Conditions: Bioequivalence
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 32
Healthy volunteers: yes

Brief summary:
The purpose on this study was to determine whether the test product, Haloperidol Tablets, 2 mg (Cycle Pharmaceuticals Ltd), and the reference product, Haloperidol Tablets, United States Pharmacopeia (USP), 2 mg (Mylan Pharmaceuticals Inc.) are bioequivalent under fed conditions.

Detailed description:
The specific aim was to conduct a single dose, open-label, randomized, two period crossover pivotal study to determine the bioequivalence of two formulations containing haloperidol 2 mg in healthy males and females under fed conditions.

A total of 32 healthy female and male volunteers (age 18 to 55 years old) were entered into the study. Volunteers were determined to be free of significant medical conditions as assessed by medical history, physical examination, and blood and urine tests. Volunteers were randomly allocated to a treatment sequence, before administration of investigational medicinal product (IMP) under fed conditions.

A wash-out period of at least 14 calendar days (minimum number of days based on half-life of the analyte) between consecutive administrations of the IMP was maintained.

Blood samples were collected at at pre-dose (0 hours), at 30 minutes, at 1 hour,

1 hour 30 minutes, 2 hours, 2 hours 30 minutes, 3 hours, 3 hours 30 minutes, 4 hours, 4 hours 30 minutes, 5 hours, 5 hours 30 minutes, 6 hours, 8 hours, 12 hours, 16 hours, 24 hours, 30 hours, 36 hours, 48 hours, 72 hours, 96 hours, 120 hours, 144 hours, 168 hours and 192 hours post-dose (total: 26 samples per treatment period).

Arms:
arm 1: Subjects received Haloperidol Tablets 2 mg Reference Product (Mylan Pharmaceuticals Inc.). Subjects also received as pre-medication Benztropine Mesylate Tablets, USP (1 mg every 10 to 12 hours), beginning 4 to 6 hours before dosing with IMP and continued for a total of 4 doses.

A high-fat, high-calorie breakfast was served 30 minute before administration of the IMP. arm 2: Subjects received Haloperidol Tablets 2 mg Test Product (Cycle Pharmaceuticals Ltd). Subjects also received as pre-medication Benztropine Mesylate Tablets, USP (1 mg every 10 to 12 hours), beginning 4 to 6 hours before dosing with IMP and continued for a total of 4 doses.

A high-fat, high-calorie breakfast was served 30 minute before administration of the IMP.

Interventions: intervention 1: Haloperidol Tablets, Mylan Pharmaceuticals Inc. intervention 2: Haloperidol Tablets, Cycle Pharmaceuticals Ltd
Intervention descriptions: intervention 1: single dose, 2 mg Haloperidol tablet intervention 2: single dose, 2 mg Haloperidol tablet

Protocol document:
Prot_000.pdf: 
Clinical Study Protocol – Amendment No. 1
A SINGLE CENTER, SINGLE DOSE, OPEN-LABEL, 
RANDOMIZED, TWO PERIOD CROSSOVER PIVOTAL STUDY 
TO DETERMINE THE BIOEQUIVALENCE OF TWO 
FORMULATIONS CONTAINING HALOPERIDOL 2 MG IN 
HEALTHY MALES AND FEMALES UNDER FED CONDITIONS
FARMOVS STUDY NUMBER:
SPONSOR STUDY NUMBER:
TEST PRODUCT:
REFERENCE PRODUCT:
DEVELOPMENT PHASE:
SPONSOR:
STUDY CENTER:
REGULATORY AUTHORITY:
Original Protocol:
Protocol Amendment No. 1:


PROTOCOL AMENDMENT NO 1 – SUMMARY OF CHANGES
Changes and Reasons
Sections Affected


SYNOPSIS
Title of the Study
Study Objectives
Primary Objective
Secondary Objective
Study Design
In-house Stay
Pharmacokinetic Sampling Times
Blood Volume


Study Population
Inclusion Criteria
In this study the concomitant use of hormonal contraceptives is NOT allowed.
Exclusion Criteria
In this study the concomitant use of hormonal contraceptives is NOT allowed.






