Conditions: Healthy
Keywords: Bioavailability Bioequivalence Praziquantel Cesol Pharmacokinetics
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 36
Healthy volunteers: yes

Brief summary:
The purpose of this study is to assess the bioequivalence (BE) of new coated Cesol tablet (Test) versus Biltricide tablets (Comparator) in healthy male participants. Praziquantel (rac-PZQ) is the active ingredient for Cesol and Biltricide tablets.

Detailed description:

Arms:
arm 1: Participants will receive first dose of Cesol on Day 1 in treatment period 1 followed by first dose of Biltricide on Day 8 in treatment period 2 followed by second dose of Cesol on Day 15 in treatment period 3 followed by second dose of Biltricide on Day 22 in treatment period 4. A washout period of 7 days will be maintained between 4 treatment periods. arm 2: Participants will receive first dose of Biltricide on Day 1 in treatment period 1 followed by first dose of Cesol on Day 8 in treatment period 2 followed by second dose of Biltricide on Day 15 in treatment period 3 followed by second dose of Cesol on Day 22 in treatment period 4. A washout period of 7 days will be maintained between 4 treatment periods.

Interventions: intervention 1: Cesol (Test) intervention 2: Biltricide (Reference)
Intervention descriptions: intervention 1: Participant will receive coated cesol tablet in sequence 1 (Day 1 and Day 15) and in sequence 2 (Day 8 and Day 22). A washout period of 7 days will be maintained between 4 treatment periods. intervention 2: Participant will receive biltricide tablet in Sequence 1 (Day 8 and Day 22) and in sequence 2 (Day 1 and Day 15). A washout period of 7 days will be maintained between 4 treatment periods.

Protocol document:
Prot_000.pdf: 
Praziquantel
Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004

Appendix 16.1.1
List of Protocols and Protocol Amendments
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MS200585_0004
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Clinical Study Protocol
Title Page
Clinical Study Protocol Title:
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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 © 2020 by Merck KGaA, Darmstadt, 
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
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1
Protocol Summary
1.1
Synopsis
Protocol Title: $ 3KDVH , RSHQODEHO UDQGRPL]HG IRXUSHULRG FURVVRYHU IXOO\ UHSOLFDWHG
UHIHUHQFHVFDOHGVLQJOHFHQWHUVWXG\ WRDVVHVVWKHELRHTXLYDOHQFHRIDVLQJOHRUDOGRVHRI PJ
RIWKH FRDWHG &HVROWDEOHWIRUPXODWLRQYHUVXVFRPSDUDWRU%LOWULFLGHLQKHDOWK\PDOHYROXQWHHUV
Short Title: %LRHTXLYDOHQFHVWXG\ RIFRDWHG&HVROWDEOHWIRUPXODWLRQYV%LOWULFLGH
Rationale: $VDUHTXLUHPHQWIRUWKHSUD]LTXDQWHOGRQDWLRQSURJUDPE\0HUFN.*D$WKH:+2
UHTXHVWHGWKHGHYHORSPHQWRIDQLPSURYHGIRUPXODWLRQRISUD]LTXDQWHOPJ WDEOHWV7KLVVWXG\
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E\WKH:+23UHTXDOLILFDWLRQ7HDP0HGLFLQHV
Objectives and Endpoints:
Objectives
Endpoints (Outcome Measures)
Primary
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Secondary
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
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Overall Design: 7KLVLVD3KDVH,FURVVRYHURSHQODEHOVLQJOHGRVHIXOO\UHSOLFDWHGUHIHUHQFH
VFDOHGUDQGRPL]HGSHULRGFOLQLFDOSKDUPDFRORJ\VWXG\ WRDVVHVVWKHUHODWLYHELRDYDLODELOLW\RI
FRDWHG&HVROWDEOHWVYHUVXVYV%LOWULFLGHLQKHDOWK\PDOHYROXQWHHUV
Number of Participants:  SDUWLFLSDQWV DUH SODQQHG WR EH UDQGRPL]HG  SDUWLFLSDQWV SHU
VHTXHQFH,IRUPRUHSDUWLFLSDQWVGURSRXWRIWKHVWXG\EHIRUHFRPSOHWLQJSHULRGDGGLWLRQDO
SDUWLFLSDQWVPD\EHUDQGRPL]HGWRPHHWWKHUHTXLUHGPLQLPDOQXPEHURIHYDOXDEOHSDUWLFLSDQWV
1  
Study Intervention Groups and Duration: 3DUWLFLSDQWV ZLOO EH UDQGRPL]HG WR RQH RI WZR
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GHVLJQWKHQXPEHUDIWHU7DQG5 UHIHUVWRWKHILUVWRU VHFRQGDGPLQLVWUDWLRQRIWKHWHVWRU UHIHUHQFH
SURGXFWUHVSHFWLYHO\ ZLWKLQWKHDVVLJQHGVHTXHQFH
Involvement of Special Committee(s): 1R
1.2
Schema
Period 1
Period 2
Period 3
Period 4
Sequence 1
(18 participants)
Test 1
Washout 
at least 7 
days
Reference
1
Washout 
at least 7 
days
Test 2
Washout 
at least 7 
days
Reference
2
Sequence 2
(18 participants)
Reference
1
Test 1
Reference
2
Test 2
Test = coated Cesol tablet, 2 tablets of praziquantel 600 mg; 
Reference = Biltricide, 2 tablets of praziquantel 600 mg.
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
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1.3
Schedule of Activities
Activity/Assessment
Screening 
(Baseline)
Treatment Period 1, 2, 3 and 4
End of 
Treatment 
/ Safety 
Follow-up
Comments
Study Day
Day -28 
to -1
Day 
-1/7/14/21
Day 1/8/15/22a
Day 
2/9/16/23
Day 27 
(+ 3 days)
a Assuming 7 days for washout between 
the 4 treatment periods.
Period Day
-1
1
2
Study Day timepoints
-1 h
-0.5 h
0 h
24 h
ICF signature available
X
Demographics (incl.
BW and BMI), medical 
history and history of 
medication
X
Smoking history, 
alcohol intake, use of 
caffeine or xanthine-
containing beverages
X
Serology test
X
Physical examinationb
X
X
X
b According to the CRO procedure.
Vital signsc (BP, HR, 
body temperature)
X
X
X
X
X
c 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.
12-Lead-ECGc
X
X
X
X
c 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.
Safety lab tests 
X
X
X
X
Drug screening urine
X
X
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PZQ
Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004

Activity/Assessment
Screening 
(Baseline)
Treatment Period 1, 2, 3 and 4
End of 
Treatment 
/ Safety 
Follow-up
Comments
Study Day
Day -28 
to -1
Day 
-1/7/14/21
Day 1/8/15/22a
Day 
2/9/16/23
Day 27 
(+ 3 days)
a Assuming 7 days for washout between 
the 4 treatment periods.
Period Day
-1
1
2
Study Day timepoints
-1 h
-0.5 h
0 h
24 h
Alcohol breath test
X
X
Confinementd
[----------------------------------X---------------------------------------]
d Confinement from the morning of 
Day -1/7/14/21 (about 20-24 hours prior 
to each IMP administration) until the 
morning of Day 2/9/16/23.
Standardized breakfast
X
In/exclusion criteria 
check/recheck
X
X
X
Randomization
Xf
f Randomization will be performed in 
eligible participants on Day 1 only.
Administration of IMP
X
PK samplingc,e
          [-------X----]
c 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.
e PK sampling at predose, 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.
AE and concomitant 
medication
X
[------------------------------------------------X-----------------------------------------------]
AE=adverse events; BP=blood pressure; CRO=Contract Research Organization; ECG=electrocardiogram; HR=heartrate; ICF=informed consent form; 
IMP=investigational medicinal product; PK=pharmacokinetics.
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
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2
Introduction
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004

