Clinical trial NCT03437447
Conditions: Healthy
Keywords: Bioavailability Bioequivalence Praziquantel Cysticide Pharmacokinetics
Sponsor: Merck KGaA, Darmstadt, Germany
Start date: 2018-06-18; Completion date: 2018-07-06
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this trial is to assess the bioequivalence (BE) of new 600 milligram (mg) Cisticid tablet (Test) versus 600 mg Biltricide tablets (Reference) at a dose of 1200 mg in healthy male participants. Praziquantel (PZQ) is the active ingredient for Cisticid and Biltricide tablets.

Detailed description:

Arms: arm 1: Cisticid (Test) in Treatment Period 1 followed by Biltricide (Reference) in Treatment Period 2 and Treatment Period 3. A washout period of 7 days will be maintained between 3 treatment periods. arm 2: Biltricide (Reference) in Treatment Period 1 followed by Cisticid (Test) in Treatment Period 2 and then Biltricide (Reference) in Treatment Period 3. A washout period of 7 days will be maintained between 3 treatment periods. arm 3: Biltricide (Reference) in Treatment Period 1 and Treatment Period 2 followed by Cisticid (Test) in Treatment Period 3. A washout period of 7 days will be maintained between 3 treatment periods.
Interventions: intervention 1: Cisticid intervention 2: Biltricide
Intervention descriptions: intervention 1: Participants received single oral dose of 1200 mg (two 600 mg tablets) Cisticid (Test) on Day 1 (Treatment Period 1) or Day 8 (Treatment Period 2) or Day 15 (Treatment Period 3). intervention 2: Participants received 600 mg of Biltricide (Reference) tablet at a dose of 1200 mg on either Day 1 (Treatment Period 1) or Day 8 (Treatment Period 2).

Protocol documents:
Prot_000.pdf: 
Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
1/85
Clinical Trial Protocol
Clinical Trial Protocol Number
MS 200585-0002
BD1604-12CEC
International non-proprietary 
name
Praziquantel
Title
A phase I, open-label, randomized, three-period, 
crossover, partial replicated, reference-scaled, single 
center trial to assess the bioequivalence of a single 
oral dose of 1200 mg of the new Cisticid® (herein 
Cisticid)
600 
mg 
tablet 
formulation 
versus 
comparator Biltricide® (herein Biltricide) in healthy 
male volunteers 
Phase
I (Bioequivalence)
IND Number
Not applicable
EudraCT Number
Not applicable
Principal Investigator
 
 
 
 
 
 
Sponsor
Merck KGaA
Frankfurter Strasse 250
64293 Darmstadt, Germany 
Medical Responsible
Merck,S.A. de C.V. Calle 5, No. 7, Frac. Industrial 
Alce Blanco, Nuacalpan de Juárez., México, C.P. 
53370
Clinical Trial Protocol Version
27 October 2017/ Version 1.0 
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries.
It is intended for restricted use only and may not – in full or part – be passed on, reproduced, 
published or used without express permission of Merck KGaA, Darmstadt, Germany, or its 
subsidiary. Copyright © 2017 by Merck KGaA, Darmstadt, Germany, or its subsidiary. All rights 
reserved.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
2/85
Protocol Table of Contents
Protocol Table of Contents ..................................................................................................2
Table of In-Text Tables .......................................................................................................6
Table of In-Text Figures......................................................................................................6
List of Abbreviations ...........................................................................................................7
1
Synopsis................................................................................................8
2
Sponsor, Investigators and Trial Administrative Structure ................13
3
Background Information.....................................................................15
3.1
Pharmacology .....................................................................................16
3.1.1
Chemical Structure .............................................................................16
3.1.2
Absorption ..........................................................................................16
3.1.3
Distribution.........................................................................................17
3.1.4
Metabolism .........................................................................................17
3.1.5
Elimination .........................................................................................17
3.1.6
Mechanism of action...........................................................................18
3.1.7
Pharmacological Properties ................................................................18
3.1.8
Adverse Reactions ..............................................................................18
4
Trial Objectives ..................................................................................19
4.1
Primary Objectives .............................................................................19
4.2
Secondary Objectives .........................................................................19
4.3
Statistical Hypothesis..........................................................................19
5
Investigational Plan ............................................................................20
5.1
Overall Trial Design and Plan ............................................................20
5.2
Discussion of Trial Design .................................................................20
5.3
Selection of Trial Population..............................................................23
5.3.1
Inclusion Criteria ................................................................................23
5.3.2
Exclusion Criteria...............................................................................24
5.4
Criteria for Initiation of Trial Treatment ............................................26
5.5
Criteria for Subject Withdrawal..........................................................26
5.5.1
Withdrawal from Trial Treatment ......................................................26
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
3/85
5.5.2
Withdrawal from the Trial..................................................................26
5.6
Premature Termination of the Trial ....................................................27
5.7
Definition of End of Trial...................................................................28
6
Investigational Medicinal Product and Other Drugs Used in the 
Trial.....................................................................................................28
6.1
Description of the Investigational Medicinal Product........................28
6.2
Dosage and Administration ................................................................30
6.3
Assignment to Treatment Groups.......................................................31
6.4
Non-investigational Medicinal Products to be used...........................31
6.5
Concomitant Medications and Therapies ...........................................31
6.5.1
Permitted Medicines...........................................................................31
6.5.2
Prohibited Medicines..........................................................................32
6.5.3
Other Interventions.............................................................................32
6.5.4
Special Precautions.............................................................................32
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions.............................................................................................33
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product...............................................................................34
6.8
Investigational Medicinal Product Accountability.............................35
6.9
Assessment of Investigational Medicinal Product Compliance .........36
6.10
Blinding ..............................................................................................36
6.11
Emergency Unblinding.......................................................................36
6.12
Treatment of Overdose .......................................................................36
6.13
Medical Care of Subjects after End of Trial.......................................37
7
Trial Procedures and Assessments......................................................37
7.1
Schedule of Assessments....................................................................38
7.1.1
Screening of Subjects .........................................................................38
7.1.2
Treatment periods 1, 2, and 3 .............................................................39
7.1.3
End of Trial (EoT) ..............................................................................40
7.2
Demographic and Other Baseline Characteristics ..............................41
7.3
Efficacy Assessments .........................................................................41
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
4/85
7.4
Assessment of Safety..........................................................................41
7.4.1
Adverse Events ...................................................................................42
7.4.2
Clinical Laboratory Assessments .......................................................49
7.4.3
Vital Signs, Physical Examinations, and Other Assessments.............49
7.5
Pharmacokinetics................................................................................50
7.5.1
Pharmacokinetics Blood Samples.......................................................50
7.5.2
Calculation of Pharmacokinetics Variables........................................54
8
Statistics..............................................................................................57
8.1
Sample Size ........................................................................................57
8.2
Randomization....................................................................................58
8.3
Endpoints............................................................................................58
8.3.1
Primary Endpoints ..............................................................................58
8.3.2
Secondary Endpoints ..........................................................................58
8.4
Description of Statistical Analyses.....................................................59
8.4.1
General Considerations.......................................................................59
8.4.2
Analysis of Primary Endpoints...........................................................59
8.4.3
Analysis of Secondary Endpoints.......................................................61
8.4.4
Analysis of Safety and Other Endpoints.............................................61
8.5
Interim and Additional Planned Analyses ..........................................62
8.6
Deviation and Exclusion to the Statistical Analysis...........................62
8.6.1
Research Subjects with Pre-dose Concentrations in the Biological 
Matrix .................................................................................................62
8.6.2
Exclusion of Data Due to Vomit or Diarrhea. ....................................62
9
Ethical and Regulatory Aspects..........................................................62
9.1
Responsibilities of the Investigator ....................................................62
9.2
Subject Information and Informed Consent .......................................63
9.3
Subject Identification and Privacy......................................................63
9.4
Emergency Medical Support and Subject Card..................................64
9.5
Medical Insurance and Subject Compensation...................................64
9.6
Ethics and Investigation Committee or Investigational Committee...65
9.7
Health Authorities...............................................................................65
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
5/85
10
Trial Management...............................................................................65
10.1
Case Report Form Handling...............................................................65
10.2
Source Data and Subject Files............................................................66
10.3
Investigator Site File and Archiving...................................................66
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities ..........................................................................................67
10.5
Changes to the Clinical Trial Protocol................................................67
10.6
Clinical Trial Report and Publication Policy......................................68
10.6.1
Clinical Trial Report...........................................................................68
10.6.2
Publication..........................................................................................68
11
References...........................................................................................69
12
Appendices .........................................................................................72
12.1
Appendix 1: Diet to be given to the Participating Subjects................73
12.2
Appendix 2: Schedule of Assessments...............................................74
12.3
Appendix 3: Normal laboratory parameters .......................................76
12.4
Appendix 4: Signature Pages and Responsible Persons for the 
Trial.....................................................................................................84
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
6/85
Table of In-Text Tables
Table 1
Undesirable Effects.............................................................................18
Table 2
Treatment Sequences of the Study. ....................................................20
Table 3
Geomean (CV %) and Range (Min-Max) of the PK Parameters 
Cmax and AUC of L-PZQ and rac-PZQ After Administration of 20, 
40 or 60 mg/kg of rac-PZQ ODT or 40 mg/kg Cisticid. ....................22
Table 4
Dosing Scheme...................................................................................30
Table 5
Record of Vital Signs..........................................................................50
Table 6
Blood Sampling Schedule...................................................................52
Table 7
Pharmacokinetic Parameters Derived from L PZQ and rac-PZQ 
Concentrations....................................................................................54
Table 8
Analysis Sets.......................................................................................58
Table 9
Diet Energy Distribution for the Study (Lunch, Dinner and 
Snacks)................................................................................................73
Table of In-Text Figures
Figure 1
Arithmetic mean (+ SD) profile of plasma L-PZQ after 
administration of 20 mg/kg L-PZQ (A) or 40 mg/kg Cisticid 500 
mg tablets............................................................................................56
Figure 2
Arithmetic mean profiles of plasma L- PZQ after administration 
of Cisticid 500 mg tablets at a dose of 40 mg/kg (B) or as crushed 
tablets (D2). ........................................................................................56
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
7/85
List of Abbreviations
A
Absorption
AE
Adverse Event
AUC
Area Under the Curve
BE
BMI
Bioequivalence
Body Mass Index
Cmax
Maximum Concentration
CRF
Case Report Form
CYP
Cytochrome
ECG
Electrocardiogram
EOT
End of Trial
FDA
Food and Drug Administration
GI
Gastrointestinal
GCP
Good Clinical Practice
IB
Investigator’s Brochure
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
ITT
Intention To Treat
IUPAC
International Union of Pure and Applied Chemistry
IUD
Intra-Uterine Device
IVRS
MOP
Interactive Voice Response System
Manual of Operations
ODT
PD
Orally Disintegrating Tablet
Pharmacodynamics
PGx
Pharmacogenetics/Pharmacogenomics
PK
Pharmacokinetics
PQP
Prequalification of Medicines Programme
PZQ
Praziquantel 
RNEC
National Registry of Clinical Trials
SAE
Serious Adverse Event
SPC
Summary Product Characteristics
WHO
World Health Organization
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
8/85
1
Synopsis
Clinical Trial Protocol Number
MS 200585-0002
Title
A phase I, open-label, randomized, three-period, 
crossover, partial replicated, reference-scaled, 
single center trial to assess the bioequivalence of 
a single oral dose of 1200 mg of the new Cisticid
600 mg tablet formulation versus comparator 
Biltricide in healthy male volunteers
Trial Phase
I (Bioequivalence) 
IND Number
Not applicable
FDA covered trial
No
EudraCT Number
Not applicable
Principal Investigator
Sponsor
Merck KGaA Darmstadt, Germany
Sponsor Legal Representative in the 
European Union
Merck KGaA 
Trial centers/countries
Mexico
Planned trial period
(first subject in-last subject out)
Dec 2017-Jan 2018
Trial Registry
RNEC (National Registry of Clinical Trials)
Objectives: 
Primary objectives: To assess the bioequivalence (BE) of the new 600 mg Cisticid tablet 
(Test) versus the comparator 600 mg tablet of Biltricide (Reference) at a dose of 1200 mg, 
administered as single dose in fed condition to healthy male volunteers.
Secondary objectives:
To assess the safety and tolerability of the new 600 mg Cisticid tablet formulation at a single 
dose of 1200 mg.
General pharmacokinetic evaluation of the new 600 mg Cisticid tablet formulation at a single 
dose of 1200 mg in comparison to the current reference of 600 mg Biltricide tablet 
Methodology: A randomized, open label, single dose, crossover design will be used with 60 
subjects in fed conditions, 3 periods, and with a 7-day washout period between 3 study 
stages.
Planned number of subjects: Sixty subjects will be randomized
Primary endpoints: The primary pharmacokinetic (PK) parameters are the area under the 
serum concentration-time curve from 0 to the time of the last quantifiable concentration 
(AUC0-t) and the maximum serum concentration (Cmax) for L-PZQ.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
9/85
Secondary endpoints: 
!
Recording, reporting and analysis adverse events (AEs), physical examination 
findings including vital signs (body temperature, systolic / diastolic blood pressure, 
and pulse rate), standard laboratory parameters hematology, biochemistry, 
urinalysis, and coagulation) and 12-lead electrocardiogram (ECG).
!
Additional pharmacokinetic parameters will be estimated: tmax, tlag, AUC0-∞, 
AUCextra, t ½ , λZ, CL/f and Vz/f of L-PZQ and tmax, tlag, AUC0-t, AUC0-∞, 
AUCextra, Cmax, t ½ , λZ, CL/f and Vz/f parameters for rac-PZQ.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
10/85
Diagnosis and key inclusion and exclusion criteria: 
Inclusion criteria
For inclusion in the study, all of the following inclusion criteria must be fulfilled:
1. Healthy males aged 18-55 years of age (inclusive at screening).
2.
A male participant must agree to use and to have their female partners willing to use 
additional non-hormonal contraception (e.g., condoms or occlusive cap [diaphragm or 
cervical/vault cap] with spermicide, non-hormonal intra-uterine device [IUD], previous 
sterilization of subject or his partner, being sexually inactive) from Day of randomization 
up to final EOT visit.
3. Gave written informed consent prior to any trial related procedure.
4. Have a body weight (BW) of > 55.0 kg to < 95 kg and a body mass index (BMI) between 
18.0 and 27.0 kg/m2. 
5. Able to communicate well with the Investigator, understanding the protocol requirements 
and restrictions, and willing to comply with the requirements of the entire trial.
6. Non-smoker (= 0 cigarettes, pipes, cigars or others) since at least three months.
7. Electrocardiogram recording (12-lead) without signs of clinically relevant pathology in 
particular QTc (Bazett) <450 ms
8. Vital signs in the following normal range (after 10 minutes in supine position):
!
systolic blood pressure: 90 to 140 mmHg
!
diastolic blood pressure: 50 to 90 mmHg
!
pulse rate: 45 to 90 bpm
!
oral body temperature between 35.0°C to 37.5°C
9. All values for biochemistry, liver function test and hematology tests of blood and urine 
within the normal range or showing no clinically relevant deviation as judged by the 
Investigator. Hematocrit and hemoglobin must be above the lower limit; upper limit may 
range up to 15 %. Remaining results, including white blood cells may range ± 15 %, if 
subject is asymptomatic
10. Negative screen for alcohol and drugs of abuse (opiate class, barbiturates, cocaine and 
metabolites, amphetamines, cannabinoids, benzodiazepines and tricyclic antidepressants) 
at screening and on each admission.
11. Negative screen for Hepatitis B surface (HBs) antigens, Hepatitis C Virus (HCV)
antibodies, Hepatitis A Virus (HAV) antibodies and Human Immunodeficiency Virus 
(HIV) 1 and 2 antibodies.
Exclusion criteria:
1. Any surgical or medical condition, including findings in the medical history or in the pre-
study assessments, or any other significant disease, that in the opinion of the Investigator, 
constitutes a risk or a contraindication for the participation of the subject in the study or 
that could interfere with the study objectives, conduct or evaluation.
2. History of surgery of the gastrointestinal tract, history of other GI tract diseases, or acute 
GI tract infections in the last 2 weeks, which could influence the gastrointestinal 
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
11/85
absorption and/or motility according to the Investigator’s opinion.
3. Any clinically relevant abnormality in the safety laboratory parameters as judged by the 
Investigator.
4. Have positive results from serology examination for Hepatitis B surface (HBs) antigen, 
Hepatitis C Virus (HCV) or Human Immunodeficiency Virus (HIV.
5. Allergy: ascertained or presumptive hypersensitivity to the active drug substance and/or 
formulations’ ingredients; history of anaphylaxis to drugs or allergic reactions in general, 
which the Investigator considers may affect the outcome of the trial.
6. History or presence of drug abuse (opiate class, barbiturates, cocaine and its main 
metabolite, amphetamines, cannabinoids, benzodiazepines and tricyclic antidepressants) 
or alcohol abuse at screening and on each admission. Alcohol abuse is defined by the 
assessment of the Investigator.
7. Loss or donation of more than 400 mL of blood within 90 days prior to first PZQ 
administration.
8. Administration of any investigational product or use of any investigational device in any 
clinical study within 30 days prior to first PZQ administration. Subjects who have used 
drugs that may affect the pharmacokinetics of PZQ from 14 days before dosing until the 
last PK sample, e.g., phenytoin, barbiturates, primidone, carbamazapine, oxcarbazepine, 
topiramate, felbamate, rifampicin, nelfinavir, ritonavir, griseofulvin, oral ketoconazole.
9. Consumption of substances known to be potent inhibitors or inducers of CYP P450s such 
as grapefruit, orange, cranberry or juices of these fruits, herbal remedies or dietary 
supplements containing St. John’s Wort, poppy seeds, cruciferic vegetables, in the two 
weeks before dosing until last PK sample.
10. Unlikely to comply with the protocol requirements, instructions and trial-related 
restrictions, e.g., uncooperative attitude, inability to return for follow-up visits, and 
improbability of completing the trial.
11. Non-acceptance or non-compliance with the study breakfast (e.g. vegetarians, vegans and 
subjects who follow special diets).
12. Excessive consumption of beverages containing xanthine (>5 cups of coffee a day or 
equivalent) or inability to stop consuming caffeine from 48 hours prior to drug 
administration until discharge from the clinic. 
13. Subject is the Investigator or any Sub-Investigator, research assistant, pharmacist, trial 
coordinator, other staff or relative thereof directly involved in the conduct of the trial.
14. Vulnerable subjects (e.g., persons kept in detention).
15. Legal incapacity or limited legal capacity.
Investigational Medicinal Product: dose/mode of administration/ dosing schedule
Test: 1200 mg of Cisticid new formulation (two 600 mg tablets), single dose administered 
orally in fed condition
Reference: 1200 mg of Biltricide (two 600 mg tablets), single dose administered orally in fed 
condition in two periods.
Planned trial and treatment duration per subject: Screening period of maximal 28 days, 
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
12/85
Three weeks dosing period including washout followed by one week of clinical follow-up.
Statistical methods: Statistical analysis will be performed using the computer program 
package SAS® System 
. If not 
stated otherwise, the level of statistical significance will be alpha=0.05. PK data evaluation 
will be performed based on standard non-compartmental methods using the validated 
software tool 
. Details on the statistical analysis 
and PK data analysis will be presented in the statistical analysis plan prior to database lock.
The statistical analysis will not be started until all data have been corrected and checked for 
plausibility and until all necessary coding and assessments have been completed.
The analysis of the primary endpoints AUC0-t and Cmax of L-PZQ will be performed using the 
PK population. Both parameters will be log-transformed before analysis. For the 
demonstration of bioequivalence different approaches will be applied for AUC0-t and Cmax. 
For AUC0-t the standard approach will be followed, i.e. the point estimate and the 90% CI of 
the Test/Reference geometric mean ratio must fall within [0.80, 1.25]. A linear mixed-effects 
model will be applied for the analysis of AUC0-t. The treatment difference TEST –
REFERENCE will be estimated, and the 90% CIs for the difference will be calculated. The 
difference and 90% CIs will be back-transformed to the original scale. If the 90% CI for the 
ratio (test/reference) lies entirely within the interval [80.00 – 125.00], then the BE criterion is 
fulfilled for AUC0-t.
For the analysis of Cmax, a reference-scaled bioequivalence approach will be applied.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
13/85
2
Sponsor, Investigators and Trial Administrative Structure 
This clinical trial will be sponsored by: 
Merck KGaA Frankfurter Strasse 250, 64293 Darmstadt, Germany
C o m m i t t e e s  
Phone: 
Filing at 
Ethics and Investigation 
Committee :
Phone: 
Filing at 
 