Sample Size
Pharmacokinetic Parameters
Primary PK Parameters for Haloperidol: 
Secondary PK Parameters for Haloperidol: 
Safety Variables
Statistical Analysis
Pharmacokinetic population: 
Safety population:




STATEMENT AND SIGNATURE: PRINCIPAL INVESTIGATOR
A SINGLE CENTER, SINGLE DOSE, OPEN-LABEL, 
RANDOMIZED, TWO PERIOD CROSSOVER PIVOTAL STUDY 
TO DETERMINE THE BIOEQUIVALENCE OF TWO 
FORMULATIONS CONTAINING HALOPERIDOL 2 MG IN 
HEALTHY MALES AND FEMALES UNDER FED CONDITIONS




1.
TABLE OF CONTENTS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


1.1.
List of Tables
 
 
1.2.
List of Figures


2.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
Citrus








3.
ETHICS
3.1.
Mandatory Approvals and Protocol Amendments 
Independent Ethics Committee 


3.2.
Ethical Conduct of the Study
3.3.
Subject Information and Informed Consent
3.3.1. Confidentiality


3.3.2. Remuneration of Subjects 
3.3.3. Indemnity


4.
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE
Principal Investigator 
Study Staff and Other Services
Study Center
Routine Safety and Analytical Laboratory 


Sponsor
Sponsor Medical Expert
Sponsor Contact Person 
Monitor 


5.
INTRODUCTION
5.1.
Background Information 
5.2.
Clinical Pharmacokinetics
Absorption: 


Distribution:
Metabolism: 
in vitro


Elimination:
Age effect: 
5.3.
Adverse Events, Contraindications and Warnings 
5.4.
Study Rationale 


5.4.1. Justification for Study Design
in vivo
5.5.
Risks and Benefits




6.
STUDY OBJECTIVES
Primary Objective
Secondary Objective


7.
INVESTIGATIONAL PLAN
7.1.
Overall Study Design and Plan: Description
7.1.1. Study Design
7.2.
Discussion of Study Design
7.2.1. Treatment Periods and Schedule of Study Assessments


Figure 7-1 
Study Flow Chart


Table 7-1 
Schedule of Study Assessments
Assessment
Screening Admission Treatment 
Period 1
Interim 
Safety 
Visit1 
Admission Treatment 
Period 2
Post-study 
Visit2


Screening only:
7.2.2. Safety and Data Monitoring Committees 
7.2.3. Interim Analyses


7.2.4. Expected Duration of Study
7.2.5. Pre-study Evaluation (Screening) 
7.2.6. Treatment Periods


7.2.7. Post-study Evaluations 
7.2.8. Sampling, Interim Handling and Storage 








ad libitum
7.3.
Selection of Study Population 
7.3.1. Inclusion Criteria


In this study the concomitant use of hormonal contraceptives is NOT 
allowed. 


7.3.2. Exclusion Criteria
In this study the concomitant use of hormonal contraceptives is NOT allowed. 




7.3.3. Withdrawal Criteria


7.3.4. Replacement of Subjects
7.3.5. Premature Termination of the Study


8.
TREATMENTS
8.1.
Products to be Administered
8.2.
Pre-medication
8.3.
Rescue Medication




8.4.3. Investigational Product Accountability 
8.4.4. Retention Samples
8.4.5. Labeling and Packaging 
8.5.
Method of Assigning Subjects to Treatment Groups
8.6.
Selection of Doses in the Study


8.7.
Selection and Timing of Dose for Each Subject
8.8.
Blinding
8.9.
Prior and Concomitant Medication 
Hypericum perforatum
In this study the concomitant use of hormonal contraceptives is NOT allowed.   