Table 1
Praziquantel enantiomers
Generic Name
Abbreviations
Alternate names
MSC# (Refers 
only to drug 
substance 
synthesized by 
the Sponsor)
Praziquantel
rac-PZQ
Generic: racemic Praziquantel
Trade: Biltricide, Cisticid, Cysticide, Cesol, Cestox
MSC1028703A
Enantiomers
Levo-
Praziquantel
L-PZQ, R-(−)-
praziquantel
R-(-)-Praziquantel, R-Praziquantel, L-Praziquantel, 
R Enantiomer, L Enantiomer
MSC2499550A
Dextro-
Praziquantel
D-PZQ, S-PZQ
D Praziquantel, S-(+)-Praziquantel, D Enantiomer, 
S Enantiomer
MSC2499551A
D-PZQ = Dextro-praziquantel, S-PZQ, MSC2499551A; PZQ = praziquantel; rac-PZQ = racemic praziquantel 
(mixture of L-PZQ and D-PZQ in a 1 to 1 ratio); L-PZQ = levo-praziquantel, R-(−)-praziquantel, MSC2499550A; S-
PZQ = S-(+)-praziquantel, dextro-praziquantel, D-PZQ, MSC2499551A.
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2.2
Background
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Benefit/Risk Assessment
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Table 2
Side effects reported after use of Biltricide
Frequencies
System Organ Class
Very Common
≥1/10
Frequently
≥ 1/100 to < 1/10
Very Rare
<1/10,000
Immune system disorders
Allergic reactions 
Eosinophilia
Nervous system disorders
Headache 
Lightheadedness
Dizziness 
Somnolence
Convulsions
Cardiac disorders
Unspecific arrhythmias
Gastrointestinal disorders
Gastrointestinal and 
abdominal pain 
Nausea
Vomiting
Anorexia
Diarrhea (bloody diarrhea 
is very rare)
Skin and subcutaneous 
tissue disorders
Urticaria
Skin rash
Pruritus
Musculoskeletal and 
connective tissue and 
bone disorders
Myalgia
General disorders and 
administration site 
conditions
Fatigue
General discomfort 
Fever
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MS200585_0004
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3
Objectives and Endpoints
Objectives
Endpoints (Outcome Measures)
Primary
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MS200585_0004
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Scientific Rationale for Study Design
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General
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5
Study Population
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Inclusion Criteria
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Exclusion Criteria
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Diagnostic Assessments
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Other Exclusions
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5.3
Lifestyle Considerations
5.3.1
Meals and Dietary Restrictions
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Caffeine, Alcohol, Tobacco, and Cannabinoids
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5.3.3
Activity
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Screen Failures
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6
Study Intervention(s)
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6.1
Study Intervention(s) Administration
Study Intervention 
Name
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Drug Name on IMP 
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Route of 
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Study Assessments and Procedures
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8.1
Efficacy Assessments and Procedures
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Safety Assessments and Procedures
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Physical Examinations
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Electrocardiograms
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Clinical Safety Laboratory Assessments
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Suicidal Risk Monitoring
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Adverse Events and Serious Adverse Events
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Follow-up of Adverse Events and Serious Adverse Events
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8.3.5
Pregnancy
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8.4
Treatment of Overdose
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MS200585_0004
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8.5
Pharmacokinetics
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Table 3
Pharmacokinetic Parameters Derived from rac-PZQ Concentrations
Cmax
Maximum observed drug concentration. 
tmax
Time of the maximum drug concentration. 
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 of last measurable 
concentration using the linear-log trapezoidal method (linear up log down).
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
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
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8.6
Pharmacodynamics
1RWDSSOLFDEOH
8.7
Pharmacogenetics
1RWDSSOLFDEOH
8.8
Biomarkers
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8.9
Immunogenicity Assessments
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
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9.3
Populations for Analyses
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Analysis Set
Description
Screening (SCR)
All participants, who provided informed consent, regardless of the participant’s randomization 
and study intervention status in the study.
Safety (SAF)
All participants, who were administered any dose of any study intervention. Analyses will 
consider participants as treated.
PK
All participants, who receive at least one dose of study intervention, have no clinically 
important protocol deviations or important events affecting PK, and provide at least one 
measurable postdose concentration. Participants will be analyzed per the actual study 
intervention they received.
The PK population will include all participants:
!
Who have completed at least one study period without any relevant protocol deviations 
and factors likely to affect the comparability of PK results
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With adequate study intervention compliance
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With evaluable PK data, i.e., nonmissing values for primary endpoints in each study 
period.
If participants received prohibited concomitant therapy or medicines, as specified in Section 
6.5, they will be excluded from the PK population. Relevant decisions will be made before 
database lock. All PK analyses will be based on this analysis set.
9.4
Statistical Analyses
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
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9.4.1
Efficacy Analyses
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9.4.2
Safety Analyses
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
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9.4.3
Other Analyses
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Appendix 1
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Appendix 2
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MS200585_0004
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Appendix 3
Contraception
Definitions:
Woman of Childbearing Potential (WOCBP)
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
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Contraception Guidance:
CONTRACEPTIVES ALLOWED DURING THE STUDY INCLUDE:
Highly Effective Methods That Have Low User Dependency
!
Implantable progestogen-only hormone contraception associated with inhibition of ovulation
!
Intrauterine device
!
Intrauterine hormone-releasing system (IUS)
!
Bilateral tubal occlusion
!
Vasectomized partner: a highly effective contraceptive method provided that the partner is the sole sexual 
partner of a WOCBP and the absence of sperm has been confirmed. Otherwise, use an additional highly 
effective method of contraception. The spermatogenesis cycle is approximately 90 days.
Highly Effective Methods That Are User Dependent
!
Combined (estrogen- and progestogen-containing) hormonal contraception associated with inhibition of 
ovulation
o
Oral
o
Intravaginal
o
Transdermal
o
Injectable
!
Progestogen-only hormone contraception associated with inhibition of ovulation
o
Oral
o
Injectable
!
Sexual abstinence: a highly effective method only if defined as refraining from intercourse during the entire 
period of risk associated with the study intervention. The reliability of sexual abstinence needs to be 
evaluated in relation to the duration of the study.
Notes:
Contraceptive use by men or women is consistent with local regulations on the use of contraceptive methods for 
clinical study participants.
Highly effective methods are those with a failure rate of <1% per year when used consistently and correctly. 
Typical use failure rates differ from those when used consistently and correctly.
If locally required, in accordance with Clinical Trial Facilitation Group (CTFG) guidelines, acceptable contraceptive 
methods are limited to those which inhibit ovulation as the primary mode of action.
Periodic abstinence (calendar, symptothermal, post-ovulation methods), withdrawal (coitus interruptus), 
spermicides only, and lactational amenorrhoea method (LAM) are not acceptable methods of contraception for 
this study. Male condom and female condom cannot be used together (due to risk of failure with friction).
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
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Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definitions
Adverse Event
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Severe:
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Related:
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Abnormal Laboratory Findings and Other Abnormal Investigational Findings
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MS200585_0004
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Serious Adverse Events
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MS200585_0004
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Reporting Serious Adverse Events
Serious Adverse Events
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MS200585_0004
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Appendix 5
Clinical Laboratory Tests
Table 4:
Protocol-Required Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet count
Mean Corpuscular Volume
WBC Count with Differentials 
and Absolute Counts a:
!
Neutrophils
!
Lymphocytes
!
Monocytes
!
Eosinophils
!
Basophils
Reticulocytes
Hemoglobin
MCH
Hematocrit
Red Blood Cell Counts
Biochemistry
Blood Urea 
Nitrogen
Creatinine
Glucose;
CK b
Potassium
Sodium
Calcium
Uric acid
Aspartate Aminotransferase
Alanine Aminotransferase
Alkaline phosphatase
γ-Glutamyltransferase
Bilirubin c
Total Protein
Triglycerides
Cholesterol
Routine 
Urinalysis
!
pH, glucose, protein, blood, ketones, [bilirubin, urobilinogen, nitrite, leukocyte esterase] by 
dipstick
!
Microscopic examination d.
Other Tests
Urine drug screen:
amphetamines, methamphetamines, barbiturates, cocaine, opiates, cannabinoids, 
benzodiazepines, methadone, tricyclic antidepressants, 3,4-methylenedioxymethamphetamine, 
and cotinine 
Serology: 
Hepatitis B surface antigen
Hepatitis C antibody
HIV1/HIV2 antibodies
Alcohol breath test
Thyroid-stimulating hormone (TSH)
CK = creatine phosphokinase; CK-MB = CK- myocardium/brain type; HIV = human immunodeficiency virus,
MCH = Mean Cell Hemoglobin; WBC = white blood cell.
a
In case of abnormal findings, manual differential blood count can be requested by the Investigator.
b
In case of an increased CK, CK-MB will be determined; if the ratio of CK-MB/CK is above 6%, troponin will be 
determined as well.
c
In case of an increased bilirubin (total) the direct bilirubin will be determined
d
Only if blood, protein, nitrite, or leukocytes are positive on the dipstick.
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MS200585_0004
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Appendix 6
Protocol Amendment History
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Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
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Appendix 7
Periodic Benefit-Risk Evaluation Report for Praziquantel 
(01 May 2015 to 30 April 2018; Sections 15-18)
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Overview of Signals: New, Ongoing, or Closed
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Increase in Liver Enzymes
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16
Signal and Risk Evaluation
16.1
Summary of Safety Concerns
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Important Identified Risks
16.1.1.1
Cardiac Arrhythmias
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16.1.1.2
Convulsions in Patients with Co-existing Neurocysticercosis
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QHXURF\VWLFHUFRVLV6XFKFDVHVZKLFKPD\RFFXUHVSHFLDOO\LQHQGHPLFUHJLRQVRITaenia solium
Cysticercus cellulosaeVKRXOGEHFODULILHGDVTXLFNO\DVSRVVLEOH
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16.1.2
Important Potential Risks
16.1.2.1
Increases of the Liver Transaminases in Patients with 
Decompensated Hepatic Insufficiency or in Patients with 
Hepatosplenic Schistosomiasis
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16.2
Signal Evaluation
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16.3
Evaluation of Risks and New Information
16.3.1
Important Identified Risks
16.3.1.1
Cardiac Arrhythmias
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RI QRQVHULRXV QRWPHGLFDOO\FRQILUPHG HYHQWVSHUWDLQLQJWRFDUGLDFDUUK\WKPLDV %RWK,&65V
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PPD


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FRQFRPLWDQWPHGLFDWLRQH[LVWH[SODLQLQJWKHUHSRUWHGHYHQW,QDGGLWLRQDQHYLGHQFHEDVHGFDXVDO
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16.3.1.2
Convulsions in Patients with Co-existing Neurocysticercosis
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16.3.2
Important Potential Risks
16.3.2.1
Increases of the Liver Transaminases in Patients with 
Decompensated Hepatic Insufficiency or in Patients with 
Hepatosplenic Schistosomiasis
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DPLQRWUDQVIHUDVH DEQRUPDO´ ³$VSDUWDWH DPLQRWUDQVIHUDVH LQFUHDVHG´ ³*DPPDJOXWDP\O
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PPD


16.4
Characterization of Risks
16.4.1
Important Identified Risks
16.4.1.1
Cardiac Arrhythmias
Frequency: 
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RI QRQVHULRXV QRWPHGLFDOO\FRQILUPHG HYHQWVSHUWDLQLQJWRFDUGLDFDUUK\WKPLDV
Seriousness:
6RPH DUUK\WKPLDV WUXO\ DUH DV\PSWRPDWLF DQG WKHVH DUH XVXDOO\ GLVFRYHUHG GXULQJ D URXWLQH
SK\VLFDO H[DPLQDWLRQ 7KHVH DUUK\WKPLDV FDQ EH FRQVLGHUHG QRQVHULRXV 6RPH V\PSWRPDWLF
DUUK\WKPLDVPD\EHVHULRXVRU OLIHWKUHDWHQLQJ%RWK ,&65VUHSRUWHGFXPXODWLYHO\ QRQVHULRXV
Severity and nature of risk:
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DUUK\WKPLDVPD\EHOLIHWKUHDWHQLQJ1RQOLIHWKUHDWHQLQJ DUUK\WKPLDVPD\KRZHYHUKDYHVHULRXV
ORQJWHUPFRQVHTXHQFHV)RUH[DPSOHDWULDODUUK\WKPLDVWKDWDUHSUHVHQWIRUDWOHDVWRIWKH
GD\DQGUHVXOWLQJLQDQDYHUDJHGDLO\KHDUWUDWHRIDWOHDVWEHDWVSHUPLQXWHPD\OHDGWROHIW
YHQWULFXODUFDUGLRP\RSDWK\DQGFRQJHVWLYHKHDUWIDLOXUH
Background incidence/prevalence:
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WKHPRVW FRPPRQ VXVWDLQHGDUUK\WKPLDZLWK DQHVWLPDWHGSUHYDOHQFHRI PLOOLRQDPRQJDOO
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Risk groups or risk factors:
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RIPHGLFLQHVVRPHRIZKLFKFDQFDXVHDUUK\WKPLDV6RPHPHGLFLQHVXVHGWRWUHDWDUUK\WKPLDVFDQ
HYHQFDXVHDUUK\WKPLDVDVDVLGHHIIHFW6RPHW\SHVRIDUUK\WKPLDKDSSHQPRUHRIWHQLQFKLOGUHQ
DQG \RXQJ DGXOWV 3DUR[\VPDO VXSUDYHQWULFXODU WDFK\FDUGLD LQFOXGLQJ :ROII3DUNLQVRQ:KLWH
V\QGURPHLVPRUHFRPPRQLQ\RXQJSHRSOH$UUK\WKPLDVDUHPRUHFRPPRQLQSHRSOHZKRKDYH
GLVHDVHVRUFRQGLWLRQVWKDWZHDNHQWKHKHDUWVXFKDVKHDUWDWWDFNKHDUWIDLOXUH RU FDUGLRP\RSDWK\
KHDUWWLVVXHWKDW
VWRRWKLFNRUVWLIIRUWKDWKDVQ
WIRUPHGQRUPDOO\OHDNLQJRUQDUURZHGKHDUWYDOYHV
ZKLFKPDNHWKHKHDUWZRUNWRRKDUGDQGFDQOHDGWRKHDUWIDLOXUHFRQJHQLWDOKHDUWGHIHFWV WKDW
DIIHFWWKHKHDUW
VVWUXFWXUHRUIXQFWLRQDQGRWKHUFRQGLWLRQVDOVRFDQUDLVHWKHULVNIRUDUUK\WKPLDV
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GLDEHWHVVOHHSDSQHDDQRYHUDFWLYHRUXQGHUDFWLYHWK\URLGJODQGKHDUWVXUJHU\FHUWDLQGUXJVVXFK
DVFRFDLQHRUDPSKHWDPLQHVRUDQLPEDODQFHRIFKHPLFDOVRURWKHUVXEVWDQFHVVXFKDVSRWDVVLXP
LQWKHEORRGVWUHDPKWWSVZZZQKOELQLKJRYQRGH6FDUULQJRUDEQRUPDOWLVVXHGHSRVLWV
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FRQGXFWLRQ/LNHZLVHWKH\FDQFDXVHWDFK\FDUGLDRULJLQDWLQJLQHLWKHUWKHDWULDRUYHQWULFOHVE\
FDXVLQJ FHOOV WR ILUH DEQRUPDOO\ RU E\ FUHDWLQJ LVODQGV RI HOHFWULFDOO\ LQHUW WLVVXH
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8QGHUVWDQG<RXU5LVNIRU$UUK\WKPLDB8&0BB$UWLFOHMVS:]60:8]D
Potential mechanisms:
3UD]LTXDQWHOLVDUDFHPLFPL[WXUHRI/3=4 DQG'3=47KH/3=4HQDQWLRPHU KDVDEHWWHU
WR[LFRORJLFDOSURILOHWKDQ'3=4RUUDF3=4)RUH[DPSOHLQUDEELWVWKDWZHUHDGPLQLVWHUHGD
VLQJOH  PJNJ LQWUDYHQRXV GRVH RI '3=4 UDF3=4 RU /3=4 WKH IUHTXHQFLHV RI HFWRSLF
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PJNJLQWUDYHQRXVGRVHRISUD]LTXDQWHODUUK\WKPLDDQGEUDG\FDUGLDDSSHDUHGLQPRVWRIWKHP
7KHVHYHULW\RIDUUK\WKPLDDQGEUDG\FDUGLDLQGXFHGE\'3=4 ZDVKLJKHUWKDQWKDWLQGXFHGE\/
3=4$UUK\WKPRJHQLF HIIHFWVRI SUD]LTXDQWHOPD\ SDUWO\EH PHGLDWHGYLDWKHFHQWUDOQHUYRXV
V\VWHPDQGWKHDUUK\WKPRJHQLFHIIHFWVRISUD]LTXDQWHOPD\EHFDXVHGPDLQO\E\'3=4>;LDRHW
DO@
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VFKLVWRVRPLDVLV>%DUWOH\3@ SchistosomaLQGXFHGSXOPRQDU\K\SHUWHQVLRQFDUULHVDJUDYH
SURJQRVLV VLQFH LW XVXDOO\ GHQRWHV DQ DGYDQFHG VWDJH RI KHSDWRVSOHQLF VFKLVWRVRPLDVLV
7KURPERVLVLQVLWXSDUWLFXODUO\RIWKHULJKWSXOPRQDU\DUWHU\DVZHOODVFDUGLDFDUUK\WKPLDVDQG
VXGGHQFDUGLDFGHDWKV\QGURPHV PD\RFFXU>+LGURQ$HWDO@
Preventability:
3DWLHQWV ZLWK FDUGLDF DUUK\WKPLDV VKRXOG EH PRQLWRUHG UHJXODUO\ GXULQJ WKHUDS\ 5RXWLQH
HOHFWURFDUGLRJUDPPRQLWRULQJFRXOGEHFRQVLGHUHGIRUHDUO\GHWHFWLRQ
3DJHRI