Investigation Committee:
C l i n i c a l  L a b o r a t o r y  
 
Tel. 
Clinical Laboratory 
and Corporate Health 
Representative:
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
14/85
The study will be conducted in one single site,
 
. Responsible for the clinical part of 
the trial including trial set-up, coordination, safety and analytical lab, monitoring, data capture, 
data management, statistical analysis, and clinical trial reporting. The bioanalytics will be 
performed at 
, under the responsibility of the Sponsor. The Sponsor will 
supervise all outsourced activities.
The Principal Investigator 
, represents all Investigators for 
decisions and discussions regarding this trial, consistent with the International Conference on 
Harmonisation (ICH) Topic E6 Good Clinical Practice (GCP; hereafter referred to as ICH GCP)
(17). The Principal Investigator will provide expert medical input and advice relating to trial 
design and execution and is responsible for the review and signoff of the clinical trial report. 
This protocol meets requirements of current clinical research regulations, including: ICH GCP, 
ethical principles for clinical research in human beings from the Declaration of Helsinki issued in 
the 64th General Assembly from the World Medical Association, Fortaleza, Brazil, October 
2013; General Health Act and General Health Act Regulations in the field of Health Research 
and the provisions stated in NOM 177-SSA1-2013 which states that “tests and procedures to 
prove that the drug is interchangeable as well as the requirements which authorized third parties, 
performing tests, should adhere”.
The study will be listed in the following registries for clinical trials: National Registry for 
Clinical Trials (RNEC) from the Mexican Ministry of Health through the Federal Commission 
for the Protection against Sanitary Risks.
Study Monitor: Monitoring will be performed by 
 
This study will be conducted according to the provisions stated in NOM 177-SSA1-2013 which 
states that "tests and procedures to prove that the drug is interchangeable as well as the 
requirements which authorized third parties, performing tests, should adhere", including the 
Good Clinical Practice (GCPs), ICH and all other applicable regulations. 
According to the General Health Act Regulations in the field of health research, second title, 
chapter I, article 17, section III which was published on the Official Gazette on April 2nd, 2014 
this study is considered an investigational study with risk higher than minimum.
Based on the non-clinical and clinical data available so far, the conduct of the trial specified in 
this clinical protocol is justified.
The investigational medicinal product (IMP) will be provided to the trial site under the
responsibility of the Sponsor’s Clinical Trial Supply department. 
Details of structures and associated procedures (e.g. PK sampling) will be defined in a separate 
Manual of Operations, which will be prepared under the supervision of the Clinical Trial Leader.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
15/85
3
Background Information
Schistosomiasis, also called Bilharzia, belongs to one of the most neglected tropical diseases 
caused by flatworms which remain one of the most prevalent parasitic diseases in developing 
countries. After malaria, schistosomiasis is the most important tropical disease in terms of human 
morbidity with significant economic and public health consequences. The disease is a severe 
chronic inflammatory disease and is endemic in about 78 developing countries, infecting more 
than 220 million people, with more than 90% of them living in Africa. They live in rural 
agricultural and peri-urban areas, and placing more than 700 million people at risk. Of the 
infected patients, 20 million suffer severe consequences from the disease. Some estimate that 
there are approximately 20,000 deaths related to schistosomiasis yearly. In many areas, 
schistosomiasis infects a large proportion of children under the age of 14 years.
The WHO recommended control strategy of schistosomiasis is based on preventive 
chemotherapy interventions targeting the majority of the at-risk population. The current gold 
standard treatment employs annual single oral dose of Praziquantel (PZQ) tablets, jointly 
developed by Bayer AG and Merck KGaA in the 1970’s, and commercialized in 1980 as 
Biltricide (Bayer) and Cisticid (Merck KGaA) for human use.  Note that Cesol® (herein Cesol)
is the tradename for the donation program, but for the purposes of this document the product is 
hereby referred to Cisticid, Praziquantel, or PZQ. Note also that Cisticid is the product that is 
approved for the Mexican market 
. Cesol and Cisticid are the identical 
600 mg final tablet presentation.
PZQ tablets consist of a racemic mixture of the two enantiomers L-PZQ and D-PZQ in a 1 to 1 
ratio. The L-PZQ enantiomer is associated with the anti-helminthic activity, whereas the D-PZQ 
has no cidal activity against worms and was reported to be responsible for the extreme bitterness 
of the product. The L-4-OH-PZQ metabolite also possesses anti-helminthic activity but only at 
much higher concentrations (the IC50 of L-trans-4-OH-PZQ was approximately 335 fold higher 
than of L-PZQ at 4 hours of incubation).
Merck KGaA is donating PZQ tablets to the World Health Organization (WHO). As a 
requirement for this Praziquantel donation program, WHO requested the development of a new 
formulation of Praziquantel tablets to address complaints of broken tablets of the current 
formulation. In addition, the request included the necessity that this formulation considers the 
development of a tablet coating to decrease the bitter tasting. This new formulation complies 
with the dissolution profile similarity, comparing with the reference selected by the WHO that in 
this case corresponds to Biltricide tablets manufactured by Bayer and sold in the US. However,
as PZQ is a Biopharmaceutics Classification System class II (= High Permeability, Low 
Solubility) compound, a biowaiver cannot be granted, and WHO Prequalification of Medicines 
Programme (PQP) requested a bioequivalence study against the original tablet. Since PZQ is 
known to be a highly variable product within blood concentration, the sponsor prefers to employ 
a replicated study design.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
16/85
WHO PQP, opposed to FDA, does not allow scaling the acceptance range for AUC but they do 
allow scaling for Cmax, which leads to a higher sample size than if scaling for both parameters 
would be incorporated. 
3.1
Pharmacology
3.1.1
Chemical Structure
Chemical Name: 
(11bR)-2-(Cyclohexylcarbonyl)-1,2,3,6,7,11b-hexahydro-4H-
pyrazino[2,1-a]isoquinolin-4-one
Recommended International 
Nonproprietary name (rINN):
R-(-)-Praziquantel
Chemical Abstracts Service 
Registry Number (CAS-RN):
57452-98-9 
Structural Formula
Molecular Formula:
C19H24N2O2
Relative Molecular Mass (L-PZQ 2.1):
312.4 g/mol
3.1.2
Absorption
Praziquantel is rapidly absorbed (80%) following oral administration with a Tmax of 
approximately 1 - 3 hours. When administered with food, the Cmax and AUC of Praziquantel are 
higher relative to the fasting state, although the variability is also increased. Praziquantel should 
always be taken with food. (36).
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
17/85
The bioavailability of Praziquantel increases with concomitant food administration. Castro et al, 
2000(6), showed that following the administration of a dose of 1800 mg ( ̴ 25 mg/kg for a 70 kg
body weight) to healthy adults, the AUC0–8h was 2.7-fold higher with a fatty diet (eggs, ham, 
orange juice, milk; _̴ 30% lipid;_̴ 50% carbohydrate), and_̴ 4-fold higher with a high-
carbohydrate content diet (tortillas, tomato, chicken, bread, orange juice;
̴ 10% lipid;_̴ 75%
carbohydrate) than without food.
Similarly, the administration to Sudanese adult males of Praziquantel at a dose of 40 mg/kg with 
food (cooked beans/10% cotton seed oil/bread) resulted in a 2.6-fold increase in the AUC0-∞.
3.1.3
Distribution
The volume of distribution is not known. Praziquantel crosses the blood–brain barrier, explaining 
its effectiveness in neurocysticercosis (18). Concentrations in breast milk are approximately one-
fourth of the plasma concentration. (32).
Praziquantel is highly protein-bound (̴ 80%, nearly exclusive to albumin), (8;11) which makes 
the levels of free drug subject to factors such as nutrition and inflammation (4).
3.1.4
Metabolism 
Praziquantel undergoes an extensive first-pass metabolism in the liver by the CYP system 
(CYP1A2, CYP3A4, CYP2B1, CYP3A5 and CYP2C19). (1;8). This makes its pharmacokinetics 
susceptible to variability due to: 

Possible Interindividual pharmacogenetics differences (no data available).

Interactions with drugs or substances taken concomitantly that induce or inhibit specific
isoenzymes of the CYP system [e.g. increased exposure with cimetidine or grapefruit 
juice (5) and decreased exposure with the anti-epileptic CYP inducers carbamazepine and 
phenytoin (3) or rifampicin (33)].