8.10.
Treatment Compliance


9.
PHARMACOKINETIC PARAMETERS AND SAFETY VARIABLES
9.1.
Pharmacokinetic and Safety Measurements
9.2.
Appropriateness of Measurements
9.3.
Drug Concentration (Pharmacokinetic) Measurements
9.3.1. Pharmacokinetic Parameters
9.3.2. Pharmacokinetic Sample Collection, Sample Handing and Storage 
9.3.3. Pharmacokinetic Drug Assays 


9.4.
Safety Variables 


10.
DATA QUALITY ASSURANCE AND DATA MANAGEMENT
10.1.
Quality Control and Source Data Verification 
10.2.
Audit/Inspections
10.3.
Study Monitoring
10.4.
Data Collection 


10.5.
Data Management 




11.
STATISTICAL METHODS
11.1.
Determination of Sample Size
11.2.
Statistical Methodology 
11.2.1. Rules for Handling Decimals
11.2.2. Pharmacokinetic Population


11.2.3. Safety Population 
11.3.
Protocol Deviations and Changes to Planned Analyses 
11.4.
Pharmacokinetic Parameters
11.4.1. Primary Pharmacokinetic Parameters for Haloperidol 


11.4.2. Secondary Pharmacokinetic Parameters for Haloperidol 
11.5.
Safety Variables 
11.5.1. Missing data for Adverse Events
11.6.
Outliers
11.7.
Presentation of PK Data, Descriptive Statistics and PK Assessment


11.8.
Analysis of Bioequivalence
11.9.
Presentation of Baseline Characteristics and Safety Data




12.
ADVERSE EVENTS
12.1.
Definitions
12.1.1. Adverse Events (or Adverse Experiences)
12.1.2. Adverse Drug Reaction
12.1.3. Unexpected Adverse Drug Reaction


12.1.4. Serious Adverse Events
Life-threatening in this context refers to a reaction in which the subject was at risk of death at the time of the 
reaction; it does not refer to a reaction that hypothetically might have caused death if more severe.
12.2.
Classification of Adverse Events
Mild: 
Moderate:
Severe:


12.3.
Definition of Adverse Events Causality 
Reasonable Possibility: 
No Reasonable Possibility:
12.4.
Adverse Events Documentation


12.5.
Reporting Procedures of Adverse Events/Serious Adverse Events
any
immediately
Sponsor Contact Person 


Sponsor Contact Person 
All AEs and SAEs have to be followed up until an outcome is known.  In the event of an 
SAE, the outcome has to be reported in the CRF, as well as to the principal investigator, 
sponsor, monitor, the IEC and the SAHPRA.


13.
LEGAL AND ADMINISTRATIVE ASPECTS
13.1.
Documentation 
13.2.
Publication of Results
13.3.
Sponsor’s Obligation 
13.4.
Clinical Study Report


14.
REFERENCES




15.
APPENDICES
15.1.
Menu 
Food
Amount
(g)
Energy
(cal)
Carbohydrate
(g)
Protein
(g)
Fat
(g)


15.2.
Subject Discharge Declaration
(Full names and surname / Volle name en van)
Signature of Subject / 
Handtekening van Deelnemer
Date / Datum
Signature of Registered Nurse or Designee
Date


15.3.
Product Information – Reference Product













































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STATISTICAL ANALYSIS PLAN
PROTOCOL NUMBER: CT-006
TITLE: A single center, single dose, open-label,
randomized, two period crossover pivotal study
to determine the bioequivalence of two
formulations containing haloperidol 2 mg in healthy males 
and females under fed conditions
VERSION NUMBER: 1.0
VERSION DATE: 09Jan2020