Impact on individual patient:
'HSHQGLQJRQWKHVHULRXVQHVVSDWLHQWVPD\EHVOLJKWO\RUVHYHUHO\DIIHFWHG 6RPHSDWLHQWVWUXO\
DUH DV\PSWRPDWLF DQG WKH DUUK\WKPLD FDQ EH GLVFRYHUHG RQO\ GXULQJ D URXWLQH SK\VLFDO
H[DPLQDWLRQ+RZHYHUPRVWSDWLHQWVDUHV\PSWRPDWLFLQVRPHZD\ZKHQDQDUUK\WKPLDRFFXUV
3DWLHQWVKDYLQJSDUR[\VPVRIDUUK\WKPLDPD\KDYHV\PSWRPVRISDOSLWDWLRQVRURXWULJKWKHDUW
UDFLQJ2WKHUV\PSWRPVPD\LQFOXGHFKHVWSDLQSXOVDWLRQVLQWKHQHFNG\VSQHDOLJKWKHDGHGQHVV
IDWLJXHVZHDWLQJ HWF$IWHUDVSHOORIDUUK\WKPLDWKHSDWLHQWPD\KDYHIUHTXHQWXULQDWLRQGXHWR
UHOHDVHRIDWULDOQDWULXUHWLFIDFWRUDSRO\SHSWLGHUHOHDVHGIURPWKHDWULDWKDWVWLPXODWHVGLXUHVLVRU
IHHOIDWLJXHGIRUKRXUVWRGD\V2WKHUDUUK\WKPLDVPD\FDXVHV\QFRSH ZLWKWKHDWWHQGDQWULVNRI
LQMXU\0RUHVHULRXVDUUK\WKPLDVPD\UHVXOWLQFDUGLDFDUUHVWRUGHDWK
Potential public health impact of safety concern:
&DUGLDFDUUK\WKPLDVVKRXOGUHVROYHZLWKDSSURSULDWHWUHDWPHQW,QDGGLWLRQJLYHQWKHXQFRPPRQ
IUHTXHQF\ EDVHGRQWKHFXPXODWLYHUHSRUWLQJUDWH WKHUHLVQRUHOHYDQWLPSDFWRQSXEOLFKHDOWK
Evidence source:
3RVWPDUNHWLQJH[SHULHQFHFXPXODWLYHUHYLHZRIFDVHVDQGOLWHUDWXUHUHYLHZ
16.4.1.2
Convulsions in Patients with Co-existing Neurocysticercosis
3UD]LTXDQWHO VKRXOG EH XVHG ZLWK FDXWLRQ EHFDXVH WKHUH LV D ULVN DOWKRXJK UDUH WKDW WKH
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WULJJHUVHL]XUHV>'HO%UXWWR2+DQG*DUFLD++@ DQG>)RJDQJ<)HWDO@
Frequency:
,QFOLQLFDOWULDOVZLWK3=4QRHYHQWRIFRQYXOVLRQVLQSDWLHQWVZLWKFRH[LVWLQJQHXURF\VWLFHUFRVLV
FRQVLGHUHGDVUHODWHGWR3=4KDYHEHHQUHSRUWHG
$ VHDUFKSHUIRUPHGLQWKH&RPSDQ\6DIHW\GDWDEDVH$5,6JXVLQJ0HG'5$YHUVLRQIRUWKH
604³&RQYXOVLRQV´EURDGVFRSHDQG37³1HXURF\VWLFHUFRVLV´GLGQRWUHYHDODQ\FDVHV
Seriousness:
&RQYXOVLRQVLQDSDWLHQWZLWKFRH[LVWLQJQHXURF\VWLFHUFRVLVLVVHULRXVEXWLVXVXDOO\UHYHUVLEOH
ZLWKDGHTXDWHWUHDWPHQW
Severity and nature of risk:
7KHFRQYXOVLRQVFDQEHVHULRXVRU OLIHWKUHDWHQLQJDQGLQWKHDEVHQFHRISRWHQWFRUWLFRVWHURLG
WUHDWPHQWPD\EHIDWDO
3DJHRI


Background incidence/prevalence:
1HXURF\VWLFHUFRVLVLVWKHPRVWFRPPRQKHOPLQWKLFLQIHFWLRQRIWKHFHQWUDOQHUYRXVV\VWHP DQGD
PDMRUFDXVHRIDFTXLUHGHSLOHSV\ZRUOGZLGH &\VWLFHUFRVLVLVFRQVLGHUHGE\WKH:+2WREHWKH
PRVWFRPPRQSUHYHQWDEOHFDXVHRIHSLOHSV\LQWKHGHYHORSLQJZRUOGZLWKDQHVWLPDWHGPLOOLRQ
SHRSOHKDYLQJHSLOHSV\FDXVHGE\Taenia solium LQIHFWLRQ>)RJDQJ<)HWDO@ 6\PSWRPDWLF
QHXURF\VWLFHUFRVLV DFFRXQWV IRU DSSUR[LPDWHO\ RQHWKLUG RI VHL]XUH GLVRUGHUV LQ GHYHORSLQJ
FRXQWULHVLQVXE6DKDUDQ$IULFD$VLDDQG/DWLQ$PHULFD
$ PHWDDQDO\VLV WKDW RQO\ LQFOXGHG $IULFDQ VWXGLHV VKRZHG D VLJQLILFDQW DVVRFLDWLRQ EHWZHHQ
HSLOHSV\DQGF\VWLFHUFRVLVZLWKDQ25 RI3UHYDOHQFHUDWHVRIIRUQHXURF\VWLFHUFRVLV
ZHUH UHSRUWHG LQ UXUDO VHWWLQJV LQ (FXDGRU 7KH WRWDO QXPEHU RI DOO SHRSOH VXIIHULQJ IURP
QHXURF\VWLFHUFRVLV LQFOXGLQJ V\PSWRPDWLF DQG DV\PSWRPDWLF FDVHV LV HVWLPDWHG VRPHZKHUH
EHWZHHQDQGPLOOLRQEDVHGRQWKHUDQJHRIHSLOHSV\SUHYDOHQFHGDWDDYDLODEOHZKLFKLV
EHWZHHQ  DQG  IRU VXE6DKDUDQ $IULFD ,Q QRQHQGHPLF DUHDV WKH SUHYDOHQFH RI
QHXURF\VWLFHUFRVLV LV WRSHULQKDELWDQWVLQVRPHZHVWHUQVWDWHVRIWKH8QLWHG6WDWHV
DQGLWLVGLDJQRVHGLQPRUHWKDQRISDWLHQWVDWWHQGLQJHPHUJHQF\URRPVEHFDXVHRIVHL]XUHV
>)RJDQJ<)HWDO@
Risk groups or risk factors:
1HXURF\VWLFHUFRVLVLVDPDMRUFDXVHRIDFTXLUHGHSLOHSV\LQPRVWRIWKHGHYHORSLQJZRUOGDQGKDV
EHHQFRQVLGHUHGDVWKHVLQJOHFDXVHH[SODLQLQJWKHLQFUHDVHGLQFLGHQFHDQGSUHYDOHQFHRIHSLOHSV\
LQWKHVHUHJLRQV%ORFKHUHWDO&DUDELQHWDO'HO%UXWWRHWDOO0HGLQDHWDO
 3UHX[ DQG 'UXHW&DEDQDF  9LOODUDQ HW DO  >'HO %UXWWR 2+ DQG *DUFLD ++
@6HL]XUHVPD\RFFXUDWDQ\VWDJHRI&\VWLFHUFL LQYROXWLRQZLWKLQWKHEUDLQSDUHQFK\PD
IURPYLDEOHF\VWVWRFDOFLILFDWLRQV8QK\JLHQLFSUDFWLFHVUHVXOWLQJLQLQJHVWLRQRITaenia solium
HJJVGLUHFWO\IURPDTaenia FDUULHU RUOHVVRIWHQE\FRQWDPLQDWHGIRRG DUHFDXVDOIDFWRUVIRU
F\VWLFHUFRVLV1HXURF\VWLFHUFRVLVLVFRPPRQZKHUHWKHUHLVFOXVWHULQJRIFRQGLWLRQVIDYRULQJWKH
WUDQVPLVVLRQRITaenia soliumLQFOXGLQJORZOHYHORIHGXFDWLRQSRYHUW\GHILFLHQWGLVSRVDORI
KXPDQIHFHVVODXJKWHULQJRISLJVZLWKRXWYHWHULQDU\FRQWURODQGSUHVHQFHRIIUHHURDPLQJSLJV
DURXQGKRXVHKROGV
7KHUDS\ZLWKWKHF\VWLFLGDOGUXJDOEHQGD]ROH GLVUXSWLQJWKHVWDEOHQHXURF\VWLFHUFRVLV GLVHDVHGXH
WRVHFRQGDU\LQIODPPDWLRQ LVDQDGGLWLRQDOULVNIDFWRU>1DVK7(HWDO@
Potential mechanisms:
7KH DQWKHOPLQWKLF WUHDWPHQW PD\ GLVUXSW WKH XVXDO VWDEOH QRQLQIODPPDWRU\ KRVW±SDUDVLWH
UHODWLRQVKLS LQLWLDWLQJ DQ DFXWH LPPXQH UHVSRQVH ZKLFK KDV EHHQ DWWULEXWHG WR LQÀDPPDWLRQ
VHFRQGDU\ WR NLOOLQJ RI WKH F\VWLFHUFL $V DOO SDUDVLWHV DUH DIIHFWHG DW WKH VDPH WLPH FOLQLFDO
GHWHULRUDWLRQLVIUHTXHQW
3DJHRI


