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
Phase: PHASE1
Conditions: Bioequivalence
Sponsor: Cycle Pharmaceuticals Ltd.

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