1 
0.05642288 
0.05642288 
0.19 
0.6701
trt 
1 
0.63660316 
0.63660316 
2.09 
0.1598
subject(sequence) 
26 13.12238367 
0.50470706 
1.66 
0.1013
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.00601538 
1.00601538 
3.31 
0.0804
period 
1 
0.05642288 
0.05642288 
0.19 
0.6701
trt 
1 
0.63660316 
0.63660316 
2.09 
0.1598
subject(sequence) 
26 13.12238367 
0.50470706 
1.66 
0.1013
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.00601538 
1.00601538 
3.31 
0.0804
period 
1 
0.05642288 
0.05642288 
0.19 
0.6701
trt 
1 
0.63660316 
0.63660316 
2.09 
0.1598
subject(sequence) 
26 13.12238367 
0.50470706 
1.66 
0.1013
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.00601538 
1.00601538 
3.31 
0.0804
period 
1 
0.05642288 
0.05642288 
0.19 
0.6701
trt 
1 
0.63660316 
0.63660316 
2.09 
0.1598
subject(sequence) 
26 13.12238367 
0.50470706 
1.66 
0.1013
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (pg/mL) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.006015 
1.006015 
1.99 
0.1699
Error 
26 
13.122384 
0.504707 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.056423 
0.056423 
0.19 
0.6701
trt 
1 
0.636603 
0.636603 
2.09 
0.1598
subject(sequence) 
26 13.122384 
0.504707 
1.66 
0.1013
Error: MS(Error) 
26 7.902201 
0.303931 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.006015 
1.006015 
1.99 
0.1699
Error 
26 
13.122384 
0.504707 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.056423 
0.056423 
0.19 
0.6701
trt 
1 
0.636603 
0.636603 
2.09 
0.1598
subject(sequence) 
26 13.122384 
0.504707 
1.66 
0.1013
Error: MS(Error) 
26 7.902201 
0.303931 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (pg/mL) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
1.006015 
1.006015 
1.99 
0.1699 
Error 
26 
13.122384 
0.504707 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.056423 
0.056423 
0.19 
0.6701
trt 
1 
0.636603 
0.636603 
2.09 
0.1598
subject(sequence) 
26 13.122384 
0.504707 
1.66 
0.1013
Error: MS(Error) 
26 7.902201 
0.303931 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.006015 
1.006015 
1.99 
0.1699
Error 
26 
13.122384 
0.504707 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.056423 
0.056423 
0.19 
0.6701
trt 
1 
0.636603 
0.636603 
2.09 
0.1598
subject(sequence) 
26 13.122384 
0.504707 
1.66 
0.1013
Error: MS(Error) 
26 7.902201 
0.303931 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (pg/mL) 
Least Squares Means 
trt 
LN_CMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
10.6114713 
0.1598
B 
10.3982305 
trt 
LN_CMAX LSMEAN 
90% Confidence Limits 
A 
10.611471 
10.433770 
10.789172 
B 
10.398230 
10.220529 
10.575932 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.213241 
-0.038066 
0.464548 
 
Dependent Variable: LN_CMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.21324084 0.14734091 1.45 
0.1598 -0.03806646 0.46454814 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 23 
101 201 202 203 204 205 301 302 303 304 404 407 408 410 411 412 
413 414 501 502 503 505 507 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
38 
Number of Observations Used 
38 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
The GLM Procedure 
Dependent Variable: LN_CLFOW 
R-Square 
Coeff Var 
Root MSE 
LN_CLFOW Mean
0.809488 
-9.734415 
0.385756 
-3.962809 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.08291686 
0.08291686 
0.56 
0.4687
period 
1 
0.03561332 
0.03561332 
0.24 
0.6328
trt 
1 
0.70236923 
0.70236923 
4.72 
0.0489
subject(sequence) 
21 7.39881399 
0.35232448 
2.37 
0.0564
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.03880462 
0.03880462 
0.26 
0.6182
period 
1 
0.16754588 
0.16754588 
1.13 
0.3080
trt 
1 
0.31055767 
0.31055767 
2.09 
0.1722
subject(sequence) 
21 7.39881399 
0.35232448 
2.37 
0.0564
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.05903403 
0.05903403 
0.40 
0.5397
period 
1 
0.16754588 
0.16754588 
1.13 
0.3080
trt 
1 
0.31055767 
0.31055767 
2.09 
0.1722
subject(sequence) 
21 7.39881399 
0.35232448 
2.37 
0.0564
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.05903403 
0.05903403 
0.40 
0.5397
period 
1 
0.16754588 
0.16754588 
1.13 
0.3080
trt 
1 
0.31055767 
0.31055767 
2.09 
0.1722
subject(sequence) 
21 7.39881399 
0.35232448 
2.37 
0.0564
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.082917 
0.082917 
0.22 
0.6420
Error 
19.441 
7.226947 
0.371746 
Error: 1.0954*MS(subject(sequence)) - 0.0954*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
0.035613 
0.035613 
0.20 
0.6564
Error 
22.064 
3.864214 
0.175134 
Error: 0.1294*MS(subject(sequence)) + 0.8706*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.702369 
0.702369 
3.96 
0.0587
Error 
22.891 
4.061091 
0.177411 
Error: 0.1405*MS(subject(sequence)) + 0.8595*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
21 7.398814 
0.352324 
2.37 
0.0564
Error: MS(Error) 
13 1.934503 
0.148808 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.038805 
0.038805 
0.10 
0.7500
Error 
19.451 
7.228050 
0.371608 
Error: 1.0948*MS(subject(sequence)) - 0.0948*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.167546 
0.167546 
1.13 
0.3080
trt 
1 
0.310558 
0.310558 
2.09 
0.1722
subject(sequence) 
21 7.398814 
0.352324 
2.37 
0.0564
Error: MS(Error) 
13 1.934503 
0.148808 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.059034 
0.059034 
0.18 
0.6735
Error 
23.75 
7.702956 
0.324333 
Error: 0.8625*MS(subject(sequence)) + 0.1375*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.167546 
0.167546 
1.13 
0.3080
trt 
1 
0.310558 
0.310558 
2.09 
0.1722
subject(sequence) 
21 7.398814 
0.352324 
2.37 
0.0564
Error: MS(Error) 
13 1.934503 
0.148808 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.059034 
0.059034 
0.18 
0.6735
Error 
23.75 
7.702956 
0.324333 
Error: 0.8625*MS(subject(sequence)) + 0.1375*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.167546 
0.167546 
1.13 
0.3080
trt 
1 
0.310558 
0.310558 
2.09 
0.1722
subject(sequence) 
21 7.398814 
0.352324 
2.37 
0.0564
Error: MS(Error) 
13 1.934503 
0.148808 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
Least Squares Means 
trt 
LN_CLFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
-4.17286608 
0.1722
B 
-3.96518120 
trt 
LN_CLFOW LSMEAN 
90% Confidence Limits 
A 
-4.172866 
-4.335778 
-4.009954 
B 
-3.965181 
-4.152228 
-3.778135 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.207685 
-0.462279 
0.046910 
 
Dependent Variable: LN_CLFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.20768488 0.14376288 -1.44 
0.1722 -0.46227937 0.04690961 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 23 
101 201 202 203 204 205 301 302 303 304 404 407 408 410 411 412 
413 414 501 502 503 505 507 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
38 
Number of Observations Used 
38 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) 
The GLM Procedure 
Dependent Variable: LN_CLFO 
R-Square 
Coeff Var 
Root MSE 
LN_CLFO Mean
0.772445 
101.1422 
0.385756 
0.381400 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.01820094 
0.01820094 
0.12 
0.7321
period 
1 
0.15040156 
0.15040156 
1.01 
0.3331
trt 
1 
0.36542174 
0.36542174 
2.46 
0.1411
subject(sequence) 
21 6.03273972 
0.28727332 
1.93 
0.1119
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00740836 
0.00740836 
0.05 
0.8269
period 
1 
0.16754588 
0.16754588 
1.13 
0.3080
trt 
1 
0.31055767 
0.31055767 
2.09 
0.1722
subject(sequence) 
21 6.03273972 
0.28727332 
1.93 
0.1119
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00335522 
0.00335522 
0.02 
0.8829
period 
1 
0.16754588 
0.16754588 
1.13 
0.3080
trt 
1 
0.31055767 
0.31055767 
2.09 
0.1722
subject(sequence) 
21 6.03273972 
0.28727332 
1.93 
0.1119
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00335522 
0.00335522 
0.02 
0.8829
period 
1 
0.16754588 
0.16754588 
1.13 
0.3080
trt 
1 
0.31055767 
0.31055767 
2.09 
0.1722
subject(sequence) 
21 6.03273972 
0.28727332 
1.93 
0.1119
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.018201 
0.018201 
0.06 
0.8082
Error 
19.085 
5.734701 
0.300487 
Error: 1.0954*MS(subject(sequence)) - 0.0954*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
0.150402 
0.150402 
0.90 
0.3533
Error 
20.484 
3.414999 
0.166719 
Error: 0.1294*MS(subject(sequence)) + 0.8706*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.365422 
0.365422 
2.17 
0.1553
Error 
21.196 
3.566563 
0.168268 
Error: 0.1405*MS(subject(sequence)) + 0.8595*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
21 6.032740 
0.287273 
1.93 
0.1119
Error: MS(Error) 
13 1.934503 
0.148808 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.007408 
0.007408 
0.02 
0.8769
Error 
19.097 
5.736667 
0.300393 
Error: 1.0948*MS(subject(sequence)) - 0.0948*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.167546 
0.167546 
1.13 
0.3080
trt 
1 
0.310558 
0.310558 
2.09 
0.1722
subject(sequence) 
21 6.032740 
0.287273 
1.93 
0.1119
Error: MS(Error) 
13 1.934503 
0.148808 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.003355 
0.003355 
0.01 
0.9119
Error 
24.345 
6.529893 
0.268229 
Error: 0.8625*MS(subject(sequence)) + 0.1375*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.167546 
0.167546 
1.13 
0.3080
trt 
1 
0.310558 
0.310558 
2.09 
0.1722
subject(sequence) 
21 6.032740 
0.287273 
1.93 
0.1119
Error: MS(Error) 
13 1.934503 
0.148808 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.003355 
0.003355 
0.01 
0.9119
Error 
24.345 
6.529893 
0.268229 
Error: 0.8625*MS(subject(sequence)) + 0.1375*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.167546 
0.167546 
1.13 
0.3080
trt 
1 
0.310558 
0.310558 
2.09 
0.1722
subject(sequence) 
21 6.032740 
0.287273 
1.93 
0.1119
Error: MS(Error) 
13 1.934503 
0.148808 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) 
Least Squares Means 
trt 
LN_CLFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
0.18972659 
0.1722
B 
0.39741148 
trt 
LN_CLFO LSMEAN 
90% Confidence Limits 
A 
0.189727 
0.026814 
0.352639 
B 
0.397411 
0.210365 
0.584458 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.207685 
-0.462279 
0.046910 
 
Dependent Variable: LN_CLFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.20768488 0.14376288 -1.44 
0.1722 -0.46227937 0.04690961 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 23 
101 201 202 203 204 205 301 302 303 304 404 407 408 410 411 412 
413 414 501 502 503 505 507 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
38 
Number of Observations Used 
38 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) 
The GLM Procedure 
Dependent Variable: LN_VZFOW 
R-Square 
Coeff Var 
Root MSE 
LN_VZFOW Mean
0.868076 
29.95886 
0.380787 
1.271034 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.17703292 
0.17703292 
1.22 
0.2892
period 
1 
0.35833365 
0.35833365 
2.47 
0.1400
trt 
1 
0.53284924 
0.53284924 
3.67 
0.0775
subject(sequence) 
21 11.33526148 
0.53977436 
3.72 
0.0091
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.21714612 
0.21714612 
1.50 
0.2428
period 
1 
0.10125275 
0.10125275 
0.70 
0.4184
trt 
1 
0.23872722 
0.23872722 
1.65 
0.2219
subject(sequence) 
21 11.33526148 
0.53977436 
3.72 
0.0091
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.01415919 
0.01415919 
0.10 
0.7596
period 
1 
0.10125275 
0.10125275 
0.70 
0.4184
trt 
1 
0.23872722 
0.23872722 
1.65 
0.2219
subject(sequence) 
21 11.33526148 
0.53977436 
3.72 
0.0091
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.01415919 
0.01415919 
0.10 
0.7596
period 
1 
0.10125275 
0.10125275 
0.70 
0.4184
trt 
1 
0.23872722 
0.23872722 
1.65 
0.2219
subject(sequence) 
21 11.33526148 
0.53977436 
3.72 
0.0091
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.177033 
0.177033 
0.31 
0.5859
Error 
20.011 
11.555255 
0.577447 
Error: 1.0954*MS(subject(sequence)) - 0.0954*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
0.358334 
0.358334 
1.83 
0.1879
Error 
26.364 
5.169085 
0.196065 
Error: 0.1294*MS(subject(sequence)) + 0.8706*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.532849 
0.532849 
2.66 
0.1145
Error 
27.367 
5.486520 
0.200482 
Error: 0.1405*MS(subject(sequence)) + 0.8595*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
21 11.335261 
0.539774 
3.72 
0.0091
Error: MS(Error) 
13 1.884985 
0.144999 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.217146 
0.217146 
0.38 
0.5465
Error 
20.017 
11.553626 
0.577180 
Error: 1.0948*MS(subject(sequence)) - 0.0948*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.101253 
0.101253 
0.70 
0.4184
trt 
1 
0.238727 
0.238727 
1.65 
0.2219
subject(sequence) 
21 11.335261 
0.539774 
3.72 
0.0091
Error: MS(Error) 
13 1.884985 
0.144999 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.014159 
0.014159 
0.03 
0.8659
Error 
22.77 
11.054446 
0.485476 
Error: 0.8625*MS(subject(sequence)) + 0.1375*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.101253 
0.101253 
0.70 
0.4184
trt 
1 
0.238727 
0.238727 
1.65 
0.2219
subject(sequence) 
21 11.335261 
0.539774 
3.72 
0.0091
Error: MS(Error) 
13 1.884985 
0.144999 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.014159 
0.014159 
0.03 
0.8659
Error 
22.77 
11.054446 
0.485476 
Error: 0.8625*MS(subject(sequence)) + 0.1375*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.101253 
0.101253 
0.70 
0.4184
trt 
1 
0.238727 
0.238727 
1.65 
0.2219
subject(sequence) 
21 11.335261 
0.539774 
3.72 
0.0091
Error: MS(Error) 
13 1.884985 
0.144999 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) 
Least Squares Means 
trt 
LN_VZFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
1.20517079 
0.2219
B 
1.38726022 
trt 
LN_VZFOW LSMEAN 
90% Confidence Limits 
A 
1.205171 
1.044357 
1.365984 
B 
1.387260 
1.202623 
1.571897 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.182089 
-0.433404 
0.069225 
 
Dependent Variable: LN_VZFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.18208942 0.14191099 -1.28 
0.2219 -0.43340434 0.06922549 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 23 
101 201 202 203 204 205 301 302 303 304 404 407 408 410 411 412 
413 414 501 502 503 505 507 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
38 
Number of Observations Used 
38 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) 
The GLM Procedure 
Dependent Variable: LN_VZFO 
R-Square 
Coeff Var 
Root MSE 
LN_VZFO Mean
0.913813 
6.781312 
0.380787 
5.615243 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.32924050 
0.32924050 
2.27 
0.1558
period 
1 
0.63634324 
0.63634324 
4.39 
0.0563
trt 
1 
0.24640477 
0.24640477 
1.70 
0.2150
subject(sequence) 
21 18.77380507 
0.89399072 
6.17 
0.0008
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.33282108 
0.33282108 
2.30 
0.1537
period 
1 
0.10125275 
0.10125275 
0.70 
0.4184
trt 
1 
0.23872722 
0.23872722 
1.65 
0.2219
subject(sequence) 
21 18.77380507 
0.89399072 
6.17 
0.0008
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.09243872 
0.09243872 
0.64 
0.4390
period 
1 
0.10125275 
0.10125275 
0.70 
0.4184
trt 
1 
0.23872722 
0.23872722 
1.65 
0.2219
subject(sequence) 
21 18.77380507 
0.89399072 
6.17 
0.0008
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.09243872 
0.09243872 
0.64 
0.4390
period 
1 
0.10125275 
0.10125275 
0.70 
0.4184
trt 
1 
0.23872722 
0.23872722 
1.65 
0.2219
subject(sequence) 
21 18.77380507 
0.89399072 
6.17 
0.0008
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.329240 
0.329240 
0.34 
0.5656
Error 
20.404 
19.699538 
0.965466 
Error: 1.0954*MS(subject(sequence)) - 0.0954*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
0.636343 
0.636343 
2.63 
0.1148
Error 
31.409 
7.597440 
0.241884 
Error: 0.1294*MS(subject(sequence)) + 0.8706*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.246405 
0.246405 
0.98 
0.3285
Error 
32.179 
8.053252 
0.250264 
Error: 0.1405*MS(subject(sequence)) + 0.8595*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
21 18.773805 
0.893991 
6.17 
0.0008
Error: MS(Error) 
13 1.884985 
0.144999 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.332821 
0.332821 
0.34 
0.5635
Error 
20.408 
19.692930 
0.964959 
Error: 1.0948*MS(subject(sequence)) - 0.0948*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.101253 
0.101253 
0.70 
0.4184
trt 
1 
0.238727 
0.238727 
1.65 
0.2219
subject(sequence) 
21 18.773805 
0.893991 
6.17 
0.0008
Error: MS(Error) 
13 1.884985 
0.144999 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.092439 
0.092439 
0.12 
0.7357
Error 
22.077 
17.461966 
0.790973 
Error: 0.8625*MS(subject(sequence)) + 0.1375*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.101253 
0.101253 
0.70 
0.4184
trt 
1 
0.238727 
0.238727 
1.65 
0.2219
subject(sequence) 
21 18.773805 
0.893991 
6.17 
0.0008
Error: MS(Error) 
13 1.884985 
0.144999 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.092439 
0.092439 
0.12 
0.7357
Error 
22.077 
17.461966 
0.790973 
Error: 0.8625*MS(subject(sequence)) + 0.1375*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.101253 
0.101253 
0.70 
0.4184
trt 
1 
0.238727 
0.238727 
1.65 
0.2219
subject(sequence) 
21 18.773805 
0.893991 
6.17 
0.0008
Error: MS(Error) 
13 1.884985 
0.144999 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) 
Least Squares Means 
trt 
LN_VZFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
5.56776347 
0.2219
B 
5.74985289 
trt 
LN_VZFO LSMEAN 
90% Confidence Limits 
A 
5.567763 
5.406950 
5.728577 
B 
5.749853 
5.565216 
5.934490 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.182089 
-0.433404 
0.069225 
 
Dependent Variable: LN_VZFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.18208942 0.14191099 -1.28 
0.2219 -0.43340434 0.06922549 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 28 
101 201 202 203 204 205 301 302 303 304 402 404 406 407 408 409 
410 411 412 413 414 501 502 503 505 506 507 508 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
56 
Number of Observations Used 
56 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) 
The GLM Procedure 
Dependent Variable: TMAX 
R-Square 
Coeff Var 
Root MSE 
TMAX Mean
0.862069 
30.47680 
34.15705 
112.0756 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
17217.7568 
17217.7568 
14.76 
0.0007
period 
1 
1236.4385 
1236.4385 
1.06 
0.3127
trt 
1 
679.7005 
679.7005 
0.58 
0.4522
subject(sequence) 
26 170454.9347 
6555.9590 
5.62 
<.0001
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
17217.7568 
17217.7568 
14.76 
0.0007
period 
1 
1236.4385 
1236.4385 
1.06 
0.3127
trt 
1 
679.7005 
679.7005 
0.58 
0.4522
subject(sequence) 
26 170454.9347 
6555.9590 
5.62 
<.0001
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
17217.7568 
17217.7568 
14.76 
0.0007
period 
1 
1236.4385 
1236.4385 
1.06 
0.3127
trt 
1 
679.7005 
679.7005 
0.58 
0.4522
subject(sequence) 
26 170454.9347 
6555.9590 
5.62 
<.0001
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
17217.7568 
17217.7568 
14.76 
0.0007
period 
1 
1236.4385 
1236.4385 
1.06 
0.3127
trt 
1 
679.7005 
679.7005 
0.58 
0.4522
subject(sequence) 
26 170454.9347 
6555.9590 
5.62 
<.0001
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
17218 
17218 
2.63 
0.1172 
Error 
26 
170455 
6555.959028 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
period 
1 
1236.438473 
1236.438473 
1.06 
0.3127
trt 
1 
679.700529 
679.700529 
0.58 
0.4522
subject(sequence) 
26 170455 
6555.959028 
5.62 
<.0001
Error: MS(Error) 
26 30334 
1166.704165 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
17218 
17218 
2.63 
0.1172
Error 
26 
170455 
6555.959028 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
1236.438473 
1236.438473 
1.06 
0.3127
trt 
1 
679.700529 
679.700529 
0.58 
0.4522
subject(sequence) 
26 170455 
6555.959028 
5.62 
<.0001
Error: MS(Error) 
26 30334 
1166.704165 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
17218 
17218 
2.63 
0.1172 
Error 
26 
170455 
6555.959028 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
1236.438473 
1236.438473 
1.06 
0.3127
trt 
1 
679.700529 
679.700529 
0.58 
0.4522
subject(sequence) 
26 170455 
6555.959028 
5.62 
<.0001
Error: MS(Error) 
26 30334 
1166.704165 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
17218 
17218 
2.63 
0.1172
Error 
26 
170455 
6555.959028 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
1236.438473 
1236.438473 
1.06 
0.3127
trt 
1 
679.700529 
679.700529 
0.58 
0.4522
subject(sequence) 
26 170455 
6555.959028 
5.62 
<.0001
Error: MS(Error) 
26 30334 
1166.704165 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) 
Least Squares Means 
trt TMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 115.559464 
0.4522
B 
108.591679 
trt TMAX LSMEAN 
90% Confidence Limits 
A 
115.559464 
104.549571 
126.569358 
B 
108.591679 
97.581785 
119.601572 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 6.967786 
-8.602555 
22.538126 
 
Dependent Variable: TMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
6.96778571 9.12885599 0.76 
0.4522 -8.60255466 22.53812609 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 23 
101 201 202 203 204 205 301 302 303 304 404 407 408 410 411 412 
413 414 501 502 503 505 507 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
38 
Number of Observations Used 
38 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) 
The GLM Procedure 
Dependent Variable: LAMZ 
R-Square 
Coeff Var 
Root MSE 
LAMZ Mean
0.982877 
17.62657 
0.001282 
0.007272 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00012625 
0.00012625 
76.83 
<.0001
period 
1 
0.00000679 
0.00000679 
4.13 
0.0631
trt 
1 
0.00000006 
0.00000006 
0.04 
0.8537
subject(sequence) 
21 0.00109304 
0.00005205 
31.68 
<.0001
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00011961 
0.00011961 
72.79 
<.0001
period 
1 
0.00000016 
0.00000016 
0.10 
0.7608
trt 
1 
0.00000000 
0.00000000 
0.00 
0.9849
subject(sequence) 
21 0.00109304 
0.00005205 
31.68 
<.0001
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00007798 
0.00007798 
47.46 
<.0001
period 
1 
0.00000016 
0.00000016 
0.10 
0.7608
trt 
1 
0.00000000 
0.00000000 
0.00 
0.9849
subject(sequence) 
21 0.00109304 
0.00005205 
31.68 
<.0001
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00007798 
0.00007798 
47.46 
<.0001
period 
1 
0.00000016 
0.00000016 
0.10 
0.7608
trt 
1 
0.00000000 
0.00000000 
0.00 
0.9849
subject(sequence) 
21 0.00109304 
0.00005205 
31.68 
<.0001
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.000126 
0.000126 
2.22 
0.1511
Error 
20.884 
0.001187 
0.000056860 
Error: 1.0954*MS(subject(sequence)) - 0.0954*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
0.000006786 
0.000006786 
0.83 
0.3695
Error 
28.774 
0.000235 
0.000008163 
Error: 0.1294*MS(subject(sequence)) + 0.8706*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
5.810284E-8 
5.810284E-8 
0.01 
0.9355
Error 
28.194 
0.000246 
0.000008727 
Error: 0.1405*MS(subject(sequence)) + 0.8595*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
21 0.001093 
0.000052050 
31.68 
<.0001
Error: MS(Error) 
13 0.000021361 
0.000001643 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000120 
0.000120 
2.10 
0.1617
Error 
20.885 
0.001187 
0.000056826 
Error: 1.0948*MS(subject(sequence)) - 0.0948*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000000159 
0.000000159 
0.10 
0.7608
trt 
1 
6.101771E-10 
6.101771E-10 
0.00 
0.9849
subject(sequence) 
21 0.001093 
0.000052050 
31.68 
<.0001
Error: MS(Error) 
13 0.000021361 
0.000001643 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000077983 
0.000077983 
1.73 
0.2026
Error 
21.211 
0.000957 
0.000045117 
Error: 0.8625*MS(subject(sequence)) + 0.1375*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000000159 
0.000000159 
0.10 
0.7608
trt 
1 
6.101771E-10 
6.101771E-10 
0.00 
0.9849
subject(sequence) 
21 0.001093 
0.000052050 
31.68 
<.0001
Error: MS(Error) 
13 0.000021361 
0.000001643 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000077983 
0.000077983 
1.73 
0.2026
Error 
21.211 
0.000957 
0.000045117 
Error: 0.8625*MS(subject(sequence)) + 0.1375*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000000159 
0.000000159 
0.10 
0.7608
trt 
1 
6.101771E-10 
6.101771E-10 
0.00 
0.9849
subject(sequence) 
21 0.001093 
0.000052050 
31.68 
<.0001
Error: MS(Error) 
13 0.000021361 
0.000001643 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) 
Least Squares Means 
trt LAMZ LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t| 
A 
0.00646826 
0.9849 
B 
0.00647746 
 
trt 
LAMZ LSMEAN 
90% Confidence Limits 
A 
0.006468 
0.005927 
0.007010 
B 
0.006477 
0.005856 
0.007099 
Least Squares Means for Effect trt 
i 
j 
Difference Between Means 
90% Confidence Limits for 
LSMean(i)-LSMean(j) 
1 2 -0.000009206 
-0.000855 
0.000837 
 
Dependent Variable: LAMZ 
Parameter Estimate 
Standard 
Error 
t Value Pr > |t| 
90% Confidence Limits 
A - B 
-9.205803E-6 0.00047772 -0.02 
0.9849 -0.000855215 0.0008368035 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) 
The GLM Procedure 
Class Level Information 
Class 
Levels Values 
subject 23 
101 201 202 203 204 205 301 302 303 304 404 407 408 410 411 412 
413 414 501 502 503 505 507 
sequence 2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
38 
Number of Observations Used 
38 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) 
The GLM Procedure 
Dependent Variable: LAMZHL 
R-Square 
Coeff Var 
Root MSE 
LAMZHL Mean
0.824637 
77.23745 
146.9343 
190.2371 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
14942.202 
14942.202 
0.69 
0.4205
period 
1 
3473.904 
3473.904 
0.16 
0.6948
trt 
1 
29.534 
29.534 
0.00 
0.9711
subject(sequence) 
21 1301373.296 
61970.157 
2.87 
0.0272
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
15431.968 
15431.968 
0.71 
0.4132
period 
1 
7687.035 
7687.035 
0.36 
0.5610
trt 
1 
1577.042 
1577.042 
0.07 
0.7912
subject(sequence) 
21 1301373.296 
61970.157 
2.87 
0.0272
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
42212.895 
42212.895 
1.96 
0.1854
period 
1 
7687.035 
7687.035 
0.36 
0.5610
trt 
1 
1577.042 
1577.042 
0.07 
0.7912
subject(sequence) 
21 1301373.296 
61970.157 
2.87 
0.0272
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
42212.895 
42212.895 
1.96 
0.1854
period 
1 
7687.035 
7687.035 
0.36 
0.5610
trt 
1 
1577.042 
1577.042 
0.07 
0.7912
subject(sequence) 
21 1301373.296 
61970.157 
2.87 
0.0272
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
14942 
14942 
0.23 
0.6390
Error 
19.715 
1297733 
65824 
Error: 1.0954*MS(subject(sequence)) - 0.0954*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
3473.903776 
3473.903776 
0.13 
0.7221
Error 
23.775 
637490 
26813 
Error: 0.1294*MS(subject(sequence)) + 0.8706*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
29.534427 
29.534427 
0.00 
0.9740
Error 
24.699 
673421 
27265 
Error: 0.1405*MS(subject(sequence)) + 0.8595*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
21 1301373 
61970 
2.87 
0.0272
Error: MS(Error) 
13 280666 
21590 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
15432 
15432 
0.23 
0.6335
Error 
19.724 
1297745 
65796 
Error: 1.0948*MS(subject(sequence)) - 0.0948*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
7687.035147 
7687.035147 
0.36 
0.5610
trt 
1 
1577.042328 
1577.042328 
0.07 
0.7912
subject(sequence) 
21 1301373 
61970 
2.87 
0.0272
Error: MS(Error) 
13 280666 
21590 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
42213 
42213 
0.75 
0.3959
Error 
23.282 
1313494 
56416 
Error: 0.8625*MS(subject(sequence)) + 0.1375*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
7687.035147 
7687.035147 
0.36 
0.5610
trt 
1 
1577.042328 
1577.042328 
0.07 
0.7912
subject(sequence) 
21 1301373 
61970 
2.87 
0.0272
Error: MS(Error) 
13 280666 
21590 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
42213 
42213 
0.75 
0.3959
Error 
23.282 
1313494 
56416 
Error: 0.8625*MS(subject(sequence)) + 0.1375*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
7687.035147 
7687.035147 
0.36 
0.5610
trt 
1 
1577.042328 
1577.042328 
0.07 
0.7912
subject(sequence) 
21 1301373 
61970 
2.87 
0.0272
Error: MS(Error) 
13 280666 
21590 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) 
Least Squares Means 
trt 
LAMZHL LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
223.656359 
0.7912
B 
208.856574 
trt 
LAMZHL LSMEAN 
90% Confidence Limits 
A 
223.656359 
161.603193 
285.709526 
B 
208.856574 
137.610653 
280.102495 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 14.799786 
-82.175073 
111.774644 
 
Dependent Variable: LAMZHL 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
14.7997857 54.7591787 0.27 
0.7912 -82.1750725 111.7746439 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*pg/mL) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
9 
101 201 202 203 204 301 402 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
18 
Number of Observations Used 
18 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*pg/mL) 
The GLM Procedure 
Dependent Variable: LN_AUCLST 
R-Square 
Coeff Var 
Root MSE 
LN_AUCLST Mean
0.724163 
2.081304 
0.328591 
15.78774 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.05754936 
0.05754936 
0.53 
0.4862
trt 
1 
0.17097803 
0.17097803 
1.58 
0.2437
subject(sequence) 
7 
2.03916611 
0.29130944 
2.70 
0.0939
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.05754936 
0.05754936 
0.53 
0.4862
trt 
1 
0.17097803 
0.17097803 
1.58 
0.2437
subject(sequence) 
7 
2.03916611 
0.29130944 
2.70 
0.0939
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.05754936 
0.05754936 
0.53 
0.4862
trt 
1 
0.17097803 
0.17097803 
1.58 
0.2437
subject(sequence) 
7 
2.03916611 
0.29130944 
2.70 
0.0939
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.05754936 
0.05754936 
0.53 
0.4862
trt 
1 
0.17097803 
0.17097803 
1.58 
0.2437
subject(sequence) 
7 
2.03916611 
0.29130944 
2.70 
0.0939
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*pg/mL) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.057549 
0.057549 
0.20 
0.6701 
Error 
7 
2.039166 
0.291309 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.170978 
0.170978 
1.58 
0.2437
subject(sequence) 
7 
2.039166 
0.291309 
2.70 
0.0939
Error: MS(Error) 
8 
0.863775 
0.107972 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.057549 
0.057549 
0.20 
0.6701
Error 
7 
2.039166 
0.291309 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.170978 
0.170978 
1.58 
0.2437
subject(sequence) 
7 
2.039166 
0.291309 
2.70 
0.0939
Error: MS(Error) 
8 
0.863775 
0.107972 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*pg/mL) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.057549 
0.057549 
0.20 
0.6701 
Error 
7 
2.039166 
0.291309 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.170978 
0.170978 
1.58 
0.2437
subject(sequence) 
7 
2.039166 
0.291309 
2.70 
0.0939
Error: MS(Error) 
8 
0.863775 
0.107972 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.057549 
0.057549 
0.20 
0.6701
Error 
7 
2.039166 
0.291309 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.170978 
0.170978 
1.58 
0.2437
subject(sequence) 
7 
2.039166 
0.291309 
2.70 
0.0939
Error: MS(Error) 
8 
0.863775 
0.107972 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*pg/mL) 
Least Squares Means 
trt LN_AUCLST LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
15.6965982 
0.2437
C 
15.8915216 
trt 
LN_AUCLST LSMEAN 
90% Confidence Limits 
B 
15.696598 
15.492286 
15.900911 
C 
15.891522 
15.687209 
16.095834 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.194923 
-0.482966 
0.093119 
 