The condition of the liver function (exposure increases with the severity of hepatic 
impairment) (20)
The main metabolite in man is trans-4-hydroxypraziquantel. D-PZQ also produces additional 
monohydroxypraziquantel metabolites (22).
3.1.5
Elimination 
Elimination of Praziquantel is essentially renal (80% within 4 days, of which 90% occurs within 
24 h); as the product is extensively metabolized, 0.01% is found in the urine as the parent 
compound (1). The terminal elimination half-life of Praziquantel is approximately 0.8 - 3 hours 
when administered with food (36).
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
18/85
3.1.6
Mechanism of action
Although the exact mechanism of killing of the parasites is unknown, Praziquantel disrupts Ca2+
homeostasis in adult worms, which induces a spasmodic muscular contraction and 
immobilization of the worm’s body (7).
Worms treated with 1 mg/mL Praziquantel stop moving immediately, as demonstrated by 
microcalorimetric studies (21). Adult worms are slightly more susceptible to Praziquantel (LC50
0.03 mg/mL at 72 h) than schistosomula (0.68 mg/mL at 72 h) (16).
3.1.7
Pharmacological Properties 
Praziquantel is widely used for the treatment and control of all Schistosoma species infecting 
humans and causing the intestinal (mainly Schistosoma mansoni and Schistosoma japonicum) 
and urinary (Schistosoma haematobium) forms of schistosomiasis (34; 12). Adult male–female 
pairs reside in the mesenteric veins and lay eggs, which sustain both the transmission and the 
pathology. Schistosomiasis develops over many years and is characterized by immunogenic 
inflammatory, granulomatous and fibrotic reactions, which are provoked by trapped schistosome 
eggs in the tissues (12). Whereas treatment is directed against the adult worms, the effects of 
treatment are customarily assessed by counting the eggs in the excreta (stools or urine).
3.1.8
Adverse Reactions
For Praziquantel, the expected occurrence of adverse reactions depends on the quantity and 
duration of Praziquantel use, the type, extent and location of parasite infestation as well as on the 
duration of infection.
The adverse reactions listed in the below occur independently from the above factors. There are 
mostly transient complaints not generally requiring any special treatment. Adverse reactions may 
partly represent endogenous reactions to the killing off of the parasites by Praziquantel
Table 1
Undesirable Effects
System organ class
Common
≥1/100 to <1/10
Very rare
< 1/10.000
Not known
Cardiac disorders
arrhythmia, 
bradycardia, ventricular 
fibrillation, auricular-
ventricular locks
Ear and labyrinth 
disorders
vertigo
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
19/85
Gastrointestinal 
disorders
abdominal pain, 
nausea, vomiting, 
diarrhea, blood in stool, 
urgency to defecate
General disorders and 
administration site 
conditions
fever, malaise 
fatigue
Metabolism and 
nutrition disorders
loss of appetite
hyperglycemia*
Nervous system 
disorders
Headache, dizziness, 
drowsiness
seizures
Skin and subcutaneous 
tissue disorders
erythema, pruritus
* in patients treated with praziquantel for neurocysticercosis
Patients with neurocysticercosis after completing treatment with praziquantel may have fever, 
nausea, vomiting, meningitis and increased intracranial pressure; symptoms associated with the 
inflammatory response induced by the destruction of cysticercoid.
4
Trial Objectives
4.1
Primary Objectives
To assess the BE of the new 600 mg Cisticid tablet versus the comparator 600 mg tablet of 
Biltricide at a dose of 1200 mg, administered as single dose in fed condition to healthy male 
volunteers (AUC0-t and Cmax of L-PZQ).
4.2
Secondary Objectives
To evaluate the safety and tolerability of the new 600 mg Cisticid tablet at a single dose of 1200 
mg. 
General pharmacokinetic evaluation of the new 600 mg Cisticid tablet formulation at a single 
dose of 1200 mg in comparison to the current reference of 600 mg Biltricide tablet 
Pharmacokinetic parameters will be determined: tmax, tlag, AUC0-∞, AUCextra, t ½, λZ, CL/f and 
Vz/f of L-PZQ and tmax, tlag, AUC0-∞, AUCextra, t ½, λZ, CL/f and Vz/f parameters of rac-PZQ). 
4.3
Statistical Hypothesis 
H0: Drug R and drug T are not bioequivalent.
H1: Drug R and drug T are bioequivalent.
Test, T: New 600 mg Cisticid tablet
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
20/85
Reference, R: 600 mg Biltricide tablet
5
Investigational Plan
5.1
Overall Trial Design and Plan
The purpose of the current relative bioavailability trial is to assess the bioequivalence (BE) of the 
the new 600 mg Cisticid tablet (Test) versus Biltricide (Reference) in healthy male volunteers
under fed conditions. 
This is a phase I, crossover, open-label, single dose, randomized, three period trial where
subjects will be randomized to one of three sequences: T-R-R, R-T-R and R-R-T where T is test 
product and R is Reference product, with a washout period of at least 1 week in between. 
The study will investigate the BE of the new 600 mg Cisticid tablet versus the comparator 600 
mg tablet of Biltricide at a dose of 1200 mg (primary endpoints AUC0-t and Cmax of L-PZQ), 
administered in fed condition in 60 healthy male volunteers. Finally safety and tolerability will 
be also investigated.
In each treatment period subjects are institutionalized the evening before dosing until 24 hours 
after dosing with a washout period of 7 days. Total duration of the study for a subject is up to 7 
weeks, including a Screening period of maximal 28 days, and 3 weeks dosing period including 
washout, and safety follow-up (EoT visit) at 7 days after third dose (period). 
The subjects will be randomized to one of the 3 treatment sequences (see Table 2 below).
Table 2
Treatment Sequences of the Study. 
Sequence
Period 1
Period 2
Period 3
1
Test
Wash-out 7 
days
Reference
Wash-out 7 
days
Reference
Wash-out 7 
days and EOT 
visit
2
Reference
Test
Reference
3
Reference
Reference
Test
5.2
Discussion of Trial Design
For the design of this BE study the following documents were taken into account: the 
recommendation from WHO PQP group regarding the design of BE studies for PZQ (WHO PQP 
Guidance Document 13 October 2015[36]) as well as the EMA Bioequivalence Guideline and 
NOM-177-SSA1-2013(10).
A cross-over study is a standard design for a bioequivalence study; a replicate design is a 
necessary prerequisite for the reference scaled approach applicable for Cmax CVs greater than 
30%. Sixty healthy male subjects who meet all inclusion and none of the exclusion criteria will 
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
21/85
be randomized and dosed to have at least 48 evaluable subjects with all assessments performed. 
The use of only male subjects is acceptable since no gender effect on the PK has been described 
for PZQ. Moreover, although there are well known differences in the response of males and 
females to drug treatment, this should not necessarily increase the within subject variability and 
thus be the reason for excluding females from a BE study. On the other hand, women have 
fluctuating hormone levels during a normal cycle. As it is known that increased levels of 
estrogen and progesterone can alter hepatic enzyme activity this might lead to fluctuations in 
metabolism over the study period and thus increase the within subject variability in women. Use 
of contraceptives also can also lead to fluctuations in estrogen and progesterone activity over a 4 
week period, with concomitant changes in hepatic enzyme activity and the risk for increased 
variability and confounding the PK data. Moreover women often have more problems with the 
obligatory breakfast prescribed for this study. For this reason only male subjects have been 
included.
Due to the different form and color of the tablets blinding is difficult. However, the PK will be 
measured at an independent laboratory, where the analyst is not aware of the treatment given. In 
addition, the PK is an independent variable that cannot be influenced by the subjects. Therefore, 
it is felt that a non-blinded study is acceptable for the defined objective. 
Following the WHO guidance, the variability of AUC rather than the CV of Cmax is the driver for 
the sample size of this trial.
A cross-over study is the optimal design for a bioequivalence study since each subject serves as 
its own control. The application of the reference scaled BE approach to Cmax requires a repeated 
administration of the reference drug. A BE study with a 3 period cross-over design is proposed.
Justification for Dose
The WHO PQP advises the use of one oral tablet of PZQ 600 mg, which corresponds to a dose of 
just below 10 mg/kg for an adult of 70 kg, in case of a BE study for Praziquantel. This dose is 
well below the therapeutic dose of 40 mg/kg, recommended by WHO (23), and the use of 
therapeutic doses in BE studies is recommended by EMA. Since it is also known that PZQ PK 
are not linear for both the commercial (36) and the new (ODT) formulations (own observations), 
and the exposure at a dose of ~ 10 mg/kg is currently unknown, it is felt that a higher dose might 
be more appropriate.  
Therefore, it is recommended that in view of the fact that 1) the individual enantiomers will  be 
measured and  the L-PZQ will be used for BE evaluation and 2) that the recommendation by 
WHO PQP is a (minimum) 600 mg dose but should take into account the LOQ of the method, 
and 3) the LLOQ for L-PZQ is 5 ng/mL and 4) mean Cmax and the range of Cmax after 
administration of 1200 mg is expected to be around 156.6 (range 38.0– 566) ng/mL and 5) 20 
mg/kg is the lowest recommended therapeutic dose, to use a dose of 1200 mg.
Mean Cmax and AUC for L-PZQ and rac-PZQ after administration of 40 mg/kg of the current 
Cisticid tablet is shown in Table 3. Mean Cmax and AUC as recently observed in an exploratory 
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
22/85
phase I study with an ODT formulation of PZQ at doses of 20, 40 and 60 mg/kg is also shown in 
the table and clearly confirmed the non-dose proportionality, already mentioned in the literature
(WHO, 2015). When the dose is decreased by a factor 2 from 40 to 20 mg/kg, Cmax and AUC 
decreased non-dose proportional by a factor 3 to 4.
The non-dose-proportionality observed after doubling the dose is a factor ~4 for L-PZQ and a 
factor ~3 for rac-PZQ. Assuming similar non-dose-proportionality at lower doses of 10 mg/kg, 
the expected Cmax for L-PZQ analyte after a dose of 10 mg/kg is around 40 ng/mL for L-PZQ 
(range 9.5 to 144 ng/mL)  and ~ 300 ng/mL (range of ~180-700) for rac-PZQ. As the current 
LLOQ for the L-PZQ is 5 ng/mL, a mean Cmax of 40 ng/mL is only 8 times higher than the 
LLOQ and does not comply with the LLOQ being < 5% of Cmax. For the racemate PZQ the 
LLOQ of 10 ng/mL is for most subjects expected to be within the pre-specified range of less than 
5% of Cmax. Since the BE comparison is to be based on L-PZQ levels for the BE endpoint, a dose 
of 1200 mg (2 tablets) is recommended, if rac-PZQ had been used for the BE endpoint, a dose of 
600 mg might have been compliant.
Choice of analyte. 
Although the WHO recommendation states that the parent compound is considered to best reflect 
the biopharmaceutical quality of the product and should be used to assess bioequivalence, the 
EMA guideline states for compounds consisting of enantiomers the following:
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
23/85
Enantiomers
The use of achiral bioanalytical methods is generally acceptable. However, the individual 
enantiomers should be measured when all the following conditions are met:
(1) the enantiomers exhibit different pharmacokinetics
(2) the enantiomers exhibit pronounced difference in pharmacodynamics
(3) the exposure (AUC) ratio of enantiomers is modified by a difference in the rate of absorption.
The individual enantiomers should also be measured if the above conditions are fulfilled or are 
unknown. If one enantiomer is pharmacologically active and the other is inactive or has a low 
contribution to activity, it is sufficient to demonstrate bioequivalence for the active enantiomer.
It is known that the PK and PD of the individual enantiomers of PZQ is clearly different (30; 35). 
Whether the exposure ratio of the enantiomers is modified by a difference in the rate of 
absorption or a difference related to differential metabolism is currently unknown. However this 
would point to the measurement of both individual enantiomers. In addition the current 
consensus is that the L-PZQ is the active enantiomer against S. mansoni and japonicum (23). 
All in all, after having received feedback from WHO PQP pinpointing the fact that a nonchiral 
method is only acceptable if it is known that the exposure ratio is not modified by a difference in 
the rate of absorption, combined with the different ratios in enantiomers seen after administration 
of 20 and 40 mg/kg to humans, it was decided to use an enantioselective method for this 
registration study and the PK parameters of L-PZQ as the primary endpoint. As the CV% for L-
PZQ were observed as being much higher than for rac-PZQ this had consequences for the sample 
size determinations. 
5.3
Selection of Trial Population
Only those subjects who meet all inclusion criteria and none of the exclusion criteria will be 
randomized. Before performing any study specific assessment which is not part of the subject's 
routine health care, the Principal Investigator will make sure that the subject has provided his 
written consent form according to the procedure described in section 9.2 Subject's Information 
and Informed Consent Form.  
!
Recruitment by invitation by means of an open announcement. 
!
Inclusion of 60 subjects in study as per protocol's criteria.
!
Male subjects to decrease overall variability (see section 5.2)
5.3.1
Inclusion Criteria
For inclusion in the study, all of the following inclusion criteria must be fulfilled:
1. Healthy males aged 18-55 years of age (inclusive at screening)
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
24/85
2. A male participant must agree to use and to have their female partners willing to use 
additional non-hormonal contraception (e.g., condoms or occlusive cap [diaphragm or 
cervical/vault cap] with spermicide, non-hormonal intra-uterine device [IUD], previous 
sterilization of subject or his partner, being sexually inactive) from Day of randomization 
up to final EOT visit
3. Gave written informed consent prior to any trial related procedure.
4. Have a body weight (BW) of > 55.0 kg to < 95 kg and a body mass index (BMI) between 
18.0 and 27.0 kg/m2. 
5. Able to communicate well with the Investigator, understanding the protocol requirements 
and restrictions, and willing to comply with the requirements of the entire trial.
6. Non-smoker (= 0 cigarettes, pipes, cigars or others) since at least three months.
7. Electrocardiogram recording (12-lead) without signs of clinically relevant pathology in 
particular QTc (Bazett) <450 ms
8. Vital signs in the following normal range (after 10 minutes in supine position):
!
systolic blood pressure: 90 to 140 mmHg
!
diastolic blood pressure: 50 to 90 mmHg
!
pulse rate: 45 to 90 bpm
!
oral body temperature between 35.0°C to 37.5°C
9. All values for biochemistry, liver function test and hematology tests of blood and urine 
within the normal range or showing no clinically relevant deviation as judged by the 
Investigator. Hematocrit and hemoglobin must be above the lower limit; upper limit may 
range up to 15 %. Remaining results, including white blood cells may range ± 15 %, if 
subject is asymptomatic.
10. Negative screen for alcohol and drugs of abuse (opiate class, barbiturates, cocaine and 
metabolites, amphetamines, cannabinoids, benzodiazepines and tricyclic antidepressants) 
at screening and on each admission.
11. Negative screen for Hepatitis B surface (HBs) antigens, Hepatitis C Virus (HCV) 
antibodies, Hepatitis A Virus (HAV) antibodies and Human Immunodeficiency Virus 
(HIV) 1 and 2 antibodies
5.3.2
Exclusion Criteria
1. Any surgical or medical condition, including findings in the medical history or in the pre-
study assessments, or any other significant disease, that in the opinion of the Investigator, 
constitutes a risk or a contraindication for the participation of the subject in the study or that 
could interfere with the study objectives, conduct or evaluation.
2. History of surgery of the gastrointestinal tract, history of other GI tract diseases, or acute GI 
tract infections in the last 2 weeks, which could influence the gastrointestinal absorption 
and/or motility according to the Investigator’s opinion.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
25/85
3. Any clinically relevant abnormality in the safety laboratory parameters as judged by the 
Investigator.
4. Have positive results from serology examination for Hepatitis B surface antigen (HBsAg), 
Hepatitis C Virus (HCV), Hepatitis A Virus (HAV), or Human Immunodeficiency Virus 
(HIV.
5. Allergy: ascertained or presumptive hypersensitivity to the active drug substance and/or 
formulations’ ingredients; history of anaphylaxis to drugs or allergic reactions in general, 
which the Investigator considers may affect the outcome of the trial.
6. History or presence of drug abuse (opiate class, barbiturates, cocaine and its main metabolite, 
amphetamines, cannabinoids, benzodiazepines and tricyclic antidepressants) or alcohol abuse 
at screening and on each admission. Alcohol abuse is defined by the assessment of the 
Investigator.
7. Loss or donation of more than 400 mL of blood within 90 days prior to first PZQ 
administration.
8. Administration of any investigational product or use of any investigational device in any 
clinical study within 30 days prior to first PZQ administration. Subjects who have used drugs 
that may affect the pharmacokinetics of PZQ from 14 days before dosing until the last PK 
sample, e.g., phenytoin, barbiturates, primidone, carbamazapine, oxcarbazepine, topiramate, 
felbamate, rifampicin, nelfinavir, ritonavir, griseofulvin, oral ketoconazole.  
9. Consumption of substances known to be potent inhibitors or inducers of CYP P450s such as 
grapefruit, orange, cranberry or juices of these fruits, herbal remedies or dietary supplements 
containing St. John’s Wort, poppy seeds, cruciferic vegetables, in the two weeks before 
dosing until last PK sample.
10. Unlikely to comply with the protocol requirements, instructions and trial-related restrictions, 
e.g., uncooperative attitude, inability to return for follow-up visits, and improbability of 
completing the trial.
11. Non-acceptance or non-compliance with the study breakfast (e.g. vegetarians, vegans and 
subjects who follow special diets).
12. Excessive consumption of beverages containing xanthine (>5 cups of coffee a day or 
equivalent) or inability to stop consuming caffeine from 48 hours prior to drug administration 
until discharge from the clinic. 
13. Subject is the Investigator or any Sub-Investigator, research assistant, pharmacist, trial 
coordinator, other staff or relative thereof directly involved in the conduct of the trial.
14. Vulnerable subjects (e.g., persons kept in detention).
15. Legal incapacity or limited legal capacity.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
26/85
5.4
Criteria for Initiation of Trial Treatment
Eligible subjects will continue screening at the time of admission to the study center (Day -1). 
Results of screening procedures performed on Day -1 as detailed Section 7.1.1, must be available 
prior to randomization. All inclusion and exclusion criteria will undergo a final verification 
before randomization.
All subjects should have negative result for oral alcohol screening at the beginning of each visit 
(day -1 for treatment period) and drugs of abuse (opioids, barbiturates, cocaine and its 
metabolites, amphetamines, methamphetamines, morphine, cannabinoids, benzodiazepines and 
tricyclic antidepressants), throughout the screening period and start of each one of the visits (day 
-1 for each treatment period).
All relevant inclusion and exclusion criteria will be rechecked on admission to the clinic in 
Period 1, 2 and 3 and before IMP administration on each dosing day. 
5.5
Criteria for Subject Withdrawal
Participant subjects in the study are free to withdraw from the study at any time and they will 
only be asked to give the reason of their withdrawal. End of study examination must be 
performed if the subject has received at least one active drug as described in section 6.7. 
Withdrawal reason should be documented in the medical chart in the case report form, if known. 
Study drug assigned to the withdrawn subject cannot be assigned to another subject. Subjects 
who withdraw will not be replaced.
5.5.1
Withdrawal from Trial Treatment 
Not applicable since only single doses will be administered.
5.5.2
Withdrawal from the Trial
Subjects are free to discontinue the trial at any time without giving their reasons.
A subject must be withdrawn in the event of any of the following:
! Withdrawal of the subject’s consent.
! Non-compliance that jeopardizes subject safety or the validity of the trial data, including lost 
to follow-up.
!
Participation in any other trial during the duration of this trial.  
!
Use of a non-permitted concomitant drug as defined in section 6.5.2 Prohibited medicines, 
where the predefined consequence is withdrawal from treatment with investigational 
medicinal product (IMP).
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
27/85
!
Occurrence of AEs, if discontinuation from the trial due to drug effects is desired or 
considered necessary by the Investigator and/or the subject (if applicable), e.g. severe 
unacceptable gastrointestinal side effects or inter-current illness.
!
Signs of liver injury, as defined by:
-
Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) > 5 x upper 
limit of normal (ULN).
-
ALT or AST > 3 x ULN and total bilirubin > 2 x ULN or international normalized 
ratio (INR) > 1.5 x ULN.
-
ALT or AST > 3 x ULN with clinical symptoms of hepatitis such as fatigue, 
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or 
eosinophilia (> 5%).
!
Vomiting within the first 6 hours after study drug administration, as vomiting interferes 
with the PK assessments in this study.
!
Not consuming the whole breakfast before/during drug administration 
Subjects may withdraw consent to participation in the clinical trial at any time without penalty 
and for any reason without prejudice to future medical care. Withdrawal of consent will be 
considered withdrawal from the trial.
If a subject failed to attend scheduled trial assessments, the Investigator must determine the 
reasons and the circumstances as completely and accurately as possible. If a subject is 
withdrawn, or chooses to withdraw, from the clinical study for any reason, the Investigator must 
make every possible effort to perform the evaluations described for the EOT visit (see Appendix 
2). If there is a medical reason for withdrawal, the subject will remain under the supervision of 
the Investigator until satisfactory health has returned. In all cases, the reason(s) for withdrawal 
must be recorded in the case report form (CRF).
If the Investigator withdraws a subject for an IMP-related reason (e.g vomiting), the subject is 
considered a dropout. In this event, the Sponsor will be provided with a reasonable medical 
justification of such a decision.
5.6
Premature Termination of the Trial
The clinical trial may be terminated prematurely or suspended at the request of Health 
Authorities or if new safety or efficacy information leads to an unfavorable risk benefit judgment 
for any IMP. The Sponsor may discontinue the trial if it becomes unjustifiable for medical or 
ethical reasons, for poor enrollment, or because of discontinuation of clinical development of an
IMP or withdrawal of an IMP or comparator from the market for safety reasons.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
28/85
Health Authorities and Independent Ethics Committees (IECs)/Institutional Review Boards 
(IRBs) will be informed about the discontinuation of the trial in accordance with applicable 
regulations.
5.7
Definition of End of Trial
The end of trial date will be the Last Subject Last Visit (LSLV) date. The trial will end when all 
treated subjects in the trial have completed/discontinued from the trial as per protocol.
A clinical trial protocol may not be considered closed as long as:
!
Any subject is still receiving any IMP.
!
Visits specified by the protocol are still taking place.
!
Procedures or interventions according to the protocol are still being undertaken in any 
subject.
!
The post-treatment follow-up period, defined in the clinical trial protocol as being part of the 
trial, has not yet been completed for any subject.
6
Investigational Medicinal Product and Other Drugs Used in 
the Trial
The term “Investigational Medicinal Product” refers to an active substance or a placebo being 
tested or used as a reference treatment or therapy in a clinical trial, including products that have a 
marketing authorization but are formulated, packaged, or administered differently from the 
authorized form, used for an unauthorized indication, or used to gain further information about 
the authorized form.  
6.1
Description of the Investigational Medicinal Product
All IMPs are manufactured in compliance with Good Manufacturing Practices. Study Sponsor 
will provide drugs to be administered to the subjects in each of the study visits.
International non-proprietary name: Praziquantel.
Test drug: New Cisticid®.
o
Dosage form: Tablet
o
Qualitative-Quantitative Formula: Each tablet contains 600 mg of Praziquantel.
o
Manufacturer: Merck, Mexico S. A. de C. V.
o
Batch: M73271-LP
o
Expiry date: 31-May-2019.
Reference drug: Biltricide®
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
29/85
o
Dosage form: Tablet
o
Qualitative-Quantitative Formula: each tablet contains 600 mg of Praziquantel.
o
Manufacturer: Bayer HealthCare Pharmaceuticals Inc.
o
Marketing Authorization Holder: Bayer HealthCare Pharmaceuticals Inc.
o
Batch: BXA6VKC
o
Expiry date: 06-Oct-2018
Reference drug should be imported as per the following quantities and specifications:
Description: Biltricide® praziquantel tablet 600 mg. 
Batch number: BXA6VKC
Quantity required for each stage of the research: 60 tablets.
200 tablets for the study.
152 tablets for the finished product analysis and dissolution profile (if apply)
200 tablets as retention sample.
Manufacturer: 
Products importer:
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
30/85
6.2
Dosage and Administration
Single dose, oral administration of 1200 mg Praziquantel (two 600 mg tablets) with 250 ml 
water, in each period, after the breakfast. A mouth check will be performed after each 
administration. The subject will take investigational medical product between 08:00 till 08:09 h, 
in 4 groups of 5 subjects each, with a 3-minute gap among each group for dosing
Subjects will enter the clinic the day before dosing (in 3 groups of 20 participants) and must fast 
overnight before IMP administration. 
Dosing in the non-fasted state should be done at 30 minutes after the start of a standardized 
normal breakfast. The breakfast should be eaten within a period of 20 minutes and time should 
be recorded. Compliance with breakfast consummation will be recorded. All subjects will fast 
for 5 hours after dosing/completion of breakfast. At 5 hours after dosing, subjects will receive a 
light lunch.
The start of dosing between the three groups listed below will be separated by approximately 
three days, e.g. Group 2 dosing will start approximately three days after Group 1 has started.
During each period one of the three treatments will be dosed from 08:00 till 08:09 h, in 4 groups 
of 5 subjects each, with a 3-minute gap among each group for dosing. Group’s distribution and 
timing can be changed due to operational reasons, as long as there is no impact in the study 
results.
Group’s distribution, subjects and dose schedules are shown in the Table 4:
Table 4
Dosing Scheme
Subgroups
No. of subjects
Dosing schedule
Group 1
A
01, 02, 03, 04 and 05
08:00 h
B
06, 07, 08, 09 and 10
08:03 h
C
11, 12, 13, 14 and 15
08:06 h
D
16, 17, 18, 19 and 20
08:09 h
Group 2
E
21, 22, 23, 24, and 25
08:00 h
F
26, 27, 28, 29, and 30
08:03 h
G
31, 32, 33, 34, and 35
08:06 h
H
36, 37, 38, 39, and 40
08:09 h
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
31/85
Subgroups
No. of subjects
Dosing schedule
Group 3
I
41, 42, 43, 44 and 45
08:00 h
J
46, 47, 48, 49 and 50
08:03 h
K
51, 52, 53, 54 and 55
08:06 h
L
56, 57, 58, 59 and 60
08:09 h
Water is not allowed until lunch. At 3 hours after treatment administration 250 ml water will be 
offered. The time and amount of water consumed at that time will be recorded. Subjects will 
leave the clinic 24 hours after dosing.
Subjects will be instructed not to consume alcohol, caffeine or xanthine-containing products 
(chocolate, tea, coffee, cola, energy drinks, etc.) from 48 hours prior to dosing until 24 hours 
after each IMP administration.
6.3
Assignment to Treatment Groups
Once it is confirmed that all inclusion criteria and none exclusion criteria have been met, subjects 
will be randomized to one of three treatment sequences in a 1:1:1 ratio.
Randomization of each subject to a treatment sequence will occur prior to dosing on Day 1. The 
Principal Investigator or delegate will allocate from the treatment kit stock (numbered 101-160 
the next available treatment kit in a sequential, chronological order starting with the lowest 
number. Randomization will be based on a unique randomization list.
6.4
Non-investigational Medicinal Products to be used
Not applicable.
6.5
Concomitant Medications and Therapies
All concomitant drugs taken by the subjects during the study, starting as per informed consent 
signature should be appropriately recorded in the CRF, stating the name, dose and indication for 
each drug. Non-pharmacological interventions or any other intervention should be recorded in 
the CRF.
6.5.1
Permitted Medicines
The occasional use of paracetamol (maximum 1000 mg per day) or ibuprofen (1200 mg to 3200 
mg daily) is allowed only after approval of the Principal Investigator.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
32/85
Any medications that are considered necessary to protect subject welfare and will not interfere 
with the trial medication may be given at the Investigator’s discretion.
Rescue medications may be administered to address anticipated adverse reactions or anticipated 
emergency situations.
6.5.2
Prohibited Medicines
Administration of any investigational product or use of any investigational device within 30 days 
prior to first administration of the IMP and during the entire clinical trial is not permitted.
No medication from screening until the last PK sample is allowed without prior approval from 
the Investigator (except for occasional use of paracetamol or ibuprofen). Attention should be 
paid to any drugs that may affect CYP450 enzyme status, e.g. phenytoin, barbiturates, 
primidone, carbamazapine, oxcarbazepine, topiramate, felbamate, rifampicin, nelfinavir, 
ritonavir, griseofulvin and oral ketoconazole.
Subjects who two weeks prior to dosing have consumed substances known to be potent inhibitors 
or inducers of CYP P450s such as grapefruit, orange, cranberry or juices of these fruits, herbal 
remedies or dietary supplements containing St. John’s Wort, poppy seeds, cruciferous vegetables
are not allowed to participate in the study.
If the administration of a non-permitted concomitant drug becomes necessary during the trial, 
e.g. because of AEs, the subject should be discontinued from the trial but only after consultation 
with the Sponsor.
6.5.3
Other Interventions
Subjects who have been exposed to agents known as inducers or inhibitors of liver enzymatic 
systems, who have taken drugs potentially toxic within 30 days prior to the study start-up, who 
require any drug throughout the study, who have history of gastrointestinal tract surgery which 
might affect gastrointestinal absorption and/or motility are not allowed to participate in the study.
6.5.4
Special Precautions
Subjects who have excessive consumption of beverages containing xanthine (>5 cups of coffee a 
day or equivalent) or inability to stop consuming caffeine from 48 hours prior to drug 
administration until discharge from the clinic are not allowed to participate in the study.
Subjects who have history or presence of drug abuse (opiate class, barbiturates, cocaine and its
main metabolite, amphetamines, cannabinoids, benzodiazepines and tricyclic antidepressants) or 
alcohol abuse at screening and on each admission are not allowed to participate in the study.
Standardization of Physical Activity
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
33/85
While resident in the trial site, the subjects will be confined to bed during the first 1 hour after
the IMP administration. Thereafter, they may get out of bed, however restricting their activity to
a minimum. Subjects should avoid excessive physical exercise throughout the trial until 
collection of the last PK sample.
Smoking Restrictions
Only non-smoking subjects or subjects who have refrained from smoking for at least 3 months
prior to Screening.
In case of adverse events, medical staff will provide medical care required depending on the 
adverse event occurred. In case of severe eventuality, which requires hospital admission, the 
Principal Investigator or medical staff on due will request the transfer of the subject to the agreed 
hospital and will contact the external ambulance service, according to the standard operating 
procedure, code: IC-PNO-033, Management of Clinical Eventualities.
6.5.5
Management of Specific Adverse Events or Adverse Drug 
Reactions
In case of adverse events, medical staff will provide immediate medical care required depending 
on the adverse event occurred. The Principal Investigator will decide the subsequent 
management, according to the standard operating procedure, code: 
, Management of 
Clinical Eventualities.
6.6
Packaging and Labeling of the Investigational Medicinal 
Product
Cisticid® Merck, Mexico S. A. de C. V.
 