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TABLE OF CONTENTS
1.
INTRODUCTION....................................................................................................................................5
2.
STUDY OBJECTIVES............................................................................................................................6
2.1
Primary Objective ..........................................................................................................................6
2.2
Secondary Objective .....................................................................................................................6
3.
ENDPOINTS ..........................................................................................................................................6
4.
SAMPLE SIZE........................................................................................................................................7
5.
RANDOMIZATION .................................................................................................................................7
6.
PLANNED ANALYSES ..........................................................................................................................7
6.1
ANALYSIS POPULATIONS ..........................................................................................................8
6.1.1
SAFETY POPULATION ............................................................................................................8
6.1.2
PK POPULATION......................................................................................................................8
6.2
DERIVED DATA ............................................................................................................................8
6.2.1
BASELINE .................................................................................................................................8
6.2.2
STUDY DAY ..............................................................................................................................9
6.2.3
MISSING/PARTIAL DATA.........................................................................................................9
6.2.4
INEXACT VALUES....................................................................................................................9
6.2.5
BLQ VALUES ............................................................................................................................9
6.2.6
OUTLIERS.................................................................................................................................9
6.3
GENERAL CONSIDERATIONS................................................................................................. 10
6.3.1
DECIMAL PLACES ................................................................................................................ 10
7.
STATISTICAL ANALYSIS................................................................................................................... 12
7.1
SUBJECT DISPOSITION........................................................................................................... 12
7.2
PROTOCOL DEVIATIONS......................................................................................................... 12
7.3
DEMOGRAPHIC DATA.............................................................................................................. 12
7.4
MEDICAL HISTORY................................................................................................................... 13
7.5
PRIOR AND CONCOMITANT MEDICATION ............................................................................ 13
7.6
DOSING INFORMATION ........................................................................................................... 13
7.7
PK ANALYSIS ............................................................................................................................ 13
7.7.1
PK Concentrations.................................................................................................................. 13
7.7.2
PK Parameters ....................................................................................................................... 14
7.7.3
Analysis of Bioequivalence..................................................................................................... 14
7.8
SAFETY ANALYSIS ................................................................................................................... 15
7.8.1
ADVERSE EVENTS (AEs) ..................................................................................................... 15
7.8.2
LABORATORY DATA ............................................................................................................ 16
7.8.3
VITAL SIGNS DATA............................................................................................................... 17
7.8.4
ELECTROCARDIOGRAM (ECG) DATA................................................................................ 17
7.8.5
PHYSICAL EXAMINATION DATA ......................................................................................... 17
8.
REFERENCES.................................................................................................................................... 17
9.
APPENDIX .......................................................................................................................................... 18
9.1
LIST OF TABLES, LISTINGS AND FIGURES ........................................................................... 18


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1.
INTRODUCTION
This document details the planned statistical analyses for the Cycle Pharmaceuticals CT-006 study titled 
a single center, single dose, open-label, randomized, two period crossover pivotal study to determine the 
bioequivalence of two formulations containing haloperidol 2 mg in healthy males and females under fed
conditions
The proposed analyses are based on the contents of the protocol, version Final 2.0, 25 Sep 2019.
This will be a single dose, open-label, laboratory-blind, randomized, two period crossover study with orally 
administered haloperidol 2 mg conducted under fed conditions in at least 24 healthy males and females at 
a single study center.
The study will comprise:
a screening period of maximum 21 days;
two treatment periods (each of which will include a profile period of 192 hours) separated by a 
wash-out period of at least 14 calendar days (minimum number of days based on half-life of the 
analyte) between consecutive administrations of the IP;
an interim visit 2 days before admission to Treatment Period 2, and
a post-study visit will be performed when the subjects attend the last PK sampling visit (192 hours 
post-dose) or within 72 hours after the subject withdrew/was withdrawn from the study.
Subjects will receive either the test or reference product, according to the randomization schedule, under 
fed conditions. Subjects will receive each product once.
Subjects will be pre-medicated with benztropine mesylate tablets, 1 mg every 10 to 12 hours beginning 4 
to 6 hours before dosing with haloperidol and continuing for a total of 4 doses to provide coverage during 
periods of substantial haloperidol levels. The start time for administration of the pre-medication will be 
recorded in the individual subject CRFs. The pre-medication will be administered with 240 mL of water. In 
the event of breakthrough acute dystonia, diphenhydramine hydrochloride 50 mg (up to 100 mg, but not 
exceeding a daily dose of 400 mg) could be administered intramuscular or intravenous.