Dependent Variable: LN_AUCLST 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.19492337 0.15489919 1.26 
0.2437 -0.09311913 0.48296586 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*pg/mL) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
8 
101 201 202 203 204 301 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
11 
Number of Observations Used 
11 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*pg/mL) 
The GLM Procedure 
Dependent Variable: LN_AUCIFO 
R-Square 
Coeff Var 
Root MSE 
LN_AUCIFO Mean
0.904625 
2.451480 
0.399149 
16.28198 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.07415386 
0.07415386 
0.47 
0.5655
trt 
1 
0.36277910 
0.36277910 
2.28 
0.2704
subject(sequence) 
6 
2.58535267 
0.43089211 
2.70 
0.2944
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04440121 
0.04440121 
0.28 
0.6503
trt 
1 
0.35468757 
0.35468757 
2.23 
0.2742
subject(sequence) 
6 
2.58535267 
0.43089211 
2.70 
0.2944
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.02708903 
0.02708903 
0.17 
0.7201
trt 
1 
0.35468757 
0.35468757 
2.23 
0.2742
subject(sequence) 
6 
2.58535267 
0.43089211 
2.70 
0.2944
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.02708903 
0.02708903 
0.17 
0.7201
trt 
1 
0.35468757 
0.35468757 
2.23 
0.2742
subject(sequence) 
6 
2.58535267 
0.43089211 
2.70 
0.2944
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*pg/mL) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.074154 
0.074154 
0.15 
0.7130
Error 
5.1578 
2.530606 
0.490633 
Error: 1.22*MS(subject(sequence)) - 0.22*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.362779 
0.362779 
1.41 
0.2731
Error 
7.2018 
1.856133 
0.257731 
Error: 0.3624*MS(subject(sequence)) + 0.6376*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
6 
2.585353 
0.430892 
2.70 
0.2944
Error: MS(Error) 
2 
0.318641 
0.159320 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*pg/mL) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.044401 
0.044401 
0.09 
0.7752
Error 
5.1649 
2.531028 
0.490046 
Error: 1.2178*MS(subject(sequence)) - 0.2178*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.354688 
0.354688 
2.23 
0.2742
subject(sequence) 
6 
2.585353 
0.430892 
2.70 
0.2944
Error: MS(Error) 
2 
0.318641 
0.159320 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.027089 
0.027089 
0.06 
0.8079
Error 
6.1708 
2.595918 
0.420675 
Error: 0.9624*MS(subject(sequence)) + 0.0376*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.354688 
0.354688 
2.23 
0.2742
subject(sequence) 
6 
2.585353 
0.430892 
2.70 
0.2944
Error: MS(Error) 
2 
0.318641 
0.159320 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*pg/mL) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.027089 
0.027089 
0.06 
0.8079
Error 
6.1708 
2.595918 
0.420675 
Error: 0.9624*MS(subject(sequence)) + 0.0376*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.354688 
0.354688 
2.23 
0.2742
subject(sequence) 
6 
2.585353 
0.430892 
2.70 
0.2944
Error: MS(Error) 
2 
0.318641 
0.159320 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*pg/mL) 
Least Squares Means 
trt LN_AUCIFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
16.1264488 
0.2742
C 
16.6127187 
trt 
LN_AUCIFO LSMEAN 
90% Confidence Limits 
B 
16.126449 
15.474909 
16.777989 
C 
16.612719 
16.054773 
17.170664 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.486270 
-1.437905 
0.465366 
 
Dependent Variable: LN_AUCIFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.48626987 0.32590416 1.49 
0.2742 -0.46536558 1.43790531 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (pg/mL) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
9 
101 201 202 203 204 301 402 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
18 
Number of Observations Used 
18 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (pg/mL) 
The GLM Procedure 
Dependent Variable: LN_CMAX 
R-Square 
Coeff Var 
Root MSE 
LN_CMAX Mean
0.742680 
3.444682 
0.366647 
10.64385 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.19249555 
0.19249555 
1.43 
0.2657
trt 
1 
0.14829852 
0.14829852 
1.10 
0.3243
subject(sequence) 
7 
2.76314852 
0.39473550 
2.94 
0.0771
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.19249555 
0.19249555 
1.43 
0.2657
trt 
1 
0.14829852 
0.14829852 
1.10 
0.3243
subject(sequence) 
7 
2.76314852 
0.39473550 
2.94 
0.0771
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.19249555 
0.19249555 
1.43 
0.2657
trt 
1 
0.14829852 
0.14829852 
1.10 
0.3243
subject(sequence) 
7 
2.76314852 
0.39473550 
2.94 
0.0771
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.19249555 
0.19249555 
1.43 
0.2657
trt 
1 
0.14829852 
0.14829852 
1.10 
0.3243
subject(sequence) 
7 
2.76314852 
0.39473550 
2.94 
0.0771
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (pg/mL) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.192496 
0.192496 
0.49 
0.5075 
Error 
7 
2.763149 
0.394736 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.148299 
0.148299 
1.10 
0.3243
subject(sequence) 
7 
2.763149 
0.394736 
2.94 
0.0771
Error: MS(Error) 
8 
1.075439 
0.134430 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.192496 
0.192496 
0.49 
0.5075
Error 
7 
2.763149 
0.394736 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.148299 
0.148299 
1.10 
0.3243
subject(sequence) 
7 
2.763149 
0.394736 
2.94 
0.0771
Error: MS(Error) 
8 
1.075439 
0.134430 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (pg/mL) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.192496 
0.192496 
0.49 
0.5075 
Error 
7 
2.763149 
0.394736 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.148299 
0.148299 
1.10 
0.3243
subject(sequence) 
7 
2.763149 
0.394736 
2.94 
0.0771
Error: MS(Error) 
8 
1.075439 
0.134430 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.192496 
0.192496 
0.49 
0.5075
Error 
7 
2.763149 
0.394736 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.148299 
0.148299 
1.10 
0.3243
subject(sequence) 
7 
2.763149 
0.394736 
2.94 
0.0771
Error: MS(Error) 
8 
1.075439 
0.134430 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (pg/mL) 
Least Squares Means 
trt 
LN_CMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
10.5646446 
0.3243
C 
10.7461803 
trt 
LN_CMAX LSMEAN 
90% Confidence Limits 
B 
10.564645 
10.336670 
10.792619 
C 
10.746180 
10.518205 
10.974155 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.181536 
-0.502938 
0.139867 
 
Dependent Variable: LN_CMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.18153574 0.17283895 1.05 
0.3243 -0.13986659 0.50293808 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
8 
101 201 202 203 204 301 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
11 
Number of Observations Used 
11 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
The GLM Procedure 
Dependent Variable: LN_CLFOW 
R-Square 
Coeff Var 
Root MSE 
LN_CLFOW Mean
0.902109 
-10.77248 
0.443098 
-4.113246 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.16198223 
0.16198223 
0.83 
0.4596
trt 
1 
0.73224034 
0.73224034 
3.73 
0.1932
subject(sequence) 
6 
2.72441644 
0.45406941 
2.31 
0.3323
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.09915049 
0.09915049 
0.51 
0.5510
trt 
1 
0.50837219 
0.50837219 
2.59 
0.2489
subject(sequence) 
6 
2.72441644 
0.45406941 
2.31 
0.3323
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00445321 
0.00445321 
0.02 
0.8941
trt 
1 
0.50837219 
0.50837219 
2.59 
0.2489
subject(sequence) 
6 
2.72441644 
0.45406941 
2.31 
0.3323
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00445321 
0.00445321 
0.02 
0.8941
trt 
1 
0.50837219 
0.50837219 
2.59 
0.2489
subject(sequence) 
6 
2.72441644 
0.45406941 
2.31 
0.3323
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.161982 
0.161982 
0.32 
0.5976
Error 
5.0095 
2.558688 
0.510766 
Error: 1.22*MS(subject(sequence)) - 0.22*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.732240 
0.732240 
2.53 
0.1572
Error 
6.798 
1.969591 
0.289733 
Error: 0.3624*MS(subject(sequence)) + 0.6376*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
6 
2.724416 
0.454069 
2.31 
0.3323
Error: MS(Error) 
2 
0.392672 
0.196336 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.099150 
0.099150 
0.19 
0.6777
Error 
5.0178 
2.560122 
0.510209 
Error: 1.2178*MS(subject(sequence)) - 0.2178*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.508372 
0.508372 
2.59 
0.2489
subject(sequence) 
6 
2.724416 
0.454069 
2.31 
0.3323
Error: MS(Error) 
2 
0.392672 
0.196336 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.004453 
0.004453 
0.01 
0.9234
Error 
6.1993 
2.754777 
0.444373 
Error: 0.9624*MS(subject(sequence)) + 0.0376*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.508372 
0.508372 
2.59 
0.2489
subject(sequence) 
6 
2.724416 
0.454069 
2.31 
0.3323
Error: MS(Error) 
2 
0.392672 
0.196336 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.004453 
0.004453 
0.01 
0.9234
Error 
6.1993 
2.754777 
0.444373 
Error: 0.9624*MS(subject(sequence)) + 0.0376*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.508372 
0.508372 
2.59 
0.2489
subject(sequence) 
6 
2.724416 
0.454069 
2.31 
0.3323
Error: MS(Error) 
2 
0.392672 
0.196336 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) 
Least Squares Means 
trt 
LN_CLFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
-3.91316447 
0.2489
C 
-4.49532836 
trt 
LN_CLFOW LSMEAN 
90% Confidence Limits 
B 
-3.913164 
-4.636444 
-3.189885 
C 
-4.495328 
-5.114708 
-3.875949 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.582164 
-0.474253 
1.638581 
 
Dependent Variable: LN_CLFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.58216389 0.36178831 -1.61 
0.2489 -1.63858054 0.47425276 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
8 
101 201 202 203 204 301 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
11 
Number of Observations Used 
11 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) 
The GLM Procedure 
Dependent Variable: LN_CLFO 
R-Square 
Coeff Var 
Root MSE 
LN_CLFO Mean
0.911563 
161.6764 
0.443098 
0.274065 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00821426 
0.00821426 
0.04 
0.8569
trt 
1 
0.32342250 
0.32342250 
1.65 
0.3280
subject(sequence) 
6 
3.71584302 
0.61930717 
3.15 
0.2602
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00110942 
0.00110942 
0.01 
0.9469
trt 
1 
0.50837219 
0.50837219 
2.59 
0.2489
subject(sequence) 
6 
3.71584302 
0.61930717 
3.15 
0.2602
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.15060463 
0.15060463 
0.77 
0.4735
trt 
1 
0.50837219 
0.50837219 
2.59 
0.2489
subject(sequence) 
6 
3.71584302 
0.61930717 
3.15 
0.2602
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.15060463 
0.15060463 
0.77 
0.4735
trt 
1 
0.50837219 
0.50837219 
2.59 
0.2489
subject(sequence) 
6 
3.71584302 
0.61930717 
3.15 
0.2602
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.008214 
0.008214 
0.01 
0.9184
Error 
5.2819 
3.762543 
0.712353 
Error: 1.22*MS(subject(sequence)) - 0.22*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.323422 
0.323422 
0.93 
0.3660
Error 
7.5308 
2.632859 
0.349611 
Error: 0.3624*MS(subject(sequence)) + 0.6376*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
6 
3.715843 
0.619307 
3.15 
0.2602
Error: MS(Error) 
2 
0.392672 
0.196336 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.001109 
0.001109 
0.00 
0.9699
Error 
5.2878 
3.761979 
0.711439 
Error: 1.2178*MS(subject(sequence)) - 0.2178*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.508372 
0.508372 
2.59 
0.2489
subject(sequence) 
6 
3.715843 
0.619307 
3.15 
0.2602
Error: MS(Error) 
2 
0.392672 
0.196336 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.150605 
0.150605 
0.25 
0.6347
Error 
6.1468 
3.708949 
0.603393 
Error: 0.9624*MS(subject(sequence)) + 0.0376*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.508372 
0.508372 
2.59 
0.2489
subject(sequence) 
6 
3.715843 
0.619307 
3.15 
0.2602
Error: MS(Error) 
2 
0.392672 
0.196336 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.150605 
0.150605 
0.25 
0.6347
Error 
6.1468 
3.708949 
0.603393 
Error: 0.9624*MS(subject(sequence)) + 0.0376*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.508372 
0.508372 
2.59 
0.2489
subject(sequence) 
6 
3.715843 
0.619307 
3.15 
0.2602
Error: MS(Error) 
2 
0.392672 
0.196336 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) 
Least Squares Means 
trt 
LN_CLFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
0.48125860 
0.2489
C 
-0.10090529 
trt 
LN_CLFO LSMEAN 
90% Confidence Limits 
B 
0.481259 
-0.242020 
1.204538 
C 
-0.100905 
-0.720284 
0.518474 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 
0.582164 
-0.474253 
1.638581 
 
Dependent Variable: LN_CLFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.58216389 0.36178831 -1.61 
0.2489 -1.63858054 0.47425276 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
8 
101 201 202 203 204 301 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
11 
Number of Observations Used 
11 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) 
The GLM Procedure 
Dependent Variable: LN_VZFOW 
R-Square 
Coeff Var 
Root MSE 
LN_VZFOW Mean
0.770703 
58.09245 
0.685302 
1.179674 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00961309 
0.00961309 
0.02 
0.8993
trt 
1 
0.23838114 
0.23838114 
0.51 
0.5501
subject(sequence) 
6 
2.90905346 
0.48484224 
1.03 
0.5680
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.02142687 
0.02142687 
0.05 
0.8507
trt 
1 
0.46004136 
0.46004136 
0.98 
0.4266
subject(sequence) 
6 
2.90905346 
0.48484224 
1.03 
0.5680
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04288477 
0.04288477 
0.09 
0.7910
trt 
1 
0.46004136 
0.46004136 
0.98 
0.4266
subject(sequence) 
6 
2.90905346 
0.48484224 
1.03 
0.5680
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04288477 
0.04288477 
0.09 
0.7910
trt 
1 
0.46004136 
0.46004136 
0.98 
0.4266
subject(sequence) 
6 
2.90905346 
0.48484224 
1.03 
0.5680
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.009613 
0.009613 
0.02 
0.8956
Error 
3.7444 
1.827974 
0.488187 
Error: 1.22*MS(subject(sequence)) - 0.22*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.238381 
0.238381 
0.50 
0.5136
Error 
4.5171 
2.146267 
0.475148 
Error: 0.3624*MS(subject(sequence)) + 0.6376*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
6 
2.909053 
0.484842 
1.03 
0.5680
Error: MS(Error) 
2 
0.939277 
0.469638 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.021427 
0.021427 
0.04 
0.8449
Error 
3.7623 
1.836568 
0.488154 
Error: 1.2178*MS(subject(sequence)) - 0.2178*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.460041 
0.460041 
0.98 
0.4266
subject(sequence) 
6 
2.909053 
0.484842 
1.03 
0.5680
Error: MS(Error) 
2 
0.939277 
0.469638 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.042885 
0.042885 
0.09 
0.7754
Error 
6.4353 
3.116445 
0.484270 
Error: 0.9624*MS(subject(sequence)) + 0.0376*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.460041 
0.460041 
0.98 
0.4266
subject(sequence) 
6 
2.909053 
0.484842 
1.03 
0.5680
Error: MS(Error) 
2 
0.939277 
0.469638 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.042885 
0.042885 
0.09 
0.7754
Error 
6.4353 
3.116445 
0.484270 
Error: 0.9624*MS(subject(sequence)) + 0.0376*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.460041 
0.460041 
0.98 
0.4266
subject(sequence) 
6 
2.909053 
0.484842 
1.03 
0.5680
Error: MS(Error) 
2 
0.939277 
0.469638 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) 
Least Squares Means 
trt 
LN_VZFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
1.48139692 
0.4266
C 
0.92759710 
trt 
LN_VZFOW LSMEAN 
90% Confidence Limits 
B 
1.481397 
0.362764 
2.600030 
C 
0.927597 
-0.030343 
1.885537 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.553800 
-1.080068 
2.187667 
 
Dependent Variable: LN_VZFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.55379982 0.55954645 -0.99 
0.4266 -2.18766737 1.08006773 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
8 
101 201 202 203 204 301 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
11 
Number of Observations Used 
11 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) 
The GLM Procedure 
Dependent Variable: LN_VZFO 
R-Square 
Coeff Var 
Root MSE 
LN_VZFO Mean
0.855335 
12.31010 
0.685302 
5.566985 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.16800486 
0.16800486 
0.36 
0.6105
trt 
1 
0.04049550 
0.04049550 
0.09 
0.7967
subject(sequence) 
6 
5.34497302 
0.89082884 
1.90 
0.3847
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.18314367 
0.18314367 
0.39 
0.5961
trt 
1 
0.46004136 
0.46004136 
0.98 
0.4266
subject(sequence) 
6 
5.34497302 
0.89082884 
1.90 
0.3847
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.27924049 
0.27924049 
0.59 
0.5213
trt 
1 
0.46004136 
0.46004136 
0.98 
0.4266
subject(sequence) 
6 
5.34497302 
0.89082884 
1.90 
0.3847
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.27924049 
0.27924049 
0.59 
0.5213
trt 
1 
0.46004136 
0.46004136 
0.98 
0.4266
subject(sequence) 
6 
5.34497302 
0.89082884 
1.90 
0.3847
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.168005 
0.168005 
0.17 
0.6972
Error 
4.7838 
4.704785 
0.983483 
Error: 1.22*MS(subject(sequence)) - 0.22*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.040496 
0.040496 
0.07 
0.8069
Error 
6.2249 
3.873577 
0.622268 
Error: 0.3624*MS(subject(sequence)) + 0.6376*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
6 
5.344973 
0.890829 
1.90 
0.3847
Error: MS(Error) 
2 
0.939277 
0.469638 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.183144 
0.183144 
0.19 
0.6847
Error 
4.7939 
4.710396 
0.982573 
Error: 1.2178*MS(subject(sequence)) - 0.2178*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.460041 
0.460041 
0.98 
0.4266
subject(sequence) 
6 
5.344973 
0.890829 
1.90 
0.3847
Error: MS(Error) 
2 
0.939277 
0.469638 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.279240 
0.279240 
0.32 
0.5918
Error 
6.2419 
5.461567 
0.874982 
Error: 0.9624*MS(subject(sequence)) + 0.0376*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.460041 
0.460041 
0.98 
0.4266
subject(sequence) 
6 
5.344973 
0.890829 
1.90 
0.3847
Error: MS(Error) 
2 
0.939277 
0.469638 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.279240 
0.279240 
0.32 
0.5918
Error 
6.2419 
5.461567 
0.874982 
Error: 0.9624*MS(subject(sequence)) + 0.0376*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.460041 
0.460041 
0.98 
0.4266
subject(sequence) 
6 
5.344973 
0.890829 
1.90 
0.3847
Error: MS(Error) 
2 
0.939277 
0.469638 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) 
Least Squares Means 
trt 
LN_VZFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
5.87582000 
0.4266
C 
5.32202018 
trt 
LN_VZFO LSMEAN 
90% Confidence Limits 
B 
5.875820 
4.757187 
6.994453 
C 
5.322020 
4.364080 
6.279960 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.553800 
-1.080068 
2.187667 
 
Dependent Variable: LN_VZFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.55379982 0.55954645 -0.99 
0.4266 -2.18766737 1.08006773 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
9 
101 201 202 203 204 301 402 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
18 
Number of Observations Used 
18 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) 
The GLM Procedure 
Dependent Variable: TMAX 
R-Square 
Coeff Var 
Root MSE 
TMAX Mean
0.709476 
32.06432 
33.76521 
105.3046 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1284.96583 
1284.96583 
1.13 
0.3194
trt 
1 
1546.58827 
1546.58827 
1.36 
0.2777
subject(sequence) 
7 
19441.71556 
2777.38794 
2.44 
0.1178
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1284.96583 
1284.96583 
1.13 
0.3194
trt 
1 
1546.58827 
1546.58827 
1.36 
0.2777
subject(sequence) 
7 
19441.71556 
2777.38794 
2.44 
0.1178
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1284.96583 
1284.96583 
1.13 
0.3194
trt 
1 
1546.58827 
1546.58827 
1.36 
0.2777
subject(sequence) 
7 
19441.71556 
2777.38794 
2.44 
0.1178
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1284.96583 
1284.96583 
1.13 
0.3194
trt 
1 
1546.58827 
1546.58827 
1.36 
0.2777
subject(sequence) 
7 
19441.71556 
2777.38794 
2.44 
0.1178
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1284.965831 
1284.965831 
0.46 
0.5182
Error 
7 
19442 
2777.387937 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
1546.588267 
1546.588267 
1.36 
0.2777
subject(sequence) 
7 
19442 
2777.387937 
2.44 
0.1178
Error: MS(Error) 
8 
9120.713962 
1140.089245 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1284.965831 
1284.965831 
0.46 
0.5182
Error 
7 
19442 
2777.387937 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
1546.588267 
1546.588267 
1.36 
0.2777
subject(sequence) 
7 
19442 
2777.387937 
2.44 
0.1178
Error: MS(Error) 
8 
9120.713962 
1140.089245 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1284.965831 
1284.965831 
0.46 
0.5182
Error 
7 
19442 
2777.387937 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
1546.588267 
1546.588267 
1.36 
0.2777
subject(sequence) 
7 
19442 
2777.387937 
2.44 
0.1178
Error: MS(Error) 
8 
9120.713962 
1140.089245 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1284.965831 
1284.965831 
0.46 
0.5182
Error 
7 
19442 
2777.387937 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
1546.588267 
1546.588267 
1.36 
0.2777
subject(sequence) 
7 
19442 
2777.387937 
2.44 
0.1178
Error: MS(Error) 
8 
9120.713962 
1140.089245 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) 
Least Squares Means 
trt TMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
113.629364 
0.2777
C 
95.090586 
trt TMAX LSMEAN 
90% Confidence Limits 
B 
113.629364 
92.634720 
134.624008 
C 
95.090586 
74.095942 
116.085230 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 18.538778 
-11.059781 
48.137337 
 
Dependent Variable: TMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-18.5387778 15.9170715 -1.16 
0.2777 -48.1373369 11.0597813 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
8 
101 201 202 203 204 301 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
11 
Number of Observations Used 
11 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) 
The GLM Procedure 
Dependent Variable: LAMZ 
R-Square 
Coeff Var 
Root MSE 
LAMZ Mean
0.979044 
25.02204 
0.001571 
0.006279 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00002833 
0.00002833 
11.48 
0.0772
trt 
1 
0.00000170 
0.00000170 
0.69 
0.4941
subject(sequence) 
6 
0.00020060 
0.00003343 
13.55 
0.0703
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00002668 
0.00002668 
10.81 
0.0814
trt 
1 
0.00000001 
0.00000001 
0.01 
0.9482
subject(sequence) 
6 
0.00020060 
0.00003343 
13.55 
0.0703
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00000850 
0.00000850 
3.44 
0.2046
trt 
1 
0.00000001 
0.00000001 
0.01 
0.9482
subject(sequence) 
6 
0.00020060 
0.00003343 
13.55 
0.0703
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00000850 
0.00000850 
3.44 
0.2046
trt 
1 
0.00000001 
0.00000001 
0.01 
0.9482
subject(sequence) 
6 
0.00020060 
0.00003343 
13.55 
0.0703
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 1 
0.000028326 
0.000028326 
0.70 
0.4345
Error 
5.8382 
0.000235 
0.000040245 
Error: 1.22*MS(subject(sequence)) - 0.22*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000001698 
0.000001698 
0.12 
0.7347
Error 
7.2909 
0.000099806 
0.000013689 
Error: 0.3624*MS(subject(sequence)) + 0.6376*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
6 
0.000201 
0.000033433 
13.55 
0.0703
Error: MS(Error) 
2 
0.000004936 
0.000002468 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000026680 
0.000026680 
0.66 
0.4471
Error 
5.8395 
0.000235 
0.000040178 
Error: 1.2178*MS(subject(sequence)) - 0.2178*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
1.3259677E-8 
1.3259677E-8 
0.01 
0.9482
subject(sequence) 
6 
0.000201 
0.000033433 
13.55 
0.0703
Error: MS(Error) 
2 
0.000004936 
0.000002468 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000008502 
0.000008502 
0.26 
0.6260
Error 
6.0345 
0.000195 
0.000032268 
Error: 0.9624*MS(subject(sequence)) + 0.0376*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
1.3259677E-8 
1.3259677E-8 
0.01 
0.9482
subject(sequence) 
6 
0.000201 
0.000033433 
13.55 
0.0703
Error: MS(Error) 
2 
0.000004936 
0.000002468 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000008502 
0.000008502 
0.26 
0.6260
Error 
6.0345 
0.000195 
0.000032268 
Error: 0.9624*MS(subject(sequence)) + 0.0376*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
1.3259677E-8 
1.3259677E-8 
0.01 
0.9482
subject(sequence) 
6 
0.000201 
0.000033433 
13.55 
0.0703
Error: MS(Error) 
2 
0.000004936 
0.000002468 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) 
Least Squares Means 
trt LAMZ LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t| 
B 
0.00555261 
0.9482 
C 
0.00545859 
 
trt 
LAMZ LSMEAN 
90% Confidence Limits 
B 
0.005553 
0.002988 
0.008117 
C 
0.005459 
0.003263 
0.007655 
Least Squares Means for Effect trt 
i 
j 
Difference Between Means 
90% Confidence Limits for 
LSMean(i)-LSMean(j) 
1 2 0.000094020 
-0.003652 
0.003840 
 
Dependent Variable: LAMZ 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.00009402 0.00128273 -0.07 
0.9482 -0.00383959 0.00365155 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
8 
101 201 202 203 204 301 404 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
11 
Number of Observations Used 
11 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) 
The GLM Procedure 
Dependent Variable: LAMZHL 
R-Square 
Coeff Var 
Root MSE 
LAMZHL Mean
0.936339 
32.11823 
52.93033 
164.7984 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
781.19473 
781.19473 
0.28 
0.6502
trt 
1 
6489.38122 
6489.38122 
2.32 
0.2674
subject(sequence) 
6 
75143.68682 
12523.94780 
4.47 
0.1941
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
390.22411 
390.22411 
0.14 
0.7448
trt 
1 
78.94660 
78.94660 
0.03 
0.8821
subject(sequence) 
6 
75143.68682 
12523.94780 
4.47 
0.1941
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
455.07734 
455.07734 
0.16 
0.7259
trt 
1 
78.94660 
78.94660 
0.03 
0.8821
subject(sequence) 
6 
75143.68682 
12523.94780 
4.47 
0.1941
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
455.07734 
455.07734 
0.16 
0.7259
trt 
1 
78.94660 
78.94660 
0.03 
0.8821
subject(sequence) 
6 
75143.68682 
12523.94780 
4.47 
0.1941
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 1 
781.194725 
781.194725 
0.05 
0.8258
Error 
5.4989 
80628 
14663 
Error: 1.22*MS(subject(sequence)) - 0.22*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
6489.381224 
6489.381224 
1.03 
0.3409
Error 
7.9553 
50316 
6324.760478 
Error: 0.3624*MS(subject(sequence)) + 0.6376*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
6 
75144 
12524 
4.47 
0.1941
Error: MS(Error) 
2 
5603.239711 
2801.619856 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
390.224108 
390.224108 
0.03 
0.8761
Error 
5.503 
80574 
14642 
Error: 1.2178*MS(subject(sequence)) - 0.2178*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
78.946602 
78.946602 
0.03 
0.8821
subject(sequence) 
6 
75144 
12524 
4.47 
0.1941
Error: MS(Error) 
2 
5603.239711 
2801.619856 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
455.077342 
455.077342 
0.04 
0.8529
Error 
6.104 
74213 
12158 
Error: 0.9624*MS(subject(sequence)) + 0.0376*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
78.946602 
78.946602 
0.03 
0.8821
subject(sequence) 
6 
75144 
12524 
4.47 
0.1941
Error: MS(Error) 
2 
5603.239711 
2801.619856 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
455.077342 
455.077342 
0.04 
0.8529
Error 
6.104 
74213 
12158 
Error: 0.9624*MS(subject(sequence)) + 0.0376*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
78.946602 
78.946602 
0.03 
0.8821
subject(sequence) 
6 
75144 
12524 
4.47 
0.1941
Error: MS(Error) 
2 
5603.239711 
2801.619856 
 


 
 
Listing 16.1.9-2 ANOVA for Treatment Comparison of Nordiazepam - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) 
Least Squares Means 
trt 
LAMZHL LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
177.749549 
0.8821
C 
185.004276 
trt 
LAMZHL LSMEAN 
90% Confidence Limits 
B 
177.749549 
91.350230 
264.148869 
C 
185.004276 
111.016320 
258.992233 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -7.254727 
-133.449010 
118.939556 
 
Dependent Variable: LAMZHL 
Parameter Estimate 
Standard 
Error 
t Value Pr > |t| 
90% Confidence Limits 
C - B 
7.25472729 43.2174336 0.17 
0.8821 -118.9395558 133.44901033 
 
 


180323 Diazepam Buccal Film DRG Crossover 
Aquestive Therapeutics 
16.1.9 Documentation of Statistical Methods 
 
Confidential 
Page 6 of 11 
Final 1.0 
Listing 16.1.9-3 Wilcoxon Signed-Rank Test for Tmax for Treatment Comparison of 
Diazepam – PK Population


 
Listing 16.1.9-3 Wilcoxon Signed-Rank Test for Tmax for Treatment Comparison of Diazepam - PK Population 
Difference 
 Statistic 
Value 
A - B 
n 
28 
 
Mean 
0.723 
 
Median 
0.367 
 
SD 
1.339 
 
Wilcoxon 
S 
116.5 
Signed-rank Test 
p-value 
0.0015 
 
C - B 
n 
9 
 
Mean 
1.276 
 
Median 
1.017 
 
SD 
1.320 
 
Wilcoxon 
S 
16 
Signed-rank Test 
p-value 
0.0234 
 
n: Number of subjects; SD: Standard Deviation. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content); 
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
  
          Page 1 of 1 
 


180323 Diazepam Buccal Film DRG Crossover 
Aquestive Therapeutics 
16.1.9 Documentation of Statistical Methods 
 
Confidential 
Page 7 of 11 
Final 1.0 
Listing 16.1.9-4 Wilcoxon Signed-Rank Test for Tmax for Treatment Comparison of 
Nordiazepam – PK Population 


 
Listing 16.1.9-4 Wilcoxon Signed-Rank Test for Tmax for Treatment Comparison of Nordiazepam - PK Population 
Difference 
 Statistic 
Value 
A - B 
n 
28 
 
Mean 
6.968 
 
Median 
0.192 
 
SD 
48.359 
 
Wilcoxon 
S 
36 
Signed-rank Test 
p-value 
0.4223 
 
C - B 
n 
9 
 
Mean 
-18.539 
 
Median 
-23.083 
 
SD 
47.751 
 
Wilcoxon 
S 
-7.5 
Signed-rank Test 
p-value 
0.4258 
 
n: Number of subjects; SD: Standard Deviation. 
Treatment A: Diazepam Buccal Film under fed conditions (breakfast with moderate fat content); 
Treatment B: Diastat® AcuDialTM rectal gel under fed conditions (breakfast with moderate fat content); 
Treatment C: Diazepam Buccal Film under fed conditions (breakfast with high fat content). 
  