Preventability:
$Q\ HDUO\ V\PSWRPV VXJJHVWLYH RI FRQYXOVLRQVLQSDWLHQWVZLWKFRH[LVWLQJQHXURF\VWLFHUFRVLV
VKRXOG EH LQYHVWLJDWHG DQG LI FRQFOXVLYH FRUWLFRVWHURLG WKHUDS\ PD\ EH LQLWLDWHG DORQJ ZLWK
PHGLFDWLRQVWRSUHYHQWRUDOOHYLDWHFRQYXOVLRQV WKDWKDYHFRPPHQFHG
Impact on individual patient:
%HWZHHQWKHQG DQGWK GD\RIWUHDWPHQWZLWK DQDQWLSDUDVLWLFDJHQW WKHUHPD\EHDQH[DFHUEDWLRQ
RIQHXURORJLFV\PSWRPV VXFKDVFRQYXOVLRQVKHDGDFKHQDXVHDDQGYRPLWLQJDQGVHL]XUHVZLWK
JHQHUDOL]DWLRQ PD\ DOVR EH QRWHG $V DOO SDUDVLWHV DUH DIIHFWHG DW WKH VDPH WLPH FOLQLFDO
GHWHULRUDWLRQLVIUHTXHQWDQGLQWKHDEVHQFHRISRWHQWDQWLLQIODPPDWRU\WKHUDS\DQGV\PSWRPDWLF
WUHDWPHQWPD\EHOHWKDO
Potential public health impact of safety concern:
,IWUHDWHGDSSURSULDWHO\ WKHFRQYXOVLRQVLQSDWLHQWVZLWKFRH[LVWLQJQHXURF\VWLFHUFRVLVVKRXOG
UHVROYH ,I XQWUHDWHG WKH FRQYXOVLRQV PD\ SURJUHVV WR D OLIHWKUHDWHQLQJ FRQGLWLRQ DQG WKH
XQGHUO\LQJ QHXURF\VWLFHUFRVLV PD\ IXUWKHU GHWHULRUDWH 7KH SURJQRVLV RI HSLOHSV\ GHSHQGV RQ
PXOWLSOHIDFWRUVUHODWHGWRGHJUHHRILQIHFWLRQDQGKRVWUHVSRQVHWRSDUDVLWH1HDUO\RISDWLHQWV
ZLWKDVROLWDU\FHUHEUDO F\VWLFHUFXV JUDQXORPD KDYHDJRRGVHL]XUHRXWFRPHIROORZLQJUHVROXWLRQ
RIWKHOHVLRQ EXWWKHSURJQRVLVRIHSLOHSV\ LQ SDWLHQWVZLWKPXOWLSOHF\VWVDQGUHVLGXDO FDOFLILFDWLRQV
LV QRW DV EHQLJQ+RZHYHUJLYHQWKHYHU\UDUHIUHTXHQF\WKHUHLVQRUHOHYDQWLPSDFWRQSXEOLF
KHDOWK
Evidence source:
/LWHUDWXUHUHYLHZ
16.4.2
Important Potential Risks
16.4.2.1
Increases of the Liver Transaminases in Patients with 
Decompensated Hepatic Insufficiency or in Patients with 
Hepatosplenic Schistosomiasis
Frequency: 
1R,&65VZHUHUHWULHYHGIROORZLQJDFXPXODWLYHUHYLHZRIWKH&RPSDQ\ VDIHW\GDWDEDVHXSWR
$SU  SHUWDLQLQJ WR WKH ULVN RI LQFUHDVH RI WKH OLYHU WUDQVDPLQDVHV LQ SDWLHQWV ZLWK
GHFRPSHQVDWHGKHSDWLFLQVXIILFLHQF\RULQSDWLHQWVZLWKKHSDWRVSOHQLFVFKLVWRVRPLDVLV
Seriousness:
,QFUHDVH RIWKHOLYHUWUDQVDPLQDVHV LVIUHTXHQWO\QRQVHULRXVEXWPD\EHVHULRXV GHSHQGLQJRQ WKH
OLYHUHQ]\PHYDOXHV
3DJHRI


Severity and nature of risk:
7KHLQFUHDVH RIWKHOLYHUWUDQVDPLQDVHVLQSDWLHQWVZLWKGHFRPSHQVDWHGKHSDWLFLQVXIILFLHQF\RULQ
SDWLHQWVZLWKKHSDWRVSOHQLFVFKLVWRVRPLDVLV VKRXOGEHPRQLWRUHGZLWKFDXWLRQVLQFHGXHWR WKH
UHGXFHG GUXJ PHWDEROLVP LQ WKH OLYHU DQGRU FROODWHUDO FLUFXODWLRQV DSSUHFLDEO\ KLJKHU VHUXP
FRQFHQWUDWLRQVRI SUD]LTXDQWHODUH UHDFKHG DQGWKHKDOIOLIHPD\ EHSURORQJHG ,Q VXFK FDVHV
WUHDWPHQWVKRXOGEHFDUULHGRXWRQDQLQSDWLHQWEDVLV
Background incidence/prevalence:
3UD]LTXDQWHOWKHUDS\KDVEHHQDVVRFLDWHGZLWKHOHYDWLRQVLQVHUXPDPLQRWUDQVIHUDVHOHYHOVLQXSWR
RISDWLHQWVEXWWKHVHDEQRUPDOLWLHVZHUHVHOIOLPLWLQJ3UD]LTXDQWHOKDVQRWEHHQDVVRFLDWHG
ZLWKFOLQLFDOO\DSSDUHQWOLYHULQMXU\ ,QDODUJHUHWURVSHFWLYHVXUYH\IURP&KLQDRIWUHDWHG
SDWLHQWVZHUHUHSRUWHGWRKDYHGHYHORSHGMDXQGLFHEXWQRVSHFLILFLQIRUPDWLRQDERXWWKHWZRFDVHV
ZDVSURYLGHG7KHUHKDYHEHHQIHZVWXGLHVRIORQJWHUPWKHUDS\ZLWKSUD]LTXDQWHODQGPRVW
FRQWUROOHG WULDOV RI WKLV DJHQW KDYH XVHG RQHGD\ FRXUVHV ZLWKRXW VHUXP DPLQRWUDQVIHUDVH
PRQLWRULQJ+RZHYHUPLOOLRQVRISHRSOHKDYHEHHQWUHDWHGZLWKSUD]LTXDQWHODVDSDUWRIODUJH
VFDOH FRQWURO VWUDWHJLHV LQ &KLQD ZKHUH S. japonicum ZDV HQGHPLF 7KH FRPELQDWLRQ RI
SUD]LTXDQWHO SUHYHQWLYH WKHUDS\ DQG VQDLO FRQWURO KDV UHVXOWHG LQ PDUNHG GHFUHDVHV LQ WKH
SUHYDOHQFH RI LQIHFWLRQ LQ WKH SRSXODWLRQ
ZLWK QR HYLGHQFH RI VLJQLILFDQW WR[LFLW\
KWWSVOLYHUWR[QLKJRY3UD]LTXDQWHOKWP
Risk groups or risk factors:
3DUDVLWLFLQIHFWLRQFDQLWVHOIUHVXOWLQKHSDWLFLPSDLUPHQW3UD]LTXDQWHOLVVLJQLILFDQWO\PHWDEROL]HG
E\WKHOLYHUDQGWKXVFRQFRPLWDQWDGPLQLVWUDWLRQRISUD]LTXDQWHOZLWKDVWURQJLQGXFHURIKHSDWLF
&<3HQ]\PHV VXFKDVULIDPSLQ LVDQDGGLWLRQDOULVNIDFWRU
Potential mechanisms:
3UD]LTXDQWHOLVH[WHQVLYHO\PHWDEROL]HGE\WKHOLYHUYLDWKHF\WRFKURPH3V\VWHPDQGPLJKW
FDXVH KHSDWLF LQMXU\ DV D UHVXOW RI D WR[LF LQWHUPHGLDWH RI LWV PHWDEROLVP 3ODVPD OHYHOV RI
SUD]LTXDQWHO DUH DIIHFWHG E\ LQGXFHUV ULIDPSLQ GHFUHDVHV GUXJ OHYHOV DQG LQKLELWRUV RI 3
DFWLYLW\
FLPHWLGLQH
NHWRFRQD]ROH
DQG
HU\WKURP\FLQ
FDQ
UHGXFH
GUXJ
OHYHOV
KWWSVOLYHUWR[QLKJRY3UD]LTXDQWHOKWP
Preventability:
3UD]LTXDQWHOVKRXOGEHXVHGZLWKFDXWLRQLQSDWLHQWVZLWKKHSDWLFGLVHDVH&HVVDWLRQRIWUHDWPHQW
VKRXOGEHXQGHUWDNHQDWRQVHWRIV\PSWRPV RUIROORZLQJGHWHFWLRQRILQFUHDVHLQWUDQVDPLQDVH
OHYHOV $GGLWLRQDOO\WUHDWPHQWLQVXFKFRQGLWLRQVVKRXOGEHFDUULHGRXWRQDQLQSDWLHQWEDVLV
Impact on individual patient:
,QXQFRPSHQVDWHGKHSDWLFLQVXIILFLHQF\DQGLQSDWLHQWVZLWKKHSDWRVSOHQLFVFKLVWRVRPLDVLV WKHUH
LVUHGXFHGKHSDWLFPHWDEROLVPRISUD]LTXDQWHO ZKLFKFDQUHVXOWLQVLJQLILFDQWO\KLJKHUDQGORQJHU
ODVWLQJ SODVPD FRQFHQWUDWLRQV RI XQPHWDEROL]HG SUD]LTXDQWHO 0LQLPDO LQFUHDVHV LQ KHSDWLF
HQ]\PHVKDYHEHHQUHSRUWHGLQVRPHSDWLHQWV
3DJHRI


Potential public health impact of safety concern:
3UD]LTXDQWHOLVXVXDOO\ZHOOWROHUDWHGDQGFOLQLFDOO\DSSDUHQWOLYHULQMXU\GXHWRLWVXVHZRXOGEH
YHU\UDUH LILWRFFXUVDWDOOKWWSVOLYHUWR[QLKJRY3UD]LTXDQWHOKWP
Evidence source:
/LWHUDWXUHUHYLHZ
16.5
Effectiveness of Risk Minimization
16.5.1
Important Identified Risks
16.5.1.1
Cardiac Arrhythmias
Safety concern
Cardiac arrhythmias
Objective(s) of the risk 
minimization measures
To inform of risk of cardiac arrhythmias
Routine risk minimization 
measures
Section 4.4 of the Merck Master SmPC Special warnings and precautions for use:
Patients with cardiac arrhythmias should be monitored during therapy. The same 
applies to patients with heart failure requiring digitalis therapy, since a digitalis-
antagonistic effect has been demonstrated in animal studies. 
Prescription-only medicine
Treatment with PZQ must be initiated and supervised by an experienced physician
Additional risk minimization 
measure(s)
No need for additional risk minimization measures
Effectiveness of risk minimization measures
How effectiveness of risk 
minimization measures for 
the safety concern will be 
measured
AE reporting rates from spontaneous reports and from safety studies
Criteria for judging the 
success of the proposed 
risk minimization measures
No increase in reporting rate / incidence of event
Planned dates for 
assessment
Periodic review of aggregated AE reports in future PBRERs, Study report:
MS200661-0005
Results of effectiveness 
measurement
EMR200585-001, EMR200661-001, and EMR200661-002: no case reporting of 
cardiac arrhythmias was detected during the reporting period
MS200661-0005: no case reporting of cardiac arrhythmias was detected during the 
reporting period
Impact of risk minimization
no increase in the reporting rate of cardiac arrhythmias was observed
Comment
none
3DJHRI