 
 
Test product will be given orally as a single dose of 1200 mg (two tablets) of Cisticid with 250 
mL of water during a breakfast. 
Biltricide Bayer HealthCare Pharmaceuticals Inc.
 
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
34/85
 
 
 
Reference product will be given orally as a single dose of 1200 mg (two tablets) of Praziquantel, 
given with 250 mL of water during a breakfast. 
All IMPs will be packaged and labeled in accordance with all applicable regulatory requirements 
and Good Manufacturing Practice Guidelines.
6.7
Preparation, Handling, and Storage of the Investigational 
Medicinal Product
IMPs will be received at the 
, 
S. C. by the Pharmacy Responsible or by the designated staff, as per the standard operating 
procedures, code: 
: Receipt, use, balance and final disposition of the study drug. 
Once drugs have been identified, they will be kept by the clinical unit until they are administered 
to the subjects.
Acceptance criteria for test and reference drugs:
!
Complete documentation:
•
Certificate of Analysis.
•
Dosage units.
•
Content assessment.
•
For test drug, letter of Good Manufacturing Practice compliance.
•
For reference drug, confirmation from Bayer that material was donated and 
belongs to a batch that has been released as commercial material. 
•
For reference drug, copy of the zero-charge invoice from the packaging site 
(Merck Spittal). 
!
Test drug with label compliant with the minimum requirements from NOM-072-SSA1-
2012, Labelling of Drugs and Herbal Remedies (25).
!
Enough quantity of test and reference drug for the trial and for retention medication.  
!
Expiry date not due at the moment of use in the clinical study.
!
Test and reference drug in good physical conditions.
Rejection criteria for test and reference drugs:
!
Evidence of tampering of primary packaging.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
35/85
!
Drug received out of the storage or transportation specifications. 
!
Evidence of damage to primary packaging (physical damage from any source e.g. impact, 
moisture, insects and rodents, etc.) 
 
 
 
6.8
Investigational Medicinal Product Accountability
The Principal Investigator, Pharmacy Responsible or designated staff at the 
 
, S. C. will be in charge for ensuring IMP 
accountability, including reconciliation of drugs and maintenance of records, according to the 
standard operating procedure, code: 
: Preparation and administration of drugs in 
clinical trials of interchangeability and 
: receipt, use, balance and final disposition 
of the study drug. 
! Upon receipt of IMP, the responsible person will check for accurate delivery and 
acknowledge receipt by signing or initialing and dating the appropriate documentation and 
returning it to the location specified. A copy will be archived for the Investigator Site File.
! IMP dispensing will be recorded on the appropriate drug accountability forms so that accurate 
records will be available for verification at each monitoring visit.
! Trial site IMP accountability records will include the following:
! Confirmation of IMP receipt, in good condition and in the defined temperature range.
! The inventory of IMP provided for the clinical trial and prepared at the site.
! The use of each dose by each subject.
! The disposition (including return, if applicable) of any unused IMP.
! Dates, quantities, batch numbers, vial numbers, expiry dates, formulation (for IMP 
prepared at the site), and the individual subject trial numbers.
The Pharmacy Responsible site should maintain records, which adequately document that
subjects were provided the doses specified in this protocol, and all IMPs provided were fully 
reconciled.
Unused IMP must not be discarded or used for any purpose other than the present trial. 
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
36/85
A Trial Monitor will periodically collect the IMP accountability forms according to the standard 
operating procedure, code: 
 Receipt, use, balance and final disposition of the study 
drug.  
The Sponsor will ship enough quantities of the test and reference product to conduct the study 
and keep enough as "retention samples" to the Clínica de 
 
  
6.9
Assessment of Investigational Medicinal Product Compliance
Throughout dosing period, dose, full intake and time will be checked and recorded in the 
appropriate forms and CRF, according to the standard operating procedure, code: 
: 
Preparation
and administration of drugs in clinical trials of interchangeability and 
biocomparability; 
, randomization in an interchangeability and biocomparability 
clinical study
A subject is compliant with the treatment only if he completes all study periods.
6.10
Blinding
Not applicable, this is an open-label trial for subjects but analysts will be blinded. 
6.11
Emergency Unblinding
Not applicable, this is an open-label trial.
6.12
Treatment of Overdose
Overdose is defined as any dose higher than the highest daily dose included in the clinical 
protocol or foreseen for a subject recruited in the study. Even though this does not meet criteria 
for serious adverse event, any overdose should be recorded in the study drug section of the CRF 
and medical chart.
It should be reported to the National Center of Pharmacovigilance (CNFV) from the Federal 
Commission for the Protection Against Sanitary Risks (
), according to the standard 
operating procedures, code: 
, Adverse event reporting in clinical and bioavailability 
studies and the Mexican Official Standard for Setting-up and Operations of Pharmacovigilance 
in Mexico, 
(29) and following procedure listed in section 7.4.1.9.
Information on overdose of PZQ in humans is not available. Treatment should be supportive and 
provide symptomatic care.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
37/85
6.13
Medical Care of Subjects after End of Trial
Subjects will sign a consent, which states that they will receive an economical compensation for 
their participation in the study. The Sponsor will pay treatment (or compensation, if applicable) 
resulting from injuries or diseases caused by their participation in the study until their resolution 
as per the clinical criteria. The Sponsor will not pay injuries caused by subject's negligence, 
irresponsible behavior or medical reasons no related to the study. 
External follow-up will be given to all subjects recruited in the study. As per the last dose of the 
drug, free appointment or telephone contact will be available as per the Principal Investigator's 
judgment, for a period equivalent to the established wash-out period.
7
Trial Procedures and Assessments
At the beginning of each period, on day -1 and one hour prior to initial dosing, a physical 
examination will be done (including general appearance, skin, head, neck (including thyroid), 
ears, nose, throat, cardiovascular and pulmonary system, abdomen, neurological, peripheral 
vascular, and musculoskeletal system, oral cavity examination) as well as vital signs 
measurement, ECG and follow-up of adverse events. Blood and urine samples will be taken (day 
-1 only, following a 10-h fasting period) for safety laboratory tests such as hematology; blood 
chemistry, and urinalysis as well as urine sample for drug screening and alcohol breath test will 
also be performed in order to check if the subject remains eligible for the study.
Subjects should inform the medical staff in charge of the study conduct about any symptom they 
might have. Likewise, medical staff will question the subjects in every study period about 
symptoms occurred since recruitment in the first period, prior and following dosing. In case they 
report any, they will be provided with care and notes will made in the appropriate documents.
During each period, the vital signs (3, 7, 11h post dose) and the PK samples (see Table 4) will be 
taken. 
During each period, safety laboratories test will be performed such as hematology, blood 
chemistry and urinalysis. Samples will be taken pre-dose (day -1 only, following a 10-h fasting
period) and at discharge (24 h post-dose). 
At the end of each period, at discharge (24 h post-dose) a clinical assessment consisting of an 
interview, physical examination (including general appearance, skin, head, neck (including 
thyroid), ears, nose, throat, cardiovascular and pulmonary system, abdomen, neurological, 
peripheral vascular, and musculoskeletal system, oral cavity examination), vital signs 
measurement, ECG and follow-up of adverse events, will be done. Blood and urine samples will 
be taken for safety laboratory tests such as hematology; blood chemistry, and urinalysis.  
At the last visit a clinical assessment consisting of an interview, physical examination (see 
above) will be performed. Weight, ECG, vital signs and adverse events follow-up will be carried 
out. Blood and urine samples will be taken for safety laboratory tests such as hematology; blood 
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Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
38/85
chemistry, and urinalysis, this visit will be performed around seven days after the last 
administration of the IMP, day 22. 
Due to operational issues, the Principal Investigator may modify start of the study (starting as per
the dosing of study drug) for one hour, as long as there is no impact on the study results.
7.1
Schedule of Assessments
Detailed schedule of study procedures/assessments is provided in Section 12.2 Appendix 2 
Schedule of Assessments.
Prior to performing any trial assessments, the Investigator will obtain written informed consent 
as described in Section 9.2
In case of several assessments planned at the same time point, the PK samples will be taken at
the predefined time point. The ECG recordings, followed by vital signs measurements, will be
performed before PK sampling. Any ECG and vital signs taken within 60 minutes predose will
be considered to have been taken at the scheduled time point. Safety laboratory samples 
collected within 15 minutes of the scheduled time point will be considered to have been taken at
the scheduled time point. Sampling for safety laboratory will be assessed after PK blood 
sampling. All actual times need to be recorded in the eCRF.
The allowed deviation from the prespecified assessment time will be:
Predose samples:
!
Within 1 hour before IMP administration
Postdose samples and assessments:
!
Up to and including 24 hours: ± 5% of scheduled time point in minutes
!
After 24 hours up to and including 96 hours: ± 1 hour 
!
After 96 hours:  + 4 hours
7.1.1
Screening of Subjects
Screening of the subjects will take place within 28 days prior to the first administration of the 
trial medication, according to the standard operating procedures, code: 
 Recruitment 
subjects, and comprises the following:
!
Informed consent for participation in the trial,
!
Inclusion/exclusion criteria checked.
!
Demographics including body height and body weight and BMI, nicotine consumption, 
smoking history, alcohol consumption, intake of caffeine or xanthine-containing 
beverages, intake of grapefruit, orange, cranberry or juices of these three fruits and other 
things as described in Section 6.5.2)
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
39/85
!
Medical history and history of medications
!
Vital signs (body temperature, as well as blood pressure (BP) and pulse rate after at least 
5 minutes rest in supine position),
!
Physical examination
!
Safety laboratory: biochemistry tests, hematological tests, urinalysis and Serology test,
!
An urine drug screen test,
!
12-lead standard ECG (after 5 minutes rest in supine position),
Concomitant medications, AEs and procedures will be continuously assessed from signature of 
informed consent to the end-of-trial examination.
If no clinically relevant finding is made at screening and the subject satisfies all of the protocol 
inclusion criteria and none of the exclusion criteria, the subject will be considered as eligible and 
will be enrolled into the clinical trial.
Subjects who fail to meet the protocol specified criteria for dosing or who withdraw their consent 
in the screening period are considered screening failures. The following data will be recorded for 
these subjects: demographics (including age, weight and height), AEs, concomitant medications 
and reason for screening failure.
7.1.2
Treatment periods 1, 2, and 3
Day -1/7/14:
!
Admission the day prior to the visit for assuring 10-h fasting period.
!
Blood and urine samples will be taken (day -1 only, following a 10-h fasting period) for 
safety laboratory tests such as hematology; blood chemistry, and urinalysis
!
Subject’s eligibility will be checked again 
!
Dinner at least 10 h before the dosing.
Day 1/ 8 / 15:
!
At 5:00 h, grooming and intake of 250 mL of water.
!
Between 05:20 and 06:30 h, electrocardiogram will be performed.
!
Post electrocardiogram the following activities will be done:
•
Catheter insertion (pre-dose sample).
•
Vital signs will be measured at 3, 7, and 11 h after dosing.
•
Adverse events and previous medication
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
40/85
!
Randomization for the first period of treatment only
!
At 07:30 h, breakfast. They will be given 20 minutes as maximum for having food, time 
should be recorded.
!
At 08:00 h, oral administration of IMP with 250 mL of water at room temperature p.o., 
according to the standard operating procedure, code: BE-PNO-012: Preparation and 
administration of drugs in interchangeability and biocomparability clinical studies.
!
From 08:15 to 20:00 h, PK sampling as per the schedule of assessments.
!
At 11.00 h, 250 mL of water
!
At 13:00 h, light lunch 
!
As from 16:00 h, lunch.
!
As from 21:00 h, dinner.
Day 2/ 9 / 16:
!
At 07:00 h, electrocardiogram will be performed.
!
At 08:00 h, safety laboratory tests (hematology, blood chemistry and urinalysis) and 
catheter removal.
!
At 08:30 h, vital signs will be measured
!
Physical examination.
!
Approximately at 10:00 h, discharge (temporarily on Day 2 and 9) from the clinical unit.
7.1.3
End of Trial (EoT) 
! Physical examination and weight measurement for each subject.
! Vital signs measurement.
! Electrocardiogram.
! Safety laboratory tests (hematology, blood chemistry and urinalysis)
Prior to performing any trial assessments that are not part of routine medical care for the subject, 
the Investigator will obtain written informed consent as described in Section 9.2.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
41/85
7.2
Demographic and Other Baseline Characteristics
At screening (within 28 days before first administration), the following demographic data will be 
collected: date of birth, sex (gender), race and ethnicity. Specify any additional critical variables 
to be assessed such as:
! Information about previous and concomitant medications, medical history data including 
medication history within the last 5 years consisting of all previous diseases as considered 
relevant by the Investigator and all previous hospital stays, previous medication consisting of all 
previous medications within the last 5 years as considered relevant by the Investigator, and all 
regularly taken medications within the last year,
! No efficacy in this study Weight, height and BMI
! Special diets
! Month prior to drug administration, nicotine consumption 
! Smoking history 
! Alcohol consumption 
! Consumption of caffeine or xanthine-containing beverages, intake of grapefruit, orange, 
cranberry or juices of these three fruits, intake of food containing xanthine and usual diet, 
physical examination, and serum virology
! Safety laboratory
! ECG 
! Vital signs 
7.3
Efficacy Assessments
Not applicable.
7.4
Assessment of Safety
The safety profile of the IMP will be assessed through the recording, reporting and analyzing of 
baseline medical conditions, adverse events (AEs), physical examination findings including vital 
signs (body temperature, blood pressure, and pulse rate), 12-lead electrocardiogram (ECG), and 
laboratory tests (hematology, biochemistry, urinalysis, and coagulation).
Comprehensive assessment of any apparent toxicity experienced by each subject will be 
performed from the time of giving informed consent and throughout the trial. The Investigator 
will report any AEs, whether observed by the Investigator or reported by the subject (see Section 
7.4.1.7). The reporting period for AEs is described in Section 7.4.1.8.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
42/85
7.4.1
Adverse Events
7.4.1.1
Adverse Event Definitions
Adverse Event
An adverse event (AE) is any untoward medical occurrence in a subject or clinical investigation 
of the subject administered a pharmaceutical product which does not necessarily have a causal 
relationship with the study drug. Therefore, an adverse event can be any unfavorable and 
unintended sign (including any abnormal laboratory finding), symptom or condition/disease
temporarily associated with the use of the investigational drug, whether or not considered related 
to that product.
In cases of surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
7.4.1.2
Adverse Event's Causality with the Investigational Product
Investigators must systematically assess the causal relationship of AEs to IMP(s) using the 
following definitions. Decisive factors for the assessment of causal relationship of an AE to the 
IMP include, but may not be limited to, temporal relationship between the AE and the IMP, 
known side effects of IMP, medical history, concomitant medication, trial procedures.
Causality will be assessed using both NOM-220-SA1-2016 (29) and Merck standard. Adverse 
event records and reporting by 
 should include causality assessment per both the NOM 
and Merck standard scale described above as follows:
Per Merck standard:
Unrelated:
Not reasonably related to the IMP/study treatment. AE could not medically 
(pharmacologically/clinically) be attributed to the IMP/study treatment under 
study in this clinical trial protocol. A reasonable alternative explanation must 
be available.
Related:
Reasonably related to the IMP/study treatment. AE could medically 
(pharmacologically/clinically) be attributed to the IMP/study treatment under 
study in this clinical trial protocol.
Per the regulation in Mexico, NOM-220-SA1-2016 (29):
Certain. It consists of an event (clinical onset or an abnormal result of laboratory test) which 
occurs within a reasonable period of time following the drug's administration and which cannot 
be explained by the natural condition's evolution, by any concomitant pathology or by other 
drugs dosing. Response to drug's stop should be clearly evident.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
43/85
Probable. It consists of an event (clinical onset or an abnormal result of laboratory test) which 
follows a reasonable period of time following the drug's administration and which can hardly be 
related to the natural condition's evolution, concomitant pathologies or to other drugs dosing. A 
clinically reasonable response is obtained upon stop of other(s) drug(s).
Possible. It consists of an event (clinical onset or an abnormal result of laboratory test) which 
follows a reasonable period of time following the drug's administration and which can hardly be 
related to the natural condition's evolution, concomitant pathologies or to other drugs dosing. 
There is no information available related to the suspect drug's dosing or this is not clear.
Suspect. It consists of an event (clinical onset or abnormal laboratory test) which follows a 
reasonable sequence of time following the drug's dosing which makes causality unlikely (but not 
impossible). It might be explained in a reasonable way since it is part of the natural evolution of 
the condition, or it is due to the presence of concomitant pathologies or other drugs dosing.
Conditional - Unclassifiable It consists of an event (clinical onset or abnormal laboratory test 
result) which cannot be properly assessed since more data are required or because additional data 
are still being analyzed.
Not evaluable - Unclassifiable It consists of a report which suggest that there is an adverse 
reaction which cannot be assessed since collected information is not enough or inconsistent. The 
report cannot be completed or checked
Other factors to be considered for adverse event's causality assessment with the study drug are:
Recovery or discontinuation, relapse or rechallenge: Subject's response following 
stopping the drug or subject's response following rechallenge should be considered based 
on the usual clinical course of the corresponding event.
Response pattern known for this type of drug: Clinical/Pre-clinical
Exposure to physical and/or mental stress: Exposure to stress may produce adverse 
changes in the receptor and provide a rationale and a better explanation for the event.
Test drug's pharmacology and pharmacokinetics: Test drug's pharmacokinetic properties 
(absorption, distribution, metabolism and excretion) as well as the subject's individual 
pharmacodynamics should be considered.
7.4.1.3
Adverse Event's Severity 
Investigators must assess the severity/intensity of AEs according to the Qualitative Toxicity Scale, as 
follows:
Mild 
The subject is aware of the event or symptom, but the event or symptom is easily tolerated.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
44/85
Moderate
The subject experiences sufficient discomfort to interfere with or reduce his or her usual level of 
activity.
Severe 
Significant impairment of functioning: the subject is unable to carry out his or her usual
activities.
7.4.1.4
Abnormal Laboratory Findings 
Abnormal laboratory findings and other abnormal findings during the study (e.g., on an ECG 
trace) should not be reported as adverse events unless they are associated with clinical signs and 
symptoms, lead to treatment discontinuation or are considered otherwise medically important by 
the Investigator. If a laboratory abnormality fulfils these criteria, the identified medical condition 
(e.g., anaemia, increased ALT) must be reported as the AE rather than the abnormal value itself.
7.4.1.5
Unexpected Adverse Event 
An unexpected adverse event is any adverse event which specificity or severity is not mentioned 
in the most recent product's information (Investigator's Brochure). Likewise, reports which 
provide important information about specificity or severity of a known adverse event, already 
documented, constitute unexpected adverse events. For instance, any event which is more 
specific or more severe than those described in the Investigator's Brochure should be considered 
"unexpected".
7.4.1.6
Serious Adverse Event
A serious adverse event (SAE) is any untoward medical occurrence which at any dose:
!
Results in death.
!
It is life-threatening.
!
Requires hospitalization or prolongs the existing hospitalization.
!
Results in persistent or significant disability or incapacity.
!
It is a congenital anomaly or birth defect.
!
It is considered as medically important event.
Some medically important events, that do not lead to death, are not life-threatening or require 
hospitalization, may be considered serious adverse events based on the appropriate medical 
judgment and may require medical or surgical intervention to prevent one of the outcomes 
previously mentioned in this definition. Examples of those medical events include: allergic 
bronchospasm which require intensive care in the emergency room or at home, blood dyscrasias 
or seizures which require hospitalization, or the development of drug's dependence or abuse.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
45/85
Life-threatening means an event in which the subject is at risk of death at the time of the event; it 
does not refer to an event that hypothetically might cause death if it were more severe.
Disability means a physical or mental disorder that significantly limits a person’s motor, sensory 
or cognitive abilities.
For reporting purposes, any suspected transmission of an infectious agent by any of the study 
drugs is considered a serious adverse reaction and all such cases should be reported in an 
expedited manner as described in section 7.4.1.9.
7.4.1.7
Recording Methods and Adverse Events Assessment 
Complete, accurate and consistent data on all adverse events occurring during the study period 
should be recorded in the appropriate section of the medical chart as well as in the eCRF of each 
subject. Among these AEs, all SAEs must be additionally documented and reported using an 
Adverse Event Safety Report Form (Clinical Trial) as described in Section 7.4.1.9. 
This information will be obtained from the subject of the study, which will be asked directly 
about the adverse event.
Documentation should be supported by a record in the subject's medical chart. Any abnormality 
in laboratory tests, considered clinically relevant, for instance, those which lead to the subject's 
withdrawal from the study, require treatment, causing evident clinical onset in the subject, 
considered relevant by the Investigator, should be reported as an adverse event. 
All adverse events should be described in detail, including subject's identity (name, age and 
gender), a description of the adverse event, its duration (onset and resolution dates and times (to 
be completed when it is important to assess the time of the AE onset, relative to the time of 
treatment administration), its severity, its relationship with the study drug, any other potential 
causal factors, any treatment given or other action taken and its outcome. In addition, serious 
cases should be identified and the appropriate seriousness criteria documented. This information 
must be consistent with the CRF, the SAE and AESI Report Forms (as applicable).
Specific guidance can be found in the eCRF Completion and Monitoring Conventions.
7.4.1.8
Definition of Reporting Period for Adverse Events 
The adverse event reporting period begins when the subject is included into the trial and until 
EoT.
7.4.1.9
Procedure for Reporting Adverse Events and Serious 
Adverse Events 
Report of adverse events will be the responsibility of the 
 