          Page 1 of 1 
 


180323 Diazepam Buccal Film DRG Crossover 
Aquestive Therapeutics 
16.1.9 Documentation of Statistical Methods 
 
Confidential 
Page 8 of 11 
Final 1.0 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
6 
101 201 302 412 414 503 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
12 
Number of Observations Used 
12 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LN_AUCLST 
R-Square 
Coeff Var 
Root MSE 
LN_AUCLST Mean
0.989131 
1.149609 
0.104716 
9.108814 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.87353230 
0.87353230 
79.66 
0.0009
period 
1 
0.02943586 
0.02943586 
2.68 
0.1767
trt 
1 
0.00942171 
0.00942171 
0.86 
0.4064
subject(sequence) 
4 
3.07934290 
0.76983573 
70.21 
0.0006
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.87353230 
0.87353230 
79.66 
0.0009
period 
1 
0.03767939 
0.03767939 
3.44 
0.1374
trt 
1 
0.00942171 
0.00942171 
0.86 
0.4064
subject(sequence) 
4 
3.07934290 
0.76983573 
70.21 
0.0006
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.87353230 
0.87353230 
79.66 
0.0009
period 
1 
0.03767939 
0.03767939 
3.44 
0.1374
trt 
1 
0.00942171 
0.00942171 
0.86 
0.4064
subject(sequence) 
4 
3.07934290 
0.76983573 
70.21 
0.0006
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.87353230 
0.87353230 
79.66 
0.0009
period 
1 
0.03767939 
0.03767939 
3.44 
0.1374
trt 
1 
0.00942171 
0.00942171 
0.86 
0.4064
subject(sequence) 
4 
3.07934290 
0.76983573 
70.21 
0.0006
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 51-62 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.873532 
0.873532 
1.13 
0.3468 
Error 
4 
3.079343 
0.769836 
 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F
*period 
1 
0.029436 0.029436 
2.68 
0.1767
trt 
1 
0.009422 0.009422 
0.86 
0.4064
subject(sequence) 
4 
3.079343 0.769836 
70.21 
0.0006
Error: MS(Error) 
4 
0.043862 0.010965 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.873532 
0.873532 
1.13 
0.3468
Error 
4 
3.079343 
0.769836 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.037679 
0.037679 
3.44 
0.1374
trt 
1 
0.009422 
0.009422 
0.86 
0.4064
subject(sequence) 
4 
3.079343 
0.769836 
70.21 
0.0006
Error: MS(Error) 
4 
0.043862 
0.010965 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 51-62 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.873532 
0.873532 
1.13 
0.3468 
Error 
4 
3.079343 
0.769836 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.037679 
0.037679 
3.44 
0.1374
trt 
1 
0.009422 
0.009422 
0.86 
0.4064
subject(sequence) 
4 
3.079343 
0.769836 
70.21 
0.0006
Error: MS(Error) 
4 
0.043862 
0.010965 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.873532 
0.873532 
1.13 
0.3468
Error 
4 
3.079343 
0.769836 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.037679 
0.037679 
3.44 
0.1374
trt 
1 
0.009422 
0.009422 
0.86 
0.4064
subject(sequence) 
4 
3.079343 
0.769836 
70.21 
0.0006
Error: MS(Error) 
4 
0.043862 
0.010965 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 51-62 
Least Squares Means 
trt LN_AUCLST LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
9.23392481 
0.4064
B 
9.17448459 
trt 
LN_AUCLST LSMEAN 
90% Confidence Limits 
A 
9.233925 
9.137260 
9.330590 
B 
9.174485 
9.077820 
9.271149 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.059440 
-0.077265 
0.196145 
 
Dependent Variable: LN_AUCLST 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.05944022 0.06412503 0.93 
0.4064 -0.07726452 0.19614497 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
6 
101 201 302 412 414 503 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
12 
Number of Observations Used 
12 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LN_AUCIFO 
R-Square 
Coeff Var 
Root MSE 
LN_AUCIFO Mean
0.995963 
0.748004 
0.068472 
9.154019 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.05980441 
1.05980441 
226.04 
0.0001
period 
1 
0.04650127 
0.04650127 
9.92 
0.0345
trt 
1 
0.02448664 
0.02448664 
5.22 
0.0843
subject(sequence) 
4 
3.49588930 
0.87397232 
186.41 
<.0001
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.05980441 
1.05980441 
226.04 
0.0001
period 
1 
0.06526465 
0.06526465 
13.92 
0.0203
trt 
1 
0.02448664 
0.02448664 
5.22 
0.0843
subject(sequence) 
4 
3.49588930 
0.87397232 
186.41 
<.0001
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.05980441 
1.05980441 
226.04 
0.0001
period 
1 
0.06526465 
0.06526465 
13.92 
0.0203
trt 
1 
0.02448664 
0.02448664 
5.22 
0.0843
subject(sequence) 
4 
3.49588930 
0.87397232 
186.41 
<.0001
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.05980441 
1.05980441 
226.04 
0.0001
period 
1 
0.06526465 
0.06526465 
13.92 
0.0203
trt 
1 
0.02448664 
0.02448664 
5.22 
0.0843
subject(sequence) 
4 
3.49588930 
0.87397232 
186.41 
<.0001
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 51-62 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
1.059804 
1.059804 
1.21 
0.3326 
Error 
4 
3.495889 
0.873972 
 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F
*period 
1 
0.046501 0.046501 
9.92 
0.0345
trt 
1 
0.024487 0.024487 
5.22 
0.0843
subject(sequence) 
4 
3.495889 0.873972 
186.41 
<.0001
Error: MS(Error) 
4 
0.018754 0.004688 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.059804 
1.059804 
1.21 
0.3326
Error 
4 
3.495889 
0.873972 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.065265 
0.065265 
13.92 
0.0203
trt 
1 
0.024487 
0.024487 
5.22 
0.0843
subject(sequence) 
4 
3.495889 
0.873972 
186.41 
<.0001
Error: MS(Error) 
4 
0.018754 
0.004688 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 51-62 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
1.059804 
1.059804 
1.21 
0.3326 
Error 
4 
3.495889 
0.873972 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.065265 
0.065265 
13.92 
0.0203
trt 
1 
0.024487 
0.024487 
5.22 
0.0843
subject(sequence) 
4 
3.495889 
0.873972 
186.41 
<.0001
Error: MS(Error) 
4 
0.018754 
0.004688 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.059804 
1.059804 
1.21 
0.3326
Error 
4 
3.495889 
0.873972 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.065265 
0.065265 
13.92 
0.0203
trt 
1 
0.024487 
0.024487 
5.22 
0.0843
subject(sequence) 
4 
3.495889 
0.873972 
186.41 
<.0001
Error: MS(Error) 
4 
0.018754 
0.004688 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 51-62 
Least Squares Means 
trt LN_AUCIFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
9.30700089 
0.0843
B 
9.21117558 
trt 
LN_AUCIFO LSMEAN 
90% Confidence Limits 
A 
9.307001 
9.243793 
9.370209 
B 
9.211176 
9.147968 
9.274384 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.095825 
0.006436 
0.185215 
 
Dependent Variable: LN_AUCIFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 90% Confidence Limits 
A - B 
0.09582531 0.04193065 2.29 
0.0843 0.00643560 0.18521503 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
6 
101 201 302 412 414 503 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
12 
Number of Observations Used 
12 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LN_CMAX 
R-Square 
Coeff Var 
Root MSE 
LN_CMAX Mean
0.825032 
4.588682 
0.263298 
5.737989 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04000138 
0.04000138 
0.58 
0.4898
period 
1 
0.20877172 
0.20877172 
3.01 
0.1577
trt 
1 
0.28386147 
0.28386147 
4.09 
0.1130
subject(sequence) 
4 
0.77494679 
0.19373670 
2.79 
0.1717
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04000138 
0.04000138 
0.58 
0.4898
period 
1 
0.06410442 
0.06410442 
0.92 
0.3907
trt 
1 
0.28386147 
0.28386147 
4.09 
0.1130
subject(sequence) 
4 
0.77494679 
0.19373670 
2.79 
0.1717
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04000138 
0.04000138 
0.58 
0.4898
period 
1 
0.06410442 
0.06410442 
0.92 
0.3907
trt 
1 
0.28386147 
0.28386147 
4.09 
0.1130
subject(sequence) 
4 
0.77494679 
0.19373670 
2.79 
0.1717
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04000138 
0.04000138 
0.58 
0.4898
period 
1 
0.06410442 
0.06410442 
0.92 
0.3907
trt 
1 
0.28386147 
0.28386147 
4.09 
0.1130
subject(sequence) 
4 
0.77494679 
0.19373670 
2.79 
0.1717
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 51-62 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.040001 
0.040001 
0.21 
0.6731 
Error 
4 
0.774947 
0.193737 
 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F
*period 
1 
0.208772 0.208772 
3.01 
0.1577
trt 
1 
0.283861 0.283861 
4.09 
0.1130
subject(sequence) 
4 
0.774947 0.193737 
2.79 
0.1717
Error: MS(Error) 
4 
0.277304 0.069326 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.040001 
0.040001 
0.21 
0.6731
Error 
4 
0.774947 
0.193737 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.064104 
0.064104 
0.92 
0.3907
trt 
1 
0.283861 
0.283861 
4.09 
0.1130
subject(sequence) 
4 
0.774947 
0.193737 
2.79 
0.1717
Error: MS(Error) 
4 
0.277304 
0.069326 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 51-62 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.040001 
0.040001 
0.21 
0.6731 
Error 
4 
0.774947 
0.193737 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.064104 
0.064104 
0.92 
0.3907
trt 
1 
0.283861 
0.283861 
4.09 
0.1130
subject(sequence) 
4 
0.774947 
0.193737 
2.79 
0.1717
Error: MS(Error) 
4 
0.277304 
0.069326 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.040001 
0.040001 
0.21 
0.6731
Error 
4 
0.774947 
0.193737 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.064104 
0.064104 
0.92 
0.3907
trt 
1 
0.283861 
0.283861 
4.09 
0.1130
subject(sequence) 
4 
0.774947 
0.193737 
2.79 
0.1717
Error: MS(Error) 
4 
0.277304 
0.069326 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 51-62 
Least Squares Means 
trt 
LN_CMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
5.55444448 
0.1130
B 
5.88070825 
trt 
LN_CMAX LSMEAN 
90% Confidence Limits 
A 
5.554444 
5.311390 
5.797499 
B 
5.880708 
5.637653 
6.123763 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 
-0.326264 
-0.669995 
0.017468 
 
Dependent Variable: LN_CMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.32626377 0.16123650 -2.02 
0.1130 -0.66999529 0.01746774 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
6 
101 201 302 412 414 503 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
12 
Number of Observations Used 
12 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LN_CLFOW 
R-Square 
Coeff Var 
Root MSE 
LN_CLFOW Mean
0.995684 
-1.805055 
0.068472 
-3.793372 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.82529228 
0.82529228 
176.03 
0.0002
period 
1 
0.04650127 
0.04650127 
9.92 
0.0345
trt 
1 
0.02448664 
0.02448664 
5.22 
0.0843
subject(sequence) 
4 
3.42986729 
0.85746682 
182.89 
<.0001
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.82529228 
0.82529228 
176.03 
0.0002
period 
1 
0.06526465 
0.06526465 
13.92 
0.0203
trt 
1 
0.02448664 
0.02448664 
5.22 
0.0843
subject(sequence) 
4 
3.42986729 
0.85746682 
182.89 
<.0001
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.82529228 
0.82529228 
176.03 
0.0002
period 
1 
0.06526465 
0.06526465 
13.92 
0.0203
trt 
1 
0.02448664 
0.02448664 
5.22 
0.0843
subject(sequence) 
4 
3.42986729 
0.85746682 
182.89 
<.0001
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.82529228 
0.82529228 
176.03 
0.0002
period 
1 
0.06526465 
0.06526465 
13.92 
0.0203
trt 
1 
0.02448664 
0.02448664 
5.22 
0.0843
subject(sequence) 
4 
3.42986729 
0.85746682 
182.89 
<.0001
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 51-62 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.825292 
0.825292 
0.96 
0.3821 
Error 
4 
3.429867 
0.857467 
 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F
*period 
1 
0.046501 0.046501 
9.92 
0.0345
trt 
1 
0.024487 0.024487 
5.22 
0.0843
subject(sequence) 
4 
3.429867 0.857467 
182.89 
<.0001
Error: MS(Error) 
4 
0.018754 0.004688 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.825292 
0.825292 
0.96 
0.3821
Error 
4 
3.429867 
0.857467 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.065265 
0.065265 
13.92 
0.0203
trt 
1 
0.024487 
0.024487 
5.22 
0.0843
subject(sequence) 
4 
3.429867 
0.857467 
182.89 
<.0001
Error: MS(Error) 
4 
0.018754 
0.004688 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 51-62 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.825292 
0.825292 
0.96 
0.3821 
Error 
4 
3.429867 
0.857467 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.065265 
0.065265 
13.92 
0.0203
trt 
1 
0.024487 
0.024487 
5.22 
0.0843
subject(sequence) 
4 
3.429867 
0.857467 
182.89 
<.0001
Error: MS(Error) 
4 
0.018754 
0.004688 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.825292 
0.825292 
0.96 
0.3821
Error 
4 
3.429867 
0.857467 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.065265 
0.065265 
13.92 
0.0203
trt 
1 
0.024487 
0.024487 
5.22 
0.0843
subject(sequence) 
4 
3.429867 
0.857467 
182.89 
<.0001
Error: MS(Error) 
4 
0.018754 
0.004688 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 51-62 
Least Squares Means 
trt 
LN_CLFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
-3.93400394 
0.0843
B 
-3.83817863 
trt 
LN_CLFOW LSMEAN 
90% Confidence Limits 
A 
-3.934004 
-3.997212 
-3.870796 
B 
-3.838179 
-3.901387 
-3.774971 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.095825 
-0.185215 
-0.006436 
 
Dependent Variable: LN_CLFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.09582531 0.04193065 -2.29 
0.0843 -0.18521503 -0.00643560 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
6 
101 201 302 412 414 503 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
12 
Number of Observations Used 
12 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LN_CLFO 
R-Square 
Coeff Var 
Root MSE 
LN_CLFO Mean
0.995963 
24.50124 
0.068472 
0.279465 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.05980441 
1.05980441 
226.04 
0.0001
period 
1 
0.04650127 
0.04650127 
9.92 
0.0345
trt 
1 
0.02448664 
0.02448664 
5.22 
0.0843
subject(sequence) 
4 
3.49588930 
0.87397232 
186.41 
<.0001
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.05980441 
1.05980441 
226.04 
0.0001
period 
1 
0.06526465 
0.06526465 
13.92 
0.0203
trt 
1 
0.02448664 
0.02448664 
5.22 
0.0843
subject(sequence) 
4 
3.49588930 
0.87397232 
186.41 
<.0001
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.05980441 
1.05980441 
226.04 
0.0001
period 
1 
0.06526465 
0.06526465 
13.92 
0.0203
trt 
1 
0.02448664 
0.02448664 
5.22 
0.0843
subject(sequence) 
4 
3.49588930 
0.87397232 
186.41 
<.0001
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.05980441 
1.05980441 
226.04 
0.0001
period 
1 
0.06526465 
0.06526465 
13.92 
0.0203
trt 
1 
0.02448664 
0.02448664 
5.22 
0.0843
subject(sequence) 
4 
3.49588930 
0.87397232 
186.41 
<.0001
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 51-62 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
1.059804 
1.059804 
1.21 
0.3326 
Error 
4 
3.495889 
0.873972 
 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F
*period 
1 
0.046501 0.046501 
9.92 
0.0345
trt 
1 
0.024487 0.024487 
5.22 
0.0843
subject(sequence) 
4 
3.495889 0.873972 
186.41 
<.0001
Error: MS(Error) 
4 
0.018754 0.004688 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.059804 
1.059804 
1.21 
0.3326
Error 
4 
3.495889 
0.873972 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.065265 
0.065265 
13.92 
0.0203
trt 
1 
0.024487 
0.024487 
5.22 
0.0843
subject(sequence) 
4 
3.495889 
0.873972 
186.41 
<.0001
Error: MS(Error) 
4 
0.018754 
0.004688 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 51-62 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
1.059804 
1.059804 
1.21 
0.3326 
Error 
4 
3.495889 
0.873972 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.065265 
0.065265 
13.92 
0.0203
trt 
1 
0.024487 
0.024487 
5.22 
0.0843
subject(sequence) 
4 
3.495889 
0.873972 
186.41 
<.0001
Error: MS(Error) 
4 
0.018754 
0.004688 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.059804 
1.059804 
1.21 
0.3326
Error 
4 
3.495889 
0.873972 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.065265 
0.065265 
13.92 
0.0203
trt 
1 
0.024487 
0.024487 
5.22 
0.0843
subject(sequence) 
4 
3.495889 
0.873972 
186.41 
<.0001
Error: MS(Error) 
4 
0.018754 
0.004688 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 51-62 
Least Squares Means 
trt 
LN_CLFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
0.12648303 
0.0843
B 
0.22230834 
trt 
LN_CLFO LSMEAN 
90% Confidence Limits 
A 
0.126483 
0.063275 
0.189691 
B 
0.222308 
0.159100 
0.285516 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.095825 
-0.185215 
-0.006436 
 
Dependent Variable: LN_CLFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.09582531 0.04193065 -2.29 
0.0843 -0.18521503 -0.00643560 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
6 
101 201 302 412 414 503 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
12 
Number of Observations Used 
12 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LN_VZFOW 
R-Square 
Coeff Var 
Root MSE 
LN_VZFOW Mean
0.850422 
149.0144 
0.249852 
0.167670 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.06679525 
0.06679525 
1.07 
0.3594
period 
1 
0.00364857 
0.00364857 
0.06 
0.8209
trt 
1 
0.00056004 
0.00056004 
0.01 
0.9291
subject(sequence) 
4 
1.34868165 
0.33717041 
5.40 
0.0656
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.06679525 
0.06679525 
1.07 
0.3594
period 
1 
0.00420387 
0.00420387 
0.07 
0.8081
trt 
1 
0.00056004 
0.00056004 
0.01 
0.9291
subject(sequence) 
4 
1.34868165 
0.33717041 
5.40 
0.0656
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.06679525 
0.06679525 
1.07 
0.3594
period 
1 
0.00420387 
0.00420387 
0.07 
0.8081
trt 
1 
0.00056004 
0.00056004 
0.01 
0.9291
subject(sequence) 
4 
1.34868165 
0.33717041 
5.40 
0.0656
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.06679525 
0.06679525 
1.07 
0.3594
period 
1 
0.00420387 
0.00420387 
0.07 
0.8081
trt 
1 
0.00056004 
0.00056004 
0.01 
0.9291
subject(sequence) 
4 
1.34868165 
0.33717041 
5.40 
0.0656
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 51-62 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.066795 
0.066795 
0.20 
0.6793 
Error 
4 
1.348682 
0.337170 
 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F
*period 
1 
0.003649 0.003649 
0.06 
0.8209
trt 
1 
0.000560 0.000560 
0.01 
0.9291
subject(sequence) 
4 
1.348682 0.337170 
5.40 
0.0656
Error: MS(Error) 
4 
0.249704 0.062426 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.066795 
0.066795 
0.20 
0.6793
Error 
4 
1.348682 
0.337170 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.004204 
0.004204 
0.07 
0.8081
trt 
1 
0.000560 
0.000560 
0.01 
0.9291
subject(sequence) 
4 
1.348682 
0.337170 
5.40 
0.0656
Error: MS(Error) 
4 
0.249704 
0.062426 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 51-62 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.066795 
0.066795 
0.20 
0.6793 
Error 
4 
1.348682 
0.337170 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.004204 
0.004204 
0.07 
0.8081
trt 
1 
0.000560 
0.000560 
0.01 
0.9291
subject(sequence) 
4 
1.348682 
0.337170 
5.40 
0.0656
Error: MS(Error) 
4 
0.249704 
0.062426 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.066795 
0.066795 
0.20 
0.6793
Error 
4 
1.348682 
0.337170 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.004204 
0.004204 
0.07 
0.8081
trt 
1 
0.000560 
0.000560 
0.01 
0.9291
subject(sequence) 
4 
1.348682 
0.337170 
5.40 
0.0656
Error: MS(Error) 
4 
0.249704 
0.062426 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 51-62 
Least Squares Means 
trt 
LN_VZFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
0.20129341 
0.9291
B 
0.18680157 
trt 
LN_VZFOW LSMEAN 
90% Confidence Limits 
A 
0.201293 
-0.029349 
0.431936 
B 
0.186802 
-0.043841 
0.417444 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.014492 
-0.311686 
0.340670 
 
Dependent Variable: LN_VZFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.01449185 0.15300260 0.09 
0.9291 -0.31168624 0.34066994 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
6 
101 201 302 412 414 503 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
12 
Number of Observations Used 
12 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LN_VZFO 
R-Square 
Coeff Var 
Root MSE 
LN_VZFO Mean
0.847614 
5.892035 
0.249852 
4.240507 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.01888858 
0.01888858 
0.30 
0.6115
period 
1 
0.00364857 
0.00364857 
0.06 
0.8209
trt 
1 
0.00056004 
0.00056004 
0.01 
0.9291
subject(sequence) 
4 
1.36582781 
0.34145695 
5.47 
0.0643
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.01888858 
0.01888858 
0.30 
0.6115
period 
1 
0.00420387 
0.00420387 
0.07 
0.8081
trt 
1 
0.00056004 
0.00056004 
0.01 
0.9291
subject(sequence) 
4 
1.36582781 
0.34145695 
5.47 
0.0643
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.01888858 
0.01888858 
0.30 
0.6115
period 
1 
0.00420387 
0.00420387 
0.07 
0.8081
trt 
1 
0.00056004 
0.00056004 
0.01 
0.9291
subject(sequence) 
4 
1.36582781 
0.34145695 
5.47 
0.0643
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.01888858 
0.01888858 
0.30 
0.6115
period 
1 
0.00420387 
0.00420387 
0.07 
0.8081
trt 
1 
0.00056004 
0.00056004 
0.01 
0.9291
subject(sequence) 
4 
1.36582781 
0.34145695 
5.47 
0.0643
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 51-62 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.018889 
0.018889 
0.06 
0.8256 
Error 
4 
1.365828 
0.341457 
 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F
*period 
1 
0.003649 0.003649 
0.06 
0.8209
trt 
1 
0.000560 0.000560 
0.01 
0.9291
subject(sequence) 
4 
1.365828 0.341457 
5.47 
0.0643
Error: MS(Error) 
4 
0.249704 0.062426 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.018889 
0.018889 
0.06 
0.8256
Error 
4 
1.365828 
0.341457 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.004204 
0.004204 
0.07 
0.8081
trt 
1 
0.000560 
0.000560 
0.01 
0.9291
subject(sequence) 
4 
1.365828 
0.341457 
5.47 
0.0643
Error: MS(Error) 
4 
0.249704 
0.062426 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 51-62 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.018889 
0.018889 
0.06 
0.8256 
Error 
4 
1.365828 
0.341457 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.004204 
0.004204 
0.07 
0.8081
trt 
1 
0.000560 
0.000560 
0.01 
0.9291
subject(sequence) 
4 
1.365828 
0.341457 
5.47 
0.0643
Error: MS(Error) 
4 
0.249704 
0.062426 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.018889 
0.018889 
0.06 
0.8256
Error 
4 
1.365828 
0.341457 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.004204 
0.004204 
0.07 
0.8081
trt 
1 
0.000560 
0.000560 
0.01 
0.9291
subject(sequence) 
4 
1.365828 
0.341457 
5.47 
0.0643
Error: MS(Error) 
4 
0.249704 
0.062426 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 51-62 
Least Squares Means 
trt 
LN_VZFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
4.26178039 
0.9291
B 
4.24728854 
trt 
LN_VZFO LSMEAN 
90% Confidence Limits 
A 
4.261780 
4.031138 
4.492423 
B 
4.247289 
4.016646 
4.477931 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.014492 
-0.311686 
0.340670 
 
Dependent Variable: LN_VZFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.01449185 0.15300260 0.09 
0.9291 -0.31168624 0.34066994 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
6 
101 201 302 412 414 503 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
12 
Number of Observations Used 
12 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: TMAX 
R-Square 
Coeff Var 
Root MSE 
TMAX Mean
0.730498 
75.37925 
0.965357 
1.280667 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.25317604 
0.25317604 
0.27 
0.6297
period 
1 
1.54083333 
1.54083333 
1.65 
0.2679
trt 
1 
3.84080004 
3.84080004 
4.12 
0.1122
subject(sequence) 
4 
4.46918363 
1.11729591 
1.20 
0.4323
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.25317604 
0.25317604 
0.27 
0.6297
period 
1 
0.26733704 
0.26733704 
0.29 
0.6206
trt 
1 
3.84080004 
3.84080004 
4.12 
0.1122
subject(sequence) 
4 
4.46918363 
1.11729591 
1.20 
0.4323
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.25317604 
0.25317604 
0.27 
0.6297
period 
1 
0.26733704 
0.26733704 
0.29 
0.6206
trt 
1 
3.84080004 
3.84080004 
4.12 
0.1122
subject(sequence) 
4 
4.46918363 
1.11729591 
1.20 
0.4323
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.25317604 
0.25317604 
0.27 
0.6297
period 
1 
0.26733704 
0.26733704 
0.29 
0.6206
trt 
1 
3.84080004 
3.84080004 
4.12 
0.1122
subject(sequence) 
4 
4.46918363 
1.11729591 
1.20 
0.4323
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 51-62 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.253176 
0.253176 
0.23 
0.6589 
Error 
4 
4.469184 
1.117296 
 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F
*period 
1 
1.540833 1.540833 
1.65 
0.2679
trt 
1 
3.840800 3.840800 
4.12 
0.1122
subject(sequence) 
4 
4.469184 1.117296 
1.20 
0.4323
Error: MS(Error) 
4 
3.727656 0.931914 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.253176 
0.253176 
0.23 
0.6589
Error 
4 
4.469184 
1.117296 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.267337 
0.267337 
0.29 
0.6206
trt 
1 
3.840800 
3.840800 
4.12 
0.1122
subject(sequence) 
4 
4.469184 
1.117296 
1.20 
0.4323
Error: MS(Error) 
4 
3.727656 
0.931914 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 51-62 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.253176 
0.253176 
0.23 
0.6589 
Error 
4 
4.469184 
1.117296 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.267337 
0.267337 
0.29 
0.6206
trt 
1 
3.840800 
3.840800 
4.12 
0.1122
subject(sequence) 
4 
4.469184 
1.117296 
1.20 
0.4323
Error: MS(Error) 
4 
3.727656 
0.931914 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.253176 
0.253176 
0.23 
0.6589
Error 
4 
4.469184 
1.117296 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.267337 
0.267337 
0.29 
0.6206
trt 
1 
3.840800 
3.840800 
4.12 
0.1122
subject(sequence) 
4 
4.469184 
1.117296 
1.20 
0.4323
Error: MS(Error) 
4 
3.727656 
0.931914 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 51-62 
Least Squares Means 
trt TMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 1.82937500 
0.1122
B 
0.62925000 
trt 
TMAX LSMEAN 
90% Confidence Limits 
A 
1.829375 
0.938238 
2.720512 
B 
0.629250 
-0.261887 
1.520387 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 1.200125 
-0.060133 
2.460383 
 
Dependent Variable: TMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
1.20012500 0.59115794 2.03 
0.1122 -0.06013316 2.46038316 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
6 
101 201 302 412 414 503 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
12 
Number of Observations Used 
12 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LAMZ 
R-Square 
Coeff Var 
Root MSE 
LAMZ Mean
0.984784 
11.99520 
0.002714 
0.022627 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00062156 
0.00062156 
84.37 
0.0008
period 
1 
0.00002840 
0.00002840 
3.86 
0.1211
trt 
1 
0.00000016 
0.00000016 
0.02 
0.8885
subject(sequence) 
4 
0.00125697 
0.00031424 
42.66 
0.0016
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00062156 
0.00062156 
84.37 
0.0008
period 
1 
0.00002391 
0.00002391 
3.25 
0.1460
trt 
1 
0.00000016 
0.00000016 
0.02 
0.8885
subject(sequence) 
4 
0.00125697 
0.00031424 
42.66 
0.0016
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00062156 
0.00062156 
84.37 
0.0008
period 
1 
0.00002391 
0.00002391 
3.25 
0.1460
trt 
1 
0.00000016 
0.00000016 
0.02 
0.8885
subject(sequence) 
4 
0.00125697 
0.00031424 
42.66 
0.0016
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00062156 
0.00062156 
84.37 
0.0008
period 
1 
0.00002391 
0.00002391 
3.25 
0.1460
trt 
1 
0.00000016 
0.00000016 
0.02 
0.8885
subject(sequence) 
4 
0.00125697 
0.00031424 
42.66 
0.0016
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 51-62 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.000622 
0.000622 
1.98 
0.2323 
Error 
4 
0.001257 
0.000314 
 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS 
Mean Square F Value 
Pr > F
*period 
1 
0.000028401 0.000028401 3.86 
0.1211
trt 
1 
0.000000164 0.000000164 0.02 
0.8885
subject(sequence) 4 
0.001257 
0.000314 
42.66 
0.0016
Error: MS(Error) 
4 
0.000029467 0.000007367 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000622 
0.000622 
1.98 
0.2323
Error 
4 
0.001257 
0.000314 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000023907 
0.000023907 
3.25 
0.1460
trt 
1 
0.000000164 
0.000000164 
0.02 
0.8885
subject(sequence) 
4 
0.001257 
0.000314 
42.66 
0.0016
Error: MS(Error) 
4 
0.000029467 
0.000007367 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 51-62 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.000622 
0.000622 
1.98 
0.2323 
Error 
4 
0.001257 
0.000314 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000023907 
0.000023907 
3.25 
0.1460
trt 
1 
0.000000164 
0.000000164 
0.02 
0.8885
subject(sequence) 
4 
0.001257 
0.000314 
42.66 
0.0016
Error: MS(Error) 
4 
0.000029467 
0.000007367 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000622 
0.000622 
1.98 
0.2323
Error 
4 
0.001257 
0.000314 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000023907 
0.000023907 
3.25 
0.1460
trt 
1 
0.000000164 
0.000000164 
0.02 
0.8885
subject(sequence) 
4 
0.001257 
0.000314 
42.66 
0.0016
Error: MS(Error) 
4 
0.000029467 
0.000007367 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 51-62 
Least Squares Means 
trt LAMZ LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t| 
A 
0.02020687 
0.8885 
B 
0.01995872 
 
trt 
LAMZ LSMEAN 
90% Confidence Limits 
A 
0.020207 
0.017701 
0.022712 
B 
0.019959 
0.017453 
0.022464 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.000248 
-0.003295 
0.003791 
 
Dependent Variable: LAMZ 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.00024814 0.00166210 0.15 
0.8885 -0.00329519 0.00379148 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
6 
101 201 302 412 414 503 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
12 
Number of Observations Used 
12 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LAMZHL 
R-Square 
Coeff Var 
Root MSE 
LAMZHL Mean
0.912041 
30.75229 
13.38035 
43.51010 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
2163.641142 
2163.641142 
12.09 
0.0254
period 
1 
231.387288 
231.387288 
1.29 
0.3191
trt 
1 
354.611103 
354.611103 
1.98 
0.2321
subject(sequence) 
4 
4675.957475 
1168.989369 
6.53 
0.0482
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
2163.641142 
2163.641142 
12.09 
0.0254
period 
1 
425.122715 
425.122715 
2.37 
0.1982
trt 
1 
354.611103 
354.611103 
1.98 
0.2321
subject(sequence) 
4 
4675.957475 
1168.989369 
6.53 
0.0482
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
2163.641142 
2163.641142 
12.09 
0.0254
period 
1 
425.122715 
425.122715 
2.37 
0.1982
trt 
1 
354.611103 
354.611103 
1.98 
0.2321
subject(sequence) 
4 
4675.957475 
1168.989369 
6.53 
0.0482
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
2163.641142 
2163.641142 
12.09 
0.0254
period 
1 
425.122715 
425.122715 
2.37 
0.1982
trt 
1 
354.611103 
354.611103 
1.98 
0.2321
subject(sequence) 
4 
4675.957475 
1168.989369 
6.53 
0.0482
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 51-62 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
2163.641142 
2163.641142 
1.85 
0.2453
Error 
4 
4675.957475 
1168.989369 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS 
Mean Square F Value 
Pr > F
*period 
1 
231.387288 
231.387288 
1.29 
0.3191
trt 
1 
354.611103 
354.611103 
1.98 
0.2321
subject(sequence) 4 
4675.957475 1168.989369 6.53 
0.0482
Error: MS(Error) 
4 
716.135395 
179.033849 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
2163.641142 
2163.641142 
1.85 
0.2453
Error 
4 
4675.957475 
1168.989369 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
425.122715 
425.122715 
2.37 
0.1982
trt 
1 
354.611103 
354.611103 
1.98 
0.2321
subject(sequence) 
4 
4675.957475 
1168.989369 
6.53 
0.0482
Error: MS(Error) 
4 
716.135395 
179.033849 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 51-62 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
2163.641142 
2163.641142 
1.85 
0.2453
Error 
4 
4675.957475 
1168.989369 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
425.122715 
425.122715 
2.37 
0.1982
trt 
1 
354.611103 
354.611103 
1.98 
0.2321
subject(sequence) 
4 
4675.957475 
1168.989369 
6.53 
0.0482
Error: MS(Error) 
4 
716.135395 
179.033849 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
2163.641142 
2163.641142 
1.85 
0.2453
Error 
4 
4675.957475 
1168.989369 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
425.122715 
425.122715 
2.37 
0.1982
trt 
1 
354.611103 
354.611103 
1.98 
0.2321
subject(sequence) 
4 
4675.957475 
1168.989369 
6.53 
0.0482
Error: MS(Error) 
4 
716.135395 
179.033849 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 51-62 
Least Squares Means 
trt 
LAMZHL LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
54.0233424 
0.2321
B 
42.4916832 
trt 
LAMZHL LSMEAN 
90% Confidence Limits 
A 
54.023342 
41.671714 
66.374970 
B 
42.491683 
30.140055 
54.843311 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 11.531659 
-5.936180 
28.999499 
 
Dependent Variable: LAMZHL 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t|
90% Confidence Limits 
A - B 
11.5316592 
8.19375941 1.41 
0.2321-5.9361805 28.9994989 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
101 201 
sequence 
1 
ABC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LN_AUCLST 
R-Square 
Coeff Var 
Root MSE 
LN_AUCLST Mean
0.995425 
0.993048 
0.089625 
9.025241 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.00308741 
0.00308741 
0.38 
0.6467
subject(sequence) 
1 
1.74458843 
1.74458843 
217.19 
0.0431
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.00308741 
0.00308741 
0.38 
0.6467
subject(sequence) 
1 
1.74458843 
1.74458843 
217.19 
0.0431
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.00308741 
0.00308741 
0.38 
0.6467
subject(sequence) 
1 
1.74458843 
1.74458843 
217.19 
0.0431
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.00308741 
0.00308741 
0.38 
0.6467
subject(sequence) 
1 
1.74458843 
1.74458843 
217.19 
0.0431
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 51-62 
The GLM Procedure 
Least Squares Means 
trt LN_AUCLST LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
9.05302332 
0.6467
C 
8.99745888 
trt 
LN_AUCLST LSMEAN 
90% Confidence Limits 
B 
9.053023 
8.652893 
9.453154 
C 
8.997459 
8.597329 
9.397589 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.055564 
-0.510305 
0.621434 
 
The GLM Procedure 
Dependent Variable: LN_AUCLST 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.05556445 0.08962497 -0.62 
0.6467 -0.62143424 0.51030535 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
101 201 
sequence 
1 
ABC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LN_AUCIFO 
R-Square 
Coeff Var 
Root MSE 
LN_AUCIFO Mean
0.999287 
0.422185 
0.038401 
9.095817 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
0 
0.00000000 
 
trt 
1 
0.00001005 
0.00001005 
0.01 
0.9476 
subject(sequence) 
1 
2.06771611 
2.06771611 
1402.17 
0.0170 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F 
sequence 
0 
0.00000000 
 
trt 
1 
0.00001005 
0.00001005 
0.01 
0.9476 
subject(sequence) 
1 
2.06771611 
2.06771611 
1402.17 
0.0170 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
0 
0.00000000 
 
trt 
1 
0.00001005 
0.00001005 
0.01 
0.9476 
subject(sequence) 
1 
2.06771611 
2.06771611 
1402.17 
0.0170 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F 
sequence 
0 
0.00000000 
 
trt 
1 
0.00001005 
0.00001005 
0.01 
0.9476 
subject(sequence) 
1 
2.06771611 
2.06771611 
1402.17 
0.0170 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 51-62 
The GLM Procedure 
Least Squares Means 
trt LN_AUCIFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
9.09740260 
0.9476
C 
9.09423224 
trt 
LN_AUCIFO LSMEAN 
90% Confidence Limits 
B 
9.097403 
8.925960 
9.268845 
C 
9.094232 
8.922790 
9.265674 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.003170 
-0.239285 
0.245626 
 