16.5.1.2
Convulsions in Patients with Co-existing Neurocysticercosis
Safety concern
Convulsions in patients with co-existing neurocysticercosis
Objective(s) of the risk 
minimization measures
To inform of risk of convulsions in patients with co-existing neurocysticercosis
Routine risk minimization 
measures
Section 4.2 of the Merck Master SmPC Posology and method of administration:
The usefulness of additional corticosteroid administration is to be decided from case 
to case; 4 to 16 mg dexamethasone daily, for example, can be considered. The 
same applies to the necessity of using drugs to prevent or alleviate convulsions.
Section 4.4 of the Merck Master SmPC Special warnings and precautions for use:
After the administration of praziquantel for treating tapeworm infection, convulsions 
have occurred in rare individual cases, which have proved to be a reaction to co-
existing neurocysticercosis. Such cases, which may occur especially in endemic 
regions of Taenia solium (Cysticercus cellulosae), should be clarified as quickly as 
possible. 
Section 4.8 of the Merck Master SmPC Undesirable effects:
applies only to tablets containing 150 mg praziquantel: Not known: Convulsions
(see section 4.4)
additional corticosteroid administration
Treatment with PZQ must be initiated and supervised by an experienced physician
Additional risk minimization 
measure(s)
No need for additional risk minimization measures
Effectiveness of risk minimization measures
How effectiveness of risk 
minimization measures for 
the safety concern will be 
measured
AE reporting rates from spontaneous reports and from safety studies
Criteria for judging the 
success of the proposed 
risk minimization measures
No increase in reporting rate / incidence of event
Planned dates for 
assessment
Periodic review of aggregated AE reports in future PBRERs, Study report:
MS200661-0005
Results of effectiveness 
measurement
EMR200585-001, EMR200661-001, and EMR200661-002: no case reporting of 
convulsions in patients with co-existing neurocysticercosis was detected during the 
reporting period
MS200661-0005: no case reporting of convulsions in patients with co-existing 
neurocysticercosis was detected during the reporting period
Impact of risk minimization
no increase in the reporting rate of convulsions in patients with co-existing 
neurocysticercosis was observed
Comment
none
3DJHRI


16.5.2
Important Potential Risks
16.5.2.1
Increases of the Liver Transaminases in Patients with 
Decompensated Hepatic Insufficiency or in Patients with 
Hepatosplenic Schistosomiasis
Safety concern
Increases of the liver transaminases in patients with decompensated hepatic 
insufficiency or in patients with hepatosplenic schistosomiasis
Objective(s) of the risk 
minimization measures
To inform of risk of increases of liver transaminases in patients with 
decompensated hepatic insufficiency or in patients with hepatosplenic 
schistosomiasis
Routine risk minimization 
measures
Section 4.4 of the Merck Master SmPC Special warnings and precautions for use:
Caution is warranted in decompensated hepatic insufficiency or in patients with 
hepatosplenic schistosomiasis since, due to reduced drug metabolisation in the 
liver and/or collateral circulations, appreciably higher serum concentrations are 
reached and the half-life may be prolonged. In such cases, treatment should be 
carried out on an inpatient basis.
Prescription-only medicine
Treatment with PZQ must be initiated and supervised by an experienced physician
Additional risk minimization 
measure(s)
No need for additional risk minimization measures
Effectiveness of risk minimization measures
How effectiveness of risk 
minimization measures for 
the safety concern will be 
measured
AE reporting rates from spontaneous reports and from safety studies
Criteria for judging the 
success of the proposed 
risk minimization measures
No increase in reporting rate / incidence of event
Planned dates for 
assessment
Periodic review of aggregated AE reports in future PBRERs, Study report:
MS200661-0005
Results of effectiveness 
measurement
EMR200585-001, EMR200661-001, and EMR200661-002: no case reporting of 
increases of liver transaminases in patients with decompensated hepatic 
insufficiency or in patients with hepatosplenic schistosomiasis was detected during 
the reporting period
MS200661-0005: one case reporting increases of liver transaminases in a patient 
with decompensated hepatic insufficiency or in a patient with hepatosplenic 
schistosomiasis was detected during the reporting period - 8120255(5)
Impact of risk minimization
no increase in the reporting rate of increases of liver transaminases in patients with 
decompensated 
hepatic 
insufficiency 
or 
in 
patients 
with 
hepatosplenic 
schistosomiasis was observed
Comment
none
3DJHRI


17
Benefit Evaluation
17.1
Important Baseline Efficacy /Effectiveness Information
,Q  DPRQJ D ODUJH QXPEHU RI UHODWHG FRPSRXQGV SUD]LTXDQWHO F\FORKH[\OFDUERQ\O
EKH[DK\GUR+S\UD]LQRDLVRTXLQROLQ RQHZDVGHYHORSHGDVDQHZEURDG
VSHFWUXPDQWKHOPLQWKLFDJHQW &KDL7KH,%' LV0D\
$IWHUUDSLGDQGUHYHUVLEOHXSWDNH SUD]LTXDQWHOKDVWZRPDMRUDQWKHOPLQWKLFHIIHFWV$WWKHORZHVW
HIIHFWLYHFRQFHQWUDWLRQVSUD]LTXDQWHOFDXVHVLQFUHDVHGPXVFXODUDFWLYLW\IROORZHGE\FRQWUDFWLRQ
DQG VSDVWLF SDUDO\VLV $W KLJKHU FRQFHQWUDWLRQV SUD]LTXDQWHO FDXVHV WHJXPHQWDO GDPDJH DQG
H[SRVHVDQXPEHURIWHJXPHQWDODQWLJHQV0F&DUWK\HWDO
7KHPDMRUDVVHWRISUD]LTXDQWHOLV LWVEURDG DQWLKHOPLQWKLFVSHFWUXPRIDFWLYLW\
3UD]LTXDQWHOLVLQGLFDWHGIRU
PJ WDEOHWV 7UHDWPHQW RI LQIHFWLRQV FDXVHG E\ Taenia saginata EHHI WDSHZRUP Taenia
solium SRUN WDSHZRUP Hymenolepis nana GZDUI WDSHZRUP Diphyllobothrium pacificum
6RXWK$PHULFDQILVKWDSHZRUP
PJ WDEOHWV 7UHDWPHQW RI LQIHFWLRQV FDXVHG E\ WKH ODUYDH RI SRUN WDSHZRUP Cysticercus
cellulosaeLQWKHFHQWUDOQHUYRXVV\VWHPQHXURF\VWLFHUFRVLV
PJWDEOHWV
! 7UHDWPHQW RI Schistosoma LQIHFWLRQV GXH WR S. haematobium S. mansoni, S.intercalatum
S.japonicum, S. mekongi
! 7UHDWPHQWRILQIHFWLRQVZLWKOLYHUIOXNHVHJClonorchis sinensis, Opisthorchis viverriniDQG
OXQJIOXNHVHJParagonimus westermani DQGRWKHUVSHFLHV
! 7UHDWPHQWRIF\VWLFHUFRVLVQHXURF\VWLFHUFRVLV SDUHQFK\PDODQGVXEDUDFKQRLG DQGYLVFHUDO
DQG FXWDQHRXV F\VWLFHUFRVLV DQG LQIHFWLRQV ZLWK LQWHVWLQDO QHPDWRGHV OLYHU FORQRUFKLDVLV
RSLVWKRUFKLDVLVDQGIDVFLROLDVLVDQGSXOPRQDU\SDUDJRQLPLDVLV
17.1.1
Infections caused by Taenia saginata, Taenia solium, 
Hymenolepis nana, Diphyllobothrium pacificum and caused 
by the larvae of pork tapeworm in the Central Nervous System 
(praziquantel 150 and 500 mg)
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17.1.2
Treatment of Schistosoma Infections and Infections with 
Liver Flukes and Lung Flukes (praziquantel 600 mg)
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17.2
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18
Integrated Benefit-Risk Analysis for Authorized Indications
18.1
Benefit-risk Context -
Medical Need and Important 
Alternatives 
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18.2
Benefit-Risk Analysis Evaluation
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PZQ
Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004

Appendix 8
Reference ranges of laboratory parameters
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SAP_001.pdf: 
PZQ
Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
Final v1.0
1/24
Integrated Analysis Plan
Clinical Trial Protocol 
Identification No.
MS200585_0004
Title
A Phase I, open-label, randomized, four-period, crossover, 
fully replicated, reference-scaled, single center study to assess 
the bioequivalence of a single oral dose of 1200 mg of the 
coated Cesol tablet formulation versus comparator Biltricide®
in healthy male volunteers
Trial Phase
1
Investigational Medicinal 
Product(s)
MSC1028703A (Praziquantel) 
Clinical Trial Protocol 
Version
09 Jan 2020 / Version 1.0
Integrated Analysis Plan 
Author
Coordinating Author
On behalf of
 
Merck
Function
Author / Biostatistician
, Nuvisan
Integrated Analysis Plan
Date and Version
  09 Jul 2020 / Final Version 1.0
Integrated Analysis Plan 
Reviewers
Function
Name
Medical Responsible, Merck
Clinical Trial Lead, Merck
 