 and it will be made according to the drug safety manual and the 
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
46/85
standard operating procedure, code: IC-PNO-039, Report of clinical and bioavailability studies 
adverse events.
Report of adverse events will be made according to the standard operating procedure, code: IC-
PNO-039, Report of clinical and bioavailability studies adverse events and the Mexican Official 
Standard for the Setting-up and Operations of Pharmacovigilance in Mexico, NOM-220-SA1-
2016 (29). Therefore, any serious adverse event or suspect serious adverse reaction should be 
notified to the National Center of Pharmacovigilance (CNFV) from the Federal Commission for 
the Protection against Sanitary Risks 
 as well as to the Sponsor within the first 24 h 
following the Investigator is aware of it. A supplemental report, as detailed as possible which 
include all information collected, should be sent within 15 days. Report to the CNFV will be 
made by the Pharmacovigilance Officer at the
 
 To comply with NOM-220-SSA1-2016 (29), mild or moderate, 
expected and unexpected adverse reactions should be reported by the study Principal Investigator 
at the 
 along with the 
clinical stage report to the CNFV.
Means to notify the Sponsor are the following:
Fax:
Telephone:
Mobile:
E-mail: 
 
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 hours after becoming aware of the event) inform the 
Sponsor or its designee in writing. All written reports should be transmitted using the SAE 
Report Form, which must be completed by the Investigator following specific completion 
instructions.
The following minimum information is required for new SAEs in the initial notification of the 
Sponsor:
! Clear identification of the Investigator/Reporter, with full contact information;
! Subject identification details (trial number, site number, subject’s initials, and date of birth);
! Trial Treatment administration details;
! Diagnosis of the event, with the description (or a brief description of signs/symptoms/clinical 
course, if the diagnosis is not available) and the date of onset; 
! Reason(s) for considering the event serious; and
! Relationship of the event to the study drug (i.e., the causality according to the Investigator).
In exceptional circumstances, an SAE (or follow-up information) may be reported by telephone.
In these cases, a written report must be sent immediately thereafter by fax or e-mail. Names, 
addresses, and telephone and fax numbers for SAE reporting will be included in the trial-specific
SAE Report Form and the Drug Safety Manual.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
47/85
Relevant pages from the CRF may be provided in parallel (for example, medical history, 
concomitant drugs). Additional documents may be provided by the Investigator, if available (for 
example, laboratory results, hospital report and autopsy report). In all cases, the information 
provided on the SAE Report Form must be consistent with the data about the event recorded in 
the CRF.
The Investigator must respond to any request for follow-up information (for example, additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for initial 
reports. This is necessary to ensure prompt assessment of the event by the Sponsor or designee 
and (as applicable) to allow the Sponsor to meet strict regulatory timelines associated with 
expedited safety reporting obligations.
Requests for follow-up will usually be made via the responsible Monitor, although in exceptional 
circumstances the Global Drug Safety department may contact the Investigator directly to obtain 
further information or to discuss the event.
The reports to Merck shall be sent in English using the Merck SAE form via fax or email within 
24 hours.
Fax No.: 
, email address: 
.
7.4.1.10
Report of Safety Information to the Health Authorities, 
Ethics and Investigation Committee and Investigational 
Committee 
According to local law and regulation, all serious and non-serious adverse events should be 
reported to the appropriate Ethics and Investigation Committee, Investigational Committee and 
to the Health Authorities. This will be carried out according to the drug safety manual and the 
standard operating procedure, code: 
, Report of clinical and bioavailability studies 
adverse events.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving trial subjects to the IEC/IRB that approved the 
trial.
In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of “findings that 
could adversely affect the safety of subjects, impact the conduct of the trial or alter the 
IEC’s/IRB’s approval/favorable opinion to continue the trial.” In particular and in line with 
respective regulations, the Sponsor/designee will inform the Investigator of AEs that are both 
serious and unexpected and are considered to be related to the administered product (“suspected 
unexpected serious adverse reactions” or SUSARs). The Investigator should place copies of 
these Safety reports in the Investigator Site File. National regulations with regard to Safety 
Report notifications to Investigators will be taken into account.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
48/85
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records of 
these notifications. When direct reporting is not clearly defined by national or site-specific 
regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB of 
any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File.
For trials covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with 
that Directive and with the related Detailed Guidance documents.
7.4.1.11
Monitoring of Subjects with Adverse Events 
Adverse events are recorded and assessed on an ongoing basis throughout the study, and they 
will be assessed for the final outcome in the 7 day follow-up following the last dose of the drug. 
Any AE that occurs during the course of a clinical trial and is considered to be possibly related to 
the IMP must be monitored and followed-up by the Investigator until stabilization or until the 
outcome is known, unless the subject is documented as “lost to follow-up”. All reasonable efforts 
should be made to collect information and these should be documented. It is also the Investigator 
responsibility to ensure that all additional and necessary therapeutic measures are taken as well 
as the follow-up procedures.
The outcome of an adverse event should be entered in the eCRF, with the terms provided below:
! Recovered without sequelae; 
! Recovered with sequelae;
! Ongoing;
! Worsening; 
! Improving;
! Died; 
! Unknown. 
In case of a fatality, the cause of death is considered as the SAE, and the death is considered as 
its outcome.
7.4.1.12
Pregnancy and In Utero drug exposure 
All pregnancies observed during the trial period will be recorded in the appropriate eCRF 
page/section for female partners of subjects' as AE or SAE depending on the outcome of the 
pregnancy. The Principal Investigator should inform immediately the Sponsor or designated 
person about any pregnancy using a Pregnancy Report Form which should be completed and 
submitted according to the same procedure for SAE referred in section 7.4.1.9.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
49/85
The Investigator or designated person should follow-up, document and report all pregnancies 
outcomes, even if subjects were withdrawn from the study.
The Investigator should inform the Sponsor or designated person about the outcome using the 
Pregnancy Report Form. In case of an abnormal outcome, the SAE Report Form will be used. In 
case subject child/fetus experienced an event, the Parent-Child/Fetus Adverse Event Report 
Form will be used.
Any abnormal outcome should be reported immediately as described in section 7.4.1.9. All 
outcomes should be reported within 45 days following the delivery. The first 6 months of life of 
the newborn should be reported only if an adverse event occurs.
In case of female partners pregnancy during the study, the subject should be withdrawn and 
study drug should be immediately withdrawn. Sponsor or designated person should be 
immediately informed and follow-up should be made as aforementioned.
Reproduction studies performed so far in rats and rabbits have revealed no evidence of impaired 
fertility or harm to the fetus due to Praziquantel.
7.4.2
Clinical Laboratory Assessments
The safety laboratory parameters (hematology, chemistry, serology, urinalysis, drugs of abuse)
are presented in Appendix 2 and will be performed in accordance with the clinical unit's standard 
operating procedures (SOPs). 
Analyses of safety laboratory will be performed under responsibility of 
, according to 
their SOPs. Detailed description of the procedures and methods will be given in separate 
laboratory manuals.
Additional clinical laboratory tests may be performed after abnormal findings, if judged 
appropriate by the Investigator. All samples should be clearly identified. All clinical laboratory 
samples will be analyzed by the laboratory at the trial site.
The total volume of blood to be withdrawn for these clinical laboratory assessments will be 
around 72 mL.
The Sponsor should receive a list of laboratory normal ranges before shipment of the IMP. Any 
change in laboratory normal ranges during the trial will additionally be forwarded to the 
Sponsor.
7.4.3
Vital Signs, Physical Examinations, and Other Assessments
At Screening, EOT and prior to each dosing, blood pressure, pulse, respiratory rate and body 
temperature (subjects should be in rest and in supine position at least 5 minutes before vital signs 
measurement; and they should be in rest and in supine position during the vital signs 
measurements) will be measured.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
50/85
These values should be within the normal range (SBP between 80 and 129 mmHg and DBP 
between 50 and 89 mmHg) in order the subject is allowed to keep on participating in the study. 
Same measurements will be made during all shifts following dosing at each one of the visits. 
Vital signs will be measured during the 3 periods as shown in the following Table 5:
Table 5
Record of Vital Signs
First Visit
Second Visit
Third visit
Admission
Admission
Admission
Pre-dose
Pre-dose
Pre-dose
Morning (3 hours post-dose 
approximately)
Morning (3 hours post-dose 
approximately)
Morning (3 hours post-dose 
approximately)
Evening (7 hours post-dose 
approximately)
Evening (7 hours post-dose 
approximately)
Evening (7 hours post-dose 
approximately)
Night (11 hours post-dose 
approximately)
Night (11 hours post-dose 
approximately)
Night (11 hours post-dose 
approximately)
24 hours post-dose 
approximately
24 hours post-dose 
approximately
24 hours post-dose 
approximately
NA
NA
EOT
In the event any subject has clinically significant changes out of normal ranges for blood 
pressure and pulse during confinement post-dose, he/she will be closely observed by the medical 
staff. Supportive measures, as appropriate, will be taken according to the current subject's 
condition until they are resolved. If change persists, continuation in the study will be considered 
by the Principal Investigator.
At Screening, EOT and prior to each dosing and 24 hours after each IMP administration, 
electrocardiograms will be taken.
7.5
Pharmacokinetics
7.5.1
Pharmacokinetics Blood Samples
Twenty-one venous blood samples of 5 mL will be taken per period with catheter or 
venipuncture for the measurement of drug's plasma concentration: Pre-dose, 0.25, 0.5, 0.75, 1.0, 
1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12.0 h following dosing.
Actual date and time of blood sampling for PK will be recorded in the CRF. Primary and back up 
samples will be shipped separately. It is planned that pooled samples for concentration range 
estimation and enantiomer detection will be prepared according to CROs SOPs. These specificity 
samples originate from some of the blood samples collected for drug assays and may be used by 
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
51/85
the analytical laboratory to determine suitable quantification ranges and enantiomer
identification (See Table 6).
7.5.1.1
Pharmacokinetics Blood Sampling Procedures
One blood sample will be collected per period at times established in the schedule. Test 
tubes with K3EDTA, specifically designed for venipuncture, will be used.
Each sample will be 5 mL. Blood withdrawn to clean catheter should be disposed prior to 
the blood sample collection (purge). Blood volume to be withdrawn by visit will be of 
105 mL approximately, 315 mL of blood in total at the end of the study.
The allowed deviation from the pre-specified assessment time will be:
o
Pre-dose samples: 