The GLM Procedure 
Dependent Variable: LN_AUCIFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.00317035 0.03840122 -0.08 
0.9476 -0.24562613 0.23928542 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
101 201 
sequence 
1 
ABC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LN_CMAX 
R-Square 
Coeff Var 
Root MSE 
LN_CMAX Mean
0.996701 
1.022835 
0.056591 
5.532719 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.27556715 
0.27556715 
86.05 
0.0684
subject(sequence) 
1 
0.69186372 
0.69186372 
216.04 
0.0432
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.27556715 
0.27556715 
86.05 
0.0684
subject(sequence) 
1 
0.69186372 
0.69186372 
216.04 
0.0432
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.27556715 
0.27556715 
86.05 
0.0684
subject(sequence) 
1 
0.69186372 
0.69186372 
216.04 
0.0432
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.27556715 
0.27556715 
86.05 
0.0684
subject(sequence) 
1 
0.69186372 
0.69186372 
216.04 
0.0432
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 51-62 
The GLM Procedure 
Least Squares Means 
trt 
LN_CMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
5.79519172 
0.0684
C 
5.27024682 
trt 
LN_CMAX LSMEAN 
90% Confidence Limits 
B 
5.795192 
5.542543 
6.047840 
C 
5.270247 
5.017598 
5.522895 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 
0.524945 
0.167646 
0.882244 
 
The GLM Procedure 
Dependent Variable: LN_CMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.52494490 0.05659061 -9.28 
0.0684 -0.88224396 -0.16764585 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
101 201 
sequence 
1 
ABC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LN_CLFOW 
R-Square 
Coeff Var 
Root MSE 
LN_CLFOW Mean
0.999296 
-1.025649 
0.038401 
-3.744090 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
0 
0.00000000 
 
trt 
1 
0.00001005 
0.00001005 
0.01 
0.9476 
subject(sequence) 
1 
2.09205676 
2.09205676 
1418.68 
0.0169 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F 
sequence 
0 
0.00000000 
 
trt 
1 
0.00001005 
0.00001005 
0.01 
0.9476 
subject(sequence) 
1 
2.09205676 
2.09205676 
1418.68 
0.0169 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
0 
0.00000000 
 
trt 
1 
0.00001005 
0.00001005 
0.01 
0.9476 
subject(sequence) 
1 
2.09205676 
2.09205676 
1418.68 
0.0169 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F 
sequence 
0 
0.00000000 
 
trt 
1 
0.00001005 
0.00001005 
0.01 
0.9476 
subject(sequence) 
1 
2.09205676 
2.09205676 
1418.68 
0.0169 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 51-62 
The GLM Procedure 
Least Squares Means 
trt 
LN_CLFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
-3.74567555 
0.9476
C 
-3.74250520 
trt 
LN_CLFOW LSMEAN 
90% Confidence Limits 
B 
-3.745676 
-3.917118 
-3.574233 
C 
-3.742505 
-3.913947 
-3.571063 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.003170 
-0.245626 
0.239285 
 
The GLM Procedure 
Dependent Variable: LN_CLFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.00317035 0.03840122 0.08 
0.9476 -0.23928542 0.24562613 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
101 201 
sequence 
1 
ABC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LN_CLFO 
R-Square 
Coeff Var 
Root MSE 
LN_CLFO Mean
0.999287 
11.37253 
0.038401 
0.337667 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
0 
0.00000000 
 
trt 
1 
0.00001005 
0.00001005 
0.01 
0.9476 
subject(sequence) 
1 
2.06771611 
2.06771611 
1402.17 
0.0170 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F 
sequence 
0 
0.00000000 
 
trt 
1 
0.00001005 
0.00001005 
0.01 
0.9476 
subject(sequence) 
1 
2.06771611 
2.06771611 
1402.17 
0.0170 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
0 
0.00000000 
 
trt 
1 
0.00001005 
0.00001005 
0.01 
0.9476 
subject(sequence) 
1 
2.06771611 
2.06771611 
1402.17 
0.0170 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F 
sequence 
0 
0.00000000 
 
trt 
1 
0.00001005 
0.00001005 
0.01 
0.9476 
subject(sequence) 
1 
2.06771611 
2.06771611 
1402.17 
0.0170 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 51-62 
The GLM Procedure 
Least Squares Means 
trt 
LN_CLFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
0.33608132 
0.9476
C 
0.33925168 
trt 
LN_CLFO LSMEAN 
90% Confidence Limits 
B 
0.336081 
0.164639 
0.507523 
C 
0.339252 
0.167810 
0.510694 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.003170 
-0.245626 
0.239285 
 
The GLM Procedure 
Dependent Variable: LN_CLFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.00317035 0.03840122 0.08 
0.9476 -0.23928542 0.24562613 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
101 201 
sequence 
1 
ABC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LN_VZFOW 
R-Square 
Coeff Var 
Root MSE 
LN_VZFOW Mean
0.507929 
87.10023 
0.257878 
0.296071 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.06357519 
0.06357519 
0.96 
0.5072
subject(sequence) 
1 
0.00506924 
0.00506924 
0.08 
0.8285
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.06357519 
0.06357519 
0.96 
0.5072
subject(sequence) 
1 
0.00506924 
0.00506924 
0.08 
0.8285
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.06357519 
0.06357519 
0.96 
0.5072
subject(sequence) 
1 
0.00506924 
0.00506924 
0.08 
0.8285
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.06357519 
0.06357519 
0.96 
0.5072
subject(sequence) 
1 
0.00506924 
0.00506924 
0.08 
0.8285
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 51-62 
The GLM Procedure 
Least Squares Means 
trt 
LN_VZFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
0.17000011 
0.5072
C 
0.42214132 
trt 
LN_VZFOW LSMEAN 
90% Confidence Limits 
B 
0.170000 
-0.981296 
1.321297 
C 
0.422141 
-0.729155 
1.573438 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.252141 
-1.880320 
1.376038 
 
The GLM Procedure 
Dependent Variable: LN_VZFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.25214122 0.25787826 0.98 
0.5072 -1.37603804 1.88032048 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
101 201 
sequence 
1 
ABC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LN_VZFO 
R-Square 
Coeff Var 
Root MSE 
LN_VZFO Mean
0.512521 
5.890553 
0.257878 
4.377828 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.06357519 
0.06357519 
0.96 
0.5072
subject(sequence) 
1 
0.00634213 
0.00634213 
0.10 
0.8093
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.06357519 
0.06357519 
0.96 
0.5072
subject(sequence) 
1 
0.00634213 
0.00634213 
0.10 
0.8093
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.06357519 
0.06357519 
0.96 
0.5072
subject(sequence) 
1 
0.00634213 
0.00634213 
0.10 
0.8093
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.06357519 
0.06357519 
0.96 
0.5072
subject(sequence) 
1 
0.00634213 
0.00634213 
0.10 
0.8093
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) Weight Group: 51-62 
The GLM Procedure 
Least Squares Means 
trt 
LN_VZFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
4.25175698 
0.5072
C 
4.50389820 
trt 
LN_VZFO LSMEAN 
90% Confidence Limits 
B 
4.251757 
3.100460 
5.403054 
C 
4.503898 
3.352602 
5.655195 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.252141 
-1.880320 
1.376038 
 
The GLM Procedure 
Dependent Variable: LN_VZFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.25214122 0.25787826 0.98 
0.5072 -1.37603804 1.88032048 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
101 201 
sequence 
1 
ABC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: TMAX 
R-Square 
Coeff Var 
Root MSE 
TMAX Mean
0.470588 
120.0000 
1.500000 
1.250000 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
1.00000000 
1.00000000 
0.44 
0.6257
subject(sequence) 
1 
1.00000000 
1.00000000 
0.44 
0.6257
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
1.00000000 
1.00000000 
0.44 
0.6257
subject(sequence) 
1 
1.00000000 
1.00000000 
0.44 
0.6257
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
1.00000000 
1.00000000 
0.44 
0.6257
subject(sequence) 
1 
1.00000000 
1.00000000 
0.44 
0.6257
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
1.00000000 
1.00000000 
0.44 
0.6257
subject(sequence) 
1 
1.00000000 
1.00000000 
0.44 
0.6257
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) Weight Group: 51-62 
The GLM Procedure 
Least Squares Means 
trt TMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
0.75000000 
0.6257
C 
1.75000000 
trt 
TMAX LSMEAN 
90% Confidence Limits 
B 
0.750000 
-5.946745 
7.446745 
C 
1.750000 
-4.946745 
8.446745 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -1.000000 
-10.470627 
8.470627 
 
The GLM Procedure 
Dependent Variable: TMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
1.00000000 1.50000000 0.67 
0.6257 -8.47062727 10.47062727 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
101 201 
sequence 
1 
ABC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LAMZ 
R-Square 
Coeff Var 
Root MSE 
LAMZ Mean
0.997732 
6.051039 
0.001393 
0.023023 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.00000626 
0.00000626 
3.22 
0.3235
subject(sequence) 
1 
0.00084772 
0.00084772 
436.78 
0.0304
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.00000626 
0.00000626 
3.22 
0.3235
subject(sequence) 
1 
0.00084772 
0.00084772 
436.78 
0.0304
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.00000626 
0.00000626 
3.22 
0.3235
subject(sequence) 
1 
0.00084772 
0.00084772 
436.78 
0.0304
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.00000626 
0.00000626 
3.22 
0.3235
subject(sequence) 
1 
0.00084772 
0.00084772 
436.78 
0.0304
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) Weight Group: 51-62 
The GLM Procedure 
Least Squares Means 
trt LAMZ LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t| 
B 
0.02427392 
0.3235 
C 
0.02177245 
 
trt 
LAMZ LSMEAN 
90% Confidence Limits 
B 
0.024274 
0.018054 
0.030494 
C 
0.021772 
0.015553 
0.027992 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.002501 
-0.006294 
0.011297 
 
The GLM Procedure 
Dependent Variable: LAMZ 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.00250147 0.00139314 -1.80 
0.3235 -0.01129742 0.00629448 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) Weight Group: 51-62 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
101 201 
sequence 
1 
ABC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) Weight Group: 51-62 
The GLM Procedure 
Dependent Variable: LAMZHL 
R-Square 
Coeff Var 
Root MSE 
LAMZHL Mean
0.928959 
37.39729 
19.61552 
52.45171 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.000000 
trt 
1 
406.408780 
406.408780 
1.06 
0.4913
subject(sequence) 
1 
4624.986296 
4624.986296 
12.02 
0.1788
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.000000 
trt 
1 
406.408780 
406.408780 
1.06 
0.4913
subject(sequence) 
1 
4624.986296 
4624.986296 
12.02 
0.1788
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.000000 
trt 
1 
406.408780 
406.408780 
1.06 
0.4913
subject(sequence) 
1 
4624.986296 
4624.986296 
12.02 
0.1788
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.000000 
trt 
1 
406.408780 
406.408780 
1.06 
0.4913
subject(sequence) 
1 
4624.986296 
4624.986296 
12.02 
0.1788
 


 
 
Listing 16.1.9-5 ANOVA for Treatment Comparison of Diazepam for Weight Group 51-62 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) Weight Group: 51-62 
The GLM Procedure 
Least Squares Means 
trt 
LAMZHL LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
42.3719162 
0.4913
C 
62.5314991 
trt 
LAMZHL LSMEAN 
90% Confidence Limits 
B 
42.371916 
-45.201494 
129.945327 
C 
62.531499 
-25.041912 
150.104910 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -20.159583 
-144.007088 
103.687922 
 
The GLM Procedure 
Dependent Variable: LAMZHL 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
20.1595828 19.6155178 1.03 
0.4913 -103.6879223 144.0070879 
 
 


180323 Diazepam Buccal Film DRG Crossover 
Aquestive Therapeutics 
16.1.9 Documentation of Statistical Methods 
 
Confidential 
Page 9 of 11 
Final 1.0 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
202 303 408 413 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LN_AUCLST 
R-Square 
Coeff Var 
Root MSE 
LN_AUCLST Mean
0.998187 
0.385829 
0.032800 
8.501081 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.09031713 
0.09031713 
83.95 
0.0117
period 
1 
0.02145914 
0.02145914 
19.95 
0.0467
trt 
1 
0.00001757 
0.00001757 
0.02 
0.9100
subject(sequence) 
2 
1.07303798 
0.53651899 
498.71 
0.0020
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.09031713 
0.09031713 
83.95 
0.0117
period 
1 
0.02145914 
0.02145914 
19.95 
0.0467
trt 
1 
0.00001757 
0.00001757 
0.02 
0.9100
subject(sequence) 
2 
1.07303798 
0.53651899 
498.71 
0.0020
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.09031713 
0.09031713 
83.95 
0.0117
period 
1 
0.02145914 
0.02145914 
19.95 
0.0467
trt 
1 
0.00001757 
0.00001757 
0.02 
0.9100
subject(sequence) 
2 
1.07303798 
0.53651899 
498.71 
0.0020
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.09031713 
0.09031713 
83.95 
0.0117
period 
1 
0.02145914 
0.02145914 
19.95 
0.0467
trt 
1 
0.00001757 
0.00001757 
0.02 
0.9100
subject(sequence) 
2 
1.07303798 
0.53651899 
498.71 
0.0020
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 63-75 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.090317 
0.090317 
0.17 
0.7214 
Error 
2 
1.073038 
0.536519 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.021459 
0.021459 
19.95 
0.0467
trt 
1 
0.000017570 
0.000017570 
0.02 
0.9100
subject(sequence) 
2 
1.073038 
0.536519 
498.71 
0.0020
Error: MS(Error) 
2 
0.002152 
0.001076 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.090317 
0.090317 
0.17 
0.7214
Error 
2 
1.073038 
0.536519 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.021459 
0.021459 
19.95 
0.0467
trt 
1 
0.000017570 
0.000017570 
0.02 
0.9100
subject(sequence) 
2 
1.073038 
0.536519 
498.71 
0.0020
Error: MS(Error) 
2 
0.002152 
0.001076 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 63-75 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.090317 
0.090317 
0.17 
0.7214 
Error 
2 
1.073038 
0.536519 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.021459 
0.021459 
19.95 
0.0467
trt 
1 
0.000017570 
0.000017570 
0.02 
0.9100
subject(sequence) 
2 
1.073038 
0.536519 
498.71 
0.0020
Error: MS(Error) 
2 
0.002152 
0.001076 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.090317 
0.090317 
0.17 
0.7214
Error 
2 
1.073038 
0.536519 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.021459 
0.021459 
19.95 
0.0467
trt 
1 
0.000017570 
0.000017570 
0.02 
0.9100
subject(sequence) 
2 
1.073038 
0.536519 
498.71 
0.0020
Error: MS(Error) 
2 
0.002152 
0.001076 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 63-75 
Least Squares Means 
trt LN_AUCLST LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
8.50256332 
0.9100
B 
8.49959937 
trt 
LN_AUCLST LSMEAN 
90% Confidence Limits 
A 
8.502563 
8.454676 
8.550451 
B 
8.499599 
8.451712 
8.547487 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.002964 
-0.064759 
0.070687 
 
Dependent Variable: LN_AUCLST 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.00296395 0.02319284 0.13 
0.9100 -0.06475879 0.07068670 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
202 303 408 413 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LN_AUCIFO 
R-Square 
Coeff Var 
Root MSE 
LN_AUCIFO Mean
0.998102 
0.409031 
0.034910 
8.534749 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.10836268 
0.10836268 
88.92 
0.0111
period 
1 
0.01560178 
0.01560178 
12.80 
0.0700
trt 
1 
0.00019420 
0.00019420 
0.16 
0.7283
subject(sequence) 
2 
1.15775241 
0.57887620 
475.00 
0.0021
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.10836268 
0.10836268 
88.92 
0.0111
period 
1 
0.01560178 
0.01560178 
12.80 
0.0700
trt 
1 
0.00019420 
0.00019420 
0.16 
0.7283
subject(sequence) 
2 
1.15775241 
0.57887620 
475.00 
0.0021
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.10836268 
0.10836268 
88.92 
0.0111
period 
1 
0.01560178 
0.01560178 
12.80 
0.0700
trt 
1 
0.00019420 
0.00019420 
0.16 
0.7283
subject(sequence) 
2 
1.15775241 
0.57887620 
475.00 
0.0021
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.10836268 
0.10836268 
88.92 
0.0111
period 
1 
0.01560178 
0.01560178 
12.80 
0.0700
trt 
1 
0.00019420 
0.00019420 
0.16 
0.7283
subject(sequence) 
2 
1.15775241 
0.57887620 
475.00 
0.0021
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 63-75 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.108363 
0.108363 
0.19 
0.7074 
Error 
2 
1.157752 
0.578876 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.015602 
0.015602 
12.80 
0.0700
trt 
1 
0.000194 
0.000194 
0.16 
0.7283
subject(sequence) 
2 
1.157752 
0.578876 
475.00 
0.0021
Error: MS(Error) 
2 
0.002437 
0.001219 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.108363 
0.108363 
0.19 
0.7074
Error 
2 
1.157752 
0.578876 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.015602 
0.015602 
12.80 
0.0700
trt 
1 
0.000194 
0.000194 
0.16 
0.7283
subject(sequence) 
2 
1.157752 
0.578876 
475.00 
0.0021
Error: MS(Error) 
2 
0.002437 
0.001219 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 63-75 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.108363 
0.108363 
0.19 
0.7074 
Error 
2 
1.157752 
0.578876 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.015602 
0.015602 
12.80 
0.0700
trt 
1 
0.000194 
0.000194 
0.16 
0.7283
subject(sequence) 
2 
1.157752 
0.578876 
475.00 
0.0021
Error: MS(Error) 
2 
0.002437 
0.001219 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.108363 
0.108363 
0.19 
0.7074
Error 
2 
1.157752 
0.578876 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.015602 
0.015602 
12.80 
0.0700
trt 
1 
0.000194 
0.000194 
0.16 
0.7283
subject(sequence) 
2 
1.157752 
0.578876 
475.00 
0.0021
Error: MS(Error) 
2 
0.002437 
0.001219 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 63-75 
Least Squares Means 
trt LN_AUCIFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
8.53967571 
0.7283
B 
8.52982180 
trt 
LN_AUCIFO LSMEAN 
90% Confidence Limits 
A 
8.539676 
8.488708 
8.590644 
B 
8.529822 
8.478854 
8.580790 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.009854 
-0.062226 
0.081933 
 
Dependent Variable: LN_AUCIFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.00985391 0.02468491 0.40 
0.7283 -0.06222566 0.08193349 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
202 303 408 413 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LN_CMAX 
R-Square 
Coeff Var 
Root MSE 
LN_CMAX Mean
0.395997 
10.38897 
0.572102 
5.506819 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.24870956 
0.24870956 
0.76 
0.4753
period 
1 
0.00507523 
0.00507523 
0.02 
0.9123
trt 
1 
0.01964743 
0.01964743 
0.06 
0.8293
subject(sequence) 
2 
0.15573658 
0.07786829 
0.24 
0.8078
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.24870956 
0.24870956 
0.76 
0.4753
period 
1 
0.00507523 
0.00507523 
0.02 
0.9123
trt 
1 
0.01964743 
0.01964743 
0.06 
0.8293
subject(sequence) 
2 
0.15573658 
0.07786829 
0.24 
0.8078
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.24870956 
0.24870956 
0.76 
0.4753
period 
1 
0.00507523 
0.00507523 
0.02 
0.9123
trt 
1 
0.01964743 
0.01964743 
0.06 
0.8293
subject(sequence) 
2 
0.15573658 
0.07786829 
0.24 
0.8078
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.24870956 
0.24870956 
0.76 
0.4753
period 
1 
0.00507523 
0.00507523 
0.02 
0.9123
trt 
1 
0.01964743 
0.01964743 
0.06 
0.8293
subject(sequence) 
2 
0.15573658 
0.07786829 
0.24 
0.8078
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 63-75 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.248710 
0.248710 
3.19 
0.2158 
Error 
2 
0.155737 
0.077868 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.005075 
0.005075 
0.02 
0.9123
trt 
1 
0.019647 
0.019647 
0.06 
0.8293
subject(sequence) 
2 
0.155737 
0.077868 
0.24 
0.8078
Error: MS(Error) 
2 
0.654600 
0.327300 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.248710 
0.248710 
3.19 
0.2158
Error 
2 
0.155737 
0.077868 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.005075 
0.005075 
0.02 
0.9123
trt 
1 
0.019647 
0.019647 
0.06 
0.8293
subject(sequence) 
2 
0.155737 
0.077868 
0.24 
0.8078
Error: MS(Error) 
2 
0.654600 
0.327300 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 63-75 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.248710 
0.248710 
3.19 
0.2158 
Error 
2 
0.155737 
0.077868 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.005075 
0.005075 
0.02 
0.9123
trt 
1 
0.019647 
0.019647 
0.06 
0.8293
subject(sequence) 
2 
0.155737 
0.077868 
0.24 
0.8078
Error: MS(Error) 
2 
0.654600 
0.327300 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.248710 
0.248710 
3.19 
0.2158
Error 
2 
0.155737 
0.077868 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.005075 
0.005075 
0.02 
0.9123
trt 
1 
0.019647 
0.019647 
0.06 
0.8293
subject(sequence) 
2 
0.155737 
0.077868 
0.24 
0.8078
Error: MS(Error) 
2 
0.654600 
0.327300 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 63-75 
Least Squares Means 
trt 
LN_CMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
5.45726168 
0.8293
B 
5.55637635 
trt 
LN_CMAX LSMEAN 
90% Confidence Limits 
A 
5.457262 
4.621998 
6.292526 
B 
5.556376 
4.721112 
6.391640 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 
-0.099115 
-1.280356 
1.082127 
 
Dependent Variable: LN_CMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.09911467 0.40453685 -0.25 
0.8293 -1.28035645 1.08212712 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
202 303 408 413 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LN_CLFOW 
R-Square 
Coeff Var 
Root MSE 
LN_CLFOW Mean
0.998313 
-1.114725 
0.034910 
-3.131690 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.13920778 
0.13920778 
114.23 
0.0086
period 
1 
0.01560178 
0.01560178 
12.80 
0.0700
trt 
1 
0.00019420 
0.00019420 
0.16 
0.7283
subject(sequence) 
2 
1.28746738 
0.64373369 
528.22 
0.0019
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.13920778 
0.13920778 
114.23 
0.0086
period 
1 
0.01560178 
0.01560178 
12.80 
0.0700
trt 
1 
0.00019420 
0.00019420 
0.16 
0.7283
subject(sequence) 
2 
1.28746738 
0.64373369 
528.22 
0.0019
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.13920778 
0.13920778 
114.23 
0.0086
period 
1 
0.01560178 
0.01560178 
12.80 
0.0700
trt 
1 
0.00019420 
0.00019420 
0.16 
0.7283
subject(sequence) 
2 
1.28746738 
0.64373369 
528.22 
0.0019
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.13920778 
0.13920778 
114.23 
0.0086
period 
1 
0.01560178 
0.01560178 
12.80 
0.0700
trt 
1 
0.00019420 
0.00019420 
0.16 
0.7283
subject(sequence) 
2 
1.28746738 
0.64373369 
528.22 
0.0019
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 63-75 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.139208 
0.139208 
0.22 
0.6876 
Error 
2 
1.287467 
0.643734 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.015602 
0.015602 
12.80 
0.0700
trt 
1 
0.000194 
0.000194 
0.16 
0.7283
subject(sequence) 
2 
1.287467 
0.643734 
528.22 
0.0019
Error: MS(Error) 
2 
0.002437 
0.001219 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.139208 
0.139208 
0.22 
0.6876
Error 
2 
1.287467 
0.643734 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.015602 
0.015602 
12.80 
0.0700
trt 
1 
0.000194 
0.000194 
0.16 
0.7283
subject(sequence) 
2 
1.287467 
0.643734 
528.22 
0.0019
Error: MS(Error) 
2 
0.002437 
0.001219 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 63-75 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.139208 
0.139208 
0.22 
0.6876 
Error 
2 
1.287467 
0.643734 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.015602 
0.015602 
12.80 
0.0700
trt 
1 
0.000194 
0.000194 
0.16 
0.7283
subject(sequence) 
2 
1.287467 
0.643734 
528.22 
0.0019
Error: MS(Error) 
2 
0.002437 
0.001219 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.139208 
0.139208 
0.22 
0.6876
Error 
2 
1.287467 
0.643734 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.015602 
0.015602 
12.80 
0.0700
trt 
1 
0.000194 
0.000194 
0.16 
0.7283
subject(sequence) 
2 
1.287467 
0.643734 
528.22 
0.0019
Error: MS(Error) 
2 
0.002437 
0.001219 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 63-75 
Least Squares Means 
trt 
LN_CLFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
-3.13661745 
0.7283
B 
-3.12676354 
trt 
LN_CLFOW LSMEAN 
90% Confidence Limits 
A 
-3.136617 
-3.187585 
-3.085649 
B 
-3.126764 
-3.177731 
-3.075796 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.009854 
-0.081933 
0.062226 
 
Dependent Variable: LN_CLFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.00985391 0.02468491 -0.40 
0.7283 -0.08193349 0.06222566 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
202 303 408 413 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LN_CLFO 
R-Square 
Coeff Var 
Root MSE 
LN_CLFO Mean
0.998102 
3.229223 
0.034910 
1.081057 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.10836268 
0.10836268 
88.92 
0.0111
period 
1 
0.01560178 
0.01560178 
12.80 
0.0700
trt 
1 
0.00019420 
0.00019420 
0.16 
0.7283
subject(sequence) 
2 
1.15775241 
0.57887620 
475.00 
0.0021
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.10836268 
0.10836268 
88.92 
0.0111
period 
1 
0.01560178 
0.01560178 
12.80 
0.0700
trt 
1 
0.00019420 
0.00019420 
0.16 
0.7283
subject(sequence) 
2 
1.15775241 
0.57887620 
475.00 
0.0021
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.10836268 
0.10836268 
88.92 
0.0111
period 
1 
0.01560178 
0.01560178 
12.80 
0.0700
trt 
1 
0.00019420 
0.00019420 
0.16 
0.7283
subject(sequence) 
2 
1.15775241 
0.57887620 
475.00 
0.0021
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.10836268 
0.10836268 
88.92 
0.0111
period 
1 
0.01560178 
0.01560178 
12.80 
0.0700
trt 
1 
0.00019420 
0.00019420 
0.16 
0.7283
subject(sequence) 
2 
1.15775241 
0.57887620 
475.00 
0.0021
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 63-75 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.108363 
0.108363 
0.19 
0.7074 
Error 
2 
1.157752 
0.578876 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.015602 
0.015602 
12.80 
0.0700
trt 
1 
0.000194 
0.000194 
0.16 
0.7283
subject(sequence) 
2 
1.157752 
0.578876 
475.00 
0.0021
Error: MS(Error) 
2 
0.002437 
0.001219 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.108363 
0.108363 
0.19 
0.7074
Error 
2 
1.157752 
0.578876 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.015602 
0.015602 
12.80 
0.0700
trt 
1 
0.000194 
0.000194 
0.16 
0.7283
subject(sequence) 
2 
1.157752 
0.578876 
475.00 
0.0021
Error: MS(Error) 
2 
0.002437 
0.001219 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 63-75 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.108363 
0.108363 
0.19 
0.7074 
Error 
2 
1.157752 
0.578876 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.015602 
0.015602 
12.80 
0.0700
trt 
1 
0.000194 
0.000194 
0.16 
0.7283
subject(sequence) 
2 
1.157752 
0.578876 
475.00 
0.0021
Error: MS(Error) 
2 
0.002437 
0.001219 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.108363 
0.108363 
0.19 
0.7074
Error 
2 
1.157752 
0.578876 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.015602 
0.015602 
12.80 
0.0700
trt 
1 
0.000194 
0.000194 
0.16 
0.7283
subject(sequence) 
2 
1.157752 
0.578876 
475.00 
0.0021
Error: MS(Error) 
2 
0.002437 
0.001219 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 63-75 
Least Squares Means 
trt 
LN_CLFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
1.07612977 
0.7283
B 
1.08598368 
trt 
LN_CLFO LSMEAN 
90% Confidence Limits 
A 
1.076130 
1.025162 
1.127098 
B 
1.085984 
1.035016 
1.136952 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.009854 
-0.081933 
0.062226 
 
Dependent Variable: LN_CLFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.00985391 0.02468491 -0.40 
0.7283 -0.08193349 0.06222566 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
202 303 408 413 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LN_VZFOW 
R-Square 
Coeff Var 
Root MSE 
LN_VZFOW Mean
0.943812 
10.17324 
0.088331 
0.868266 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.01194838 
0.01194838 
1.53 
0.3415
period 
1 
0.10103255 
0.10103255 
12.95 
0.0693
trt 
1 
0.05015616 
0.05015616 
6.43 
0.1267
subject(sequence) 
2 
0.09897914 
0.04948957 
6.34 
0.1362
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.01194838 
0.01194838 
1.53 
0.3415
period 
1 
0.10103255 
0.10103255 
12.95 
0.0693
trt 
1 
0.05015616 
0.05015616 
6.43 
0.1267
subject(sequence) 
2 
0.09897914 
0.04948957 
6.34 
0.1362
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.01194838 
0.01194838 
1.53 
0.3415
period 
1 
0.10103255 
0.10103255 
12.95 
0.0693
trt 
1 
0.05015616 
0.05015616 
6.43 
0.1267
subject(sequence) 
2 
0.09897914 
0.04948957 
6.34 
0.1362
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.01194838 
0.01194838 
1.53 
0.3415
period 
1 
0.10103255 
0.10103255 
12.95 
0.0693
trt 
1 
0.05015616 
0.05015616 
6.43 
0.1267
subject(sequence) 
2 
0.09897914 
0.04948957 
6.34 
0.1362
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 63-75 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.011948 
0.011948 
0.24 
0.6718 
Error 
2 
0.098979 
0.049490 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.101033 
0.101033 
12.95 
0.0693
trt 
1 
0.050156 
0.050156 
6.43 
0.1267
subject(sequence) 
2 
0.098979 
0.049490 
6.34 
0.1362
Error: MS(Error) 
2 
0.015605 
0.007802 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.011948 
0.011948 
0.24 
0.6718
Error 
2 
0.098979 
0.049490 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.101033 
0.101033 
12.95 
0.0693
trt 
1 
0.050156 
0.050156 
6.43 
0.1267
subject(sequence) 
2 
0.098979 
0.049490 
6.34 
0.1362
Error: MS(Error) 
2 
0.015605 
0.007802 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 63-75 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.011948 
0.011948 
0.24 
0.6718 
Error 
2 
0.098979 
0.049490 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.101033 
0.101033 
12.95 
0.0693
trt 
1 
0.050156 
0.050156 
6.43 
0.1267
subject(sequence) 
2 
0.098979 
0.049490 
6.34 
0.1362
Error: MS(Error) 
2 
0.015605 
0.007802 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.011948 
0.011948 
0.24 
0.6718
Error 
2 
0.098979 
0.049490 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.101033 
0.101033 
12.95 
0.0693
trt 
1 
0.050156 
0.050156 
6.43 
0.1267
subject(sequence) 
2 
0.098979 
0.049490 
6.34 
0.1362
Error: MS(Error) 
2 
0.015605 
0.007802 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 63-75 
Least Squares Means 
trt 
LN_VZFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
0.78908533 
0.1267
B 
0.94744593 
trt 
LN_VZFOW LSMEAN 
90% Confidence Limits 
A 
0.789085 
0.660123 
0.918048 
B 
0.947446 
0.818484 
1.076408 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.158361 
-0.340741 
0.024020 
 
Dependent Variable: LN_VZFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.15836060 0.06245926 -2.54 
0.1267 -0.34074073 0.02401953 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
202 303 408 413 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LN_VZFO 
R-Square 
Coeff Var 
Root MSE 
LN_VZFO Mean
0.940999 
1.738447 
0.088331 
5.081013 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.02347924 
0.02347924 
3.01 
0.2249
period 
1 
0.10103255 
0.10103255 
12.95 
0.0693
trt 
1 
0.05015616 
0.05015616 
6.43 
0.1267
subject(sequence) 
2 
0.07420835 
0.03710417 
4.76 
0.1737
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.02347924 
0.02347924 
3.01 
0.2249
period 
1 
0.10103255 
0.10103255 
12.95 
0.0693
trt 
1 
0.05015616 
0.05015616 
6.43 
0.1267
subject(sequence) 
2 
0.07420835 
0.03710417 
4.76 
0.1737
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.02347924 
0.02347924 
3.01 
0.2249
period 
1 
0.10103255 
0.10103255 
12.95 
0.0693
trt 
1 
0.05015616 
0.05015616 
6.43 
0.1267
subject(sequence) 
2 
0.07420835 
0.03710417 
4.76 
0.1737
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.02347924 
0.02347924 
3.01 
0.2249
period 
1 
0.10103255 
0.10103255 
12.95 
0.0693
trt 
1 
0.05015616 
0.05015616 
6.43 
0.1267
subject(sequence) 
2 
0.07420835 
0.03710417 
4.76 
0.1737
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 63-75 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.023479 
0.023479 
0.63 
0.5097 
Error 
2 
0.074208 
0.037104 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.101033 
0.101033 
12.95 
0.0693
trt 
1 
0.050156 
0.050156 
6.43 
0.1267
subject(sequence) 
2 
0.074208 
0.037104 
4.76 
0.1737
Error: MS(Error) 
2 
0.015605 
0.007802 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.023479 
0.023479 
0.63 
0.5097
Error 
2 
0.074208 
0.037104 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.101033 
0.101033 
12.95 
0.0693
trt 
1 
0.050156 
0.050156 
6.43 
0.1267
subject(sequence) 
2 
0.074208 
0.037104 
4.76 
0.1737
Error: MS(Error) 
2 
0.015605 
0.007802 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 63-75 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.023479 
0.023479 
0.63 
0.5097 
Error 
2 
0.074208 
0.037104 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.101033 
0.101033 
12.95 
0.0693
trt 
1 
0.050156 
0.050156 
6.43 
0.1267
subject(sequence) 
2 
0.074208 
0.037104 
4.76 
0.1737
Error: MS(Error) 
2 
0.015605 
0.007802 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.023479 
0.023479 
0.63 
0.5097
Error 
2 
0.074208 
0.037104 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.101033 
0.101033 
12.95 
0.0693
trt 
1 
0.050156 
0.050156 
6.43 
0.1267
subject(sequence) 
2 
0.074208 
0.037104 
4.76 
0.1737
Error: MS(Error) 
2 
0.015605 
0.007802 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 63-75 
Least Squares Means 
trt 
LN_VZFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
5.00183256 
0.1267
B 
5.16019315 
trt 
LN_VZFO LSMEAN 
90% Confidence Limits 
A 
5.001833 
4.872870 
5.130795 
B 
5.160193 
5.031231 
5.289155 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.158361 
-0.340741 
0.024020 
 