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2.
STUDY OBJECTIVES
2.1
Primary Objective
To determine whether the test product, Haloperidol Tablets, 2 mg (Cycle Pharmaceuticals Ltd.), and the 
reference product, Haloperidol Tablets, USP, 2 mg (Mylan Pharmaceuticals Inc.) are bioequivalent.
For this purpose, the PK profile of haloperidol will be compared after administration of a single dose of 2 mg 
of each of the two formulations, under fed conditions.
2.2
Secondary Objective
To evaluate the safety and tolerability of Haloperidol Tablets, 2 mg in healthy males and females.
3.
ENDPOINTS
The primary pharmacokinetic (PK) parameters are:
Parameter
Unit
Description
Cmax
ng/mL
Maximum observed plasma concentration
AUC(0-t)
h*ng/mL
Area under the plasma concentration versus time curve, from time zero to 
t, where t is the time of the last quantifiable concentration
AUC(0-
)
h*ng/mL
Area under the plasma concentration versus time curve, with 
extrapolation to infinity
The secondary PK parameters are:
Parameter
Unit
Description
Tmax
h
Time to maximum observed plasma concentration
z
1/h
Terminal elimination rate constant
T(1/2)
h
Apparent terminal elimination half-life


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4.
SAMPLE SIZE
Based on a bioequivalence range of 80.00% to 125.00% for Cmax, AUC(0-t) and AUC(0-
), a within-subject 
CV% of 22.5%, and a "test/reference" mean ratio between 0.95 and 1.05, 24 subjects are needed to achieve 
a power of 80% at an alpha level of 0.05 to show bioequivalence.
Up to 32 eligible subjects will be enrolled in the study to complete the study with at least 24 evaluable 
subjects.
5.
RANDOMIZATION
A randomization schedule will be provided by Biostatistics. The randomization schedule will be generated 
utilizing the PROC PLAN procedure of SAS® software or appropriate equivalent.
Subjects will be randomized to one of two treatment sequences (AB or BA) and will be assigned 
randomization numbers 01 - 32, sequentially.
Subjects who withdraw or are withdrawn from the study will not be replaced, unless fewer complete the 
study than the estimated number of evaluable subjects.
This is an open-label, laboratory-blind study.
6. PLANNED ANALYSES
This statistical analysis plan (SAP) describes all pre-planned analyses as specified in the protocol, adding 
clarification and details where appropriate.
The data listings, descriptive statistics, statistical analysis and graphs of this study will be generated using 
SAS/STAT® and SAS/GRAPH® software version 9.4 (or higher).
Calculation of the PK parameters will be performed with Certara Phoenix® WinNonlin® version 8.1 (or 
higher).


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If circumstances should arise during the study rendering the analysis inappropriate, or if in the meantime 
improved methods of analysis should come to light, different analyses may be made.  Any deviations from 
the statistical methodology, reasons for such deviations and all alternative or additional statistical analyses 
that may be performed, will be described in the clinical study report (CSR).
6.1
ANALYSIS POPULATIONS
6.1.1
SAFETY POPULATION
All subjects who received at least one dose of IP will be included in the safety analysis for the study.
6.1.2
PK POPULATION
All subjects who complete the PK sampling in all periods and for whom primary PK parameters can be 
calculated for all treatment periods, and who have no major protocol deviations thought to impact the 
analysis of the PK data will be included in the statistical PK analysis for the study.
Data from subjects who experienced vomiting during the course of the study may be deleted from the 
statistical analysis if vomiting occurred at or before 2 times median Tmax of the reference product.
For subjects with pre-
adjustments in all PK measurements and calculations if the pre-dose concentration is 
5% of Cmax.  If the 
pre-dose value is > 5% of Cmax
bioequivalence evaluations.
6.2
DERIVED DATA
This section describes the derivations required for statistical analysis. 
6.2.1
BASELINE
Study Baseline is defined as the last non-missing measurement (scheduled, unscheduled or 
repeat) collected before the first administration of IP;
Period Baseline is defined as the last non-missing measurement (scheduled, unscheduled or 
repeat) collected before the first administration of IP in each period.