Merck
, 
Merck
, Merck
 Merck
, 
Merck
, Merck
Biostatistician, Merck
This document is the property of Merck KGaA, Darmstadt, Germany, or one of its affiliated companies.
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 affiliate. 
Copyright © 2020 by Merck KGaA, Darmstadt, Germany or its affiliate. All rights reserved.
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PZQ
Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
Final v1.0
2/24
Signature Page
Integrated Analysis Plan: MS200585-0004
A Phase I, open-label, randomized, four-period, crossover, fully replicated, reference-scaled, 
single center study to assess the bioequivalence of a single oral dose of 1200 mg of the coated 
Cesol tablet formulation versus comparator Biltricide® in healthy male volunteers
Approval of the IAP by all Merck Data Analysis Responsible is documented within 
ELDORADO. With the approval within Eldorado, the Merck responsible for each of the analysis 
also takes responsibility that all reviewers’ comments are addressed adequately.
Merck responsible
Date
Signature
,
Via ELDORADO approval process
,
Via ELDORADO approval process
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PZQ
Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
Final v1.0
3/24
1
Table of Contents
Integrated Analysis Plan ......................................................................................................1
Signature Page
..............................................................................................................2
1
Table of Contents..................................................................................3
2
List of Abbreviations and Definition of Terms ....................................5
3
Modification History ............................................................................6
4
Purpose of the Integrated Analysis Plan...............................................6
5
Objectives and Endpoints .....................................................................7
6
Overview of Planned Analyses.............................................................8
6.1
Interim Analysis....................................................................................8
6.2
Final Analysis .......................................................................................8
7
Changes to the Planned Analyses in the Clinical Study Protocol ........8
8
Protocol Deviations and Analysis Sets.................................................8
8.1
Definition of Protocol Deviations and Analysis Sets ...........................8
8.2
Definition of Analysis Sets...................................................................9
9
General Specifications for Data Analyses ..........................................10
10
Trial Participants.................................................................................11
10.1
Disposition of Participants and Discontinuations...............................12
10.2
Protocol Deviations ............................................................................13
10.2.1
Important Protocol Deviations............................................................13
10.2.2
Reasons Leading to the Exclusion from an Analysis Set ...................13
11
Demographics and Other Baseline Characteristics.............................13
11.1
Demographics.....................................................................................13
11.2
Medical History ..................................................................................14
11.3
Other Baseline Characteristics............................................................14
12
Previous or Concomitant Medications/Procedures.............................14
13
Treatment Compliance and Exposure.................................................15
14
Efficacy Analyses ...............................................................................15
15
Safety Analyses ..................................................................................15
15.1
Adverse Events ...................................................................................15
15.1.1
All Adverse Events.............................................................................16
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PZQ
Bioequivalence study of coated Cesol tablet formulation vs Biltricide
MS200585_0004
Final v1.0
4/24
15.1.2
Adverse Events Leading to Treatment Discontinuation.....................17
15.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events ...................................................................................17
15.2.1
Deaths .................................................................................................17
15.2.2
Serious Adverse Events ......................................................................17
15.3
Clinical Laboratory Evaluation...........................................................17
15.4
Vital Signs ..........................................................................................18
15.5
ECG Evaluation..................................................................................18
16
Analyses of Other Endpoints..............................................................19
16.1
Pharmacokinetics................................................................................19
General Specifications for Plasma Concentration Data.....................................................19
General Specifications for PK Parameter Data..................................................................20
16.1.1
Planned Analyses of PK Parameter Data............................................20
16.1.2
Plasma Concentration Data.................................................................22
16.1.3
Estimation of Individual PK Parameters ............................................22
17
References...........................................................................................24
18
Appendices .........................................................................................24
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2
List of Abbreviations and Definition of Terms
AE
Adverse Event
ANOVA
Analysis of variance
BMI
Body Mass Index
CI
Confidence Interval
eCRF
Electronic Case Report Form
CSP
Clinical Study Protocol
CSR
Clinical Study Report
CV
Coefficient of variation
CVWR
Within-subject coefficient of variation for the reference treatment
ECG
Electrocardiogram
GeoCV%
Geometric Coefficient of Variation
GeoMean
Geometric Mean
GMR
Geometric Mean Ratio
IAP
Integrated Analysis Plan
ICH
International Conference on Harmonization
I.e.
That is
LCI
Lower Confidence Interval Bound
LLOQ
Lower Limit of Quantification
MCAR
Missing Completely at Random
MedDRA
Medical Dictionary for Regulatory Activities
NCI-CTCAE
National Cancer Institute – Common Terminology Criteria for Adverse 
Events
N.R.
No result
Max
Maximum
Min
Minimum
PT
Preferred Term
PK
Pharmacokinetics
PZQ
Praziquantel
Q1
First Quartile
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Q3
Third Quartile
QTcF
Corrected QT interval per Fridericia’s formula
SAE
Serious Adverse Event
SEM
Standard Error of the Mean
SOC
System Organ Class
TEAE
Treatment Emergent Adverse Event
UCI
Upper Confidence Interval Bound
ULOQ
Upper Limit of Quantification
3
Modification History
Unique
Identifier for
Version
Date of
IAP Version
Author
Changes from the Previous Version
Final 1.0
09-Jul-2020
Original Document
4
Purpose of the Integrated Analysis Plan
The purpose of this integrated analysis plan (IAP) is to document technical and detailed 
specifications for the final analysis of data collected for protocol MS200585_0004. Results of the 
analyses described in this IAP will be included in the Clinical Study Report (CSR). Additionally, 
the planned analyses identified in this IAP will be included in regulatory submissions or future 
manuscripts. Any post-hoc, or unplanned analyses performed to provide results for inclusion in 
the CSR but not identified in this prospective IAP will be clearly identified in the CSR. 
The IAP is based upon section 9 (Statistical Considerations) of the clinical study protocol (CSP) 
and is prepared in compliance with ICH E9. 
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5
Objectives and Endpoints
Objectives
Endpoints (Outcome 
Measures)
IAP section
Primary
To assess the BE of the 
600 mg coated Cesol tablet 
versus the comparator 
600 mg tablet of Biltricide at 
a dose of 1200 mg with 
regard to rac-PZQ
PK parameters Cmax and area 
under 
the 
plasma 
concentration-time 
curve 
from 
time 
zero 
to 
last 
measurable 
concentration 
(AUC0-t) of rac-PZQ after 
single dose administration
Section 16.1
Secondary
To evaluate the safety and 
tolerability of the 600 mg 
coated Cesol tablet versus the 
comparator 600 mg tablet of 
Biltricide at a dose of 
1200 mg
Occurrence of TEAEs and 
treatment related AEs per 
Qualitative Toxicity Scale
Standard 
laboratory 
hematology and biochemical 
parameters, vital signs (body 
temperature, 
systolic 
and 
diastolic blood pressure, and 
pulse 
rate) 
and 
ECG 
parameters.
Section 15
To assess the BE of the 
600 mg coated Cesol tablet 
versus the comparator 
600 mg tablet of Biltricide at 
a dose of 1200 mg with 
regard to PZQ enantiomers
PK parameters Cmax and 
area 
under 
the 
plasma 
concentration-time 
curve 
from time zero to last 
measurable 
concentration 
(AUC0-t) of R-(-)-PZQ and 
S-(+)-PZQ after single dose 
administration
Section 16.1
To further characterize the 
PK profile of the 600 mg 
coated Cesol tablet versus the 
comparator 600 mg tablet of 
Biltricide at a dose of 1200 
mg
PK parameters of rac-PZQ, 
R-(-)-PZQ and S-(+)-PZQ 
after single dosing: AUC0-∞, 
time to reach maximum 
plasma concentration (tmax), 
tlag, t½, λz, CL/f and VZ/f
Section 16.1
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6
Overview of Planned Analyses
6.1
Interim Analysis
No interim analysis is planned for this study.
6.2
Final Analysis
The final, planned analyses identified in the CSP and in this IAP will be performed after the last 
participant has completed the last visit, i.e. end of treatment/safety follow-up visit with all trial 
data in-house, all data queries resolved, and the database locked. 
A data review meeting will be held prior to database lock for the final analysis. In addition, no 
database can be locked until this IAP has been approved.
7
Changes to the Planned Analyses in the Clinical Study 
Protocol
There are no changes to the planned analyses in the CSP.
8
Protocol Deviations and Analysis Sets
8.1
Definition of Protocol Deviations and Analysis Sets
Important protocol deviations are protocol deviations that might significantly affect the 
completeness, accuracy, and/or reliability of the study data or that might significantly affect a 
participant's rights, safety, or well-being. 
The following deviations will be identified and confirmed prior to or at the Data Review Meeting 
at the latest. 
Important protocol deviations include
!
Deviations from the inclusion and exclusion criteria
!
Concomitant medication violations (see Section 6.5.2 of the protocol)
!
Use of prohibited medicines (see Section 6.5.3 of the protocol)
!
Participants who receive incorrect treatment or dose
!
Sample processing errors that may lead to inaccurate bioanalytical results
!
Vomiting or diarrhea following oral dosing (these instances will be discussed on a case-by-
case basis)
!
Deviation from Good Clinical Practice
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!
Non-compliance to study procedures or deviations from study procedures likely to affect the 
primary endpoints (e.g. participant develops withdrawal criteria whilst in the study but is not 
withdrawn)
!
Deviation from study medication compliance in terms of medical conditions and/or AEs that 
may have interfered with drug disposition or with respect to factors likely to affect the 
primary endpoints
All important protocol deviations will be documented in Clinical Data Interchange Standard 
Consortium (CDISC) Study Data Tabulation Model (SDTM) datasets whether identified through 
sites monitoring or medical review. 
8.2
Definition of Analysis Sets
Analysis Set
Description
Screening (SCR)
The Screening Analysis Set will include all participants, who provided 
informed consent, regardless of the participant’s randomization and study 
intervention status in the study.
Safety (SAF)
The Safety Analysis Set will include all participants who were 
administered any dose of any study intervention. Analyses will consider 
participants as treated. All safety analyses will be based on this analysis 
set.
PK
The PK Analysis Set will include all participants, who receive at least one 
dose of study intervention, have no clinically important protocol 
deviations or important events affecting PK, and provide at least one 
measurable postdose concentration. Participants will be analyzed per the 
actual study intervention they received.
The PK population will include all participants:
! Who have completed at least one study period without any relevant 
protocol deviations and factors likely to affect the comparability of PK 
results
! With adequate study intervention compliance
! With evaluable PK data, i.e., nonmissing values for primary endpoints 
in each completed study period.
If participants received prohibited concomitant therapy or medicines, as 
specified in Section 6.5 of the CSP, they will be excluded from the PK 
population. Relevant decisions will be made before database lock. All PK 
analyses will be based on this analysis.
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9
General Specifications for Data Analyses
Statistical analyses will be performed using the computer program package SAS® System for 
Windows™ (Version 9.4 or later; SAS Institute, Cary, North Carolina, USA).
The results of this trial will be reported using summary tables, figures, and data listings, as 
appropriate. All data will be summarized by treatment sequence, period, treatment and/or 
scheduled time point, as appropriate. All individual data will be listed as measured in the 
individual participant data listing. Repeated and unscheduled measurements will be included in 
the listings. 
For demographic, baseline and safety assessments, continuous measurements will be 
summarized by means of descriptive statistics (i.e. number and percentage of observations, 
number and percentage of missing observations, mean, standard deviation [SD], median, the first 
and third quartile [Q1 and Q3], minimum [Min], and maximum [Max]) and categorical data will 
be summarized by means of frequency tables (i.e., count and percentages), if not stated 
otherwise. 
Percentages are based on the number of subjects dosed with each treatment in summary tables by 
treatment T1, T2, R1, R2, or the number of subjects in the respective analysis population for 
summary tables by total treatment T and R [N]. A respective footnote will be provided in the 
summary tables. 
Mean, Median, Q1, Q3, Min, Max will have the same precision as the SDTM data (decimal 
places). SD will be presented with one decimal place more than the mean. For participant
disposition and demographic tables the denominator will be the number of participants in the 
analysis set. Counts of missing observations will be included as a separate category.
If not otherwise specified, ‘baseline’ refers to the last scheduled measurement before 
administration of the first drug in each period. 
If no baseline or previous to baseline evaluations per period exist then the baseline value will be 
treated as missing.
The following calculations and derivations, as applicable, will be used: 
! Change from baseline: post-baseline visit value - baseline value 
! Duration of AE (in days hh:mm) = end date and time - start date and time of the AE, if 
missing time for either the beginning or end then = end date – start date + 1; in case of 
multiple records for the same AE, the duration will be calculated over all these records
! Days hh:mm from dosing = start date and time of the event - date and time dose 
administration (for TEAEs), if missing time for either the dosing or event then days hh:mm 
from dosing = event start date – date of dose administration + 1
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! Rel. Day in period of AE = start date of the event – date of First Admin in period + 1 (for AEs 
on or after the day of dosing)
! Rel. Day in study of AE = start date of the event – date of First Admin (for AEs before the 
day of dosing of the study only) 
Repeated and unscheduled measurements will be included in the listings, but not used for 
statistical analysis or summary tables, unless the repeated measurement was performed due to 
unreliable values/technical reasons, e.g., clotted samples.
In this phase 1 PK study, missing observations will be assumed to be missing completely at 
random (MCAR). No action will be taken to handle missing data. A participant who withdraws 
prior to the last planned observation in a trial period will be included in the analyses up to the 
time of discontinuation.
The following treatment labels will be used:
Treatment Tx: x. administration of coated Cesol tablet, 2 tablets of praziquantel 600 mg per 
period,
Treatment Rx: x. administration of Biltricide®, 2 tablets of praziquantel 600 mg per period
where x=1 or x=2 defines the first and second administration of test or reference product, 
respectively. These labels will be used in listings and summaries by first treatment and second 
treatment. 
Treatment Total T: coated Cesol tablet, 2 tablets of praziquantel 600 mg per period,
Treatment Total R: Biltricide®, 2 tablets of praziquantel 600 mg per period,
whereby these treatment labels will be used in summaries by total treatment.
10
Trial Participants
The subsections in this section include specifications for reporting participant disposition and 
treatment/trial discontinuations. Additionally, procedures for reporting protocol deviations are 
provided.
Considering the study objectives, it is planned to enroll 36 participants in the study to ensure 
inclusion of at least 32 evaluable participants for the treatment comparisons.
The participants will be randomized to one of the two treatment sequences: T1-R1-T2-R2 or R1-
T1-R2-T2, where T is Test product and R is Reference product, with a washout period of at least 
1 week in between. 
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Period 1