Dependent Variable: LN_VZFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.15836060 0.06245926 -2.54 
0.1267 -0.34074073 0.02401953 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
202 303 408 413 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: TMAX 
R-Square 
Coeff Var 
Root MSE 
TMAX Mean
0.688311 
116.3511 
1.243502 
1.068750 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.51728200 
1.51728200 
0.98 
0.4263
period 
1 
1.54528200 
1.54528200 
1.00 
0.4228
trt 
1 
1.48781250 
1.48781250 
0.96 
0.4301
subject(sequence) 
2 
2.27909450 
1.13954725 
0.74 
0.5757
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.51728200 
1.51728200 
0.98 
0.4263
period 
1 
1.54528200 
1.54528200 
1.00 
0.4228
trt 
1 
1.48781250 
1.48781250 
0.96 
0.4301
subject(sequence) 
2 
2.27909450 
1.13954725 
0.74 
0.5757
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.51728200 
1.51728200 
0.98 
0.4263
period 
1 
1.54528200 
1.54528200 
1.00 
0.4228
trt 
1 
1.48781250 
1.48781250 
0.96 
0.4301
subject(sequence) 
2 
2.27909450 
1.13954725 
0.74 
0.5757
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.51728200 
1.51728200 
0.98 
0.4263
period 
1 
1.54528200 
1.54528200 
1.00 
0.4228
trt 
1 
1.48781250 
1.48781250 
0.96 
0.4301
subject(sequence) 
2 
2.27909450 
1.13954725 
0.74 
0.5757
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 63-75 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
1.517282 
1.517282 
1.33 
0.3678 
Error 
2 
2.279094 
1.139547 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
period 
1 
1.545282 
1.545282 
1.00 
0.4228
trt 
1 
1.487813 
1.487813 
0.96 
0.4301
subject(sequence) 
2 
2.279095 
1.139547 
0.74 
0.5757
Error: MS(Error) 
2 
3.092595 
1.546297 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.517282 
1.517282 
1.33 
0.3678
Error 
2 
2.279094 
1.139547 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
1.545282 
1.545282 
1.00 
0.4228
trt 
1 
1.487813 
1.487813 
0.96 
0.4301
subject(sequence) 
2 
2.279095 
1.139547 
0.74 
0.5757
Error: MS(Error) 
2 
3.092595 
1.546297 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 63-75 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
1.517282 
1.517282 
1.33 
0.3678 
Error 
2 
2.279094 
1.139547 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
1.545282 
1.545282 
1.00 
0.4228
trt 
1 
1.487813 
1.487813 
0.96 
0.4301
subject(sequence) 
2 
2.279095 
1.139547 
0.74 
0.5757
Error: MS(Error) 
2 
3.092595 
1.546297 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.517282 
1.517282 
1.33 
0.3678
Error 
2 
2.279094 
1.139547 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
1.545282 
1.545282 
1.00 
0.4228
trt 
1 
1.487813 
1.487813 
0.96 
0.4301
subject(sequence) 
2 
2.279095 
1.139547 
0.74 
0.5757
Error: MS(Error) 
2 
3.092595 
1.546297 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 63-75 
Least Squares Means 
trt TMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 1.50000000 
0.4301
B 
0.63750000 
trt 
TMAX LSMEAN 
90% Confidence Limits 
A 
1.500000 
-0.315504 
3.315504 
B 
0.637500 
-1.178004 
2.453004 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.862500 
-1.705010 
3.430010 
 
Dependent Variable: TMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.86250000 0.87928870 0.98 
0.4301 -1.70501034 3.43001034 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
202 303 408 413 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LAMZ 
R-Square 
Coeff Var 
Root MSE 
LAMZ Mean
0.948689 
21.40862 
0.004371 
0.020416 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00009919 
0.00009919 
5.19 
0.1503
period 
1 
0.00002579 
0.00002579 
1.35 
0.3652
trt 
1 
0.00003954 
0.00003954 
2.07 
0.2868
subject(sequence) 
2 
0.00054187 
0.00027093 
14.18 
0.0659
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00009919 
0.00009919 
5.19 
0.1503
period 
1 
0.00002579 
0.00002579 
1.35 
0.3652
trt 
1 
0.00003954 
0.00003954 
2.07 
0.2868
subject(sequence) 
2 
0.00054187 
0.00027093 
14.18 
0.0659
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00009919 
0.00009919 
5.19 
0.1503
period 
1 
0.00002579 
0.00002579 
1.35 
0.3652
trt 
1 
0.00003954 
0.00003954 
2.07 
0.2868
subject(sequence) 
2 
0.00054187 
0.00027093 
14.18 
0.0659
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00009919 
0.00009919 
5.19 
0.1503
period 
1 
0.00002579 
0.00002579 
1.35 
0.3652
trt 
1 
0.00003954 
0.00003954 
2.07 
0.2868
subject(sequence) 
2 
0.00054187 
0.00027093 
14.18 
0.0659
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 63-75 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000099193 
0.000099193 
0.37 
0.6066
Error 
2 
0.000542 
0.000271 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000025787 
0.000025787 
1.35 
0.3652
trt 
1 
0.000039543 
0.000039543 
2.07 
0.2868
subject(sequence) 
2 
0.000542 
0.000271 
14.18 
0.0659
Error: MS(Error) 
2 
0.000038206 
0.000019103 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000099193 
0.000099193 
0.37 
0.6066
Error 
2 
0.000542 
0.000271 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000025787 
0.000025787 
1.35 
0.3652
trt 
1 
0.000039543 
0.000039543 
2.07 
0.2868
subject(sequence) 
2 
0.000542 
0.000271 
14.18 
0.0659
Error: MS(Error) 
2 
0.000038206 
0.000019103 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 63-75 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000099193 
0.000099193 
0.37 
0.6066
Error 
2 
0.000542 
0.000271 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000025787 
0.000025787 
1.35 
0.3652
trt 
1 
0.000039543 
0.000039543 
2.07 
0.2868
subject(sequence) 
2 
0.000542 
0.000271 
14.18 
0.0659
Error: MS(Error) 
2 
0.000038206 
0.000019103 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000099193 
0.000099193 
0.37 
0.6066
Error 
2 
0.000542 
0.000271 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000025787 
0.000025787 
1.35 
0.3652
trt 
1 
0.000039543 
0.000039543 
2.07 
0.2868
subject(sequence) 
2 
0.000542 
0.000271 
14.18 
0.0659
Error: MS(Error) 
2 
0.000038206 
0.000019103 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 63-75 
Least Squares Means 
trt LAMZ LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t| 
A 
0.02263887 
0.2868 
B 
0.01819235 
 
trt 
LAMZ LSMEAN 
90% Confidence Limits 
A 
0.022639 
0.016258 
0.029020 
B 
0.018192 
0.011811 
0.024574 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.004447 
-0.004578 
0.013471 
 
Dependent Variable: LAMZ 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.00444652 0.00309055 1.44 
0.2868 -0.00457784 0.01347089 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
202 303 408 413 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LAMZHL 
R-Square 
Coeff Var 
Root MSE 
LAMZHL Mean
0.992313 
7.735473 
3.247983 
41.98816 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
402.676341 
402.676341 
38.17 
0.0252
period 
1 
43.461721 
43.461721 
4.12 
0.1795
trt 
1 
22.577445 
22.577445 
2.14 
0.2810
subject(sequence) 
2 
2254.889672 
1127.444836 
106.87 
0.0093
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
402.676341 
402.676341 
38.17 
0.0252
period 
1 
43.461721 
43.461721 
4.12 
0.1795
trt 
1 
22.577445 
22.577445 
2.14 
0.2810
subject(sequence) 
2 
2254.889672 
1127.444836 
106.87 
0.0093
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
402.676341 
402.676341 
38.17 
0.0252
period 
1 
43.461721 
43.461721 
4.12 
0.1795
trt 
1 
22.577445 
22.577445 
2.14 
0.2810
subject(sequence) 
2 
2254.889672 
1127.444836 
106.87 
0.0093
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
402.676341 
402.676341 
38.17 
0.0252
period 
1 
43.461721 
43.461721 
4.12 
0.1795
trt 
1 
22.577445 
22.577445 
2.14 
0.2810
subject(sequence) 
2 
2254.889672 
1127.444836 
106.87 
0.0093
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 63-75 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
402.676341 
402.676341 
0.36 
0.6107
Error 
2 
2254.889672 
1127.444836 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
period 
1 
43.461721 
43.461721 
4.12 
0.1795
trt 
1 
22.577445 
22.577445 
2.14 
0.2810
subject(sequence) 
2 
2254.889672 
1127.444836 
106.87 
0.0093
Error: MS(Error) 
2 
21.098782 
10.549391 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
402.676341 
402.676341 
0.36 
0.6107
Error 
2 
2254.889672 
1127.444836 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
43.461721 
43.461721 
4.12 
0.1795
trt 
1 
22.577445 
22.577445 
2.14 
0.2810
subject(sequence) 
2 
2254.889672 
1127.444836 
106.87 
0.0093
Error: MS(Error) 
2 
21.098782 
10.549391 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 63-75 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
402.676341 
402.676341 
0.36 
0.6107
Error 
2 
2254.889672 
1127.444836 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
43.461721 
43.461721 
4.12 
0.1795
trt 
1 
22.577445 
22.577445 
2.14 
0.2810
subject(sequence) 
2 
2254.889672 
1127.444836 
106.87 
0.0093
Error: MS(Error) 
2 
21.098782 
10.549391 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
402.676341 
402.676341 
0.36 
0.6107
Error 
2 
2254.889672 
1127.444836 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
43.461721 
43.461721 
4.12 
0.1795
trt 
1 
22.577445 
22.577445 
2.14 
0.2810
subject(sequence) 
2 
2254.889672 
1127.444836 
106.87 
0.0093
Error: MS(Error) 
2 
21.098782 
10.549391 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 63-75 
Least Squares Means 
trt 
LAMZHL LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
40.3082215 
0.2810
B 
43.6680910 
trt 
LAMZHL LSMEAN 
90% Confidence Limits 
A 
40.308222 
35.566190 
45.050253 
B 
43.668091 
38.926060 
48.410122 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -3.359869 
-10.066114 
3.346375 
 
Dependent Variable: LAMZHL 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-3.35986944 2.29667055 -1.46 
0.2810 -10.06611433 3.34637545 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
1 
202 
sequence 
1 
BAC 
trt 
2 
B C 
Number of Observations Read 
2 
Number of Observations Used 
2 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LN_AUCLST 
R-Square 
Coeff Var 
Root MSE 
LN_AUCLST Mean
1.000000 
8.989924 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.00749245 
0.00749245 
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.00749245 
0.00749245 
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.00749245 
0.00749245 
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.00749245 
0.00749245 
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 63-75 
The GLM Procedure 
Least Squares Means 
trt LN_AUCLST LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
8.92871712 
C 
9.05112994 
trt 
LN_AUCLST LSMEAN 
90% Confidence Limits 
B 
8.928717 
C 
9.051130 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.122413 
 
The GLM Procedure 
Dependent Variable: LN_AUCLST 
Parameter 
Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.12241283 
 0.00000000 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
1 
202 
sequence 
1 
BAC 
trt 
2 
B C 
Number of Observations Read 
2 
Number of Observations Used 
2 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LN_AUCIFO 
R-Square 
Coeff Var 
Root MSE 
LN_AUCIFO Mean
1.000000 
9.152155 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.05815112 
0.05815112 
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.05815112 
0.05815112 
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.05815112 
0.05815112 
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.05815112 
0.05815112 
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 63-75 
The GLM Procedure 
Least Squares Means 
trt LN_AUCIFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
8.98163980 
C 
9.32267095 
trt 
LN_AUCIFO LSMEAN 
90% Confidence Limits 
B 
8.981640 
C 
9.322671 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.341031 
 
The GLM Procedure 
Dependent Variable: LN_AUCIFO 
Parameter 
Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.34103116 
 0.00000000 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
1 
202 
sequence 
1 
BAC 
trt 
2 
B C 
Number of Observations Read 
2 
Number of Observations Used 
2 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LN_CMAX 
R-Square 
Coeff Var 
Root MSE 
LN_CMAX Mean
1.000000 
5.618963 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.36116740 
0.36116740 
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.36116740 
0.36116740 
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.36116740 
0.36116740 
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.36116740 
0.36116740 
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 63-75 
The GLM Procedure 
Least Squares Means 
trt 
LN_CMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
6.04391467 
C 
5.19401185 
trt 
LN_CMAX LSMEAN 
90% Confidence Limits 
B 
6.043915 
C 
5.194012 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.849903 
 
The GLM Procedure 
Dependent Variable: LN_CMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.84990282 
 0.00000000 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
1 
202 
sequence 
1 
BAC 
trt 
2 
B C 
Number of Observations Read 
2 
Number of Observations Used 
2 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LN_CLFOW 
R-Square 
Coeff Var 
Root MSE 
LN_CLFOW Mean
1.000000 
-3.758794 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.05815112 
0.05815112 
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.05815112 
0.05815112 
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.05815112 
0.05815112 
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.05815112 
0.05815112 
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 63-75 
The GLM Procedure 
Least Squares Means 
trt 
LN_CLFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
-3.58827888 
C 
-3.92931004 
trt 
LN_CLFOW LSMEAN 
90% Confidence Limits 
B 
-3.588279 
C 
-3.929310 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.341031 
 
The GLM Procedure 
Dependent Variable: LN_CLFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.34103116 
 0.00000000 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
1 
202 
sequence 
1 
BAC 
trt 
2 
B C 
Number of Observations Read 
2 
Number of Observations Used 
2 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LN_CLFO 
R-Square 
Coeff Var 
Root MSE 
LN_CLFO Mean
1.000000 
0.463650 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.05815112 
0.05815112 
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.05815112 
0.05815112 
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.05815112 
0.05815112 
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.05815112 
0.05815112 
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 63-75 
The GLM Procedure 
Least Squares Means 
trt 
LN_CLFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
0.63416568 
C 
0.29313453 
trt 
LN_CLFO LSMEAN 
90% Confidence Limits 
B 
0.634166 
C 
0.293135 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.341031 
 
The GLM Procedure 
Dependent Variable: LN_CLFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.34103116 
 0.00000000 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
1 
202 
sequence 
1 
BAC 
trt 
2 
B C 
Number of Observations Read 
2 
Number of Observations Used 
2 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LN_VZFOW 
R-Square 
Coeff Var 
Root MSE 
LN_VZFOW Mean
1.000000 
1.259065 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.17042279 
0.17042279 
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.17042279 
0.17042279 
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.17042279 
0.17042279 
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.17042279 
0.17042279 
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 63-75 
The GLM Procedure 
Least Squares Means 
trt 
LN_VZFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
0.96715507 
C 
1.55097489 
trt 
LN_VZFOW LSMEAN 
90% Confidence Limits 
B 
0.967155 
C 
1.550975 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.583820 
 
The GLM Procedure 
Dependent Variable: LN_VZFOW 
Parameter 
Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.58381983 
 0.00000000 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
1 
202 
sequence 
1 
BAC 
trt 
2 
B C 
Number of Observations Read 
2 
Number of Observations Used 
2 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LN_VZFO 
R-Square 
Coeff Var 
Root MSE 
LN_VZFO Mean
1.000000 
5.481510 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.17042279 
0.17042279 
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.17042279 
0.17042279 
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.17042279 
0.17042279 
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.17042279 
0.17042279 
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) Weight Group: 63-75 
The GLM Procedure 
Least Squares Means 
trt 
LN_VZFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
5.18959963 
C 
5.77341946 
trt 
LN_VZFO LSMEAN 
90% Confidence Limits 
B 
5.189600 
C 
5.773419 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.583820 
 
The GLM Procedure 
Dependent Variable: LN_VZFO 
Parameter 
Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.58381983 
 0.00000000 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
1 
202 
sequence 
1 
BAC 
trt 
2 
B C 
Number of Observations Read 
2 
Number of Observations Used 
2 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: TMAX 
R-Square 
Coeff Var 
Root MSE 
TMAX Mean
1.000000 
1.375000 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.78125000 
0.78125000 
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.78125000 
0.78125000 
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.78125000 
0.78125000 
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.78125000 
0.78125000 
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) Weight Group: 63-75 
The GLM Procedure 
Least Squares Means 
trt TMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
0.75000000 
C 
2.00000000 
trt 
TMAX LSMEAN 
90% Confidence Limits 
B 
0.750000 
C 
2.000000 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -1.250000 
 
The GLM Procedure 
Dependent Variable: TMAX 
Parameter 
Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
1.25000000 
 0.00000000 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
1 
202 
sequence 
1 
BAC 
trt 
2 
B C 
Number of Observations Read 
2 
Number of Observations Used 
2 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LAMZ 
R-Square 
Coeff Var 
Root MSE 
LAMZ Mean
1.000000 
0.007339 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.00002011 
0.00002011 
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.00002011 
0.00002011 
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.00002011 
0.00002011 
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.00000000 
trt 
1 
0.00002011 
0.00002011 
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) Weight Group: 63-75 
The GLM Procedure 
Least Squares Means 
trt LAMZ LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t| 
B 
0.01050994 
 
C 
0.00416814 
 
trt 
LAMZ LSMEAN 
90% Confidence Limits 
B 
0.010510 
C 
0.004168 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.006342 
 
The GLM Procedure 
Dependent Variable: LAMZ 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.00634180 
 0.00000000 
0.00000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) Weight Group: 63-75 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
1 
202 
sequence 
1 
BAC 
trt 
2 
B C 
Number of Observations Read 
2 
Number of Observations Used 
2 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) Weight Group: 63-75 
The GLM Procedure 
Dependent Variable: LAMZHL 
R-Square 
Coeff Var 
Root MSE 
LAMZHL Mean
1.000000 
116.1240 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.000000 
trt 
1 
5034.544709 
5034.544709 
subject(sequence) 
0 
0.000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.000000 
trt 
1 
5034.544709 
5034.544709 
subject(sequence) 
0 
0.000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.000000 
trt 
1 
5034.544709 
5034.544709 
subject(sequence) 
0 
0.000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
0 
0.000000 
trt 
1 
5034.544709 
5034.544709 
subject(sequence) 
0 
0.000000 
 


 
 
Listing 16.1.9-6 ANOVA for Treatment Comparison of Diazepam for Weight Group 63-75 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) Weight Group: 63-75 
The GLM Procedure 
Least Squares Means 
trt 
LAMZHL LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
65.951593 
C 
166.296445 
trt 
LAMZHL LSMEAN 
90% Confidence Limits 
B 
65.951593 
C 
166.296445 
Least Squares Means for Effect trt 
i 
j 
Difference Between Means 90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -100.344852 
 
The GLM Procedure 
Dependent Variable: LAMZHL 
Parameter 
Estimate 
Standard 
Error 
t Value 
Pr > |t| 90% Confidence Limits 
C - B 
100.344852 
0.000000 
0.000000 
 
 


180323 Diazepam Buccal Film DRG Crossover 
Aquestive Therapeutics 
16.1.9 Documentation of Statistical Methods 
 
Confidential 
Page 10 of 11 
Final 1.0 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
6 
205 301 406 410 411 501 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
12 
Number of Observations Used 
12 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LN_AUCLST 
R-Square 
Coeff Var 
Root MSE 
LN_AUCLST Mean
0.964977 
1.738422 
0.154632 
8.894970 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.12739488 
1.12739488 
47.15 
0.0024
period 
1 
0.02008228 
0.02008228 
0.84 
0.4113
trt 
1 
0.02193858 
0.02193858 
0.92 
0.3924
subject(sequence) 
4 
1.46581263 
0.36645316 
15.33 
0.0108
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.12739488 
1.12739488 
47.15 
0.0024
period 
1 
0.02008228 
0.02008228 
0.84 
0.4113
trt 
1 
0.02193858 
0.02193858 
0.92 
0.3924
subject(sequence) 
4 
1.46581263 
0.36645316 
15.33 
0.0108
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.12739488 
1.12739488 
47.15 
0.0024
period 
1 
0.02008228 
0.02008228 
0.84 
0.4113
trt 
1 
0.02193858 
0.02193858 
0.92 
0.3924
subject(sequence) 
4 
1.46581263 
0.36645316 
15.33 
0.0108
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.12739488 
1.12739488 
47.15 
0.0024
period 
1 
0.02008228 
0.02008228 
0.84 
0.4113
trt 
1 
0.02193858 
0.02193858 
0.92 
0.3924
subject(sequence) 
4 
1.46581263 
0.36645316 
15.33 
0.0108
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 76-87 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
1.127395 
1.127395 
3.08 
0.1543 
Error 
4 
1.465813 
0.366453 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.020082 
0.020082 
0.84 
0.4113
trt 
1 
0.021939 
0.021939 
0.92 
0.3924
subject(sequence) 
4 
1.465813 
0.366453 
15.33 
0.0108
Error: MS(Error) 
4 
0.095644 
0.023911 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.127395 
1.127395 
3.08 
0.1543
Error 
4 
1.465813 
0.366453 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.020082 
0.020082 
0.84 
0.4113
trt 
1 
0.021939 
0.021939 
0.92 
0.3924
subject(sequence) 
4 
1.465813 
0.366453 
15.33 
0.0108
Error: MS(Error) 
4 
0.095644 
0.023911 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 76-87 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
1.127395 
1.127395 
3.08 
0.1543 
Error 
4 
1.465813 
0.366453 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.020082 
0.020082 
0.84 
0.4113
trt 
1 
0.021939 
0.021939 
0.92 
0.3924
subject(sequence) 
4 
1.465813 
0.366453 
15.33 
0.0108
Error: MS(Error) 
4 
0.095644 
0.023911 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.127395 
1.127395 
3.08 
0.1543
Error 
4 
1.465813 
0.366453 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.020082 
0.020082 
0.84 
0.4113
trt 
1 
0.021939 
0.021939 
0.92 
0.3924
subject(sequence) 
4 
1.465813 
0.366453 
15.33 
0.0108
Error: MS(Error) 
4 
0.095644 
0.023911 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 76-87 
Least Squares Means 
trt LN_AUCLST LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
8.85221198 
0.3924
B 
8.93772725 
trt 
LN_AUCLST LSMEAN 
90% Confidence Limits 
A 
8.852212 
8.717632 
8.986792 
B 
8.937727 
8.803147 
9.072307 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.085515 
-0.275840 
0.104809 
 
Dependent Variable: LN_AUCLST 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.08551527 0.08927691 -0.96 
0.3924 -0.27583996 0.10480942 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
6 
205 301 406 410 411 501 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
12 
Number of Observations Used 
12 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LN_AUCIFO 
R-Square 
Coeff Var 
Root MSE 
LN_AUCIFO Mean
0.963280 
2.122888 
0.192833 
9.083543 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.57345243 
1.57345243 
42.31 
0.0029
period 
1 
0.02783629 
0.02783629 
0.75 
0.4357
trt 
1 
0.00812175 
0.00812175 
0.22 
0.6646
subject(sequence) 
4 
2.29244990 
0.57311247 
15.41 
0.0107
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.57345243 
1.57345243 
42.31 
0.0029
period 
1 
0.02783629 
0.02783629 
0.75 
0.4357
trt 
1 
0.00812175 
0.00812175 
0.22 
0.6646
subject(sequence) 
4 
2.29244990 
0.57311247 
15.41 
0.0107
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.57345243 
1.57345243 
42.31 
0.0029
period 
1 
0.02783629 
0.02783629 
0.75 
0.4357
trt 
1 
0.00812175 
0.00812175 
0.22 
0.6646
subject(sequence) 
4 
2.29244990 
0.57311247 
15.41 
0.0107
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.57345243 
1.57345243 
42.31 
0.0029
period 
1 
0.02783629 
0.02783629 
0.75 
0.4357
trt 
1 
0.00812175 
0.00812175 
0.22 
0.6646
subject(sequence) 
4 
2.29244990 
0.57311247 
15.41 
0.0107
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 76-87 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
1.573452 
1.573452 
2.75 
0.1729 
Error 
4 
2.292450 
0.573112 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.027836 
0.027836 
0.75 
0.4357
trt 
1 
0.008122 
0.008122 
0.22 
0.6646
subject(sequence) 
4 
2.292450 
0.573112 
15.41 
0.0107
Error: MS(Error) 
4 
0.148739 
0.037185 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.573452 
1.573452 
2.75 
0.1729
Error 
4 
2.292450 
0.573112 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.027836 
0.027836 
0.75 
0.4357
trt 
1 
0.008122 
0.008122 
0.22 
0.6646
subject(sequence) 
4 
2.292450 
0.573112 
15.41 
0.0107
Error: MS(Error) 
4 
0.148739 
0.037185 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 76-87 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
1.573452 
1.573452 
2.75 
0.1729 
Error 
4 
2.292450 
0.573112 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.027836 
0.027836 
0.75 
0.4357
trt 
1 
0.008122 
0.008122 
0.22 
0.6646
subject(sequence) 
4 
2.292450 
0.573112 
15.41 
0.0107
Error: MS(Error) 
4 
0.148739 
0.037185 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.573452 
1.573452 
2.75 
0.1729
Error 
4 
2.292450 
0.573112 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.027836 
0.027836 
0.75 
0.4357
trt 
1 
0.008122 
0.008122 
0.22 
0.6646
subject(sequence) 
4 
2.292450 
0.573112 
15.41 
0.0107
Error: MS(Error) 
4 
0.148739 
0.037185 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 76-87 
Least Squares Means 
trt LN_AUCIFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
9.10955867 
0.6646
B 
9.05752745 
trt 
LN_AUCIFO LSMEAN 
90% Confidence Limits 
A 
9.109559 
8.941731 
9.277386 
B 
9.057527 
8.889700 
9.225355 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.052031 
-0.185312 
0.289375 
 
Dependent Variable: LN_AUCIFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.05203123 0.11133243 0.47 
0.6646 -0.18531246 0.28937491 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
7 
205 301 406 410 411 501 506 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
14 
Number of Observations Used 
14 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LN_CMAX 
R-Square 
Coeff Var 
Root MSE 
LN_CMAX Mean
0.663147 
6.456680 
0.353705 
5.478128 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.14298687 
0.14298687 
1.14 
0.3339
period 
1 
0.05353200 
0.05353200 
0.43 
0.5419
trt 
1 
0.48189892 
0.48189892 
3.85 
0.1069
subject(sequence) 
5 
0.55304583 
0.11060917 
0.88 
0.5521
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.14298687 
0.14298687 
1.14 
0.3339
period 
1 
0.10769335 
0.10769335 
0.86 
0.3961
trt 
1 
0.48189892 
0.48189892 
3.85 
0.1069
subject(sequence) 
5 
0.55304583 
0.11060917 
0.88 
0.5521
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.14298687 
0.14298687 
1.14 
0.3339
period 
1 
0.10769335 
0.10769335 
0.86 
0.3961
trt 
1 
0.48189892 
0.48189892 
3.85 
0.1069
subject(sequence) 
5 
0.55304583 
0.11060917 
0.88 
0.5521
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.14298687 
0.14298687 
1.14 
0.3339
period 
1 
0.10769335 
0.10769335 
0.86 
0.3961
trt 
1 
0.48189892 
0.48189892 
3.85 
0.1069
subject(sequence) 
5 
0.55304583 
0.11060917 
0.88 
0.5521
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 76-87 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.142987 
0.142987 
1.29 
0.3071 
Error 
5 
0.553046 
0.110609 
 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F
*period 
1 
0.053532 0.053532 
0.43 
0.5419
trt 
1 
0.481899 0.481899 
3.85 
0.1069
subject(sequence) 
5 
0.553046 0.110609 
0.88 
0.5521
Error: MS(Error) 
5 
0.625537 0.125107 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.142987 
0.142987 
1.29 
0.3071
Error 
5 
0.553046 
0.110609 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.107693 
0.107693 
0.86 
0.3961
trt 
1 
0.481899 
0.481899 
3.85 
0.1069
subject(sequence) 
5 
0.553046 
0.110609 
0.88 
0.5521
Error: MS(Error) 
5 
0.625537 
0.125107 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 76-87 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.142987 
0.142987 
1.29 
0.3071 
Error 
5 
0.553046 
0.110609 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.107693 
0.107693 
0.86 
0.3961
trt 
1 
0.481899 
0.481899 
3.85 
0.1069
subject(sequence) 
5 
0.553046 
0.110609 
0.88 
0.5521
Error: MS(Error) 
5 
0.625537 
0.125107 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.142987 
0.142987 
1.29 
0.3071
Error 
5 
0.553046 
0.110609 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.107693 
0.107693 
0.86 
0.3961
trt 
1 
0.481899 
0.481899 
3.85 
0.1069
subject(sequence) 
5 
0.553046 
0.110609 
0.88 
0.5521
Error: MS(Error) 
5 
0.625537 
0.125107 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 76-87 
Least Squares Means 
trt 
LN_CMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
5.30526255 
0.1069
B 
5.68016767 
trt 
LN_CMAX LSMEAN 
90% Confidence Limits 
A 
5.305263 
5.033083 
5.577442 
B 
5.680168 
5.407988 
5.952347 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 
-0.374905 
-0.759825 
0.010015 
 
Dependent Variable: LN_CMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.37490513 0.19102264 -1.96 
0.1069 -0.75982499 0.01001474 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
7 
205 301 406 410 411 501 506 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
13 
Number of Observations Used 
13 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LN_CLFOW 
R-Square 
Coeff Var 
Root MSE 
LN_CLFOW Mean
0.966101 
-4.963592 
0.192833 
-3.884957 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.04930375 
1.04930375 
28.22 
0.0060
period 
1 
0.00397640 
0.00397640 
0.11 
0.7601
trt 
1 
0.32070448 
0.32070448 
8.62 
0.0425
subject(sequence) 
5 
2.86497841 
0.57299568 
15.41 
0.0101
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.12723610 
1.12723610 
30.31 
0.0053
period 
1 
0.02783629 
0.02783629 
0.75 
0.4357
trt 
1 
0.12753294 
0.12753294 
3.43 
0.1377
subject(sequence) 
5 
2.86497841 
0.57299568 
15.41 
0.0101
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.70022141 
0.70022141 
18.83 
0.0123
period 
1 
0.02783629 
0.02783629 
0.75 
0.4357
trt 
1 
0.12753294 
0.12753294 
3.43 
0.1377
subject(sequence) 
5 
2.86497841 
0.57299568 
15.41 
0.0101
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.70022141 
0.70022141 
18.83 
0.0123
period 
1 
0.02783629 
0.02783629 
0.75 
0.4357
trt 
1 
0.12753294 
0.12753294 
3.43 
0.1377
subject(sequence) 
5 
2.86497841 
0.57299568 
15.41 
0.0101
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 76-87 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
1.049304 
1.049304 
1.71 
0.2481
Error 
4.955 
3.036931 
0.612903 
Error: 1.0745*MS(subject(sequence)) - 0.0745*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
0.003976 
0.003976 
0.07 
0.8029
Error 
8.2446 
0.493559 
0.059865 
Error: 0.0423*MS(subject(sequence)) + 0.9577*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.320704 
0.320704 
5.62 
0.0455
Error 
7.9206 
0.451711 
0.057030 
Error: 0.037*MS(subject(sequence)) + 0.963*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
5 
2.864978 
0.572996 
15.41 
0.0101
Error: MS(Error) 
4 
0.148739 
0.037185 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 76-87 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.127236 
1.127236 
1.84 
0.2335
Error 
4.9552 
3.035991 
0.612685 
Error: 1.0741*MS(subject(sequence)) - 0.0741*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.027836 
0.027836 
0.75 
0.4357
trt 
1 
0.127533 
0.127533 
3.43 
0.1377
subject(sequence) 
5 
2.864978 
0.572996 
15.41 
0.0101
Error: MS(Error) 
4 
0.148739 
0.037185 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.700221 
0.700221 
1.25 
0.3134
Error 
5.0185 
2.800906 
0.558112 
Error: 0.9722*MS(subject(sequence)) + 0.0278*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.027836 
0.027836 
0.75 
0.4357
trt 
1 
0.127533 
0.127533 
3.43 
0.1377
subject(sequence) 
5 
2.864978 
0.572996 
15.41 
0.0101
Error: MS(Error) 
4 
0.148739 
0.037185 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 76-87 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.700221 
0.700221 
1.25 
0.3134
Error 
5.0185 
2.800906 
0.558112 
Error: 0.9722*MS(subject(sequence)) + 0.0278*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.027836 
0.027836 
0.75 
0.4357
trt 
1 
0.127533 
0.127533 
3.43 
0.1377
subject(sequence) 
5 
2.864978 
0.572996 
15.41 
0.0101
Error: MS(Error) 
4 
0.148739 
0.037185 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 76-87 
Least Squares Means 
trt 
LN_CLFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
-4.05335533 
0.1377
B 
-3.84717342 
trt 
LN_CLFOW LSMEAN 
90% Confidence Limits 
A 
-4.053355 
-4.210343 
-3.896367 
B 
-3.847173 
-4.025181 
-3.669166 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.206182 
-0.443526 
0.031162 
 