Within 1 hour before IMP administration
o
Post-dose samples and assessments:

Up to and including 24 hours: ± 5% of scheduled time point in minutes

After 24 hours up to and including 96 hours: ± 1 hour 

After 96 hours:  + 4 hours. 
Each sample will be centrifuged at 1500 x g for 10minutes at 4 °C [39.2 °F] (± 2 °C 
[35.6 °F – 42.8°F]).
Resulting plasma volume will be transferred into 1.5 or 2 mL cryotubes. One tube serves 
as back-up sample.
Plasma tubes will be identified with Study No. (##), Case No. (C##), Sample No. (S##) and Visit 
No. (V#). They will be kept frozen at a temperature lower than or equal to - 20 °C, according to 
the standard operating procedures, code: 
, Early organization for the conduct of an 
interchangeability and biocomparability study; and 
: Processing and packaging of 
biological samples for interchangeability and biocomparability studies, 
: Samples
transportation from the clinical unit to the analytical unit; until their delivery at the analytical 
unit.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
52/85
Table 6
Blood Sampling Schedule
Clinical Phase
NUMBER OF SUBJECTS:
60
GENDER:
Male
BIOLOGICAL MATRIX:
Plasma
DOSAGE FORM:
Tablet
FORMULATION:
600 mg Praziquantel
DOSE AND DOSAGE UNITS:
1200 mg Praziquantel
WASH-OUT TIME:
07 days
ANTI-COAGULANT:
K3EDTA
BLOOD VOLUME 
WITHDRAWN BY 
SAMPLE:
5 mL
TOTAL OF SAMPLES BY 
SUBJECT IN EACH PERIOD:
21
Sampling Interval
Phase
Sample
Time
Unit
Total Number of Samples
--
0
-1.5
h
No. of 
Cases
Samples
Periods
Total
A
1
0.25
h
60
21
3
3780
A
2
0.50
h
A
3
0.75
h
Diet
~ Cmáx
4
1.00
h
Standardized by the clinic
~ Cmáx
5
1.50
h
~ Cmáx
6
2.00
h
~ Cmáx
7
2.50
h
~ Cmáx
8
3.00
h
~ Cmáx
9
3.50
h
~ Cmáx
10
4.00
h
E
11
4.50
h
E
12
5.00
h
E
13
5.50
h
E
14
6.00
h
E
15
6.50
h
E
16
7.00
h
E
17
8.00
h
E
18
9.00
h
E
19
10.00
h
E
20
12.00
h
Each subject will participate for around 40 h confined for each of the periods within the 7-days
wash-out period. The wash-out period starts per the time of drug's intake in the first period and 
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
53/85
thus includes the 12 h period for sampling and the approx. 14 h period on day -1 to day 1 of the 
second period (until second administration)
7.5.1.2
Samples Shipment
To ensure transportation conditions of biological samples from the laboratory, where they were 
processed for freezing and storage, to the analytical unit do not affect samples' stability, it is 
essential to comply with the following guidelines:
1. The Study Principal Investigator or the Sub-Investigator will define shipment's date and 
time in accordance with the analytical unit, as well as the transportation to be used and 
approximate time for itinerary.
2. Mechanism of control and security for samples shipment will be defined by the person in 
charge of transportation in agreement with the Principal Investigator or Sub-Investigator.
3. The Samples Processing and Pharmacy Coordinator or a designated person will sign a list 
of material to be shipped, with a detailed description by subject for tubes quantity and 
codes.
4. An internal temperature reading system will be available in the freezer. A reading will be 
made at least every 15 minutes with its appropriate record.
5. In addition, reading at the moment of departure of the material from the samples 
processing area, as well as a reading at the reception at the analytical unit will be made.
6. Samples transportation is the responsibility of the clinical unit where samples collection 
and processing took place.
7. Transportation and delivery shall be performed by a specialized courier company which 
will be contracted by the Principal Investigator in agreement with the Sponsor. Samples 
will be delivered directly to the 
 per pre-
established instructions.
8. All samples should arrive deep frozen (- 20 °C [- 4.0 °F] as maximum).
7.5.1.3
Samples Receipt, Check and Storage by the Analytical Unit 
1. The Person responsible for the study or designated person from the analytical area will 
receive samples (along with documentation) and check 100 % with the assistance from 
analysts and Quality Assurance. They will record any remarks on the appropriate form
(with a focus on the temperature at the time of receipt and a remark observation if any 
dry ice is still left in the shipment box/container). Once review is finished the person 
responsible for the study or designated person will store samples frozen (- 20 °C [- 4.0 
°F] as maximum) in controlled storage.
2. Quality Assurance will confirm accuracy and reliability of operations.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
54/85
Samples which do not meet acceptance criteria will be rejected (refer to Manual of Operations
(MOP). In addition to those which don't have documentation along with them. In such instances, 
the clinical unit should be informed about the reason why samples were rejected. Rejected 
biological specimens will be kept at the analytical unit until the analytical unit and the clinical 
unit makes an agreement about their disposition.
Further details e.g. on the collection, processing, labeling, and shipping of the samples will be 
detailed in the trial MOP.
Back up samples will be kept in the Clinical Unit, they should not be sent at the same time as the 
primary samples.
7.5.1.4
Handling of Biological Specimens by the Analytical Unit 
Biological specimens will be handled and processed as described in the appropriate analytical 
Method description.
7.5.1.5
Biological Specimens Disposition
As agreed with the Sponsor or 30 calendar days following the final report, samples will be 
removed from the ultra-freezer and will be stored in a transient warehouse for infectious 
biological hazard residues until they are collected for their final disposition by an authorized 
designated company.
7.5.1.6
Ultra-frozen Samples Labeling
Cryotubes will be identified with labels according to the standard operating procedure, code: 
, early organization for the conduct of an interchangeability and biocomparability 
study. Each cryotube will state the study number, subject's number, period and number of 
samples specified in the protocol. Labels will be digitally designed and printed using thermal 
printer. Label and printing type will ensure that that printing and adhesion resist several freezing 
and thaw cycles.
7.5.2
Calculation of Pharmacokinetics Variables
The following non-compartmental PK parameters will be calculated from the individual plasma 
L PZQ and rac-PZQ concentration-time data obtained on Days 1,8 and 15, respectively, using 
commercial software Phoenix®/WinNonlin® (Version 6.3 or higher).
Table 7
Pharmacokinetic Parameters Derived from L PZQ and rac-PZQ 
Concentrations
Cmax
Maximum observed drug concentration. 
tmax
Time of the maximum drug concentration. 
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
55/85
tlag
Time prior to the first measurable (non-zero) concentration; calculated as last time 
point at which the concentration is <LLOQ before the occurrence of the first 
quantifiable concentration
∀z
Terminal rate constant.
t1/2
Terminal elimination half-life. 
AUC0-t
Area under the drug concentration-time curve from time zero to the time last 
measurable concentration.
AUC0-∞
Area under the drug concentration-time curve from time zero extrapolated to 
infinity. 
%AUCextra
Percentage of AUC0-∞ obtained by extrapolation
CL/f
Apparent clearance
VZ/f
Apparent volume of distribution during terminal phase
The bioanalytical assessment will be outsourced to a third party vendor under the responsibility 
of Merck. PK parameter estimation and generation of PK TLFs will be outsourced to a third 
party vendor under the responsibility of Merck. Statistical analysis of Praziquantel will be 
conducted by the 
, 
according to their standard operating procedures and in accordance with the NOM-177-SSA1-
2013 (28).
 
 
 
 
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
56/85
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
57/85
8
Statistics 
8.1
Sample Size
Information on Praziquantel currently available to the WHO PQP Group indicated that the 
intrasubject variability for Praziquantel is around 50-60% for Cmax and 35% for AUC, placing 
this compound in the highly variable drug class. The data from the Merck Serono phase I study 
performed recently, where Cisticid was used as comparator and different doses of PZQ ODT 
formulations were examined, confirmed this information and indicated for L-PZQ a CV% of 
34.5 for AUC in the overall population and of 39.5% in non-whites, and a CV% for Cmax of 52%. 
The sample size calculation was performed using the R-functions sampleN.RSABE and 
sampleN.TOST of the package PowerTOST, which takes advantage of the reference-scaled 
approach suggested by the EMA.
Points to consider:
!
For this clinical study comparison, the reference scaled approach is only applicable for 
Cmax. For AUC conventional BE limits apply [0.80 – 1.25].
!
In 
general, 
the 
reference 
scaled 
approach 
is 
applicable 
for 
CV<=50%: 
For CVs >50% fixed BE margins need to be used [0.70 – 1.43].
!
Regulatory constant applied for reference scaled approach (EMA): 0.76 
The following assumptions were made:
!
Assumed true mean Test/Reference ratio for primary PK: 0.95
!
Cmax Coefficient of variation (Reference): 45 - 55%
!
Cmax Coefficient of variation (Test):          45 - 55%
!
AUC Coefficient of variation (Reference):  39.5%
!
AUC Coefficient of variation (Test):           39.5%
!
One-side alpha: 0.05 (corresponds to 90% confidence level)
!
Power: 80%
!
Drop-out (DO) rate: 20% (agreed with CRO)
For this comparison the conventional BE margins [0.80 – 1.25] need to be applied for AUC. 
Therefore the rather high CV for AUC of L-PZQ determines the sample size for this trial. 
 
 
Together with the assumptions above, 48 evaluable subjects will provide 80% power to 
demonstrate BE. Taking a drop-out rate of 20% into account, 60 subjects should be randomized 
in this BE trial.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
58/85
8.2
Randomization
Valid statistical inferences are generally derived by assuming that errors in the observations are 
distributed independently, in random variables. Randomization generally ensures validity of this 
hypothesis. Full randomization of subjects to the treatment's sequence will be made according to 
the design sequences based on the internal procedures from the 
compliant with the
(28) using the
.
A total of 60 subjects are to be enrolled in the trial and randomized to one of 3 treatment 
sequences, such that 20 subjects are assigned to each treatment sequence.
8.3
Endpoints
Statistical analysis for determining bioequivalence will be calculated using the computer 
program package SAS® System 
.
8.3.1
Primary Endpoints
The primary endpoints are the PK parameters AUC0-t and Cmax for L-PZQ.
8.3.2
Secondary Endpoints
-
Additional pharmacokinetic parameters will be estimated: tmax, tlag, AUC0-∞, AUCextra, t 
½, λZ, CL/f and Vz/f of L-PZQ and tmax, tlag, AUC0-t, AUC0-∞, AUCextra, Cmax, t ½, λZ, 
CL/f and Vz/f parameters of rac-PZQ.
-
To assess safety and tolerability of 1200 mg of the Cisticid tablets administered in fed 
condition. Safety will be assessed by AEs, standard laboratory parameters hematology, 
biochemistry, urinalysis, and coagulation), vital signs (body temperature, systolic blood 
pressure, diastolic blood pressure, and pulse rate) and 12-lead electrocardiogram (ECG)
Analysis Sets
Table 8
Analysis Sets
For purposes of analysis, the following analysis sets are defined:
Population
Description
Enrolled 
All participants who sign informed consent
Safety
The Safety Analysis Set will include all subjects who receive at least one dose of trial treatment. 
Subjects will be analyzed according to the actual treatment they receive.
Pharmacokinetic
All subjects that received all administrations of treatment and have PK parameters for AUC0-t and Cmax
in all periods and without any relevant protocol violations and factors likely to affect the comparability 
of PK results.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
59/85
8.4
Description of Statistical Analyses
8.4.1
General Considerations
Statistical analysis will be performed using the computer program package SAS® System 
. If not stated otherwise, the level of 
statistical significance will be alpha=0.05. PK data evaluation will be performed based on 
standard non-compartmental methods using the validated software tool 
 
. Details on the statistical analysis and PK data analysis will be presented in 
the statistical analysis plan prior to database lock.
The statistical analysis will not be started until all data have been corrected and checked for 
plausibility, and until all necessary coding and assessments have been completed.
Medical history and AE terms will be coded with Medical Dictionary for Regulatory Activities 
(MedDRA), version 18.0 or later; concomitant medication will be coded with WHO (World 
Health Organization) Drug Dictionary, WHO Drug Reference List and Anatomical Therapeutic 
Chemical Classification System, latest version. Medical History will be coded according to 
MedDRA, latest version. Versions of dictionaries used for coding will be defined in the Data 
Management Plan (DMP).
All data recorded during the trial will be presented in individual data listings.
All data will be evaluated as observed, no imputation method for missing values will be used
except for missing dates/times in AE data which will be performed for the classification of 
treatment-emergence, assigning AEs to treatment periods and for calculation of duration. The 
handling of concentration values below the limit of quantification (BLQ) will be described in the 
statistical analysis plan.
Summary statistics will be provided for all endpoints.
8.4.2
Analysis of Primary Endpoints
The analysis of the primary endpoints AUC0-t and Cmax of L-PZQ will be performed using the PK 
population. For the demonstration of bioequivalence different approaches will be applied for 
AUC0-t and Cmax For AUC0-t the standard approach will be followed, i.e. the point estimate and 
the 90% CI of the Test/Reference geometric mean ratio must fall within [0.80, 1.25]. AUC0-t of 
L-PZQ will be log-transformed and analyzed using a generalized linear model as given by the 
SAS code below: 
PROC GLM DATA=PK;
CLASS SEQ SUBJ PER TRT;
MODEL LNPARAM = SEQ PER TRT SUBJ(TRT) / DDFM=SATTERTH;
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
60/85
LSMEANS TRT / ADJUST=T PDIFF CL ALPHA=0.10.
TEST H=SEQ E=SUBJ(TRT);
RUN;
QUIT;
The treatment difference TEST – REFERENCE will be estimated, and the 90% CIs for the 
difference in LS-means will be calculated. The difference and 90% CIs will be back-transformed 
to the original scale. If the 90% CI for the ratio (test/reference) lies entirely within the interval 
[80.00 – 125.00], then the BE criterion is fulfilled for AUC0-t.
For the analysis of Cmax, a reference-scaled bioequivalence approach will be applied as follows: 
Point estimate and 90% confidence interval will be computed as described above for AUC. If 
CVWR ≤30% for Cmax (i.e. the within-subject CV for the reference drug is ≤30%), then the 
common acceptance range for bioequivalence will apply. For 30% < CVWR ≤ 50% the acceptance 
interval will be widened according to [U, L] = exp [± k·sWR], where U is the upper limit of the 
acceptance range, L is the lower limit of the acceptance range, k is the regulatory constant set to 
0.760 and sWR is the intrasubject standard deviation of the log-transformed values of Cmax of 
the reference product. sWR will be calculated using the data under reference treatment only. For 
all values of CVWR greater than 50% the acceptance range is fixed to [69.84 – 143.19]. 
The geometric mean ratio for Cmax should always lie within [80.00 – 125.00].
a.
Descriptive statistics and boxplots will be provided by treatment. 
 