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6.3
GENERAL CONSIDERATIONS
Summaries will be presented by treatment sequence or treatment group, unless otherwise stated. Listings 
will be sorted in the following order: subject number, parameter, and visit; unless otherwise stated.
For demographic and safety data, continuous variables will be summarized using the number of non-
missing observations (n), mean, standard deviation (SD), minimum (min), median, and maximum (max).
PK data (concentrations and parameters), continuous variables will be summarized using n, arithmetic 
mean, geometric mean, SD, min, median, max and coefficient of variation percentage (CV%).
Categorical variables will be summarized by presenting the frequency and percent. Percentages will be 
based on the subject population unless otherwise specified. For each variable, all categories will be shown. 
Zero frequencies (but not the percent) within a category will be presented.
All post-baseline repeat/unscheduled assessments will be listed only. Only scheduled post-baseline safety 
measurements will be summarized, if appropriate.
6.3.1
DECIMAL PLACES
The following rules will be followed with regards to the number of decimal places and presentation of data 
in the tables and listings of clinical data:
All data will be listed according to the number of decimal places presented in the source data.
Mean and median will be presented to one more decimal place than the source data.
Min and max values will be presented to the same number of decimal places as the source data.
SD will be presented to two more decimal places than the source data.
A maximum of three decimal places will apply to all summary statistics.
The following rules will be followed with regards to the number of decimal places and presentation of 
data in the tables and listings of concentration data:
The individual concentrations will be reported to the same precision as the source data (for 
example, if the source data is presented to five significant digits, the individual values will be 
presented to five significant digits).


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The arithmetic mean, geometric mean, SD, and median will be tabulated to one more 
significant digit compared to the source data, but with a maximum of four significant digits. 
Min and max values will be tabulated to the same precision as the source data, but with a 
maximum of four significant digits.
CV% will be presented to one decimal place.
The following rules will be followed with regards to the number of decimal places and presentation of 
data in the tables and listings of PK parameters:
Individual PK parameters will be presented to four significant digits, with the exception of Tmax,
which will be presented to two decimal places.  In addition, parameters directly derived from 
source data (e.g., Cmax,) will be reported with the same precision as the source data (if this is 
not four significant digits).
The arithmetic mean, geometric mean, SD, and median values will be reported to four 
significant digits; all other descriptive statistics will be reported to three significant digits except 
for CV% which will be presented to one decimal place. 
For Tmax the minimum and maximum will be presented to two decimals places and the rest of 
the descriptive statistics to three decimal places.
P-values will be presented to four decimal places.
Estimates and confidence intervals in the form of percentages will be presented to two decimal 
places.


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7.
STATISTICAL ANALYSIS
7.1
SUBJECT DISPOSITION
Subject disposition will be summarized by treatment sequence and overall for all enrolled subjects as 
follows:
The number of subjects who were enrolled, who were randomized and who are in each analysis 
population;
The number of early withdrawals and the reasons for withdrawals.
All disposition data, including reasons for exclusion from analysis populations, will be listed for all enrolled 
subjects.
7.2
PROTOCOL DEVIATIONS
All protocol deviation data will be listed for all enrolled subjects.
7.3
DEMOGRAPHIC DATA
Demographic characteristics will be summarized by treatment sequence and overall for the Safety and PK 
populations, for each of the following variables:
Age (years)
Age group (>=18 to <=35; >=36 to <=55)
Race (Black, Caucasian, Mixed Race, Other)
Gender (Male, Female)
Height (cm)
Weight (kg)
BMI (kg / m^2)
BMI group ( 25, 25- 30, 30- 35, >35)
If the Safety and PK populations are the same, a single Demographics table will be produced for the 
Safety/PK populations.


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All demographic data will be listed for all subjects in the Safety population.
7.4
MEDICAL HISTORY
All medical history data will be listed for all subjects in the Safety population.
Medical history data will be coded using the Medical Dictionary of Regulated Activities (MedDRA®
Version 22.1) primary System Organ Class (SOC) and Preferred Term (PT).
7.5
PRIOR AND CONCOMITANT MEDICATION
All prior and concomitant medications will be listed separately for all subjects in the Safety population.
A prior medication is a medication which stopped before first administration of IP, while a concomitant 
medication is a medication which is ongoing at end of study or stopped after first administration of IP.
Medications will be coded using the World Health Organization (WHO) Drug Dictionary Version Sep2019.
In situations with missing medication start/end dates/times, available data will be used for prior/concomitant
assignment. If the assignment is inconclusive, worst-case will be assumed and the medication will be 
assigned as concomitant.
7.6
DOSING INFORMATION
All dosing information will be listed for all subjects in the Safety population.
7.7
PK ANALYSIS
7.7.1
PK Concentrations
All PK blood sampling times, including time deviations, will be listed for all subjects in the Safety population
(to ensure data for subjects excluded from the PK population are listed).
PK concentration data will be summarized descriptively (n, arithmetic mean, geometric mean, SD, min, 
median, max, CV%) by treatment group for the PK population.
The arithmetic and geometric mean plasma concentrations versus scheduled time profiles for each 
treatment group, as well as the combined individual plasma concentrations versus actual time profiles for 