Dependent Variable: LN_CLFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.20618191 0.11133243 -1.85 
0.1377 -0.44352559 0.03116178 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
7 
205 301 406 410 411 501 506 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
13 
Number of Observations Used 
13 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LN_CLFO 
R-Square 
Coeff Var 
Root MSE 
LN_CLFO Mean
0.967079 
34.30586 
0.192833 
0.562101 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.10473169 
1.10473169 
29.71 
0.0055
period 
1 
0.00520841 
0.00520841 
0.14 
0.7272
trt 
1 
0.33042950 
0.33042950 
8.89 
0.0407
subject(sequence) 
5 
2.92899343 
0.58579869 
15.75 
0.0097
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.18703340 
1.18703340 
31.92 
0.0048
period 
1 
0.02783629 
0.02783629 
0.75 
0.4357
trt 
1 
0.12753294 
0.12753294 
3.43 
0.1377
subject(sequence) 
5 
2.92899343 
0.58579869 
15.75 
0.0097
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.73180313 
0.73180313 
19.68 
0.0114
period 
1 
0.02783629 
0.02783629 
0.75 
0.4357
trt 
1 
0.12753294 
0.12753294 
3.43 
0.1377
subject(sequence) 
5 
2.92899343 
0.58579869 
15.75 
0.0097
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.73180313 
0.73180313 
19.68 
0.0114
period 
1 
0.02783629 
0.02783629 
0.75 
0.4357
trt 
1 
0.12753294 
0.12753294 
3.43 
0.1377
subject(sequence) 
5 
2.92899343 
0.58579869 
15.75 
0.0097
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 76-87 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
1.104732 
1.104732 
1.76 
0.2421
Error 
4.956 
3.105712 
0.626660 
Error: 1.0745*MS(subject(sequence)) - 0.0745*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
0.005208 
0.005208 
0.09 
0.7763
Error 
8.2931 
0.500957 
0.060406 
Error: 0.0423*MS(subject(sequence)) + 0.9577*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.330430 
0.330430 
5.75 
0.0435
Error 
7.9739 
0.458527 
0.057504 
Error: 0.037*MS(subject(sequence)) + 0.963*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
5 
2.928993 
0.585799 
15.75 
0.0097
Error: MS(Error) 
4 
0.148739 
0.037185 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 76-87 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.187033 
1.187033 
1.89 
0.2276
Error 
4.9562 
3.104746 
0.626437 
Error: 1.0741*MS(subject(sequence)) - 0.0741*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.027836 
0.027836 
0.75 
0.4357
trt 
1 
0.127533 
0.127533 
3.43 
0.1377
subject(sequence) 
5 
2.928993 
0.585799 
15.75 
0.0097
Error: MS(Error) 
4 
0.148739 
0.037185 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.731803 
0.731803 
1.28 
0.3086
Error 
5.0181 
2.863142 
0.570559 
Error: 0.9722*MS(subject(sequence)) + 0.0278*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.027836 
0.027836 
0.75 
0.4357
trt 
1 
0.127533 
0.127533 
3.43 
0.1377
subject(sequence) 
5 
2.928993 
0.585799 
15.75 
0.0097
Error: MS(Error) 
4 
0.148739 
0.037185 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 76-87 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.731803 
0.731803 
1.28 
0.3086
Error 
5.0181 
2.863142 
0.570559 
Error: 0.9722*MS(subject(sequence)) + 0.0278*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.027836 
0.027836 
0.75 
0.4357
trt 
1 
0.127533 
0.127533 
3.43 
0.1377
subject(sequence) 
5 
2.928993 
0.585799 
15.75 
0.0097
Error: MS(Error) 
4 
0.148739 
0.037185 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 76-87 
Least Squares Means 
trt 
LN_CLFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
0.39108899 
0.1377
B 
0.59727089 
trt 
LN_CLFO LSMEAN 
90% Confidence Limits 
A 
0.391089 
0.234101 
0.548077 
B 
0.597271 
0.419263 
0.775279 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.206182 
-0.443526 
0.031162 
 
Dependent Variable: LN_CLFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.20618191 0.11133243 -1.85 
0.1377 -0.44352559 0.03116178 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
7 
205 301 406 410 411 501 506 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
13 
Number of Observations Used 
13 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LN_VZFOW 
R-Square 
Coeff Var 
Root MSE 
LN_VZFOW Mean
0.827623 
54.35284 
0.457834 
0.842336 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.55584599 
0.55584599 
2.65 
0.1788
period 
1 
0.47525416 
0.47525416 
2.27 
0.2066
trt 
1 
0.01535182 
0.01535182 
0.07 
0.8001
subject(sequence) 
5 
2.97913450 
0.59582690 
2.84 
0.1667
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.61287645 
0.61287645 
2.92 
0.1625
period 
1 
0.22564597 
0.22564597 
1.08 
0.3581
trt 
1 
0.10173215 
0.10173215 
0.49 
0.5244
subject(sequence) 
5 
2.97913450 
0.59582690 
2.84 
0.1667
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.31250150 
0.31250150 
1.49 
0.2891
period 
1 
0.22564597 
0.22564597 
1.08 
0.3581
trt 
1 
0.10173215 
0.10173215 
0.49 
0.5244
subject(sequence) 
5 
2.97913450 
0.59582690 
2.84 
0.1667
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.31250150 
0.31250150 
1.49 
0.2891
period 
1 
0.22564597 
0.22564597 
1.08 
0.3581
trt 
1 
0.10173215 
0.10173215 
0.49 
0.5244
subject(sequence) 
5 
2.97913450 
0.59582690 
2.84 
0.1667
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 76-87 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.555846 
0.555846 
0.89 
0.3909
Error 
4.7556 
2.970298 
0.624593 
Error: 1.0745*MS(subject(sequence)) - 0.0745*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
0.475254 
0.475254 
2.10 
0.2066
Error 
5.005 
1.130933 
0.225959 
Error: 0.0423*MS(subject(sequence)) + 0.9577*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.015352 
0.015352 
0.07 
0.8041
Error 
4.8758 
1.091772 
0.223916 
Error: 0.037*MS(subject(sequence)) + 0.963*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
5 
2.979134 
0.595827 
2.84 
0.1667
Error: MS(Error) 
4 
0.838447 
0.209612 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 76-87 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.612876 
0.612876 
0.98 
0.3695
Error 
4.7568 
2.970329 
0.624435 
Error: 1.0741*MS(subject(sequence)) - 0.0741*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.225646 
0.225646 
1.08 
0.3581
trt 
1 
0.101732 
0.101732 
0.49 
0.5244
subject(sequence) 
5 
2.979134 
0.595827 
2.84 
0.1667
Error: MS(Error) 
4 
0.838447 
0.209612 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.312501 
0.312501 
0.53 
0.4971
Error 
5.1004 
2.984223 
0.585099 
Error: 0.9722*MS(subject(sequence)) + 0.0278*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.225646 
0.225646 
1.08 
0.3581
trt 
1 
0.101732 
0.101732 
0.49 
0.5244
subject(sequence) 
5 
2.979134 
0.595827 
2.84 
0.1667
Error: MS(Error) 
4 
0.838447 
0.209612 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 76-87 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.312501 
0.312501 
0.53 
0.4971
Error 
5.1004 
2.984223 
0.585099 
Error: 0.9722*MS(subject(sequence)) + 0.0278*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.225646 
0.225646 
1.08 
0.3581
trt 
1 
0.101732 
0.101732 
0.49 
0.5244
subject(sequence) 
5 
2.979134 
0.595827 
2.84 
0.1667
Error: MS(Error) 
4 
0.838447 
0.209612 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 76-87 
Least Squares Means 
trt 
LN_VZFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
0.87243886 
0.5244
B 
0.68829023 
trt 
LN_VZFOW LSMEAN 
90% Confidence Limits 
A 
0.872439 
0.499711 
1.245167 
B 
0.688290 
0.265656 
1.110924 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.184149 
-0.379363 
0.747661 
 
Dependent Variable: LN_VZFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.18414862 0.26433041 0.70 
0.5244 -0.37936331 0.74766056 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
7 
205 301 406 410 411 501 506 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
13 
Number of Observations Used 
13 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LN_VZFO 
R-Square 
Coeff Var 
Root MSE 
LN_VZFO Mean
0.829814 
8.655693 
0.457834 
5.289394 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.59638193 
0.59638193 
2.85 
0.1669
period 
1 
0.48789867 
0.48789867 
2.33 
0.2018
trt 
1 
0.01331260 
0.01331260 
0.06 
0.8134
subject(sequence) 
5 
2.99060271 
0.59812054 
2.85 
0.1658
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.65717146 
0.65717146 
3.14 
0.1513
period 
1 
0.22564597 
0.22564597 
1.08 
0.3581
trt 
1 
0.10173215 
0.10173215 
0.49 
0.5244
subject(sequence) 
5 
2.99060271 
0.59812054 
2.85 
0.1658
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.33371526 
0.33371526 
1.59 
0.2756
period 
1 
0.22564597 
0.22564597 
1.08 
0.3581
trt 
1 
0.10173215 
0.10173215 
0.49 
0.5244
subject(sequence) 
5 
2.99060271 
0.59812054 
2.85 
0.1658
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.33371526 
0.33371526 
1.59 
0.2756
period 
1 
0.22564597 
0.22564597 
1.08 
0.3581
trt 
1 
0.10173215 
0.10173215 
0.49 
0.5244
subject(sequence) 
5 
2.99060271 
0.59812054 
2.85 
0.1658
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 76-87 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 
1 
0.596382 
0.596382 
0.95 
0.3764
Error 
4.7565 
2.982607 
0.627057 
Error: 1.0745*MS(subject(sequence)) - 0.0745*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
0.487899 
0.487899 
2.16 
0.2016
Error 
5.0088 
1.132283 
0.226057 
Error: 0.0423*MS(subject(sequence)) + 0.9577*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.013313 
0.013313 
0.06 
0.8173
Error 
4.8792 
1.092935 
0.224001 
Error: 0.037*MS(subject(sequence)) + 0.963*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
5 
2.990603 
0.598121 
2.85 
0.1658
Error: MS(Error) 
4 
0.838447 
0.209612 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 76-87 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.657171 
0.657171 
1.05 
0.3551
Error 
4.7578 
2.982633 
0.626899 
Error: 1.0741*MS(subject(sequence)) - 0.0741*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.225646 
0.225646 
1.08 
0.3581
trt 
1 
0.101732 
0.101732 
0.49 
0.5244
subject(sequence) 
5 
2.990603 
0.598121 
2.85 
0.1658
Error: MS(Error) 
4 
0.838447 
0.209612 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.333715 
0.333715 
0.57 
0.4843
Error 
5.1 
2.995371 
0.587329 
Error: 0.9722*MS(subject(sequence)) + 0.0278*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.225646 
0.225646 
1.08 
0.3581
trt 
1 
0.101732 
0.101732 
0.49 
0.5244
subject(sequence) 
5 
2.990603 
0.598121 
2.85 
0.1658
Error: MS(Error) 
4 
0.838447 
0.209612 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 76-87 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.333715 
0.333715 
0.57 
0.4843
Error 
5.1 
2.995371 
0.587329 
Error: 0.9722*MS(subject(sequence)) + 0.0278*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.225646 
0.225646 
1.08 
0.3581
trt 
1 
0.101732 
0.101732 
0.49 
0.5244
subject(sequence) 
5 
2.990603 
0.598121 
2.85 
0.1658
Error: MS(Error) 
4 
0.838447 
0.209612 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 76-87 
Least Squares Means 
trt 
LN_VZFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
5.31688317 
0.5244
B 
5.13273455 
trt 
LN_VZFO LSMEAN 
90% Confidence Limits 
A 
5.316883 
4.944155 
5.689611 
B 
5.132735 
4.710101 
5.555368 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.184149 
-0.379363 
0.747661 
 
Dependent Variable: LN_VZFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.18414862 0.26433041 0.70 
0.5244 -0.37936331 0.74766056 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
7 
205 301 406 410 411 501 506 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
14 
Number of Observations Used 
14 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: TMAX 
R-Square 
Coeff Var 
Root MSE 
TMAX Mean
0.547486 
51.70082 
0.529380 
1.023929 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04136010 
0.04136010 
0.15 
0.7166
period 
1 
0.03837779 
0.03837779 
0.14 
0.7265
trt 
1 
0.58717038 
0.58717038 
2.10 
0.2074
subject(sequence) 
5 
1.02838533 
0.20567707 
0.73 
0.6287
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04136010 
0.04136010 
0.15 
0.7166
period 
1 
0.09202752 
0.09202752 
0.33 
0.5914
trt 
1 
0.58717038 
0.58717038 
2.10 
0.2074
subject(sequence) 
5 
1.02838533 
0.20567707 
0.73 
0.6287
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04136010 
0.04136010 
0.15 
0.7166
period 
1 
0.09202752 
0.09202752 
0.33 
0.5914
trt 
1 
0.58717038 
0.58717038 
2.10 
0.2074
subject(sequence) 
5 
1.02838533 
0.20567707 
0.73 
0.6287
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.04136010 
0.04136010 
0.15 
0.7166
period 
1 
0.09202752 
0.09202752 
0.33 
0.5914
trt 
1 
0.58717038 
0.58717038 
2.10 
0.2074
subject(sequence) 
5 
1.02838533 
0.20567707 
0.73 
0.6287
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 76-87 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.041360 
0.041360 
0.20 
0.6726 
Error 
5 
1.028385 
0.205677 
 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F
*period 
1 
0.038378 0.038378 
0.14 
0.7265
trt 
1 
0.587170 0.587170 
2.10 
0.2074
subject(sequence) 
5 
1.028385 0.205677 
0.73 
0.6287
Error: MS(Error) 
5 
1.401213 0.280243 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.041360 
0.041360 
0.20 
0.6726
Error 
5 
1.028385 
0.205677 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.092028 
0.092028 
0.33 
0.5914
trt 
1 
0.587170 
0.587170 
2.10 
0.2074
subject(sequence) 
5 
1.028385 
0.205677 
0.73 
0.6287
Error: MS(Error) 
5 
1.401213 
0.280243 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 76-87 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.041360 
0.041360 
0.20 
0.6726 
Error 
5 
1.028385 
0.205677 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.092028 
0.092028 
0.33 
0.5914
trt 
1 
0.587170 
0.587170 
2.10 
0.2074
subject(sequence) 
5 
1.028385 
0.205677 
0.73 
0.6287
Error: MS(Error) 
5 
1.401213 
0.280243 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.041360 
0.041360 
0.20 
0.6726
Error 
5 
1.028385 
0.205677 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.092028 
0.092028 
0.33 
0.5914
trt 
1 
0.587170 
0.587170 
2.10 
0.2074
subject(sequence) 
5 
1.028385 
0.205677 
0.73 
0.6287
Error: MS(Error) 
5 
1.401213 
0.280243 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 76-87 
Least Squares Means 
trt TMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 1.22300000 
0.2074
B 
0.80916667 
trt 
TMAX LSMEAN 
90% Confidence Limits 
A 
1.223000 
0.815638 
1.630362 
B 
0.809167 
0.401804 
1.216529 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.413833 
-0.162264 
0.989931 
 
Dependent Variable: TMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.41383333 0.28589761 1.45 
0.2074 -0.16226418 0.98993085 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
7 
205 301 406 410 411 501 506 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
13 
Number of Observations Used 
13 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LAMZ 
R-Square 
Coeff Var 
Root MSE 
LAMZ Mean
0.873885 
28.10434 
0.002893 
0.010293 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00000004 
0.00000004 
0.01 
0.9469
period 
1 
0.00000565 
0.00000565 
0.67 
0.4575
trt 
1 
0.00002119 
0.00002119 
2.53 
0.1868
subject(sequence) 
5 
0.00020508 
0.00004102 
4.90 
0.0744
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00000000 
0.00000000 
0.00 
0.9827
period 
1 
0.00000681 
0.00000681 
0.81 
0.4181
trt 
1 
0.00001972 
0.00001972 
2.36 
0.1996
subject(sequence) 
5 
0.00020508 
0.00004102 
4.90 
0.0744
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00000001 
0.00000001 
0.00 
0.9790
period 
1 
0.00000681 
0.00000681 
0.81 
0.4181
trt 
1 
0.00001972 
0.00001972 
2.36 
0.1996
subject(sequence) 
5 
0.00020508 
0.00004102 
4.90 
0.0744
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00000001 
0.00000001 
0.00 
0.9790
period 
1 
0.00000681 
0.00000681 
0.81 
0.4181
trt 
1 
0.00001972 
0.00001972 
2.36 
0.1996
subject(sequence) 
5 
0.00020508 
0.00004102 
4.90 
0.0744
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 76-87 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 1 
4.2090894E-8 
4.2090894E-8 
0.00 
0.9764
Error 
4.8584 
0.000211 
0.000043447 
Error: 1.0745*MS(subject(sequence)) - 0.0745*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
0.000005647 
0.000005647 
0.58 
0.4769
Error 
5.7064 
0.000055641 
0.000009751 
Error: 0.0423*MS(subject(sequence)) + 0.9577*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
trt 
1 
0.000021191 
0.000021191 
2.21 
0.1919 
Error 
5.494 
0.000052620 
0.000009578 
 
Error: 0.037*MS(subject(sequence)) + 0.963*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
5 
0.000205 
0.000041015 
4.90 
0.0744
Error: MS(Error) 
4 
0.000033475 
0.000008369 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 76-87 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
4.4420302E-9 
4.4420302E-9 
0.00 
0.9923
Error 
4.8591 
0.000211 
0.000043433 
Error: 1.0741*MS(subject(sequence)) - 0.0741*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F 
period 
1 
0.000006809 
0.000006809 
0.81 
0.4181 
trt 
1 
0.000019719 
0.000019719 
2.36 
0.1996 
subject(sequence) 
5 
0.000205 
0.000041015 
4.90 
0.0744 
Error: MS(Error) 
4 
0.000033475 
0.000008369 
 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
6.5762621E-9 
6.5762621E-9 
0.00 
0.9903
Error 
5.0583 
0.000203 
0.000040108 
Error: 0.9722*MS(subject(sequence)) + 0.0278*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000006809 
0.000006809 
0.81 
0.4181
trt 
1 
0.000019719 
0.000019719 
2.36 
0.1996
subject(sequence) 
5 
0.000205 
0.000041015 
4.90 
0.0744
Error: MS(Error) 
4 
0.000033475 
0.000008369 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 76-87 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
6.5762621E-9 
6.5762621E-9 
0.00 
0.9903
Error 
5.0583 
0.000203 
0.000040108 
Error: 0.9722*MS(subject(sequence)) + 0.0278*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000006809 
0.000006809 
0.81 
0.4181
trt 
1 
0.000019719 
0.000019719 
2.36 
0.1996
subject(sequence) 
5 
0.000205 
0.000041015 
4.90 
0.0744
Error: MS(Error) 
4 
0.000033475 
0.000008369 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 76-87 
Least Squares Means 
trt LAMZ LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t| 
A 
0.00904945 
0.1996 
B 
0.01161324 
 
trt 
LAMZ LSMEAN 
90% Confidence Limits 
A 
0.009049 
0.006694 
0.011405 
B 
0.011613 
0.008943 
0.014284 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.002564 
-0.006124 
0.000997 
 
Dependent Variable: LAMZ 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.00256379 0.00167020 -1.54 
0.1996 -0.00612439 0.00099681 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
7 
205 301 406 410 411 501 506 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
13 
Number of Observations Used 
13 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LAMZHL 
R-Square 
Coeff Var 
Root MSE 
LAMZHL Mean
0.658688 
115.2892 
120.4972 
104.5173 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
9566.77716 
9566.77716 
0.66 
0.4625
period 
1 
17411.68113 
17411.68113 
1.20 
0.3350
trt 
1 
15198.84251 
15198.84251 
1.05 
0.3641
subject(sequence) 
5 
69906.18556 
13981.23711 
0.96 
0.5294
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
9246.29628 
9246.29628 
0.64 
0.4696
period 
1 
18021.71774 
18021.71774 
1.24 
0.3277
trt 
1 
14534.90061 
14534.90061 
1.00 
0.3737
subject(sequence) 
5 
69906.18556 
13981.23711 
0.96 
0.5294
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
8891.77606 
8891.77606 
0.61 
0.4776
period 
1 
18021.71774 
18021.71774 
1.24 
0.3277
trt 
1 
14534.90061 
14534.90061 
1.00 
0.3737
subject(sequence) 
5 
69906.18556 
13981.23711 
0.96 
0.5294
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
8891.77606 
8891.77606 
0.61 
0.4776
period 
1 
18021.71774 
18021.71774 
1.24 
0.3277
trt 
1 
14534.90061 
14534.90061 
1.00 
0.3737
subject(sequence) 
5 
69906.18556 
13981.23711 
0.96 
0.5294
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 76-87 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*sequence 1 
9566.777155 
9566.777155 
0.69 
0.4512
Error 
4.2783 
59645 
13941 
Error: 1.0745*MS(subject(sequence)) - 0.0745*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
*period 
1 
17412 
17412 
1.20 
0.3301
Error 
4.3414 
62937 
14497 
Error: 0.0423*MS(subject(sequence)) + 0.9577*MS(Error) 
* This test assumes one or more other fixed effects are zero. 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
15199 
15199 
1.05 
0.3601
Error 
4.2971 
62306 
14500 
Error: 0.037*MS(subject(sequence)) + 0.963*MS(Error) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
subject(sequence) 
5 
69906 
13981 
0.96 
0.5294
Error: MS(Error) 
4 
58078 
14520 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 76-87 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
9246.296277 
9246.296277 
0.66 
0.4583
Error 
4.282 
59697 
13941 
Error: 1.0741*MS(subject(sequence)) - 0.0741*MS(Error) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
18022 
18022 
1.24 
0.3277
trt 
1 
14535 
14535 
1.00 
0.3737
subject(sequence) 
5 
69906 
13981 
0.96 
0.5294
Error: MS(Error) 
4 
58078 
14520 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
8891.776063 
8891.776063 
0.64 
0.4597
Error 
5.2953 
74114 
13996 
Error: 0.9722*MS(subject(sequence)) + 0.0278*MS(Error) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F 
period 
1 
18022 
18022 
1.24 
0.3277 
trt 
1 
14535 
14535 
1.00 
0.3737 
subject(sequence) 
5 
69906 
13981 
0.96 
0.5294 
Error: MS(Error) 
4 
58078 
14520 
 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 76-87 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
8891.776063 
8891.776063 
0.64 
0.4597
Error 
5.2953 
74114 
13996 
Error: 0.9722*MS(subject(sequence)) + 0.0278*MS(Error) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
18022 
18022 
1.24 
0.3277
trt 
1 
14535 
14535 
1.00 
0.3737
subject(sequence) 
5 
69906 
13981 
0.96 
0.5294
Error: MS(Error) 
4 
58078 
14520 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 76-87 
Least Squares Means 
trt 
LAMZHL LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
141.400412 
0.3737
B 
71.794615 
trt 
LAMZHL LSMEAN 
90% Confidence Limits 
A 
141.400412 
43.302149 
239.498674 
B 
71.794615 
-39.438359 
183.027590 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 69.605796 
-78.704837 
217.916429 
 
Dependent Variable: LAMZHL 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
69.6057962 69.5690862 1.00 
0.3737 -78.7048366 217.9164290 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
301 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LN_AUCLST 
R-Square 
Coeff Var 
Root MSE 
LN_AUCLST Mean
0.814181 
2.448131 
0.222785 
9.100215 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.20699244 
0.20699244 
4.17 
0.2899
trt 
1 
0.01047938 
0.01047938 
0.21 
0.7258
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.20699244 
0.20699244 
4.17 
0.2899
trt 
1 
0.01047938 
0.01047938 
0.21 
0.7258
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.20699244 
0.20699244 
4.17 
0.2899
trt 
1 
0.01047938 
0.01047938 
0.21 
0.7258
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.20699244 
0.20699244 
4.17 
0.2899
trt 
1 
0.01047938 
0.01047938 
0.21 
0.7258
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 76-87 
The GLM Procedure 
Least Squares Means 
trt LN_AUCLST LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
9.15139922 
0.7258
C 
9.04903038 
trt 
LN_AUCLST LSMEAN 
90% Confidence Limits 
B 
9.151399 
8.156775 
10.146023 
C 
9.049030 
8.054407 
10.043654 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.102369 
-1.304242 
1.508979 
 
The GLM Procedure 
Dependent Variable: LN_AUCLST 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.10236884 0.22278522 -0.46 
0.7258 -1.50897936 1.30424169 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
301 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LN_AUCIFO 
R-Square 
Coeff Var 
Root MSE 
LN_AUCIFO Mean
0.932143 
1.708233 
0.157513 
9.220795 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.34080541 
0.34080541 
13.74 
0.1678
trt 
1 
0.00000719 
0.00000719 
0.00 
0.9892
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.34080541 
0.34080541 
13.74 
0.1678
trt 
1 
0.00000719 
0.00000719 
0.00 
0.9892
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.34080541 
0.34080541 
13.74 
0.1678
trt 
1 
0.00000719 
0.00000719 
0.00 
0.9892
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.34080541 
0.34080541 
13.74 
0.1678
trt 
1 
0.00000719 
0.00000719 
0.00 
0.9892
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 76-87 
The GLM Procedure 
Least Squares Means 
trt LN_AUCIFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
9.21945385 
0.9892
C 
9.22213570 
trt 
LN_AUCIFO LSMEAN 
90% Confidence Limits 
B 
9.219454 
8.516239 
9.922668 
C 
9.222136 
8.518921 
9.925350 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.002682 
-0.997177 
0.991814 
 
The GLM Procedure 
Dependent Variable: LN_AUCIFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.00268185 0.15751262 0.02 
0.9892 -0.99181367 0.99717736 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
301 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LN_CMAX 
R-Square 
Coeff Var 
Root MSE 
LN_CMAX Mean
0.263645 
10.67177 
0.587305 
5.503351 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00664457 
0.00664457 
0.02 
0.9122
trt 
1 
0.11685348 
0.11685348 
0.34 
0.6644
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00664457 
0.00664457 
0.02 
0.9122
trt 
1 
0.11685348 
0.11685348 
0.34 
0.6644
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00664457 
0.00664457 
0.02 
0.9122
trt 
1 
0.11685348 
0.11685348 
0.34 
0.6644
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00664457 
0.00664457 
0.02 
0.9122
trt 
1 
0.11685348 
0.11685348 
0.34 
0.6644
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 76-87 
The GLM Procedure 
Least Squares Means 
trt 
LN_CMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
5.67427068 
0.6644
C 
5.33243229 
trt 
LN_CMAX LSMEAN 
90% Confidence Limits 
B 
5.674271 
3.052250 
8.296291 
C 
5.332432 
2.710412 
7.954453 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 
0.341838 
-3.366259 
4.049935 
 
The GLM Procedure 
Dependent Variable: LN_CMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.34183838 0.58730486 -0.58 
0.6644 -4.04993531 3.36625855 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
301 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LN_CLFOW 
R-Square 
Coeff Var 
Root MSE 
LN_CLFOW Mean
0.930720 
-3.964760 
0.157513 
-3.972816 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.30870751 
0.30870751 
12.44 
0.1759
trt 
1 
0.02459644 
0.02459644 
0.99 
0.5014
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.30870751 
0.30870751 
12.44 
0.1759
trt 
1 
0.02459644 
0.02459644 
0.99 
0.5014
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.30870751 
0.30870751 
12.44 
0.1759
trt 
1 
0.02459644 
0.02459644 
0.99 
0.5014
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.30870751 
0.30870751 
12.44 
0.1759
trt 
1 
0.02459644 
0.02459644 
0.99 
0.5014
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 76-87 
The GLM Procedure 
Least Squares Means 
trt 
LN_CLFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
-3.89439993 
0.5014
C 
-4.05123246 
trt 
LN_CLFOW LSMEAN 
90% Confidence Limits 
B 
-3.894400 
-4.597614 
-3.191185 
C 
-4.051232 
-4.754447 
-3.348018 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.156833 
-0.837663 
1.151328 
 
The GLM Procedure 
Dependent Variable: LN_CLFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.15683253 0.15751262 -1.00 
0.5014 -1.15132804 0.83766299 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
301 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LN_CLFO 
R-Square 
Coeff Var 
Root MSE 
LN_CLFO Mean
0.936419 
33.36523 
0.157513 
0.472086 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.34080541 
0.34080541 
13.74 
0.1678
trt 
1 
0.02459644 
0.02459644 
0.99 
0.5014
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.34080541 
0.34080541 
13.74 
0.1678
trt 
1 
0.02459644 
0.02459644 
0.99 
0.5014
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.34080541 
0.34080541 
13.74 
0.1678
trt 
1 
0.02459644 
0.02459644 
0.99 
0.5014
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.34080541 
0.34080541 
13.74 
0.1678
trt 
1 
0.02459644 
0.02459644 
0.99 
0.5014
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 76-87 
The GLM Procedure 
Least Squares Means 
trt 
LN_CLFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
0.55050231 
0.5014
C 
0.39366978 
trt 
LN_CLFO LSMEAN 
90% Confidence Limits 
B 
0.550502 
-0.152712 
1.253717 
C 
0.393670 
-0.309545 
1.096884 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 
0.156833 
-0.837663 
1.151328 
 
The GLM Procedure 
Dependent Variable: LN_CLFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.15683253 0.15751262 -1.00 
0.5014 -1.15132804 0.83766299 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
301 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LN_VZFOW 
R-Square 
Coeff Var 
Root MSE 
LN_VZFOW Mean
0.677827 
40.68762 
0.281952 
0.692967 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00005645 
0.00005645 
0.00 
0.9830
trt 
1 
0.16719912 
0.16719912 
2.10 
0.3843
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00005645 
0.00005645 
0.00 
0.9830
trt 
1 
0.16719912 
0.16719912 
2.10 
0.3843
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00005645 
0.00005645 
0.00 
0.9830
trt 
1 
0.16719912 
0.16719912 
2.10 
0.3843
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00005645 
0.00005645 
0.00 
0.9830
trt 
1 
0.16719912 
0.16719912 
2.10 
0.3843
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 76-87 
The GLM Procedure 
Least Squares Means 
trt 
LN_VZFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
0.48851732 
0.3843
C 
0.89741721 
trt 
LN_VZFOW LSMEAN 
90% Confidence Limits 
B 
0.488517 
-0.770256 
1.747291 
C 
0.897417 
-0.361356 
2.156191 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.408900 
-2.189074 
1.371274 
 
The GLM Procedure 
Dependent Variable: LN_VZFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.40889990 0.28195191 1.45 
0.3843 -1.37127442 2.18907421 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
301 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LN_VZFO 
R-Square 
Coeff Var 
Root MSE 
LN_VZFO Mean
0.678310 
5.487720 
0.281952 
5.137870 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00042674 
0.00042674 
0.01 
0.9534
trt 
1 
0.16719912 
0.16719912 
2.10 
0.3843
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00042674 
0.00042674 
0.01 
0.9534
trt 
1 
0.16719912 
0.16719912 
2.10 
0.3843
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00042674 
0.00042674 
0.01 
0.9534
trt 
1 
0.16719912 
0.16719912 
2.10 
0.3843
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00042674 
0.00042674 
0.01 
0.9534
trt 
1 
0.16719912 
0.16719912 
2.10 
0.3843
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) Weight Group: 76-87 
The GLM Procedure 
Least Squares Means 
trt 
LN_VZFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
4.93341956 
0.3843
C 
5.34231945 
trt 
LN_VZFO LSMEAN 
90% Confidence Limits 
B 
4.933420 
3.674646 
6.192193 
C 
5.342319 
4.083546 
6.601093 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.408900 
-2.189074 
1.371274 
 
The GLM Procedure 
Dependent Variable: LN_VZFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.40889990 0.28195191 1.45 
0.3843 -1.37127442 2.18907421 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
301 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: TMAX 
R-Square 
Coeff Var 
Root MSE 
TMAX Mean
0.500070 
50.63480 
0.508500 
1.004250 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00007225 
0.00007225 
0.00 
0.9894
trt 
1 
0.25857225 
0.25857225 
1.00 
0.5000
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00007225 
0.00007225 
0.00 
0.9894
trt 
1 
0.25857225 
0.25857225 
1.00 
0.5000
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00007225 
0.00007225 
0.00 
0.9894
trt 
1 
0.25857225 
0.25857225 
1.00 
0.5000
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00007225 
0.00007225 
0.00 
0.9894
trt 
1 
0.25857225 
0.25857225 
1.00 
0.5000
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) Weight Group: 76-87 
The GLM Procedure 
Least Squares Means 
trt TMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
0.75000000 
0.5000
C 
1.25850000 
trt 
TMAX LSMEAN 
90% Confidence Limits 
B 
0.750000 
-1.520196 
3.020196 
C 
1.258500 
-1.011696 
3.528696 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.508500 
-3.719043 
2.702043 
 