 
PROC GLM DATA=PK;
CLASS SEQ SUBJ PER TRT GROUP;
MODEL LNPARAM = SEQ PER TRT GROUP GROUP*TRT SUBJ(TRT) / DDFM=SATTERTH;
LSMEANS TRT / ADJUST=T PDIFF CL ALPHA=0.10.
TEST H=SEQ E=SUBJ(TRT);
RUN;
QUIT;
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
61/85
8.4.3
Analysis of Secondary Endpoints
All secondary endpoints will be listed and descriptively analyzed. 
There will be no formal statistical comparison of the secondary PK endpoints. Treatment ratio 
and 90% confidence interval will be presented for AUC0-∞of L-PZQ and for all the secondary 
PK endpoints for rac-PZQ (tmax, tlag, AUC0-t, AUC0-∞, AUCextra, Cmax, t ½ , λZ, CL/f and Vz/f). 
For tmax the Hodges-Lehmann shift estimate will be calculated together with the 90% confidence 
interval according to Tukey.
8.4.4
Analysis of Safety and Other Endpoints
8.4.4.1
Safety endpoints
In general, for the evaluation of safety parameters, the numerical values will be summarized 
descriptively (N, arithmetic mean, median, standard deviation, minimum and maximum values). 
Categorical variables will be presented in frequency tables by the number of observations and 
percentages.
AE counts and subjects with AEs will be summarized for each treatment by system organ class 
and preferred term. In addition AEs will be tabulated and listed per subject and analyzed by 
severity and relationship to trial drug. 
Subjects who prematurely withdrew from the trial or from treatment will be displayed in a 
by-subject listing, and summarized by primary withdrawal reason for each treatment sequence.
Safety laboratory parameters will be listed for each subject including changes from baseline and 
flags for measurements outside the reference ranges, where applicable. Laboratory parameters 
(hematology and clinical chemistry) will be summarized by time point including both absolute 
values and changes from baseline. 
Vital signs and ECG parameters will be listed by subject including changes from baseline, and 
summarized by treatment and time point using descriptive statistics. Physical examination 
assessments will be listed for each subject.
8.4.4.2
Further endpoints
Demographic parameters (such as age, height, weight) and other baseline characteristics will be 
summarized by means of tabulated descriptive statistics for all subjects by sequence group and 
overall. Subject habits (including alcohol consumption and smoking history), medical history, 
prior and concomitant medications and exposure to IMP will be listed for each subject.
L-PZQ and rac-PZQ concentrations will be listed by subject, by treatment, by period and time 
point for each treatment and summarized by treatment and time point. Individual and mean 
concentration versus time plots will be prepared.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
62/85
Further details will be described in the statistical analysis plan.
8.5
Interim and Additional Planned Analyses
No interim analysis is planned.
8.6
Deviation and Exclusion to the Statistical Analysis 
All deviations should be justified with statistical or scientific data and any change to the original 
statistical plan should be documented, in the study master file and in the pharmacokinetics
statistical report as well as in the final study report. Subjects' data will not be replaced. Any
missing data will be considered as non-existent data. Likewise, data cannot be removed from the 
statistical analysis, except in the following events.
8.6.1
Research Subjects with Pre-dose Concentrations in the 
Biological Matrix
In the event pre-dose concentration is < 5 % of the Cmax value for a research subject, subject's 
data can be included. When pre-dose value is > 5 % of the Cmax, research subjects data should be 
removed from all study bioequivalence assessments.
8.6.2
Exclusion of Data Due to Vomit or Diarrhea.
Data from research subjects who experience vomiting and diarrhea throughout the 
bioequivalence study for immediate release products can be removed from the statistical analysis 
if vomiting and diarrhea occur after 6 hours post administration. 
9
Ethical and Regulatory Aspects
9.1
Responsibilities of the Investigator
The Principal Investigator is responsible for the study conduct at the site. She will make sure that 
the study is conducted according to the clinical trial protocol, ethical principles established in the 
Declaration of Helsinki, ICH, GCP and established regulation NOM-177-SSA1-2013 (28), 
which states tests and procedures to show that a drug is interchangeable as well as the 
requirements which Authorized Third-Parties should fulfill to perform the tests. The Investigator 
should ensure that only subjects who have provided their informed consent are included in the 
study.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
63/85
9.2
Subject Information and Informed Consent
An unconditional requirement for each subject before their participation in the study is to have a 
written informed consent, which should be given before any study-related activity is carried out. 
Therefore, the Principal Investigator or designated personnel should provide appropriate 
information before obtaining informed consent.
Subject's Information Sheet should be elaborated in Spanish, according to the ICH GCP and will 
be provided by the Sponsor with the purpose to get the informed consent. Besides providing 
written information to the potential subject, Investigator or designated person will inform them 
verbally all relevant aspects of the study, using language chosen so that information can be fully 
and easily understood by the subjects. Subject will be given enough time to read the information 
and ask questions and request additional information and explanations.
After providing information to the subject, informed consent form should be signed and dated by 
the subject, the Principal Investigator or designated personnel and two witnesses.
The dated and signed informed consent will be kept in the study site and should be securely filed 
so that files can be retrieved at any moment for monitoring, auditing and inspection purposes. A 
copy of the signed and dated informed consent form should be provided to the subject before 
their participation in the study.
Whenever new relevant information arises for the informed consent, the Investigator will revise 
subject's information and any other written information to be provided to the subjects, which 
should be submitted to the Committees for review and approval. 
Revised and approved version of the written information will be used. The Principal Investigator 
or designated personnel will explain each subject all changes made to the previous version and 
will obtain a new written consent to continue his participation in the study. Subject will be given 
enough time to read the information and ask questions, and request additional information and 
explanations about changes.
9.3
Subject Identification and Privacy
A unique number is assigned to each subject that corresponds to their clinical file number, this 
number will be used as subject's identification in the study, as well as in the clinical study 
database. Once it is confirmed that all inclusion criteria and none exclusion criteria have been 
met, a consecutive number in ascendant order will be assigned to subjects. For each one of these 
numbers, it will correspond one of the three sequences as described in section 6.3. 
All data collected from study subjects will be recorded in appropriate charts. Only the 
Investigator will be able to link the test's data for a subject by means of an identification list 
which will be located at the site. For each subject, clinical data will be available for verification 
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
64/85
purposes by the monitor, audits and regulatory inspections, but subject's confidentiality will be 
strictly kept. 
Data protection and confidentiality will be kept during data entry, processing, submission and 
storage. Subjects will be informed about it and they will be requested to provide their consent for 
data management according to the national regulations.
The Ministry of Health, Ethics and Investigation Committee and the Investigational Committee 
will be the only authorized bodies for reviewing study documentation, (which includes 
participant subject's identity data) and documents considered confidential by 
 
 and by the analytical 
unit from Merck.
9.4
Emergency Medical Support and Subject Card
Subjects will be provided with Emergency Medical Support cards supplied by the Sponsor for
use during trial participation in order to provide the subjects with a way of identifying
themselves as participating in a clinical trial and to give health care providers access to any
information about this participation that may be needed to determine the course of medical
treatment for the subject.
The first point of contact for all emergencies will be the clinical trial Investigator caring for the
affected subject. The Investigator agrees to provide his or her emergency contact information on
the card for this purpose. If the Investigator is available when an event occurs, they will answer
any questions. Any subsequent action will follow the standard process established for the
Investigator.
In cases where the Investigator is not available, the Phase I facility will provide the appropriate
means to contact a physician. This includes the provision of a 24-hour contact number at the
facility, whereby the health care providers will be given access to an appropriate physician to 
assist with the medical emergency.
9.5
Medical Insurance and Subject Compensation
Subjects will sign a consent which states that they will receive a compensation for their 
participation in the study. 
The Sponsor will pay treatment (or compensation, if applicable) resulting from injuries or 
diseases caused by their participation in the study until their resolution as per the clinical criteria. 
The Sponsor will not pay injuries caused by subject's negligence, irresponsible behavior or 
medical reasons not related to the study.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
65/85
9.6
Ethics and Investigation Committee or
Investigational 
Committee 
Before study start-up, approval from the Ethics and Investigation Committee and from the 
Investigational Committee has to be obtained. They should provide a list of the members who 
compose it, as per request from the Study Sponsor or Principal Investigator. If necessary due to 
amendments to the clinical trial protocol, case report form or informed consent form, a new 
approval should be got from both Committees.
The IEC will be asked to document the date of the meeting at which the favorable opinion or
approval was given and the members and voting members present. Written evidence of favorable
opinion or approval that clearly identifies the trial, the clinical trial protocol version, and the
Subject Information and Informed Consent Form version reviewed should be provided. Where
possible, copies of the meeting minutes should be obtained.
Amendments to this clinical trial protocol will also be submitted to the concerned IEC, before
implementation of substantial changes (see Section 10.5). Relevant safety information will be
submitted to the IEC during the course of the trial in accordance with national regulations and 
requirements.
9.7
Health Authorities
The clinical study as well as the appropriate documents will be submitted to the health 
authorities, according to the local and national applicable regulations.
10
Trial Management
10.1
Case Report Form Handling
An Electronic Case Report Forms will be completed by authorized medical staff according to the 
standard operating procedure, code: 
: Good Documentation Practices, with legible 
letter and without amendments.
The main purpose of the eCRF is to obtain data required by the clinical trial protocol in a 
complete, accurate, legible and timely. The data in the eCRF should be consistent with the 
relevant source documents.
The Investigator or designee is responsible for ensuring that the data collected in the course of 
this trial is accurate and documented appropriately on all applicable forms. They will then be 
processed, evaluated, and stored in anonymous form in accordance with applicable data 
protection regulations. The Investigator must ensure that the eCRFs and any other associated 
documents forwarded to Sponsor or its designated organization contain no mention of any 
subject names.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
66/85
The data will be entered into a validated database. The Sponsor or its designee will be 
responsible for data processing, in accordance with the Sponsor’s data management procedures. 
Database lock will occur once quality control and quality assurance procedures have been 
completed. PDF files of the eCRFs will be provided to the Investigators at the completion of the 
trial.
10.2
Source Data and Subject Files
The Principal Investigator should keep a paper or electronic file (medical file, and original 
medical records) for each subject in the study. It should be possible to identify each subject by 
means of this file. This file will contain the following subject's demographic and medical 
information and should be as complete as possible.
Subject's complete name, date of birth, sex, height and weight.
Medical history. 
Previous and concomitant medications / therapies (including changes during the study).
Study identification; that is, subject's number provided by the clinical study Sponsor, and 
subject's number. 
Study recruitment dates (informed consent) and visits to the site.
Any medical exam and pre-defined clinical findings in this clinical trial protocol.
All adverse events.
Date when the subject abandoned the study, including any reason for study withdrawal.
All documents which contain source data should be shown, including but not limited to, 
electrocardiograms and laboratory tests results. These documents should have subject's number 
and date of procedure. If possible, this information should be printed by the equipment used to 
perform the assessment or measurement. As necessary, medical assessment should be conducted; 
all assessments should be documented, signed and dated by the Principal Investigator.
10.3
Investigator Site File and Archiving
At the beginning of the study, the Principal Investigator will receive a master file for the site 
which contains all necessary study documents to be completed throughout the study and which 
will be updated as necessary. Master file should be available for Monitor's review, Sponsor's 
audits and Health Authorities' inspection during and following study. It should be securely filed 
for at least 15 years (or more, according to the local needs or otherwise stated by the Sponsor) 
following study completion. Documents to be filed include the subject's identification list and the 
signed informed consent by the subject. In the even the master file cannot be kept at the site 
anymore, the Principal Investigator should inform the Sponsor/designated person.
All subjects' source documents (medical charts) should be stored at the site as long as possible, 
as allowed by applicable guidelines and/or according to the ICH GCP guidelines, whatever is 
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
67/85
longer. In any case, the Principal Investigator should ensure that no destruction of medical charts 
is done without written approval from the Sponsor.
10.4
Monitoring, Quality Assurance and Inspection by Health 
Authorities
Quality assurance is performed by means of follow-up to the standard operating procedures, 
codes: 
, Elaboration of quality assurance report for clinical trials; 
, 
First stage of quality control and quality assurance review during clinical studies conduct; 
, Second stage of quality control and quality assurance review during clinical studies 
conduct; and 
, Third stage of quality assurance review during clinical studies 
conduct. 
Quality Management follows up the conduct of the study by means of quality control monitoring 
for the review of compliance with the clinical trial protocol, internal standard operating 
procedures, and applicable guidelines according to the GCP (ICH E6R1).
Discrepancies and areas of improvement identified are followed up according to the standard 
operating procedure, code: 
, Discrepancies identification and follow-up, and 
potential causes of discrepancies and continuing improvement. All information collected is 
analyzed for the preparation and issue of the Quality Assurance report.
This trial will be monitored in accordance with the ICH GCP, and any other applicable 
regulations. The site Monitor will perform visits to the trial site at regular intervals.
Audits may be conducted at any time during or after the trial to ensure the validity and integrity 
of the trial data. Representatives of the Quality Assurance unit from the Sponsor or a designated 
organization, as well as Health Authorities, must be permitted to access all trial documents and 
other materials at the site, including the Investigator Site File, the completed CRFs, all IMP and
IMP accountability records, and the original medical records or files for each subject.
10.5
Changes to the Clinical Trial Protocol
Trial protocol amendments can be issued by the Principal Investigator and agreed with the 
Sponsor or vice-versa. Substantial changes should be approved by the Ethics and Investigation 
Committee and by the Investigational Committee.
Administrative changes which do not affect the study will be agreed with and approved by the 
Sponsor, the analytical unit and by the Principal Investigator. They will also be notified to the 
Ethics and Investigation Committee and to the Investigational Committee.
When a protocol deviation occurs during the clinical stage, the Principal Investigator should 
assess it and consider if study subject's continuation may affect protocol's outcome. Sponsor will 
be informed and jointly they will make a decision about subject's continuation in the study.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
68/85
10.6
Clinical Trial Report and Publication Policy
10.6.1
Clinical Trial Report
After study completion, the Principal Investigator with Sponsor's advice will prepare a clinical 
trial report and according to the Mexican Official Standard Mexican Official Standard and ICH 
Topic E3, which states tests and procedures to prove that a drug is interchangeable. 
Requirements which authorized third parties should fulfill for interchangeability tests. 
Requirements for performing biocomparability studies and requirements which authorized third 
parties, investigational sites and hospitals conducting biocomparability tests should fulfill 
(NOM-177-SSA1-2013) (28) and applicable guidelines.
10.6.2
Publication
All data and results, and all intellectual property rights for data and outcomes from the study will 
be property of Merck, which may use data for different purposes such as, submission to 
government health authorities or submission to other investigators.
The Investigator, although is free to use data derived from the study for scientific purposes, 
should discuss any publication with Merck in advance and obtain Sponsor's written consent for 
the pursued publication.
The Sponsor acknowledges the Investigator's right to publish outcomes once the study is 
completed. Anyway, the Investigator should submit a draft of the paper or summary to be 
published to Merck 30 days before submitting the final version for publication.
It will be reviewed soon and approval will not be unnecessarily delayed. In case of controversies 
between the Sponsor and the Investigators, publication content will be discussed in order to find 
a satisfactory solution for both parties.
Posting of data on the results of this bioequivalence trial is planned and may occur 12 months 
after the last clinic visit of the final trial subject or another appropriate date to meet applicable 
requirements
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
69/85
11
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bioavailability of praziquantel. Neurology 1992; 42: 492–6.
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2013; 102: 2953–94.
5. Castro N, Jung H, Medina R et al. Interaction between grapefruit juice and praziquantel 
in humans. Antimicrob Agents Chemother 2002; 46: 1614–6.
6. Castro N, Medina R, Sotelo J et al. Bioavailability of Praziquantel increases with 
concomitant administration of food. Antimicrob Agents Chemother 2000; 44: 2903–4.
7. Chan JD, Zarowiecki M, Marchant JS. Ca2+ channels and Praziquantel: a view from the 
free world. Parasitol Int 2013; 62: 619–28.
8. Dollery CT. Praziquantel. In: Therapeutic Drugs. Edinburgh, UK: Churchill Livingstone, 
1999; 184–8.
9. Ethical Principles for Medical Research in Humans contained in the Declaration of 
Helsinki, published on the 64th General Assembly from the Worldwide Medical 
Association, Fortaleza, Brazil; October 2013.
10. European Medicines Agency. Science Medicines Health. Guideline on the Investigation 
of Drug Interactions. 21 June 2012. Date for coming into effect 1 January 2013.
11. Gonzalez-Esquivel D, Rivera J, Castro N et al. In vitro characterization of some 
biopharmaceutical properties of Praziquantel. Int J Pharm 2005; 295: 93–9.
12. Gryseels B. Schistosomiasis. Infect Dis Clin North Am 2012; 26: 383–97.
13. Guidance for Industry, Food-Effect Bioavailability and Fed Bioequivalence Studies. U.S. 
Department of Health and Human Services. Food and Drug Administration. Center for 
Drug Evaluation and Research (CDER). December 2002.
14. Guideline on the Investigation of Bioequivalence. CPMP/QWP/EWP/1401/98 Rev.1, 20 
Jan 2010.
15. Homeida M, Leahy W, Copeland S et al. Pharmacokinetic interaction between 
Praziquantel and albendazole in Sudanese men. Ann Trop Med Parasitol 1994; 88: 551–
9.
16. Ingram K, Yaremenko IA, Krylov IB et al. Identification of antischistosomal leads by 
evaluating bridged 1, 2, 4, 5-tetraoxanes, alphaperoxides, and tricyclic monoperoxides. J 
Med Chem 2012; 55: 8700–11.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
70/85
17. International Conference on Harmonization of Technical Requirements for Registration 
of Pharmaceuticals for Human Use - ICH Harmonized Tripartite Guideline - Guideline 
for Good Clinical Practice E6(R1) - June 10th, 1996.
18. Jung-Cook H. Pharmacokinetic variability of anthelmintics: implications for the 
treatment of neurocysticercosis. Expert Rev Clin Pharmacol 2012; 5: 21–30.
19. Kearns GL, Abdel-Rahman SM, Alander SW et al. Developmental pharmacology-drug 
disposition, action, and therapy in infants and children. N Engl J Med 2003; 349: 1157–
67.
20. Mandour ME, el Turabi H, Homeida MM et al. Pharmacokinetics of Praziquantel in 
healthy volunteers and patients with schistosomiasis. Trans R Soc Trop Med Hyg 1990; 
84: 389–93.
21. Manneck T, Braissant O, Haggenmu¨ ller Y et al. Isothermal microcalorimetry to study 
drugs against Schistosoma mansoni. J Clin Microbiol 2011; 49: 1217–25.
22. Meier H, Blaschke G. Investigation of Praziquantel metabolism in isolated rat 
hepatocytes. J Pharm Biomed Anal 2001; 26: 409–15.
23. Meister I, Ingram-Sieber K, Cowan N, et al. Activity of Praziquantel enantiomers and 
main metabolites against Schistosoma mansoni. Antimicrob Agents Chemother. 2014; 58 
(9):5466-72.
24. Merck, Cisticid (Praziquantel) tablets prescribing information, July 2007.
25. Mexican Official Standard for Drugs and Herbal Remedies Labeling (NOM-072-SSA1-
2012).
26. Mexican Official Standard for Medical Charts (NOM-004-SSA3-2012).
27. Mexican Official Standard for the Prevention, Treatment and Control of Hypertension 
(NOM-030-SSA2-1999).
28. Mexican Official Standard which states tests and procedures to prove that a drug is 
interchangeable. Requirements which authorized third parties should
fulfill for 
interchangeability tests. Requirements for performing biocomparability studies. 
Requirements which authorized third parties, investigational sites and hospitals 
conducting biocomparability tests should fulfill (NOM-177-SSA1-2013).
29. Mexican Official Standard. Setting-up and Operations of Pharmacovigilance (NOM-220-
SSA1-2016).
30. Olliario P, Delgado-Romero P, Keiser J. The little we know about the pharmacokinetics 
and pharmacodynamics of praziquantel (racemate and R-enantiomer).  Antimicrob 
Chemother 2014; 69: 863–870.
31. Piero Olliaro, Petra Delgado-Romero and Jennifer Keiser. The little we know about the 
pharmacokinetics and pharmacodynamics of praziquantel (racemate and R-enantiomer). J 
Antimicrob Chemother 2014; 69: 863–870.
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
71/85
32. Putter J, Held F. Quantitative studies on the occurrence of Praziquantel in milk and 
plasma of lactating women. Eur J Drug Metab Pharmacokinet 1979; 4: 193–8.
33. Ridtitid W, Wongnawa M, Mahatthanatrakul W et al. Rifampin markedly decreases 
plasma concentrations of Praziquantel in healthy volunteers. Clin. Pharmacol Ther 2002; 
72: 505–13.
34. Utzinger J, Keiser J. Schistosomiasis and soil-transmitted helminthiasis: common drugs 
for treatment and control. Expert Opin Pharmacother 2004; 5: 263–85.
35. Westhoff F, G. Blaschke G, High-performance liquid chromatographic determination of 
the stereoselective biotransformation of the chiral drug praziquantel Journal of 
Chromatography 1992; 578: 265-71.
36. WHO Prequalification Notes on the design of bioequivalence study: Praziquantel. 
Guidance Document. 13 October 2015.
37. WHO Technical report series 992, WHO Expert Committee on Specifications for 
Pharmaceutical Preparations. Forty-ninth report. 2015. Annex 7.
38. WHO. Preventive Chemotherapy in Human Helminthiasis: Coordinated Use of 
Anthelminthic Drugs in Control Interventions: A Manual for Health Professionals and 
Programme Managers. Geneva: WHO, 2006.
39. Investigator Brochure MSC1028703A L-PZQ 2.1
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
72/85
12
Appendices
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
73/85
12.1
Appendix 1:
Diet to be given to the Participating Subjects
Diet to be given to subjects following dose in each of the periods will be the same in quantity 
and content to that provided during the previous period.
Study breakfast: Ham sandwich, 240 mL of whole milk, ½ piece of gelatin water and fruit 
(melon, papaya with maple syrup) containing 302.5 Kilocalories (76 g) carbohydrates, 82.5
Kilocalories (21 g) proteins and 165 Kilocalories (18 g) Lipids for a total of 550 Kilocalories.
The rest of the diet (such as lunch, dinner and snacks) will be as shown in the following Table 9
Below:
Table 9
Diet Energy Distribution for the Study (Lunch, Dinner and Snacks)
Energetic Distribution
Group
%
g
Kilocalories
Carbohydrates
55 g
275 g
1100
Proteins
15 g
75 g
300
Lipids
30 g
67 g
600
Total Kcal
----
----
2000
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
74/85
12.2
Appendix 2:
Schedule of Assessments 
Activity/Assessment
Screening 
(Baseline)
End of Treatment / safety FU
Study Week
Day -21 to -
1
-1 D
Day 1/8/15
Day 2/9/16
Day 22 (+ 7 days)
Study Day
-1 h
-0.5 h
0 h
4 h
24 h
ICF signature
X
Demographics, medical history and history of medication
X
Smoking history, alcohol intake, use of caffeine or xanthine-
containing beverages
X
Serology test
X
Physical examination3
X
X
X
Vital signs (BP, HR, Temperature)5
X
X
X
X
X
12-Lead-ECG
X
X
X
X4
Safety lab tests 
X
X
X
X
Drug screening urine
X
X
Oral alcohol test
X
Confinement 1
[---------X-------------------------]
Breakfast
X
In/exclusion criteria check/recheck
X
X
X
Administration of IMP
X
PK sampling 2
[----X------------------------------]
AE and concomitant medication
[---------X-----------------------------------------------------]
*At visits where assessment time points coincide with each other, the following procedure should be followed:  perform vital signs and ECG assessments within 15 min before the 
specific time point and PK blood sampling on time.
1
Confinement from the evening of Day -1 (at least 12 hours prior to each IMP administration on Day 1) until the morning of Day 2.
2
PK sampling at pre-dose, 0.25, 0.5, 0.75, 1.0, 1.5, 2.0, 2.5, 3.0, 3.5, 4.0, 4.5, 5.0, 5.5, 6.0, 6.5, 7.0, 8.0, 9.0, 10.0 and 12 hours
3
According to the CRO procedure.
4
ECG .
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
75/85
5
VS will be measurement predose, 3, 7, 11 and 24 h after IMP administration
Biochemistry (albumin, alanine aminotransferase, aspartate aminotransferase, protein total, total bilirubin, conjugated bilirubin, unconjugated bilirubin, globulin, albumin/ globulin 
ratio, blood urea nitrogen, glucose, urea, creatinine, uric acid, cholesterol and triglycerides)
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
76/85
12.3
Appendix 3:
Normal laboratory parameters 
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
77/85
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
78/85
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
79/85
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
80/85
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
81/85
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
82/85
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
83/85
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
84/85
12.4
Appendix 4:
Signature Pages and Responsible Persons for 
the Trial 
C
l
i
n
i
c
a
l
 