Period 2
Period 3
Period 4
Sequence 1
(18 participants)
Test 1
Washout 
at least 7 
days
Reference
1
Washout 
at least 7 
days
Test 2
Washout 
at least 7 
days
Reference
2
Sequence 2
(18 participants)
Reference
1
Test 1
Reference
2
Test 2
Test = coated Cesol tablet, 2 tablets of praziquantel 600 mg; 
Reference = Biltricide, 2 tablets of praziquantel 600 mg.
10.1
Disposition of Participants and Discontinuations
This following will be presented in a summary table: 
! Total number of participants screened (i.e., participants who gave informed consent)
! Number of screened participants who discontinued from the trial prior to treatment overall 
and grouped by the main reason for discontinuation:
o
Participant did not meet all eligibility criteria
o
Withdrew consent
o
Other (COVID-19-related and COVID-19-non-related)
! Number of randomized participants
! Number of randomized participants who did not receive treatment (as applicable)
! Number of treated participants by treatment T1, T2, R1, R2 and overall
! Number and percentage of treated participants who completed study by treatment T1, T2, R1, 
R2 and overall
! Number and percentage of treated participants who discontinued the study overall and number 
of subjects who discontinued  treatment by treatment T1, T2, R1, R2, with the primary reason 
of discontinuation: :
o
Adverse event
o
Lost to follow-up
o
Protocol non-compliance
o
Death
o
Withdrew consent
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o
Other (COVID-19-related and COVID-19-non-related)
A listing of discontinued participants will be provided.
A listing of participants affected by the COVID-19 related study disruption by unique subject 
number identifier will also be provided.
10.2
Protocol Deviations
10.2.1
Important Protocol Deviations
Listings of important protocol deviations will be provided including the date and relative day in 
relation to dosing in the relevant period.
10.2.2
Reasons Leading to the Exclusion from an Analysis Set
All criteria/reasons leading to the exclusion of a participant from an analysis set will be listed 
based on the safety set. 
Reasons for excluding individual PK concentrations will also be listed separately and flagged in 
the main listing based on the Safety Analysis Set.
11
Demographics and Other Baseline Characteristics
11.1
Demographics
Summaries will be given for both the safety and the PK set, if different.
Demographic characteristics will be listed by participant and treatment sequence and 
summarized by treatment sequence and overall using the following information from the 
Screening/Baseline Visit eCRF pages. 
Demographic characteristics:
!
Sex: male, female, undifferentiated
!
Race: American Indian or Alaska Native, Asian, Black or African American, Native 
Hawaiian or Pacific Islander, White, Other
!
Ethnic origin - Hispanic or Latino: yes, no
!
Ethnic origin - Japanese: yes, no
!
Age (years): summary statistics
!
Height (cm) at Screening : summary statistics
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!
Weight (kg) at Screening : summary statistics
!
BMI (kg/m²) at Screening: summary statistics
Age will be taken from the eCRF and cannot be derived from the data because only the year of 
birth is collected in the eCRF.
BMI will be re-derived (ie, not taken directly from the database) according to the following 
formula:
! BMI (kg/m²) = weight (kg) / (height (m) * height (m))
11.2
Medical History
The medical history will be listed by participant including the preferred term (PT) and MedDRA 
system organ class (SOC) body using MedDRA, current version.
11.3
Other Baseline Characteristics
Other baseline characteristics will be listed by participant and summarized by treatment sequence 
and overall using the following information from the Screening/Baseline Visit eCRF pages. 
Other baseline characteristics may include:
!
Smoking status
!
Alcohol consumption
12
Previous or Concomitant Medications/Procedures
Previous medications are medications, other than trial medications and pre-medications for trial 
drug, which started and stopped before first administration of trial drug. 
Concomitant treatments are medications, other than trial medications, which are taken by 
participants any time on-trial (on or after the first day of trial drug treatment for each 
participant). 
In case the date values will not allow to unequivocally allocate a medication to previous or 
concomitant medication the medication will be considered as concomitant medication.
Any previous and concomitant medication will be encoded with WHO-DD, latest version. Prior 
and concomitant medications will be listed by participant (safety set).
The following information will be displayed in a listing: generic or trade name (as reported in 
CRF), WHO drug name, dose/unit, route, frequency, reason for use, start/end date and time.
Concomitant procedures will be presented in a data listing.
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13
Treatment Compliance and Exposure
The dosing of each participant is monitored by the study nurse or investigator. A listing of date 
and time of each drug administration and each blood sampling, including time deviations as well 
as measured rac-PZQ, R-(-)-PZQ and S-(+)-PZQ concentration, will be provided sorted by 
participant.
14
Efficacy Analyses
Not applicable.
15
Safety Analyses
The subsections in this section include specifications for summarizing safety endpoints that are 
common across clinical trials such as adverse events, laboratory tests and vital signs.
Safety data analysis will be conducted on the Safety Analysis Set. 
15.1
Adverse Events
Adverse Events will be listed by treatment T1, T2, R1, R2.
Generally, the number and percentage of participants experiencing at least one TEAE will be
summarized by treatment T1, T2, R1, R2, by total T, total R and overall as well as the number of 
events. 
A TEAE is an AE with onset after start of treatment or with onset date before the treatment start 
date but worsening after the treatment start date.
Tables by relationship to trial drug and by 
severity will be generated. AEs will be coded using Medical Dictionary for Regulatory Activities
(MedDRA) terminology, latest version. 
If an event was reported more than once, the worst severity will be tabulated.
Incomplete TEAE-related dates will be handled as follows:
! In case the onset date is missing completely or missing partially but the onset month and year, 
or the onset year are equal to the start of trial treatment then the onset date will be replaced by 
the minimum of start of trial treatment and TEAE resolution date. 
! In all other cases the missing onset day or missing onset month will be replaced by 1.
! Incomplete stop dates will be replaced by the last day of the month (if day is missing only), if 
not resulting in a date later than the date of the participant's death. In the latter case, the date 
of death will be used to impute the incomplete stop date. 
! In all other cases the incomplete stop date will not be imputed. 
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15.1.1
All Adverse Events
All AEs recorded during the course of the trial (i.e. assessed from signature of informed consent 
until the end of treatment/safety follow-up visit) will be coded according to MedDRA latest 
version and assigned to a SOC and PT.
TEAEs will be summarized by worst severity, using MedDRA latest version PT as event 
category and MedDRA primary SOC body term as Body System category. The severity of AEs 
will be assessed by the investigator per the Qualitative Toxicity Scale as detailed in the study 
protocol: mild, moderate, severe.
TEAEs related to trial treatment are those events with relationship related, or missing, or 
unknown.
The following will be summarized in an overview table with the number and percentage of 
participants (and the number of events) by treatment and overall:
! Any TEAEs
! Any trial treatment-related TEAEs 
! Any serious TEAEs 
! Any trial treatment-related serious TEAEs 
! Any severe TEAE 
! Any trial treatment-related severe TEAEs
! Any TEAEs leading to death
! Any trial treatment-related TEAEs leading to death
TEAEs will be summarized by treatment and total T, total R and overall in tables with:
! The number and percentage of participants by treatment with at least one TEAE and the 
number of events overall and by SOC and PT. SOC terms will be sorted alphabetically and 
PTs within each SOC term will be sorted by descending overall frequency. 
! The number and percentage of participants by treatment with at least one non-serious TEAE 
and the number of non-serious TEAE applying frequency threshold of 5% according to SOC
(i.e. SOCs events with frequency > 5% in any arm). SOC terms will be sorted alphabetically 
and PTs within each SOC term will be sorted by descending overall frequency.
In addition the following tables will be provided. SOC terms will be sorted alphabetically and 
PTs within each SOC term will be sorted by descending frequency (based on all treatment 
groups combined): 
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! A table by severity of TEAEs with the number and percentage of participants by treatment 
with at least one TEAE and the number of events by SOC and PT. 
! A table by relationship to trial treatment with the number and percentage of participants by 
treatment with at least one TEAE and the number of events by SOC and PT. 
Pre-treatment AEs (AEs with onset after informed consent but before start of treatment) and 
TEAEs will be listed separately.
15.1.2
Adverse Events Leading to Treatment Discontinuation
TEAEs leading to permanent discontinuation of trial treatment will be summarized by treatment
and overall including number of participants, percentage and number of events.
A listing of TEAEs leading to permanent discontinuation of a trial treatment will additionally be 
provided.
15.2
Deaths, Other Serious Adverse Events, and Other Significant 
Adverse Events
15.2.1
Deaths
All deaths as well as reason for death will be based on information from the “Report of 
Participant Death” CRFs. 
Listing of deaths, if any, will be provided displaying date and cause of death (including TEAE 
leading to death and relatedness to trial treatment, when applicable), and date and time of 
treatment administration.
15.2.2
Serious Adverse Events
A summary table of serious adverse events (SAEs), if any, by treatment and overall will be 
provided displaying the number and percentage of participants by treatment with at least one 
SAE and the number of SAEs overall and by SOC and PT. SOC terms and PTs within each SOC 
term will be sorted alphabetically.
Listing of SAEs, if any, will be provided in addition.
15.3
Clinical Laboratory Evaluation
All laboratory data will be reported with SI units. Laboratory parameters will be listed by 
participant and treatment T1, T2, R1, R2 and time-point and summarized indicating the treatment 
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T and R at the respective time-point using descriptive statistics for absolute values and change 
from baseline (period-baseline) over time. 
Laboratory values that are outside the normal range will also be flagged in the data listings, 
along with corresponding normal ranges. Any out-of-range values will additionally be listed 
separately. 
See Appendix 5 of the CSP for a table of the safety laboratory evaluations.
Safety laboratory values are separated into:
! Hematology
! Biochemistry
! Urinalysis
! Other tests
Summary tables will be produced for the groups Hematology and Biochemistry.
15.4
Vital Signs
Vital signs will be listed by participant and time-point and summarized for absolute values and 
changes-from-baseline (period-baseline) by time point and treatment T1, T2, R1 and R2 using 
descriptive statistics. Descriptive statistics tables will start at baseline.
15.5
ECG Evaluation
ECG data will be listed by participant and time-point and summarized by absolute values and 
changes-from-baseline (period-baseline) by treatment T1, T2, R1 and R2 using descriptive 
statistics. Descriptive statistics tables will start at baseline. Clinically significant ECG findings 
for individual participants will be listed and summarized.
The time intervals (PR, QRS, RR, QT and corrected QT intervals [based on Fridericia’s formula, 
QTcF]) will be summarized descriptively by treatment.
The Fridericia’s Correction (QTcF) is derived as follows: 
Fridericia’s Correction (QTcF) 
3 RR
QT
QTc f ∀
where: RR = RR-interval measured in seconds.
Observed QTcF values will be categorized according to their absolute values into the categories
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! ≤430 ms,
! > 430 and ≤450 ms,
! > 450 and ≤ 480 ms,
! > 480 and ≤ 500 ms, and
! > 500 ms,
and categorized according to their absolute change from period baseline into the categories
! ≤30 ms,
! > 30 and ≤ 60 ms, and
! > 60 ms.
The number and percentage of participants by these categories at any post-dose assessment will 
be tabulated by treatment T1, T2, R1 and R2. All ECG measurements and changes from period 
baseline will be listed, with abnormalities (as reported of the investigator on the ECG eCRF 
page) indicated.
Investigator reported interpretation results will also be tabulated by treatment T1, T2, R1 and R2
using the number and percentage of participants for each interpretation category (Normal, 
Abnormal Not Clinically Significant [NCS], Abnormal Clinically Significant [CS]).
16
Analyses of Other Endpoints
16.1
Pharmacokinetics
General Specifications for Plasma Concentration Data
PK evaluation will be performed by the Clinical PK/PD Group, Merck Healthcare KGaA, 
Darmstadt, Germany, or by a CRO selected by the Sponsor.  
Concentrations of rac-PZQ, R-(-)-PZQ and S-(+)-PZQ in plasma will be presented in tables and 
descriptively summarized by treatment T1, T2, R1, R2 and nominal time point using number of 
observations (n), Mean, SD, standard error of the mean (SEM), median, Min, Max, and CV%. 
Descriptive statistics of concentration data will be calculated using values with the same 
precision as the source data, and rounded for reporting purposes only. The following conventions 
will be applied when reporting descriptive statistics of PK concentration data:
Mean, Min, Median, Max: 
3 significant digits
SD, SEM:
4 significant digits
CV%:
1 decimal place 
Values below the lower limit of quantification of the assay (LLOQ) will be taken as zero for 
summary statistics of PK concentration data. Missing concentrations (e.g., no sample, 
insufficient sample volume for analysis, no result, or result not valid) will be reported and used 
generally as “no result” (“N.R.”). Pre-dose samples that occur before the first drug 
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administration will be assigned a time of 0 hours, as if the sample had been taken simultaneously 
with the study drug administration.
All available concentration data will be listed. Data of participants not in the PK analysis set or 
invalid data will be flagged accordingly. Any flags will be included in SDTM and ADaM, 
respectively.
General Specifications for PK Parameter Data
PK parameter data will be descriptively summarized: n, Mean, SEM, SD, CV%, Min, median, 
Max, geometric mean (GeoMean), the geometric coefficient of variation (GeoCV%) and the 
95% confidence interval (CI) for the GeoMean (LCI 95% GM, UCI 95% GM). 
PK parameter Cmax will be reported with the same precision as the source data. All other PK 
parameters will be reported to 3 significant figures. In export datasets, as well as in the SDTM 
PP domain, PK parameters will be provided with full precision, and will not be rounded. 
Descriptive statistics of PK parameter data will be calculated using full precision values, and 
rounded for reporting purposes only. 
The following conventions will be applied when reporting descriptive/inferential statistics of PK 
parameter data:
Mean, Min, Median, Max, GeoMean, 95% CI: 
3 significant digits
SD, SEM:
4 significant digits
CV%, GeoCV%:
1 decimal place 
Ratio of GeoMean (in %) and 95% CI
2 decimal places
To ensure a reliable estimate of the extent of exposure, AUCextra should be less than or equal to 
20%. If AUCextra is greater than 20%, all parameters derived using λz (i.e. λz, t1/2, AUC0-#,
AUCextra, Vz/f, CL/F) will be listed, but set to missing for the calculation of descriptive statistics. 
All statistical analyses and descriptive summaries of pharmacokinetic data will be performed on 
the PK Analysis Set. All available data will be listed. Data of participants not in the PK analysis 
set or invalid data will be flagged accordingly. Any flags will be included in SDTM and ADaM, 
respectively.
16.1.1
Planned Analyses of PK Parameter Data
The following PK parameter tables will be produced:
!
Summary of PK parameters by treatment T1, T2, R1 and R2 of all analytes.
The following listing will be produced:
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!
Individual PK parameters listed by treatment T1, T2, R1, R2. Excluded PK parameters will 
be flagged.
The following figures will be produced for PK parameters:
!
Boxplots for the Cmax and AUC0-t by treatment T1, T2, R1, R2 of all analytes.
The analysis of the primary endpoints AUC0-t and Cmax of rac-PZQ will be performed using the 
PK population. The analysis of the secondary endpoints AUC0-t and Cmax of R-(-)-PZQ and S-
(+)-PZQ will use a similar approach.
For the analysis of AUC0-t and Cmax, a reference-scaled BE approach will be applied as follows: 
The within-subject variability of the reference product will be calculated from a linear model 
fitted to the log-transformed PK parameters Cmax and AUC0-t, obtained under reference treatment 
only, with sequence, subject within sequence, period included as fixed effects, described in 
Section 3.4 of Question 8 in EMA/618604/2008 Rev. 13: Questions & Answers: positions on 
specific questions addressed to the Pharmacokinetics Working Party (PKWP). In this analysis, 
only participants with evaluable data from both administrations of the reference product will be 
included. If the within-subject coefficient of variation for the reference treatment (CVWR) ≤30% 
for Cmax or AUC0-t (i.e. the within-subject CV for the reference drug is ≤30%), then the common 
acceptance range (80.00% to 125.00%) for BE will apply for the respective PK parameter. For 
30% < CVWR ≤50% the acceptance interval will be widened according to [, ] =