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each subject, will be presented graphically on a linear (concentration) linear (time) and log (concentration) 
linear (time) scale. The time axis will be presented in equal intervals (e.g. 0h, 4h, 8h etc.).
All PK concentration data will be listed for all subjects in the Safety population (to ensure data for subjects 
excluded from the PK population are listed).
7.7.2
PK Parameters
The Day 1 pre-dose concentrations of haloperidol will be used for baseline. Where possible, the PK 
parameters will then be estimated on baseline subtracted plasma concentrations of haloperidol. 
Pharmacokinetic parameters will be calculated on the baseline subtracted concentrations (even if some 
values are negative, they are used for computing AUC as they are).
Source data shall be used in all derived PK parameter calculations without prior rounding.
The PK parameters will be calculated for each subject using non-compartmental analysis and using the 
actual sampling time (relative to IP administration).
PK parameter data will be summarized descriptively (n, arithmetic mean, geometric mean, SD, min, median, 
max, CV%) by treatment group for the PK population. For Tmax only the median, min and max, and for T1/2
the mean, median, min and max values will be presented.
All PK parameter data will be listed for all subjects in the Safety population (to ensure data for subjects 
excluded from the PK population are listed).
7.7.3
Analysis of Bioequivalence
The test product will be compared to the reference product by means of statistical analysis with respect to 
the primary PK parameters using an analysis of variance (ANOVA) with sequence, subject(sequence), 
product and period effects after logarithmic transformation of the data. Point estimates and 90% CIs for the 
"test/reference" geometric mean ratios of these parameters will be obtained by taking the antilog of the 
-
Bioequivalence of the test and reference products will be assessed on the basis of the 90% CIs for 
estimates of the geometric mean ratios between the primary PK parameters of the test and reference 
products in relation to the conventional bioequivalence range of 80.00% to 125.00%.




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CONFIDENTIAL
In situations with missing data, worst-case will be applied, that is, seriousness will be assigned as yes if 
seriousness is missing, severity will be assigned as severe if severity is missing, and causality will be 
assigned as related.
All AEs will be coded using MedDRA® Version 22.1.
The following summaries will be presented for AEs:
Incidence of all TEAEs; serious AEs (SAEs); treatment-related TEAEs; treatment-related SAEs;
Mild, Moderate and Severe TEAEs; TEAEs leading to study withdrawal; TEAEs leading to death;
Incidence of TEAEs by SOC and PT;
Incidence of Treatment-Related TEAEs by SOC and PT;
Incidence of Serious TEAEs by SOC and PT;
Incidence of TEAEs by SOC and PT, by Worst Causality;
Incidence of TEAEs by SOC and PT, by Maximum Intensity.
In counting the number of TEAEs reported, a subject reporting multiple events within the same SOC and 
PT will only be counted once within that SOC and PT, at the worst causality and the maximum intensity.
SOC will be presented in descending order of overall frequency and then alphabetically, followed by PT in 
descending order of overall frequency and then alphabetically within SOC.
All AEs will be listed for all subjects in the Safety population.
Separate listings of AEs leading to death, SAEs and AEs leading to treatment discontinuation will be 
provided.
7.8.2
LABORATORY DATA
Hematology, and clinical chemistry results will be summarized for the Safety population. Urinalysis, 
serology, drugs of abuse, tobacco use, and alcohol breath test data will be listed only.
Abnormal hematology and clinical chemistry results (for all visits including unscheduled visits) will be 
limits of the reference range) and "High" (values higher than the upper limit of the reference range). Clinical 
significance will be indicated as "NCS" (abnormal, not clinically significant) or "CS" (abnormal, clinically 
significant). Where possible and applicable, repeat measurements will be marked
.