U
n
i
t
Name:
Signature
Role:
 
Date:
Name:
Signature:
Role:
Date:
Name:
Signature:
Role:
Date:
Name:
Signature:
Role:
Date:
Address:
Telephone:
A
n
a
l
y
t
i
c
a
l
 
U
n
i
t
 
Name:
Signature:
Role:
Date:
Name:
Signature:
Role:
 
Date:
Address:
Telephone:
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Substance Code
Praziquantel
Short title Praziquantel Bioequivalence Study 
Protocol Number
MS 200585-0002
85/85
S
p
o
n
s
o
r
Name
Signature:
Role:
Date:
Address:
Merck,S.A. de C.V. Calle 5, No. 7, Frac. Industrial Alce Blanco, Nuacalpan de 
Juárez., México, C.P. 53370
Telephone:
Name
Signature:
Role:
Date:
Address:
Merck Institute for Pharmacometrics, – Building I, CH-1015 Lausanne, 
Switzerland, an affiliate of Merck KGaA, Darmstadt, Germany.
Telephone:
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2. Table of Contents 
 
 
 
1 
 
Singature page 
2
2 
 
Table of contents 
3
3 
 
List of abbreviation and definition of terms 
4
4 
 
Modification history 
6
5 
 
Purpose of the statistical analysis plan 
6
6 
 
Summary of clinical trial features 
6
 6.1 Primary objectives and endpoint 
6
 6.2 Secondary objectives and endpoint 
7
 6.3 Overall trial design and plan 
7
7 
 
Sample size 
8
8 
 
Overview of planned analyses 
9
 8.1 Interim analysis 
9
9 
 
Changes to the planned analyses in the clinical trial protocol 
10
10 
 
Protocol deviations and analysis sets 
10
 10.1 Definition of protocol deviations and analysis sets 
10
11 
 
General specifications of statistical analyses 
11
12 
 
Protocol deviations   
11
 12.1 Important protocol deviations 
11
 12.2 Reasons leading to the exclusion from an analysis set 
11
13 
 
Demographics and other baseline characteristics 
12
 13.1 Demographics   
12
14 
 
Treatment compliance and exposure 
13
15 
 
Endpoint evaluation 
14
 15.1 Primary endpoint analyses 
14
 15.2 Bioavailability statistics 
14
 15.3 Box and whiskers plots 
17
 15.4 Secondary endpoint analyses 
20
 15.5 Other endpoint analyses 
22
16 
 
Estimation of individual pharmacokinetic parameters 
32
17 
 
Safety evaluation 
34
 17.1 Pharmacokinetic parameter's outliers 
34
18 
 
Averse events 
38
19 
 
References 
38
20 
 
Appendices 
38
 
 


BD1604-12CEC  
Bioavailability of a Praziquantel fixed combination tablet 
 
MS200585-0002 
Version 1.0 
 
 
3  
List of Abbreviations and Definition of Terms  
 
 
AE  
Adverse Event  
AUC   
Area under the plasma concentration-time curve  
AUC0→∞   
The AUC from time zero (dosing time) extrapolated to infinity  
AUC0→t   
The AUC from time zero (= dosing time) to the last sampling time (t
last) at 
which the concentration is at or above the lower limit of quantification  
AUCextra%   
The AUC from time t
last extrapolated to infinity given as percentage of 
AUC0→  
BE  
Bioequivalence  
BMI   
Body Mass Index  
CI  
Confidence Interval  
CL/f   
The apparent total body clearance of drug following extravascular 
administration.  
Cmax   
Maximum observed plasma concentration  
CRF   
Case Report Form  
CRO   
Contract Research Organization  
CSR   
Clinical Study Report  
CTR   
Clinical Trial Report  
CTMS   
Clinical Trial Management System  
CTP   
Clinical Trial Protocol  
CV  
Coefficient of Variation (%)  
CYP   
Cytochrome P 450  
ECG    
Electrocardiogram  
ECOG    
Eastern Cooperative Oncology Group  
eCRF   
Electronic Case Report Form  
GCP   
Good Clinical Practice  
GeoCV%   
Geometric Coefficient of Variation  
GeoMean   
Geometric Mean  
GIR  
Glucophage Immediate Release   
HR  
Hazard ratio  


BD1604-12CEC 
Bioavailability of a Praziquantel fixed combination tablet 
 
MS200585-0002 
Version 1.0 
 
HAV  
Hepatitis A Virus  
HbA1C  
Glycosylated Hemoglobin Type A1C   
HBsAg  
Hepatitis B Surface Antigen  
HCV  
Hepatitis C Virus  
HIV  
Human Immunodeficiency Virus  
ICF  
Informed Consent Form  
ICH  
International Conference on Harmonization  
IMP  
Investigational Medicinal Product  
LLOQ  
Lower Level of Quantification  
Max  
Maximum  
Mean  
Arithmetic mean  
Min  
Minimum  
MedDRA  
Medical Dictionary For Regulatory Activities  
MRI  
Magnetic Resonance Imaging  
MSS  
Merck Santé s.a.s. in Semoy  
N  
Number of non-missing observations  
PK  
Pharmacokinetics  
PR  
Partial Response  
PT  
Preferred team  
QoL  
Quality of Life  
SAE  
Serious Adverse Event  
SASS  
Sino-American Shanghai Squibb Pharmaceuticals Ltd  
SAP  
Statistical Analysis Plan  
SBP  
Systolic Blood Pressure  
SD  
Standard Deviation  
SDTM  
Study Data Tabulation Model  
SEM  
Standard Error of the Mean  
SOC  
System Organ Class  
t1/2  
Apparent terminal half-life  
T2DM  
Type 2 Diabetes Mellitus  
TEAE  
Treatment-Emergent Adverse Event  
TLF  
Tables, Listings, and Figures  


BD1604-12CEC 
Bioavailability of a Praziquantel fixed combination tablet 
 
MS200585-0002 
Version 1.0 
 
tlast  
The last sampling time at which the concentration is at or above the lower 
limit of quantification  
tmax  
The time to reach the maximum observed concentration   
TP  
Treponema Pallidum  
Vz/f  
Apparent volume of distribution during the terminal phase following 
extravascular administration  
λz  
Terminal elimination rate constant  
WHO  
World Health Organisation  
  
4  
Modification History  
 
 
 
5  
Purpose of the Statistical Analysis Plan  
The purpose of this SAP is to document technical and detailed specifications for the final analysis 
of data collected for protocol BD1604-12CEC MS200585-002. Results of the analyses described 
in this SAP will be included in the Clinical Study Report (CSR). Additionally, the planned analyses 
identified in this SAP will be included in regulatory submissions or future manuscripts. Any post-
hoc.   
The SAP is based upon section 9 (Statistical and Pharmacokinetical Analysis) of the trial protocol 
and is prepared in compliance with ICH E9.  
6  
Summary of Clinical Trial Features  
6.1  
Primary Objectives and Endpoints  
 
  To demonstrate bioequivalence of the fixed combination of praziquantel tablets 600 mg as 
Cisticid® product compared to Biltricide® tablets 600 mg, given as single dose to 1200 mg, 
healthy volunteers in fasting state.  
 Calculate the primary endpoints AUC0-t, AUC0-∞ and Cmax. 
 
 
Unique  
Identifier for  
SAP Version 
DATE OF SAP 
Version  
Author
CHANGE 
DESCRIPTION from the 
previous version 
LEVEL 
 
May 2019 
DRM 
New Document 
1.0 


BD1604-12CEC 
Bioavailability of a Praziquantel fixed combination tablet 
 
MS200585-0002 
Version 1.0 
 
6.2  
Secondary Objectives and Endpoints  
• 
The secondary endpoints variable are volume of distribution Ke, half-life elimination, 
clearance, and median residence time all these parameters will be presented only for 
informative reasons for both medications. 
• 
To compare the safety and tolerability of all the experimental treatments. 
 
6.3 
Overall Trial Design and Plan  
This randomized, open-label, single dose, a 3-periods and 3-sequences crossover design  with a 7-
day wash-out period.    
The bioequivalence will be evaluated with primary endpoints are AUC0-t, AUC0-∞ or Cmax for 
enantiomers and racemic mixture of praziquantel.  
 
The subjects will be randomized to one of the 2 treatment in 3 periods, 3 sequences (see table 
below). Ten subjects will be randomized to each treatment sequence with a minimum proportion 
of 30% for each sex in each treatment sequence.  
 
Sequence 
Period 1 
Wash-out 
period 
Period 2 
Wash-out 
period 
Period 3 
PRR 
Cisticid®
Biltricide® 
Biltricide® 
RPR 
Biltricide® 
Cisticid® 
Biltricide® 
RRP 
Biltricide® 
Biltricide® 
Cisticid® 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
7  
Sample Size  
The sample size estimation is based on the CV intrasubject variability of praziquantel.  
 
 


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BD1604-12CEC 
Bioavailability of a Praziquantel fixed combination tablet 
 
MS200585-0002 
Version 1.0 
 
CLASS SEQ SUBJ PER TRT GROUP;  
MODEL LNPARAM=SEQ PER TRT GROUP GROUP*TRT SUBJ(TRT)/ DDFM= 
SATTERTH; 
LSMEANS TRT/ ADJUST=T PDIFF CL ALPHA=0.10. 
TEST H=SEQ E=SUBJ(TRT); 
RUN; 
QUIT; 
 
Statistical analysis for secondary parameters 
The secondary pharmacokinetics parameters (Tmax, AUCextrapolated, t½, Cl/F and Vd/F) going 
to be analyzed by descriptive statistics  
 
 
 
9  
Changes to the Planned Analyses in the Clinical Trial Protocol  
The statistical methods as described in the protocol were adopted.   
There are no changes to the planned analyses.  
10  
Protocol Deviations and Analysis Sets  
10.1  
Definition of Protocol Deviations and Analysis Sets  
All deviations should be justified with statistical or scientific data and any change to the original 
statistical plan should be documented, in the study master file and in the pharmacokinetics 
statistical report as well as in the final study report. Subjects' data will not be replaced. Any missing 
data will be considered as non-existent data. Likewise, data cannot be removed from the statistical 
analysis, except in the following events. 
 Research Subjects with Pre-dose Concentrations in the Biological Matrix 
In the event pre-dose concentration is < 5 % of the Cmax value for a research subject, subject's data 
can be included without any adjustment to measurement and pharmacokinetic calculations. When 
pre-dose value is > 5 % of the Cmax, research subject should be removed from all study 
bioequivalence assessments. 
 Exclusion of data due to vomit or diarrhea. 
Data from research subjects who experience vomiting and diarrhea throughout the bioequivalence 
study for immediate release products can be removed from the statistical analysis if vomiting and 
diarrhea occur before 2 fold the median for tmax or 2 fold tmax value obtained from the research 
subject in a given period.  
 Research subject with very low plasma concentrations for study drugs. 


BD1604-12CEC 
Bioavailability of a Praziquantel fixed combination tablet 
 
MS200585-0002 
Version 1.0 
 
As established by NOM-177-SSA1-2013, research subjects in a cross designed who 
provide evaluable data for test drug and reference drug, or who do not have evaluable data in the 
single period of a parallel design, should not be either included in the statistical analysis. 
It is considered that a research subject has very low concentrations, if the AUC is lower than 5 % 
of the geometric means for the reference drug's AUC (it should be calculated without including 
outliers). Exclusion of data due to this reason will only be accepted prior scientific rationale and 
review of the case by the COFEPRIS. 
 
11  
General Specifications for Statistical Analyses  
Pharmacokinetic parameters (non-compartmental analysis) and statistical analysis for determining 
bioequivalence will be calculated using Phoenix WinNonlin 8.0 software. 
The results of this trial will be reported using summary tables, figures, and data listings, as 
appropriate. All data will be summarized by treatment and/or scheduled time point, as appropriate.  
12  
Protocol Deviations  
12.1  
Important Protocol Deviations  
Not applicable. No deviation was observed in the study 
12.2  
Reasons Leading to the Exclusion from an Analysis Set  
 Research Subjects with Pre-dose Concentrations in the Biological Matrix 
In the event pre-dose concentration is less than 5 % of the Cmax value for a research subject, subject's 
data can be included. When pre-dose value is greater than 5 % of the Cmax, research subjects data 
should be removed from all study of food effect on bioavailability. 
 Exclusion of data due to vomit or diarrhea. 
Data from research subjects who experience vomiting and diarrhea throughout the study for 
immediate release products can be removed from the statistical analysis if vomiting and diarrhea 
occur before 2 fold the median for tmax or 2 fold tmax value obtained from the research subject in a 
given period.  
 Research subject with very low plasma concentrations for study drugs. 
As established by NOM-177-SSA1-2013, research subjects in a cross designed who 
provide evaluable data for test drug and reference drug, or who do not have evaluable data in the 
single period of a parallel design, should not be either included in the statistical analysis. 
It is considered that a research subject has very low concentrations, if the AUC is lower than 5 % 
of the geometric means for the reference drug's AUC (it should be calculated without including 
outliers). Exclusion of data due to this reason will only be accepted prior scientific rationale and 
review of the case by the COFEPRIS. 


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BD1604-12CEC 
Bioavailability of a Praziquantel fixed combination tablet 
 
MS200585-0002 
Version 1.0 
 
 
 
 
 
 
 
 
Figure 15.3.1 Box and Whiskers Plot for the L-praziquantel Pharmacokinetic Parameters 
 
a)  
   
b) 
   
c) 
     
d) 
    
 
a) 
Plot for the tmax parameter, b) Plot for the Cmax, 
c) Plot for the AUC0-t; and d) Plot for the AUC0-. 
Form P is the Cisticid® test formulation, form R1 is Biltricide® first administration and formulation R2 is Biltricide® 
second administration 
 
 
 
 
 


BD1604-12CEC 
Bioavailability of a Praziquantel fixed combination tablet 
 
MS200585-0002 
Version 1.0 
 
 
 
 
 
 
 
Table 15.3.2. Box and Whiskers Plot for the racemic mixture of praziquantel Pharmacokinetic 
Parameters  
 
a) 
     
b) 
   
c) 
     
d) 
      
 
a) 
Plot for the tmax parameter, b) Plot for the Cmax, 
c) Plot for the AUC0-t; and d) Plot for the AUC0-. 
Form P is the Cisticid® test formulation, form R1 is Biltricide® first administration and formulation R2 is Biltricide® second 
administration 
 
As shown in figure 15.3.2, the tmax parameter has no differences in the variation following  
 


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