The GLM Procedure 
Dependent Variable: TMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.50850000 0.50850000 1.00 
0.5000 -2.70204265 3.71904265 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
301 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LAMZ 
R-Square 
Coeff Var 
Root MSE 
LAMZ Mean
0.998640 
2.704657 
0.000275 
0.010153 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00002754 
0.00002754 
365.23 
0.0333
trt 
1 
0.00002782 
0.00002782 
368.87 
0.0331
subject(sequence) 
0 
0.00000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00002754 
0.00002754 
365.23 
0.0333
trt 
1 
0.00002782 
0.00002782 
368.87 
0.0331
subject(sequence) 
0 
0.00000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00002754 
0.00002754 
365.23 
0.0333
trt 
1 
0.00002782 
0.00002782 
368.87 
0.0331
subject(sequence) 
0 
0.00000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00002754 
0.00002754 
365.23 
0.0333
trt 
1 
0.00002782 
0.00002782 
368.87 
0.0331
subject(sequence) 
0 
0.00000000 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) Weight Group: 76-87 
The GLM Procedure 
Least Squares Means 
trt LAMZ LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t| 
B 
0.01279051 
0.0331 
C 
0.00751627 
 
trt 
LAMZ LSMEAN 
90% Confidence Limits 
B 
0.012791 
0.011564 
0.014017 
C 
0.007516 
0.006290 
0.008742 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.005274 
0.003540 
0.007008 
 
The GLM Procedure 
Dependent Variable: LAMZ 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.00527424 0.00027461 -19.21 
0.0331 -0.00700808 -0.00354039 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) Weight Group: 76-87 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
2 
301 406 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
4 
Number of Observations Used 
4 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) Weight Group: 76-87 
The GLM Procedure 
Dependent Variable: LAMZHL 
R-Square 
Coeff Var 
Root MSE 
LAMZHL Mean
0.899909 
27.41894 
21.98952 
80.19828 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
2165.315655 
2165.315655 
4.48 
0.2810
trt 
1 
2182.123274 
2182.123274 
4.51 
0.2801
subject(sequence) 
0 
0.000000 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
2165.315655 
2165.315655 
4.48 
0.2810
trt 
1 
2182.123274 
2182.123274 
4.51 
0.2801
subject(sequence) 
0 
0.000000 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
2165.315655 
2165.315655 
4.48 
0.2810
trt 
1 
2182.123274 
2182.123274 
4.51 
0.2801
subject(sequence) 
0 
0.000000 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
2165.315655 
2165.315655 
4.48 
0.2810
trt 
1 
2182.123274 
2182.123274 
4.51 
0.2801
subject(sequence) 
0 
0.000000 
 


 
 
Listing 16.1.9-7 ANOVA for Treatment Comparison of Diazepam for Weight Group 76-87 
kg - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) Weight Group: 76-87 
The GLM Procedure 
Least Squares Means 
trt 
LAMZHL LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
56.841678 
0.2801
C 
103.554880 
trt 
LAMZHL LSMEAN 
90% Confidence Limits 
B 
56.841678 
-41.330441 
155.013796 
C 
103.554880 
5.382761 
201.726999 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -46.713202 
-185.549544 
92.123140 
 
The GLM Procedure 
Dependent Variable: LAMZHL 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
46.7132024 21.9895163 2.12 
0.2801 -92.1231396 185.5495443 
 
 


180323 Diazepam Buccal Film DRG Crossover 
Aquestive Therapeutics 
16.1.9 Documentation of Statistical Methods 
 
Confidential 
Page 11 of 11 
Final 1.0 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 88-
111 kg - PK Population 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
11 
203 204 304 402 404 407 409 502 505 507 508 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
22 
Number of Observations Used 
22 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LN_AUCLST 
R-Square 
Coeff Var 
Root MSE 
LN_AUCLST Mean
0.624540 
10.97272 
0.944959 
8.611893 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.34347906 
0.34347906 
0.38 
0.5505
period 
1 
0.00482396 
0.00482396 
0.01 
0.9430
trt 
1 
2.32311575 
2.32311575 
2.60 
0.1412
subject(sequence) 
9 
10.69654172 
1.18850464 
1.33 
0.3385
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.34347906 
0.34347906 
0.38 
0.5505
period 
1 
0.04315122 
0.04315122 
0.05 
0.8309
trt 
1 
2.32311575 
2.32311575 
2.60 
0.1412
subject(sequence) 
9 
10.69654172 
1.18850464 
1.33 
0.3385
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.34347906 
0.34347906 
0.38 
0.5505
period 
1 
0.04315122 
0.04315122 
0.05 
0.8309
trt 
1 
2.32311575 
2.32311575 
2.60 
0.1412
subject(sequence) 
9 
10.69654172 
1.18850464 
1.33 
0.3385
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.34347906 
0.34347906 
0.38 
0.5505
period 
1 
0.04315122 
0.04315122 
0.05 
0.8309
trt 
1 
2.32311575 
2.32311575 
2.60 
0.1412
subject(sequence) 
9 
10.69654172 
1.18850464 
1.33 
0.3385
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.343479 
0.343479 
0.29 
0.6039
Error 
9 
10.696542 
1.188505 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F 
* period 
1 
0.004824 
0.004824 
0.01 
0.9430 
 trt 
1 
2.323116 
2.323116 
2.60 
0.1412 
 subject(sequence) 9 
10.696542 1.188505 
1.33 
0.3385 
 Error: MS(Error) 
9 
8.036520 
0.892947 
 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.343479 
0.343479 
0.29 
0.6039
Error 
9 
10.696542 
1.188505 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.043151 
0.043151 
0.05 
0.8309
trt 
1 
2.323116 
2.323116 
2.60 
0.1412
subject(sequence) 
9 
10.696542 
1.188505 
1.33 
0.3385
Error: MS(Error) 
9 
8.036520 
0.892947 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.343479 
0.343479 
0.29 
0.6039 
Error 
9 
10.696542 
1.188505 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.043151 
0.043151 
0.05 
0.8309
trt 
1 
2.323116 
2.323116 
2.60 
0.1412
subject(sequence) 
9 
10.696542 
1.188505 
1.33 
0.3385
Error: MS(Error) 
9 
8.036520 
0.892947 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.343479 
0.343479 
0.29 
0.6039
Error 
9 
10.696542 
1.188505 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.043151 
0.043151 
0.05 
0.8309
trt 
1 
2.323116 
2.323116 
2.60 
0.1412
subject(sequence) 
9 
10.696542 
1.188505 
1.33 
0.3385
Error: MS(Error) 
9 
8.036520 
0.892947 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 88-111 
Least Squares Means 
trt LN_AUCLST LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
8.92679321 
0.1412
B 
8.27417958 
trt 
LN_AUCLST LSMEAN 
90% Confidence Limits 
A 
8.926793 
8.402339 
9.451248 
B 
8.274180 
7.749725 
8.798634 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.652614 
-0.089077 
1.394304 
 
Dependent Variable: LN_AUCLST 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.65261363 0.40460708 1.61 
0.1412 -0.08907684 1.39430410 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
11 
203 204 304 402 404 407 409 502 505 507 508 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
22 
Number of Observations Used 
22 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LN_AUCIFO 
R-Square 
Coeff Var 
Root MSE 
LN_AUCIFO Mean
0.810830 
6.590357 
0.587678 
8.917241 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.69862990 
0.69862990 
2.02 
0.1887
period 
1 
0.23085126 
0.23085126 
0.67 
0.4347
trt 
1 
1.60598632 
1.60598632 
4.65 
0.0594
subject(sequence) 
9 
10.78744135 
1.19860459 
3.47 
0.0389
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.69862990 
0.69862990 
2.02 
0.1887
period 
1 
0.35246442 
0.35246442 
1.02 
0.3388
trt 
1 
1.60598632 
1.60598632 
4.65 
0.0594
subject(sequence) 
9 
10.78744135 
1.19860459 
3.47 
0.0389
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.69862990 
0.69862990 
2.02 
0.1887
period 
1 
0.35246442 
0.35246442 
1.02 
0.3388
trt 
1 
1.60598632 
1.60598632 
4.65 
0.0594
subject(sequence) 
9 
10.78744135 
1.19860459 
3.47 
0.0389
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.69862990 
0.69862990 
2.02 
0.1887
period 
1 
0.35246442 
0.35246442 
1.02 
0.3388
trt 
1 
1.60598632 
1.60598632 
4.65 
0.0594
subject(sequence) 
9 
10.78744135 
1.19860459 
3.47 
0.0389
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.698630 
0.698630 
0.58 
0.4647
Error 
9 
10.787441 
1.198605 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F 
* period 
1 
0.230851 
0.230851 
0.67 
0.4347 
 trt 
1 
1.605986 
1.605986 
4.65 
0.0594 
 subject(sequence) 9 
10.787441 1.198605 
3.47 
0.0389 
 Error: MS(Error) 
9 
3.108289 
0.345365 
 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.698630 
0.698630 
0.58 
0.4647
Error 
9 
10.787441 
1.198605 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.352464 
0.352464 
1.02 
0.3388
trt 
1 
1.605986 
1.605986 
4.65 
0.0594
subject(sequence) 
9 
10.787441 
1.198605 
3.47 
0.0389
Error: MS(Error) 
9 
3.108289 
0.345365 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.698630 
0.698630 
0.58 
0.4647 
Error 
9 
10.787441 
1.198605 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.352464 
0.352464 
1.02 
0.3388
trt 
1 
1.605986 
1.605986 
4.65 
0.0594
subject(sequence) 
9 
10.787441 
1.198605 
3.47 
0.0389
Error: MS(Error) 
9 
3.108289 
0.345365 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.698630 
0.698630 
0.58 
0.4647
Error 
9 
10.787441 
1.198605 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.352464 
0.352464 
1.02 
0.3388
trt 
1 
1.605986 
1.605986 
4.65 
0.0594
subject(sequence) 
9 
10.787441 
1.198605 
3.47 
0.0389
Error: MS(Error) 
9 
3.108289 
0.345365 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 88-111 
Least Squares Means 
trt LN_AUCIFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
9.17228121 
0.0594
B 
8.62966640 
trt 
LN_AUCIFO LSMEAN 
90% Confidence Limits 
A 
9.172281 
8.846118 
9.498444 
B 
8.629666 
8.303504 
8.955829 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.542615 
0.081351 
1.003879 
 
Dependent Variable: LN_AUCIFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 90% Confidence Limits 
A - B 
0.54261480 0.25162870 2.16 
0.0594 0.08135098 1.00387863 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
11 
203 204 304 402 404 407 409 502 505 507 508 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
22 
Number of Observations Used 
22 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LN_CMAX 
R-Square 
Coeff Var 
Root MSE 
LN_CMAX Mean
0.462659 
19.25038 
0.955689 
4.964517 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.05327995 
0.05327995 
0.06 
0.8146
period 
1 
0.73440347 
0.73440347 
0.80 
0.3932
trt 
1 
0.94378043 
0.94378043 
1.03 
0.3359
subject(sequence) 
9 
5.34614197 
0.59401577 
0.65 
0.7341
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.05327995 
0.05327995 
0.06 
0.8146
period 
1 
0.88687719 
0.88687719 
0.97 
0.3502
trt 
1 
0.94378043 
0.94378043 
1.03 
0.3359
subject(sequence) 
9 
5.34614197 
0.59401577 
0.65 
0.7341
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.05327995 
0.05327995 
0.06 
0.8146
period 
1 
0.88687719 
0.88687719 
0.97 
0.3502
trt 
1 
0.94378043 
0.94378043 
1.03 
0.3359
subject(sequence) 
9 
5.34614197 
0.59401577 
0.65 
0.7341
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.05327995 
0.05327995 
0.06 
0.8146
period 
1 
0.88687719 
0.88687719 
0.97 
0.3502
trt 
1 
0.94378043 
0.94378043 
1.03 
0.3359
subject(sequence) 
9 
5.34614197 
0.59401577 
0.65 
0.7341
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.053280 
0.053280 
0.09 
0.7714 
Error 
9 
5.346142 
0.594016 
 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F
*period 
1 
0.734403 0.734403 
0.80 
0.3932
trt 
1 
0.943780 0.943780 
1.03 
0.3359
subject(sequence) 
9 
5.346142 0.594016 
0.65 
0.7341
Error: MS(Error) 
9 
8.220065 0.913341 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.053280 
0.053280 
0.09 
0.7714
Error 
9 
5.346142 
0.594016 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.886877 
0.886877 
0.97 
0.3502
trt 
1 
0.943780 
0.943780 
1.03 
0.3359
subject(sequence) 
9 
5.346142 
0.594016 
0.65 
0.7341
Error: MS(Error) 
9 
8.220065 
0.913341 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.053280 
0.053280 
0.09 
0.7714 
Error 
9 
5.346142 
0.594016 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.886877 
0.886877 
0.97 
0.3502
trt 
1 
0.943780 
0.943780 
1.03 
0.3359
subject(sequence) 
9 
5.346142 
0.594016 
0.65 
0.7341
Error: MS(Error) 
9 
8.220065 
0.913341 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.053280 
0.053280 
0.09 
0.7714
Error 
9 
5.346142 
0.594016 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.886877 
0.886877 
0.97 
0.3502
trt 
1 
0.943780 
0.943780 
1.03 
0.3359
subject(sequence) 
9 
5.346142 
0.594016 
0.65 
0.7341
Error: MS(Error) 
9 
8.220065 
0.913341 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 88-111 
Least Squares Means 
trt 
LN_CMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
5.16800682 
0.3359
B 
4.75204239 
trt 
LN_CMAX LSMEAN 
90% Confidence Limits 
A 
5.168007 
4.637597 
5.698416 
B 
4.752042 
4.221633 
5.282452 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 
0.415964 
-0.334148 
1.166077 
 
Dependent Variable: LN_CMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.41596444 0.40920138 1.02 
0.3359 -0.33414790 1.16607677 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
11 
203 204 304 402 404 407 409 502 505 507 508 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
22 
Number of Observations Used 
22 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LN_CLFOW 
R-Square 
Coeff Var 
Root MSE 
LN_CLFOW Mean
0.840724 
-15.77847 
0.587678 
-3.724556 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.95042330 
0.95042330 
2.75 
0.1315
period 
1 
0.20430477 
0.20430477 
0.59 
0.4615
trt 
1 
2.49367461 
2.49367461 
7.22 
0.0249
subject(sequence) 
9 
12.75844172 
1.41760464 
4.10 
0.0236
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.95042330 
0.95042330 
2.75 
0.1315
period 
1 
0.35246442 
0.35246442 
1.02 
0.3388
trt 
1 
2.49367461 
2.49367461 
7.22 
0.0249
subject(sequence) 
9 
12.75844172 
1.41760464 
4.10 
0.0236
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.95042330 
0.95042330 
2.75 
0.1315
period 
1 
0.35246442 
0.35246442 
1.02 
0.3388
trt 
1 
2.49367461 
2.49367461 
7.22 
0.0249
subject(sequence) 
9 
12.75844172 
1.41760464 
4.10 
0.0236
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.95042330 
0.95042330 
2.75 
0.1315
period 
1 
0.35246442 
0.35246442 
1.02 
0.3388
trt 
1 
2.49367461 
2.49367461 
7.22 
0.0249
subject(sequence) 
9 
12.75844172 
1.41760464 
4.10 
0.0236
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.950423 
0.950423 
0.67 
0.4340
Error 
9 
12.758442 
1.417605 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F 
* period 
1 
0.204305 
0.204305 
0.59 
0.4615 
 trt 
1 
2.493675 
2.493675 
7.22 
0.0249 
 subject(sequence) 9 
12.758442 1.417605 
4.10 
0.0236 
 Error: MS(Error) 
9 
3.108289 
0.345365 
 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.950423 
0.950423 
0.67 
0.4340
Error 
9 
12.758442 
1.417605 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.352464 
0.352464 
1.02 
0.3388
trt 
1 
2.493675 
2.493675 
7.22 
0.0249
subject(sequence) 
9 
12.758442 
1.417605 
4.10 
0.0236
Error: MS(Error) 
9 
3.108289 
0.345365 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.950423 
0.950423 
0.67 
0.4340 
Error 
9 
12.758442 
1.417605 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.352464 
0.352464 
1.02 
0.3388
trt 
1 
2.493675 
2.493675 
7.22 
0.0249
subject(sequence) 
9 
12.758442 
1.417605 
4.10 
0.0236
Error: MS(Error) 
9 
3.108289 
0.345365 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.950423 
0.950423 
0.67 
0.4340
Error 
9 
12.758442 
1.417605 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.352464 
0.352464 
1.02 
0.3388
trt 
1 
2.493675 
2.493675 
7.22 
0.0249
subject(sequence) 
9 
12.758442 
1.417605 
4.10 
0.0236
Error: MS(Error) 
9 
3.108289 
0.345365 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 88-111 
Least Squares Means 
trt 
LN_CLFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
-4.04365537 
0.0249
B 
-3.36750918 
trt 
LN_CLFOW LSMEAN 
90% Confidence Limits 
A 
-4.043655 
-4.369818 
-3.717493 
B 
-3.367509 
-3.693672 
-3.041346 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.676146 
-1.137410 
-0.214882 
 
Dependent Variable: LN_CLFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.67614620 0.25162870 -2.69 
0.0249 -1.13741002 -0.21488237 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
11 
203 204 304 402 404 407 409 502 505 507 508 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
22 
Number of Observations Used 
22 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LN_CLFO 
R-Square 
Coeff Var 
Root MSE 
LN_CLFO Mean
0.820251 
63.91414 
0.587678 
0.919481 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.69862990 
0.69862990 
2.02 
0.1887
period 
1 
0.20430477 
0.20430477 
0.59 
0.4615
trt 
1 
2.49367461 
2.49367461 
7.22 
0.0249
subject(sequence) 
9 
10.78744135 
1.19860459 
3.47 
0.0389
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.69862990 
0.69862990 
2.02 
0.1887
period 
1 
0.35246442 
0.35246442 
1.02 
0.3388
trt 
1 
2.49367461 
2.49367461 
7.22 
0.0249
subject(sequence) 
9 
10.78744135 
1.19860459 
3.47 
0.0389
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.69862990 
0.69862990 
2.02 
0.1887
period 
1 
0.35246442 
0.35246442 
1.02 
0.3388
trt 
1 
2.49367461 
2.49367461 
7.22 
0.0249
subject(sequence) 
9 
10.78744135 
1.19860459 
3.47 
0.0389
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.69862990 
0.69862990 
2.02 
0.1887
period 
1 
0.35246442 
0.35246442 
1.02 
0.3388
trt 
1 
2.49367461 
2.49367461 
7.22 
0.0249
subject(sequence) 
9 
10.78744135 
1.19860459 
3.47 
0.0389
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.698630 
0.698630 
0.58 
0.4647
Error 
9 
10.787441 
1.198605 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F 
* period 
1 
0.204305 
0.204305 
0.59 
0.4615 
 trt 
1 
2.493675 
2.493675 
7.22 
0.0249 
 subject(sequence) 9 
10.787441 1.198605 
3.47 
0.0389 
 Error: MS(Error) 
9 
3.108289 
0.345365 
 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.698630 
0.698630 
0.58 
0.4647
Error 
9 
10.787441 
1.198605 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.352464 
0.352464 
1.02 
0.3388
trt 
1 
2.493675 
2.493675 
7.22 
0.0249
subject(sequence) 
9 
10.787441 
1.198605 
3.47 
0.0389
Error: MS(Error) 
9 
3.108289 
0.345365 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.698630 
0.698630 
0.58 
0.4647 
Error 
9 
10.787441 
1.198605 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.352464 
0.352464 
1.02 
0.3388
trt 
1 
2.493675 
2.493675 
7.22 
0.0249
subject(sequence) 
9 
10.787441 
1.198605 
3.47 
0.0389
Error: MS(Error) 
9 
3.108289 
0.345365 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.698630 
0.698630 
0.58 
0.4647
Error 
9 
10.787441 
1.198605 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.352464 
0.352464 
1.02 
0.3388
trt 
1 
2.493675 
2.493675 
7.22 
0.0249
subject(sequence) 
9 
10.787441 
1.198605 
3.47 
0.0389
Error: MS(Error) 
9 
3.108289 
0.345365 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 88-111 
Least Squares Means 
trt 
LN_CLFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
0.59767495 
0.0249
B 
1.27382115 
trt 
LN_CLFO LSMEAN 
90% Confidence Limits 
A 
0.597675 
0.271512 
0.923838 
B 
1.273821 
0.947658 
1.599984 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.676146 
-1.137410 
-0.214882 
 
Dependent Variable: LN_CLFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.67614620 0.25162870 -2.69 
0.0249 -1.13741002 -0.21488237 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
11 
203 204 304 402 404 407 409 502 505 507 508 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
22 
Number of Observations Used 
22 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LN_VZFOW 
R-Square 
Coeff Var 
Root MSE 
LN_VZFOW Mean
0.530952 
83.84526 
1.109423 
1.323179 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.27195823 
0.27195823 
0.22 
0.6495
period 
1 
0.01551644 
0.01551644 
0.01 
0.9131
trt 
1 
3.73511476 
3.73511476 
3.03 
0.1155
subject(sequence) 
9 
8.51675186 
0.94630576 
0.77 
0.6491
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.27195823 
0.27195823 
0.22 
0.6495
period 
1 
0.00266729 
0.00266729 
0.00 
0.9639
trt 
1 
3.73511476 
3.73511476 
3.03 
0.1155
subject(sequence) 
9 
8.51675186 
0.94630576 
0.77 
0.6491
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.27195823 
0.27195823 
0.22 
0.6495
period 
1 
0.00266729 
0.00266729 
0.00 
0.9639
trt 
1 
3.73511476 
3.73511476 
3.03 
0.1155
subject(sequence) 
9 
8.51675186 
0.94630576 
0.77 
0.6491
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.27195823 
0.27195823 
0.22 
0.6495
period 
1 
0.00266729 
0.00266729 
0.00 
0.9639
trt 
1 
3.73511476 
3.73511476 
3.03 
0.1155
subject(sequence) 
9 
8.51675186 
0.94630576 
0.77 
0.6491
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.271958 
0.271958 
0.29 
0.6049 
Error 
9 
8.516752 
0.946306 
 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F 
* period 
1 
0.015516 
0.015516 
0.01 
0.9131 
 trt 
1 
3.735115 
3.735115 
3.03 
0.1155 
 subject(sequence) 9 
8.516752 
0.946306 
0.77 
0.6491 
 Error: MS(Error) 
9 
11.077366 1.230818 
 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.271958 
0.271958 
0.29 
0.6049
Error 
9 
8.516752 
0.946306 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.002667 
0.002667 
0.00 
0.9639
trt 
1 
3.735115 
3.735115 
3.03 
0.1155
subject(sequence) 
9 
8.516752 
0.946306 
0.77 
0.6491
Error: MS(Error) 
9 
11.077366 
1.230818 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.271958 
0.271958 
0.29 
0.6049 
Error 
9 
8.516752 
0.946306 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.002667 
0.002667 
0.00 
0.9639
trt 
1 
3.735115 
3.735115 
3.03 
0.1155
subject(sequence) 
9 
8.516752 
0.946306 
0.77 
0.6491
Error: MS(Error) 
9 
11.077366 
1.230818 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.271958 
0.271958 
0.29 
0.6049
Error 
9 
8.516752 
0.946306 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.002667 
0.002667 
0.00 
0.9639
trt 
1 
3.735115 
3.735115 
3.03 
0.1155
subject(sequence) 
9 
8.516752 
0.946306 
0.77 
0.6491
Error: MS(Error) 
9 
11.077366 
1.230818 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 88-111 
Least Squares Means 
trt 
LN_VZFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
0.91957377 
0.1155
B 
1.74708271 
trt 
LN_VZFOW LSMEAN 
90% Confidence Limits 
A 
0.919574 
0.303841 
1.535306 
B 
1.747083 
1.131350 
2.362815 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.827509 
-1.698286 
0.043268 
 
Dependent Variable: LN_VZFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.82750894 0.47502636 -1.74 
0.1155 -1.69828590 0.04326803 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
11 
203 204 304 402 404 407 409 502 505 507 508 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
22 
Number of Observations Used 
22 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LN_VZFO 
R-Square 
Coeff Var 
Root MSE 
LN_VZFO Mean
0.511939 
18.59196 
1.109423 
5.967215 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.14626067 
0.14626067 
0.12 
0.7382
period 
1 
0.01551644 
0.01551644 
0.01 
0.9131
trt 
1 
3.73511476 
3.73511476 
3.03 
0.1155
subject(sequence) 
9 
7.72241356 
0.85804595 
0.70 
0.7002
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.14626067 
0.14626067 
0.12 
0.7382
period 
1 
0.00266729 
0.00266729 
0.00 
0.9639
trt 
1 
3.73511476 
3.73511476 
3.03 
0.1155
subject(sequence) 
9 
7.72241356 
0.85804595 
0.70 
0.7002
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.14626067 
0.14626067 
0.12 
0.7382
period 
1 
0.00266729 
0.00266729 
0.00 
0.9639
trt 
1 
3.73511476 
3.73511476 
3.03 
0.1155
subject(sequence) 
9 
7.72241356 
0.85804595 
0.70 
0.7002
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.14626067 
0.14626067 
0.12 
0.7382
period 
1 
0.00266729 
0.00266729 
0.00 
0.9639
trt 
1 
3.73511476 
3.73511476 
3.03 
0.1155
subject(sequence) 
9 
7.72241356 
0.85804595 
0.70 
0.7002
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.146261 
0.146261 
0.17 
0.6894 
Error 
9 
7.722414 
0.858046 
 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F 
* period 
1 
0.015516 
0.015516 
0.01 
0.9131 
 trt 
1 
3.735115 
3.735115 
3.03 
0.1155 
 subject(sequence) 9 
7.722414 
0.858046 
0.70 
0.7002 
 Error: MS(Error) 
9 
11.077366 1.230818 
 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.146261 
0.146261 
0.17 
0.6894
Error 
9 
7.722414 
0.858046 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.002667 
0.002667 
0.00 
0.9639
trt 
1 
3.735115 
3.735115 
3.03 
0.1155
subject(sequence) 
9 
7.722414 
0.858046 
0.70 
0.7002
Error: MS(Error) 
9 
11.077366 
1.230818 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.146261 
0.146261 
0.17 
0.6894 
Error 
9 
7.722414 
0.858046 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.002667 
0.002667 
0.00 
0.9639
trt 
1 
3.735115 
3.735115 
3.03 
0.1155
subject(sequence) 
9 
7.722414 
0.858046 
0.70 
0.7002
Error: MS(Error) 
9 
11.077366 
1.230818 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.146261 
0.146261 
0.17 
0.6894
Error 
9 
7.722414 
0.858046 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.002667 
0.002667 
0.00 
0.9639
trt 
1 
3.735115 
3.735115 
3.03 
0.1155
subject(sequence) 
9 
7.722414 
0.858046 
0.70 
0.7002
Error: MS(Error) 
9 
11.077366 
1.230818 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Vd/F (L) Weight Group: 88-111 
Least Squares Means 
trt 
LN_VZFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
5.56090410 
0.1155
B 
6.38841304 
trt 
LN_VZFO LSMEAN 
90% Confidence Limits 
A 
5.560904 
4.945172 
6.176636 
B 
6.388413 
5.772681 
7.004145 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.827509 
-1.698286 
0.043268 
 
Dependent Variable: LN_VZFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-0.82750894 0.47502636 -1.74 
0.1155 -1.69828590 0.04326803 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
11 
203 204 304 402 404 407 409 502 505 507 508 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
22 
Number of Observations Used 
22 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: TMAX 
R-Square 
Coeff Var 
Root MSE 
TMAX Mean
0.669722 
79.33433 
0.875058 
1.103000 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.59202165 
0.59202165 
0.77 
0.4021
period 
1 
6.15015564 
6.15015564 
8.03 
0.0196
trt 
1 
1.22817855 
1.22817855 
1.60 
0.2371
subject(sequence) 
9 
6.00394735 
0.66710526 
0.87 
0.5797
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.59202165 
0.59202165 
0.77 
0.4021
period 
1 
5.61184527 
5.61184527 
7.33 
0.0241
trt 
1 
1.22817855 
1.22817855 
1.60 
0.2371
subject(sequence) 
9 
6.00394735 
0.66710526 
0.87 
0.5797
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.59202165 
0.59202165 
0.77 
0.4021
period 
1 
5.61184527 
5.61184527 
7.33 
0.0241
trt 
1 
1.22817855 
1.22817855 
1.60 
0.2371
subject(sequence) 
9 
6.00394735 
0.66710526 
0.87 
0.5797
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.59202165 
0.59202165 
0.77 
0.4021
period 
1 
5.61184527 
5.61184527 
7.33 
0.0241
trt 
1 
1.22817855 
1.22817855 
1.60 
0.2371
subject(sequence) 
9 
6.00394735 
0.66710526 
0.87 
0.5797
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.592022 
0.592022 
0.89 
0.3708 
Error 
9 
6.003947 
0.667105 
 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS Mean Square F Value 
Pr > F
*period 
1 
6.150156 6.150156 
8.03 
0.0196
trt 
1 
1.228179 1.228179 
1.60 
0.2371
subject(sequence) 
9 
6.003947 0.667105 
0.87 
0.5797
Error: MS(Error) 
9 
6.891533 0.765726 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.592022 
0.592022 
0.89 
0.3708
Error 
9 
6.003947 
0.667105 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
5.611845 
5.611845 
7.33 
0.0241
trt 
1 
1.228179 
1.228179 
1.60 
0.2371
subject(sequence) 
9 
6.003947 
0.667105 
0.87 
0.5797
Error: MS(Error) 
9 
6.891533 
0.765726 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.592022 
0.592022 
0.89 
0.3708 
Error 
9 
6.003947 
0.667105 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
5.611845 
5.611845 
7.33 
0.0241
trt 
1 
1.228179 
1.228179 
1.60 
0.2371
subject(sequence) 
9 
6.003947 
0.667105 
0.87 
0.5797
Error: MS(Error) 
9 
6.891533 
0.765726 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.592022 
0.592022 
0.89 
0.3708
Error 
9 
6.003947 
0.667105 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
5.611845 
5.611845 
7.33 
0.0241
trt 
1 
1.228179 
1.228179 
1.60 
0.2371
subject(sequence) 
9 
6.003947 
0.667105 
0.87 
0.5797
Error: MS(Error) 
9 
6.891533 
0.765726 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Tmax (h) Weight Group: 88-111 
Least Squares Means 
trt TMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 1.32528333 
0.2371
B 
0.85076667 
trt 
TMAX LSMEAN 
90% Confidence Limits 
A 
1.325283 
0.839624 
1.810943 
B 
0.850767 
0.365107 
1.336426 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.474517 
-0.212309 
1.161342 
 
Dependent Variable: TMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.47451667 0.37467730 1.27 
0.2371 -0.21230913 1.16134246 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
11 
203 204 304 402 404 407 409 502 505 507 508 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
22 
Number of Observations Used 
22 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LAMZ 
R-Square 
Coeff Var 
Root MSE 
LAMZ Mean
0.660697 
38.44030 
0.002853 
0.007423 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00000972 
0.00000972 
1.19 
0.3028
period 
1 
0.00000474 
0.00000474 
0.58 
0.4649
trt 
1 
0.00000587 
0.00000587 
0.72 
0.4177
subject(sequence) 
9 
0.00012234 
0.00001359 
1.67 
0.2285
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00000972 
0.00000972 
1.19 
0.3028
period 
1 
0.00000380 
0.00000380 
0.47 
0.5119
trt 
1 
0.00000587 
0.00000587 
0.72 
0.4177
subject(sequence) 
9 
0.00012234 
0.00001359 
1.67 
0.2285
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00000972 
0.00000972 
1.19 
0.3028
period 
1 
0.00000380 
0.00000380 
0.47 
0.5119
trt 
1 
0.00000587 
0.00000587 
0.72 
0.4177
subject(sequence) 
9 
0.00012234 
0.00001359 
1.67 
0.2285
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00000972 
0.00000972 
1.19 
0.3028
period 
1 
0.00000380 
0.00000380 
0.47 
0.5119
trt 
1 
0.00000587 
0.00000587 
0.72 
0.4177
subject(sequence) 
9 
0.00012234 
0.00001359 
1.67 
0.2285
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000009724 
0.000009724 
0.72 
0.4196
Error 
9 
0.000122 
0.000013594 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS 
Mean Square F Value 
Pr > F
*period 
1 
0.000004743 0.000004743 0.58 
0.4649
trt 
1 
0.000005875 0.000005875 0.72 
0.4177
subject(sequence) 9 
0.000122 
0.000013594 1.67 
0.2285
Error: MS(Error) 
9 
0.000073276 0.000008142 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000009724 
0.000009724 
0.72 
0.4196
Error 
9 
0.000122 
0.000013594 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000003796 
0.000003796 
0.47 
0.5119
trt 
1 
0.000005875 
0.000005875 
0.72 
0.4177
subject(sequence) 
9 
0.000122 
0.000013594 
1.67 
0.2285
Error: MS(Error) 
9 
0.000073276 
0.000008142 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000009724 
0.000009724 
0.72 
0.4196
Error 
9 
0.000122 
0.000013594 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000003796 
0.000003796 
0.47 
0.5119
trt 
1 
0.000005875 
0.000005875 
0.72 
0.4177
subject(sequence) 
9 
0.000122 
0.000013594 
1.67 
0.2285
Error: MS(Error) 
9 
0.000073276 
0.000008142 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000009724 
0.000009724 
0.72 
0.4196
Error 
9 
0.000122 
0.000013594 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
0.000003796 
0.000003796 
0.47 
0.5119
trt 
1 
0.000005875 
0.000005875 
0.72 
0.4177
subject(sequence) 
9 
0.000122 
0.000013594 
1.67 
0.2285
Error: MS(Error) 
9 
0.000073276 
0.000008142 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: Kel (/h) Weight Group: 88-111 
Least Squares Means 
trt LAMZ LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t| 
A 
0.00800245 
0.4177 
B 
0.00696467 
 
trt 
LAMZ LSMEAN 
90% Confidence Limits 
A 
0.008002 
0.006419 
0.009586 
B 
0.006965 
0.005381 
0.008548 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.001038 
-0.001202 
0.003277 
 