(∓ ), 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  is the intrasubject standard 
deviation of the log-transformed values of Cmax or AUC0-t of the reference product, and CVWR = 
exp(
 ) −1.  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% to 143.19%]. 
An analysis of variance (ANOVA) with treatment, period, sequence and subject within sequence 
as fixed effects, will be fitted to log-transformed PK parameters AUC0-t and Cmax according to 
Method A in Question 8 in EMA/618604/2008 Rev. 13. Only participants with at least one valid 
PK parameter under both reference and test treatment will be included in this model. Least-
squares mean differences between treatments will be derived on the log-scale together with 90% 
confidence intervals.
Estimates and confidence intervals will be back-transformed to the natural scale. Bioequivalence 
will be accepted if, firstly, the back-transformed 90% confidence intervals are included in the 
acceptance range, and, secondly, the geometric mean ratios are contained in the conventional 
acceptance range 80.00% to 125.00%.
The estimated within-subject variability CVWR may be inflated in the presence of outliers.  In 
order to exclude such inflation, sensitivity analyses will be performed.  In these analyses, outliers 
will be identified using graphical methods by plotting the PK parameter after the first 
administration (R1) against the corresponding value after the second administration (R2), and/or 
statistical methods (such as identifying subjects whose studentized residuals fall outside the 
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interquartile range and/or outside the whiskers), and the acceptance range will be based on CVWR
calculated with outliers removed from the dataset.
16.1.2
Plasma Concentration Data
The following tables will be produced for all analytes:
! Summary of plasma concentrations by treatment T1, T2, R1, and R2 and nominal time.
The following figures will be produced for plasma concentrations of all analytes:
! Arithmetic mean plasma concentration-time profiles overlaying all treatments on linear and 
semi-logarithmic scale
! Arithmetic mean plasma concentration-time profiles overlaying all treatments on linear scale 
including SD error bars
! Individual plasma concentration-time profiles overlaying participants, for each treatment T1, 
T2, R1 and R2 separately on linear and semi-logarithmic scale
! Individual plasma concentration-time profiles overlaying all treatments identified as T1, T2, 
R1, R2, separately for each participant on linear and semi-logarithmic scale
The following listing will be produced:
! Plasma concentrations will be listed by nominal time and treatment T1, T2, R1, R2. Excluded 
plasma concentrations will be flagged.
! PK sampling date, actual time, nominal time, deviation from scheduled time and 
concentration by nominal time and treatment T1, T2, R1, and R2.
16.1.3
Estimation of Individual PK Parameters
The following non-compartmental PK parameters will be calculated from the individual plasma 
rac-PZQ, R-(-)-PZQ and S-(+)-PZQ concentration-time data using commercial software 
Phoenix®/WinNonlin® (Version 6.3 or higher) at 
. Cmax and AUC0-t are the main 
parameters for further statistical analysis.
Symbol
Definition
AUC0-t
The area under the concentration-time curve (AUC) from time zero (= dosing 
time) to the last sampling time (tlast) at which the concentration is at or above 
the lower limit of quantification. Calculated using the mixed log-linear 
trapezoidal rule (linear up, log down).
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Symbol
Definition
AUC0-#
The AUC from time zero (dosing time) extrapolated to infinity, based on the 
predicted value for the concentration at tlast , as estimated using the linear 
regression from λz determination. AUC0-∞= AUC0-t + Clast pred/ λz.
AUCextra%
The AUC from time tlast extrapolated to infinity given as percentage of 
AUC0-#. AUCextra% = (extrapolated area/AUC0-∞)*100. The predicted AUC0-∞ 
should be used.
CL/f
The apparent oral clearance.
CL/f = Dose p.o. /AUC0-∞. The predicted AUC0-∞ should be used.
Cmax
Maximum observed concentration.
t1/2
Apparent terminal half-life. t1/2 = ln (2)/λz.
tlag
The time prior to the first measurable (non zero) concentration.
tmax
The time to reach the maximum observed concentration collected during a 
dosing interval (i.e., 1st occurrence in case of multiple/identical Cmax values).
VZ/f
The apparent volume of distribution during the terminal phase following 
extravascular administration. Vz/f = Dose/(AUC0-∞*λz) following single dose. 
∃z
Terminal first order (elimination) rate constant. Determined from the terminal 
slope of the log-transformed concentration curve using linear regression on 
terminal data points of the curve.
The following PK parameters will be calculated for diagnostic purposes and listed, but will not 
be summarized:
!
First (λz low) and last (λz upp) time point of the time interval of the log-linear regression to 
determine λz. 
!
Number of data points (Nλ) included in the log-linear regression analysis to determine λz.
!
Goodness of fit statistic (adjusted Rsq) for calculation of λz.  
The predose sample will be considered as if it had been taken simultaneously with the 
administration of study intervention. 
Plasma concentrations below lower limit of quantification (LLOQ) before the last quantifiable 
data point will be taken as zero for calculating the AUC (i.e., embedded below the limit of 
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quantitation values set to zero). Plasma concentrations below LLOQ after the last quantifiable 
data point will not be considered for the determination of λz.
PK parameters will be calculated using the actual elapsed time since dosing, given with a 
precision of 14 significant digits or the SAS format Best12. In cases where the actual sampling 
time is missing, calculations will be performed using the scheduled time. Otherwise, there will 
be no further imputation of missing data.The regression analysis should contain data from at 
least 3 different time points in the terminal phase consistent with the assessment of a straight line 
on the log-transformed scale. Phoenix WinNonlin best fit methodology will be used as standard. 
However, in some cases, further adjustment may be made by the pharmacokineticist, if 
warranted, after agreement with the Sponsor. The last quantifiable concentration should always 
be included in the regression analysis, while the concentration at tmax and any <LLOQ 
concentrations that occur after the last quantifiable data point should not be used. 
The coefficient of correlation (R²) should be ≥0.8 and the observation period over which the 
regression line is estimated should be at least twofold the resulting t1/2 itself. If these criteria are 
not met, then the corresponding values should be flagged in the listing displaying Individual 
Plasma Pharmacokinetic Diagnostic Parameters for Each Treatment. Any flags should be 
included in the study specific SDTM/ADaM. Then the rate constants and all derived parameters 
(e.g. AUC0-∞, %AUCextra, CL/f, t1/2, and VZ/f) will be included in the parameter listings and will 
be discussed appropriately in alignment with the protocol lead and quantitative pharmacology 
representative.
The Phoenix WinNonlin NCA Core Output will be provided in a separate listing.
17
References
EMA/618604/2008 
Rev. 
13:
https://www.ema.europa.eu/en/documents/scientific-
guideline/questions-answers-positions-specific-questions-addressed-pharmacokinetics-working-
party_en.pdf
18
Appendices
None.
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