Dependent Variable: LAMZ 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
0.00103779 0.00122174 0.85 
0.4177 -0.00120180 0.00327738 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
11 
203 204 304 402 404 407 409 502 505 507 508 
sequence 
2 
AB BA 
period 
2 
1 2 
trt 
2 
A B 
Number of Observations Read 
22 
Number of Observations Used 
22 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LAMZHL 
R-Square 
Coeff Var 
Root MSE 
LAMZHL Mean
0.574882 
99.33196 
138.5731 
139.5051 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
5649.2726 
5649.2726 
0.29 
0.6007
period 
1 
25232.1129 
25232.1129 
1.31 
0.2812
trt 
1 
3972.7356 
3972.7356 
0.21 
0.6600
subject(sequence) 
9 
198852.1366 
22094.6818 
1.15 
0.4189
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
5649.2726 
5649.2726 
0.29 
0.6007
period 
1 
23243.5863 
23243.5863 
1.21 
0.2998
trt 
1 
3972.7356 
3972.7356 
0.21 
0.6600
subject(sequence) 
9 
198852.1366 
22094.6818 
1.15 
0.4189
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
5649.2726 
5649.2726 
0.29 
0.6007
period 
1 
23243.5863 
23243.5863 
1.21 
0.2998
trt 
1 
3972.7356 
3972.7356 
0.21 
0.6600
subject(sequence) 
9 
198852.1366 
22094.6818 
1.15 
0.4189
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
5649.2726 
5649.2726 
0.29 
0.6007
period 
1 
23243.5863 
23243.5863 
1.21 
0.2998
trt 
1 
3972.7356 
3972.7356 
0.21 
0.6600
subject(sequence) 
9 
198852.1366 
22094.6818 
1.15 
0.4189
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
5649.272565 
5649.272565 
0.26 
0.6253
Error 
9 
198852 
22095 
Error: MS(subject(sequence)) 
Source 
DF 
Type I SS 
Mean Square F Value 
Pr > F
*period 
1 
25232 
25232 
1.31 
0.2812
trt 
1 
3972.735582 3972.735582 0.21 
0.6600
subject(sequence) 9 
198852 
22095 
1.15 
0.4189
Error: MS(Error) 
9 
172823 
19203 
* This test assumes one or more other fixed effects are zero. 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
5649.272565 
5649.272565 
0.26 
0.6253
Error 
9 
198852 
22095 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
period 
1 
23244 
23244 
1.21 
0.2998
trt 
1 
3972.735582 
3972.735582 
0.21 
0.6600
subject(sequence) 
9 
198852 
22095 
1.15 
0.4189
Error: MS(Error) 
9 
172823 
19203 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
5649.272565 
5649.272565 
0.26 
0.6253
Error 
9 
198852 
22095 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
period 
1 
23244 
23244 
1.21 
0.2998
trt 
1 
3972.735582 
3972.735582 
0.21 
0.6600
subject(sequence) 
9 
198852 
22095 
1.15 
0.4189
Error: MS(Error) 
9 
172823 
19203 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
5649.272565 
5649.272565 
0.26 
0.6253
Error 
9 
198852 
22095 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
period 
1 
23244 
23244 
1.21 
0.2998
trt 
1 
3972.735582 
3972.735582 
0.21 
0.6600
subject(sequence) 
9 
198852 
22095 
1.15 
0.4189
Error: MS(Error) 
9 
172823 
19203 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: A vs B 
Dependent Variable: T1/2 el (h) Weight Group: 88-111 
Least Squares Means 
trt 
LAMZHL LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
A 
124.548382 
0.6600
B 
151.536062 
trt 
LAMZHL LSMEAN 
90% Confidence Limits 
A 
124.548382 
47.639963 
201.456802 
B 
151.536062 
74.627643 
228.444482 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -26.987680 
-135.752610 
81.777250 
 
Dependent Variable: LAMZHL 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
A - B 
-26.9876797 59.3334584 -0.45 
0.6600 -135.7526097 81.7772502 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
203 204 402 404 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LN_AUCLST 
R-Square 
Coeff Var 
Root MSE 
LN_AUCLST Mean
0.443329 
5.254932 
0.467887 
8.903767 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.36557536 
0.36557536 
1.67 
0.2868
trt 
1 
0.10103184 
0.10103184 
0.46 
0.5456
subject(sequence) 
2 
0.05642733 
0.02821366 
0.13 
0.8837
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.36557536 
0.36557536 
1.67 
0.2868
trt 
1 
0.10103184 
0.10103184 
0.46 
0.5456
subject(sequence) 
2 
0.05642733 
0.02821366 
0.13 
0.8837
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.36557536 
0.36557536 
1.67 
0.2868
trt 
1 
0.10103184 
0.10103184 
0.46 
0.5456
subject(sequence) 
2 
0.05642733 
0.02821366 
0.13 
0.8837
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.36557536 
0.36557536 
1.67 
0.2868
trt 
1 
0.10103184 
0.10103184 
0.46 
0.5456
subject(sequence) 
2 
0.05642733 
0.02821366 
0.13 
0.8837
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.365575 
0.365575 
12.96 
0.0693 
Error 
2 
0.056427 
0.028214 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.101032 
0.101032 
0.46 
0.5456
subject(sequence) 
2 
0.056427 
0.028214 
0.13 
0.8837
Error: MS(Error) 
3 
0.656755 
0.218918 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.365575 
0.365575 
12.96 
0.0693
Error 
2 
0.056427 
0.028214 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.101032 
0.101032 
0.46 
0.5456
subject(sequence) 
2 
0.056427 
0.028214 
0.13 
0.8837
Error: MS(Error) 
3 
0.656755 
0.218918 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.365575 
0.365575 
12.96 
0.0693 
Error 
2 
0.056427 
0.028214 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.101032 
0.101032 
0.46 
0.5456
subject(sequence) 
2 
0.056427 
0.028214 
0.13 
0.8837
Error: MS(Error) 
3 
0.656755 
0.218918 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCLST 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.365575 
0.365575 
12.96 
0.0693
Error 
2 
0.056427 
0.028214 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.101032 
0.101032 
0.46 
0.5456
subject(sequence) 
2 
0.056427 
0.028214 
0.13 
0.8837
Error: MS(Error) 
3 
0.656755 
0.218918 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-t (h*ng/mL) Weight Group: 88-111 
Least Squares Means 
trt LN_AUCLST LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
8.66796917 
0.5456
C 
8.89272663 
trt 
LN_AUCLST LSMEAN 
90% Confidence Limits 
B 
8.667969 
8.073303 
9.262635 
C 
8.892727 
8.298060 
9.487393 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.224757 
-1.003358 
0.553843 
 
Dependent Variable: LN_AUCLST 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.22475747 0.33084602 0.68 
0.5456 -0.55384345 1.00335839 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
203 204 402 404 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LN_AUCIFO 
R-Square 
Coeff Var 
Root MSE 
LN_AUCIFO Mean
0.498012 
5.187536 
0.468583 
9.032871 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.50748249 
0.50748249 
2.31 
0.2258
trt 
1 
0.06707153 
0.06707153 
0.31 
0.6190
subject(sequence) 
2 
0.07893896 
0.03946948 
0.18 
0.8439
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.50748249 
0.50748249 
2.31 
0.2258
trt 
1 
0.06707153 
0.06707153 
0.31 
0.6190
subject(sequence) 
2 
0.07893896 
0.03946948 
0.18 
0.8439
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.50748249 
0.50748249 
2.31 
0.2258
trt 
1 
0.06707153 
0.06707153 
0.31 
0.6190
subject(sequence) 
2 
0.07893896 
0.03946948 
0.18 
0.8439
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.50748249 
0.50748249 
2.31 
0.2258
trt 
1 
0.06707153 
0.06707153 
0.31 
0.6190
subject(sequence) 
2 
0.07893896 
0.03946948 
0.18 
0.8439
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.507482 
0.507482 
12.86 
0.0697 
Error 
2 
0.078939 
0.039469 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.067072 
0.067072 
0.31 
0.6190
subject(sequence) 
2 
0.078939 
0.039469 
0.18 
0.8439
Error: MS(Error) 
3 
0.658711 
0.219570 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.507482 
0.507482 
12.86 
0.0697
Error 
2 
0.078939 
0.039469 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.067072 
0.067072 
0.31 
0.6190
subject(sequence) 
2 
0.078939 
0.039469 
0.18 
0.8439
Error: MS(Error) 
3 
0.658711 
0.219570 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.507482 
0.507482 
12.86 
0.0697 
Error 
2 
0.078939 
0.039469 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.067072 
0.067072 
0.31 
0.6190
subject(sequence) 
2 
0.078939 
0.039469 
0.18 
0.8439
Error: MS(Error) 
3 
0.658711 
0.219570 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_AUCIFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.507482 
0.507482 
12.86 
0.0697
Error 
2 
0.078939 
0.039469 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.067072 
0.067072 
0.31 
0.6190
subject(sequence) 
2 
0.078939 
0.039469 
0.18 
0.8439
Error: MS(Error) 
3 
0.658711 
0.219570 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: AUC0-inf (h*ng/mL) Weight Group: 88-111 
Least Squares Means 
trt LN_AUCIFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
8.79589362 
0.6190
C 
8.97902135 
trt 
LN_AUCIFO LSMEAN 
90% Confidence Limits 
B 
8.795894 
8.200342 
9.391445 
C 
8.979021 
8.383470 
9.574573 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.183128 
-0.962888 
0.596632 
 
Dependent Variable: LN_AUCIFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.18312773 0.33133856 0.55 
0.6190 -0.59663231 0.96288777 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
203 204 402 404 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LN_CMAX 
R-Square 
Coeff Var 
Root MSE 
LN_CMAX Mean
0.422220 
8.993728 
0.448513 
4.986958 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.09754320 
0.09754320 
0.48 
0.5363
trt 
1 
0.09487043 
0.09487043 
0.47 
0.5416
subject(sequence) 
2 
0.24859694 
0.12429847 
0.62 
0.5960
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.09754320 
0.09754320 
0.48 
0.5363
trt 
1 
0.09487043 
0.09487043 
0.47 
0.5416
subject(sequence) 
2 
0.24859694 
0.12429847 
0.62 
0.5960
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.09754320 
0.09754320 
0.48 
0.5363
trt 
1 
0.09487043 
0.09487043 
0.47 
0.5416
subject(sequence) 
2 
0.24859694 
0.12429847 
0.62 
0.5960
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.09754320 
0.09754320 
0.48 
0.5363
trt 
1 
0.09487043 
0.09487043 
0.47 
0.5416
subject(sequence) 
2 
0.24859694 
0.12429847 
0.62 
0.5960
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.097543 
0.097543 
0.78 
0.4691 
Error 
2 
0.248597 
0.124298 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.094870 
0.094870 
0.47 
0.5416
subject(sequence) 
2 
0.248597 
0.124298 
0.62 
0.5960
Error: MS(Error) 
3 
0.603493 
0.201164 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.097543 
0.097543 
0.78 
0.4691
Error 
2 
0.248597 
0.124298 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.094870 
0.094870 
0.47 
0.5416
subject(sequence) 
2 
0.248597 
0.124298 
0.62 
0.5960
Error: MS(Error) 
3 
0.603493 
0.201164 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.097543 
0.097543 
0.78 
0.4691 
Error 
2 
0.248597 
0.124298 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.094870 
0.094870 
0.47 
0.5416
subject(sequence) 
2 
0.248597 
0.124298 
0.62 
0.5960
Error: MS(Error) 
3 
0.603493 
0.201164 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.097543 
0.097543 
0.78 
0.4691
Error 
2 
0.248597 
0.124298 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.094870 
0.094870 
0.47 
0.5416
subject(sequence) 
2 
0.248597 
0.124298 
0.62 
0.5960
Error: MS(Error) 
3 
0.603493 
0.201164 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cmax (ng/mL) Weight Group: 88-111 
Least Squares Means 
trt 
LN_CMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
4.81430790 
0.5416
C 
5.03210417 
trt 
LN_CMAX LSMEAN 
90% Confidence Limits 
B 
4.814308 
4.244265 
5.384351 
C 
5.032104 
4.462061 
5.602147 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 
-0.217796 
-0.964158 
0.528566 
 
Dependent Variable: LN_CMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.21779627 0.31714689 0.69 
0.5416 -0.52856563 0.96415818 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
203 204 402 404 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LN_CLFOW 
R-Square 
Coeff Var 
Root MSE 
LN_CLFOW Mean
0.651142 
-12.11538 
0.468583 
-3.867674 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.77546793 
0.77546793 
3.53 
0.1568
trt 
1 
0.20054600 
0.20054600 
0.91 
0.4097
subject(sequence) 
2 
0.25347050 
0.12673525 
0.58 
0.6136
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.77546793 
0.77546793 
3.53 
0.1568
trt 
1 
0.20054600 
0.20054600 
0.91 
0.4097
subject(sequence) 
2 
0.25347050 
0.12673525 
0.58 
0.6136
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.77546793 
0.77546793 
3.53 
0.1568
trt 
1 
0.20054600 
0.20054600 
0.91 
0.4097
subject(sequence) 
2 
0.25347050 
0.12673525 
0.58 
0.6136
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.77546793 
0.77546793 
3.53 
0.1568
trt 
1 
0.20054600 
0.20054600 
0.91 
0.4097
subject(sequence) 
2 
0.25347050 
0.12673525 
0.58 
0.6136
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.775468 
0.775468 
6.12 
0.1319 
Error 
2 
0.253471 
0.126735 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.200546 
0.200546 
0.91 
0.4097
subject(sequence) 
2 
0.253471 
0.126735 
0.58 
0.6136
Error: MS(Error) 
3 
0.658711 
0.219570 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.775468 
0.775468 
6.12 
0.1319
Error 
2 
0.253471 
0.126735 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.200546 
0.200546 
0.91 
0.4097
subject(sequence) 
2 
0.253471 
0.126735 
0.58 
0.6136
Error: MS(Error) 
3 
0.658711 
0.219570 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.775468 
0.775468 
6.12 
0.1319 
Error 
2 
0.253471 
0.126735 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.200546 
0.200546 
0.91 
0.4097
subject(sequence) 
2 
0.253471 
0.126735 
0.58 
0.6136
Error: MS(Error) 
3 
0.658711 
0.219570 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.775468 
0.775468 
6.12 
0.1319
Error 
2 
0.253471 
0.126735 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.200546 
0.200546 
0.91 
0.4097
subject(sequence) 
2 
0.253471 
0.126735 
0.58 
0.6136
Error: MS(Error) 
3 
0.658711 
0.219570 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F/kg ((L/h)/kg) Weight Group: 88-111 
Least Squares Means 
trt 
LN_CLFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
-3.52959127 
0.4097
C 
-3.84625040 
trt 
LN_CLFOW LSMEAN 
90% Confidence Limits 
B 
-3.529591 
-4.125143 
-2.934040 
C 
-3.846250 
-4.441802 
-3.250699 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.316659 
-0.463101 
1.096419 
 
Dependent Variable: LN_CLFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.31665913 0.33133856 -0.96 
0.4097 -1.09641917 0.46310091 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
203 204 402 404 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LN_CLFO 
R-Square 
Coeff Var 
Root MSE 
LN_CLFO Mean
0.544358 
58.29234 
0.468583 
0.803851 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.50748249 
0.50748249 
2.31 
0.2258
trt 
1 
0.20054600 
0.20054600 
0.91 
0.4097
subject(sequence) 
2 
0.07893896 
0.03946948 
0.18 
0.8439
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.50748249 
0.50748249 
2.31 
0.2258
trt 
1 
0.20054600 
0.20054600 
0.91 
0.4097
subject(sequence) 
2 
0.07893896 
0.03946948 
0.18 
0.8439
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.50748249 
0.50748249 
2.31 
0.2258
trt 
1 
0.20054600 
0.20054600 
0.91 
0.4097
subject(sequence) 
2 
0.07893896 
0.03946948 
0.18 
0.8439
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.50748249 
0.50748249 
2.31 
0.2258
trt 
1 
0.20054600 
0.20054600 
0.91 
0.4097
subject(sequence) 
2 
0.07893896 
0.03946948 
0.18 
0.8439
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.507482 
0.507482 
12.86 
0.0697 
Error 
2 
0.078939 
0.039469 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.200546 
0.200546 
0.91 
0.4097
subject(sequence) 
2 
0.078939 
0.039469 
0.18 
0.8439
Error: MS(Error) 
3 
0.658711 
0.219570 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.507482 
0.507482 
12.86 
0.0697
Error 
2 
0.078939 
0.039469 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.200546 
0.200546 
0.91 
0.4097
subject(sequence) 
2 
0.078939 
0.039469 
0.18 
0.8439
Error: MS(Error) 
3 
0.658711 
0.219570 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.507482 
0.507482 
12.86 
0.0697 
Error 
2 
0.078939 
0.039469 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.200546 
0.200546 
0.91 
0.4097
subject(sequence) 
2 
0.078939 
0.039469 
0.18 
0.8439
Error: MS(Error) 
3 
0.658711 
0.219570 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_CLFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.507482 
0.507482 
12.86 
0.0697
Error 
2 
0.078939 
0.039469 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.200546 
0.200546 
0.91 
0.4097
subject(sequence) 
2 
0.078939 
0.039469 
0.18 
0.8439
Error: MS(Error) 
3 
0.658711 
0.219570 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Cl/F (L/h) Weight Group: 88-111 
Least Squares Means 
trt 
LN_CLFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
1.10759394 
0.4097
C 
0.79093481 
trt 
LN_CLFO LSMEAN 
90% Confidence Limits 
B 
1.107594 
0.512042 
1.703146 
C 
0.790935 
0.195383 
1.386486 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.316659 
-0.463101 
1.096419 
 
Dependent Variable: LN_CLFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.31665913 0.33133856 -0.96 
0.4097 -1.09641917 0.46310091 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
203 204 402 404 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LN_VZFOW 
R-Square 
Coeff Var 
Root MSE 
LN_VZFOW Mean
0.449575 
63.64188 
0.548837 
0.862384 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.16265602 
0.16265602 
0.54 
0.5157
trt 
1 
0.45894271 
0.45894271 
1.52 
0.3049
subject(sequence) 
2 
0.11649724 
0.05824862 
0.19 
0.8337
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.16265602 
0.16265602 
0.54 
0.5157
trt 
1 
0.45894271 
0.45894271 
1.52 
0.3049
subject(sequence) 
2 
0.11649724 
0.05824862 
0.19 
0.8337
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.16265602 
0.16265602 
0.54 
0.5157
trt 
1 
0.45894271 
0.45894271 
1.52 
0.3049
subject(sequence) 
2 
0.11649724 
0.05824862 
0.19 
0.8337
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.16265602 
0.16265602 
0.54 
0.5157
trt 
1 
0.45894271 
0.45894271 
1.52 
0.3049
subject(sequence) 
2 
0.11649724 
0.05824862 
0.19 
0.8337
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.162656 
0.162656 
2.79 
0.2367 
Error 
2 
0.116497 
0.058249 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.458943 
0.458943 
1.52 
0.3049
subject(sequence) 
2 
0.116497 
0.058249 
0.19 
0.8337
Error: MS(Error) 
3 
0.903667 
0.301222 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.162656 
0.162656 
2.79 
0.2367
Error 
2 
0.116497 
0.058249 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.458943 
0.458943 
1.52 
0.3049
subject(sequence) 
2 
0.116497 
0.058249 
0.19 
0.8337
Error: MS(Error) 
3 
0.903667 
0.301222 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.162656 
0.162656 
2.79 
0.2367 
Error 
2 
0.116497 
0.058249 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.458943 
0.458943 
1.52 
0.3049
subject(sequence) 
2 
0.116497 
0.058249 
0.19 
0.8337
Error: MS(Error) 
3 
0.903667 
0.301222 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFOW 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.162656 
0.162656 
2.79 
0.2367
Error 
2 
0.116497 
0.058249 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.458943 
0.458943 
1.52 
0.3049
subject(sequence) 
2 
0.116497 
0.058249 
0.19 
0.8337
Error: MS(Error) 
3 
0.903667 
0.301222 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F/kg (L/kg) Weight Group: 88-111 
Least Squares Means 
trt 
LN_VZFOW LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
1.18422404 
0.3049
C 
0.70519235 
trt 
LN_VZFOW LSMEAN 
90% Confidence Limits 
B 
1.184224 
0.486673 
1.881775 
C 
0.705192 
0.007642 
1.402743 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.479032 
-0.434277 
1.392340 
 
Dependent Variable: LN_VZFOW 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.47903169 0.38808644 -1.23 
0.3049 -1.39234013 0.43427676 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
203 204 402 404 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LN_VZFO 
R-Square 
Coeff Var 
Root MSE 
LN_VZFO Mean
0.393998 
9.917712 
0.548837 
5.533908 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.05526159 
0.05526159 
0.18 
0.6973
trt 
1 
0.45894271 
0.45894271 
1.52 
0.3049
subject(sequence) 
2 
0.07332197 
0.03666098 
0.12 
0.8896
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.05526159 
0.05526159 
0.18 
0.6973
trt 
1 
0.45894271 
0.45894271 
1.52 
0.3049
subject(sequence) 
2 
0.07332197 
0.03666098 
0.12 
0.8896
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.05526159 
0.05526159 
0.18 
0.6973
trt 
1 
0.45894271 
0.45894271 
1.52 
0.3049
subject(sequence) 
2 
0.07332197 
0.03666098 
0.12 
0.8896
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.05526159 
0.05526159 
0.18 
0.6973
trt 
1 
0.45894271 
0.45894271 
1.52 
0.3049
subject(sequence) 
2 
0.07332197 
0.03666098 
0.12 
0.8896
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.055262 
0.055262 
1.51 
0.3444 
Error 
2 
0.073322 
0.036661 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.458943 
0.458943 
1.52 
0.3049
subject(sequence) 
2 
0.073322 
0.036661 
0.12 
0.8896
Error: MS(Error) 
3 
0.903667 
0.301222 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.055262 
0.055262 
1.51 
0.3444
Error 
2 
0.073322 
0.036661 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.458943 
0.458943 
1.52 
0.3049
subject(sequence) 
2 
0.073322 
0.036661 
0.12 
0.8896
Error: MS(Error) 
3 
0.903667 
0.301222 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
0.055262 
0.055262 
1.51 
0.3444 
Error 
2 
0.073322 
0.036661 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.458943 
0.458943 
1.52 
0.3049
subject(sequence) 
2 
0.073322 
0.036661 
0.12 
0.8896
Error: MS(Error) 
3 
0.903667 
0.301222 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LN_VZFO 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.055262 
0.055262 
1.51 
0.3444
Error 
2 
0.073322 
0.036661 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.458943 
0.458943 
1.52 
0.3049
subject(sequence) 
2 
0.073322 
0.036661 
0.12 
0.8896
Error: MS(Error) 
3 
0.903667 
0.301222 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Vd/F (L) Weight Group: 88-111 
Least Squares Means 
trt 
LN_VZFO LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
5.82140924 
0.3049
C 
5.34237756 
trt 
LN_VZFO LSMEAN 
90% Confidence Limits 
B 
5.821409 
5.123858 
6.518960 
C 
5.342378 
4.644827 
6.039928 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 0.479032 
-0.434277 
1.392340 
 
Dependent Variable: LN_VZFO 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-0.47903169 0.38808644 -1.23 
0.3049 -1.39234013 0.43427676 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
203 204 402 404 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: TMAX 
R-Square 
Coeff Var 
Root MSE 
TMAX Mean
0.749116 
73.44244 
1.038935 
1.414625 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.86093704 
1.86093704 
1.72 
0.2806
trt 
1 
6.51063613 
6.51063613 
6.03 
0.0912
subject(sequence) 
2 
1.29724633 
0.64862317 
0.60 
0.6033
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.86093704 
1.86093704 
1.72 
0.2806
trt 
1 
6.51063613 
6.51063613 
6.03 
0.0912
subject(sequence) 
2 
1.29724633 
0.64862317 
0.60 
0.6033
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.86093704 
1.86093704 
1.72 
0.2806
trt 
1 
6.51063613 
6.51063613 
6.03 
0.0912
subject(sequence) 
2 
1.29724633 
0.64862317 
0.60 
0.6033
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.86093704 
1.86093704 
1.72 
0.2806
trt 
1 
6.51063613 
6.51063613 
6.03 
0.0912
subject(sequence) 
2 
1.29724633 
0.64862317 
0.60 
0.6033
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
1.860937 
1.860937 
2.87 
0.2324 
Error 
2 
1.297246 
0.648623 
 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
6.510636 
6.510636 
6.03 
0.0912
subject(sequence) 
2 
1.297246 
0.648623 
0.60 
0.6033
Error: MS(Error) 
3 
3.238158 
1.079386 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.860937 
1.860937 
2.87 
0.2324
Error 
2 
1.297246 
0.648623 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
6.510636 
6.510636 
6.03 
0.0912
subject(sequence) 
2 
1.297246 
0.648623 
0.60 
0.6033
Error: MS(Error) 
3 
3.238158 
1.079386 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F 
sequence 
1 
1.860937 
1.860937 
2.87 
0.2324 
Error 
2 
1.297246 
0.648623 
 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
6.510636 
6.510636 
6.03 
0.0912
subject(sequence) 
2 
1.297246 
0.648623 
0.60 
0.6033
Error: MS(Error) 
3 
3.238158 
1.079386 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: TMAX 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1.860937 
1.860937 
2.87 
0.2324
Error 
2 
1.297246 
0.648623 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
6.510636 
6.510636 
6.03 
0.0912
subject(sequence) 
2 
1.297246 
0.648623 
0.60 
0.6033
Error: MS(Error) 
3 
3.238158 
1.079386 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Tmax (h) Weight Group: 88-111 
Least Squares Means 
trt TMAX LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
0.79095833 
0.0912
C 
2.59520833 
trt 
TMAX LSMEAN 
90% Confidence Limits 
B 
0.790958 
-0.529488 
2.111405 
C 
2.595208 
1.274762 
3.915655 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -1.804250 
-3.533120 
-0.075380 
 
Dependent Variable: TMAX 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 90% Confidence Limits 
C - B 
1.80425000 0.73463805 2.46 
0.0912 0.07537968 3.53312032 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
203 204 402 404 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LAMZ 
R-Square 
Coeff Var 
Root MSE 
LAMZ Mean
0.779248 
18.43795 
0.001672 
0.009066 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00002132 
0.00002132 
7.63 
0.0700
trt 
1 
0.00000528 
0.00000528 
1.89 
0.2629
subject(sequence) 
2 
0.00000299 
0.00000150 
0.54 
0.6325
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00002132 
0.00002132 
7.63 
0.0700
trt 
1 
0.00000528 
0.00000528 
1.89 
0.2629
subject(sequence) 
2 
0.00000299 
0.00000150 
0.54 
0.6325
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00002132 
0.00002132 
7.63 
0.0700
trt 
1 
0.00000528 
0.00000528 
1.89 
0.2629
subject(sequence) 
2 
0.00000299 
0.00000150 
0.54 
0.6325
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.00002132 
0.00002132 
7.63 
0.0700
trt 
1 
0.00000528 
0.00000528 
1.89 
0.2629
subject(sequence) 
2 
0.00000299 
0.00000150 
0.54 
0.6325
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000021316 
0.000021316 
14.24 
0.0636
Error 
2 
0.000002993 
0.000001497 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000005281 
0.000005281 
1.89 
0.2629
subject(sequence) 
2 
0.000002993 
0.000001497 
0.54 
0.6325
Error: MS(Error) 
3 
0.000008382 
0.000002794 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000021316 
0.000021316 
14.24 
0.0636
Error 
2 
0.000002993 
0.000001497 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000005281 
0.000005281 
1.89 
0.2629
subject(sequence) 
2 
0.000002993 
0.000001497 
0.54 
0.6325
Error: MS(Error) 
3 
0.000008382 
0.000002794 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000021316 
0.000021316 
14.24 
0.0636
Error 
2 
0.000002993 
0.000001497 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000005281 
0.000005281 
1.89 
0.2629
subject(sequence) 
2 
0.000002993 
0.000001497 
0.54 
0.6325
Error: MS(Error) 
3 
0.000008382 
0.000002794 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZ 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
0.000021316 
0.000021316 
14.24 
0.0636
Error 
2 
0.000002993 
0.000001497 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
0.000005281 
0.000005281 
1.89 
0.2629
subject(sequence) 
2 
0.000002993 
0.000001497 
0.54 
0.6325
Error: MS(Error) 
3 
0.000008382 
0.000002794 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: Kel (/h) Weight Group: 88-111 
Least Squares Means 
trt LAMZ LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t| 
B 
0.00919589 
0.2629 
C 
0.01082078 
 
trt 
LAMZ LSMEAN 
90% Confidence Limits 
B 
0.009196 
0.007071 
0.011320 
C 
0.010821 
0.008696 
0.012945 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 -0.001625 
-0.004407 
0.001157 
 
Dependent Variable: LAMZ 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
0.00162489 0.00118198 1.37 
0.2629 -0.00115673 0.00440651 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) Weight Group: 88-111 
The GLM Procedure 
Class Level Information 
Class 
Levels 
Values 
subject 
4 
203 204 402 404 
sequence 
2 
ABC BAC 
trt 
2 
B C 
Number of Observations Read 
8 
Number of Observations Used 
8 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) Weight Group: 88-111 
The GLM Procedure 
Dependent Variable: LAMZHL 
R-Square 
Coeff Var 
Root MSE 
LAMZHL Mean
0.717423 
18.29114 
14.72222 
80.48823 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1233.320675 
1233.320675 
5.69 
0.0971
trt 
1 
270.127861 
270.127861 
1.25 
0.3456
subject(sequence) 
2 
147.396875 
73.698437 
0.34 
0.7360
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1233.320675 
1233.320675 
5.69 
0.0971
trt 
1 
270.127861 
270.127861 
1.25 
0.3456
subject(sequence) 
2 
147.396875 
73.698437 
0.34 
0.7360
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1233.320675 
1233.320675 
5.69 
0.0971
trt 
1 
270.127861 
270.127861 
1.25 
0.3456
subject(sequence) 
2 
147.396875 
73.698437 
0.34 
0.7360
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1233.320675 
1233.320675 
5.69 
0.0971
trt 
1 
270.127861 
270.127861 
1.25 
0.3456
subject(sequence) 
2 
147.396875 
73.698437 
0.34 
0.7360
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) Weight Group: 88-111 
The GLM Procedure 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type I SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1233.320675 
1233.320675 
16.73 
0.0549
Error 
2 
147.396875 
73.698437 
Error: MS(subject(sequence)) 
Source 
DF Type I SS 
Mean Square 
F Value 
Pr > F
trt 
1 
270.127861 
270.127861 
1.25 
0.3456
subject(sequence) 
2 
147.396875 
73.698437 
0.34 
0.7360
Error: MS(Error) 
3 
650.230939 
216.743646 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type II SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1233.320675 
1233.320675 
16.73 
0.0549
Error 
2 
147.396875 
73.698437 
Error: MS(subject(sequence)) 
Source 
DF Type II SS 
Mean Square 
F Value 
Pr > F
trt 
1 
270.127861 
270.127861 
1.25 
0.3456
subject(sequence) 
2 
147.396875 
73.698437 
0.34 
0.7360
Error: MS(Error) 
3 
650.230939 
216.743646 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) Weight Group: 88-111 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type III SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1233.320675 
1233.320675 
16.73 
0.0549
Error 
2 
147.396875 
73.698437 
Error: MS(subject(sequence)) 
Source 
DF Type III SS 
Mean Square 
F Value 
Pr > F
trt 
1 
270.127861 
270.127861 
1.25 
0.3456
subject(sequence) 
2 
147.396875 
73.698437 
0.34 
0.7360
Error: MS(Error) 
3 
650.230939 
216.743646 
 
Tests of Hypotheses for Mixed Model Analysis of Variance 
Dependent Variable: LAMZHL 
Source 
DF 
Type IV SS 
Mean Square 
F Value 
Pr > F
sequence 
1 
1233.320675 
1233.320675 
16.73 
0.0549
Error 
2 
147.396875 
73.698437 
Error: MS(subject(sequence)) 
Source 
DF Type IV SS 
Mean Square 
F Value 
Pr > F
trt 
1 
270.127861 
270.127861 
1.25 
0.3456
subject(sequence) 
2 
147.396875 
73.698437 
0.34 
0.7360
Error: MS(Error) 
3 
650.230939 
216.743646 
 


 
 
Listing 16.1.9-8 ANOVA for Treatment Comparison of Diazepam for Weight Group 
88-111 kg - PK Population 
Comparison: C vs B 
Dependent Variable: T1/2 el (h) Weight Group: 88-111 
Least Squares Means 
trt 
LAMZHL LSMEAN 
H0:LSMean1=LSMean2 
Pr > |t|
B 
79.1305102 
0.3456
C 
67.5088094 
trt 
LAMZHL LSMEAN 
90% Confidence Limits 
B 
79.130510 
60.419140 
97.841880 
C 
67.508809 
48.797439 
86.220179 
Least Squares Means for Effect trt 
i 
j 
Difference Between 
Means 
90% Confidence Limits for LSMean(i)-LSMean(j) 
1 2 11.621701 
-12.877233 
36.120635 
 
Dependent Variable: LAMZHL 
Parameter Estimate 
Standard 
Error 
t Value 
Pr > |t| 
90% Confidence Limits 
C - B 
-11.6217008 10.4101788 -1.12 
0.3456 -36.1206350 12.8772334