Conditions: Relapsing Multiple Sclerosis (RMS)
Keywords: Multiple Sclerosis Cladribine Microgynon®
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 28
Healthy volunteers: no

Brief summary:
The purpose of this study was to investigate the potential effects of cladribine on the pharmacokinetics (PK) of monophasic oral contraceptive microgynon® by assessment of its constituents, ethinyl estradiol (EE) and levonorgestrel (LNG).

Detailed description:

Arms:
arm 1: Period 1: Participants received a single once daily dose of Microgynon® tablet from Day 1-8 followed by 5-day once-daily Cladribine 10 to 20 milligram(mg) depending on body weight along with Microgynon® tablet once daily from Day 9-28.

Period 2: Participants received a single once daily dose of Microgynon® tablet from Day 1-8 followed by 5-day once-daily Cladribine matched Placebo along with Microgynon® from Day 9-14. From Day 15-28 participants received once daily Microgynon® along with 5-day once-daily Cladribine 10 to 20 mg depending on body weight. arm 2: Participants 5-day once daily Period 1: Participants received a single once daily dose of Microgynon® tablet from Day 1-8 followed by 5-day once-daily Cladribine matched Placebo along with Microgynon® tablet once daily from Day 9-28.

Period 2: Participants received a single once daily dose of Microgynon® tablet from Day 1-8 followed by 5-day once-daily Cladribine 10 to 20 mg depending on body weight along with Microgynon® tablet once daily from Day 9-28. arm 3: Participants received Microgynon® for 21 days, starting on the first day of the menstrual cycle.

Interventions: intervention 1: Cladribine intervention 2: Placebo intervention 3: Microgynon®
Intervention descriptions: intervention 1: Participants received cladribine once-daily for 5 consecutive days in treatment period 1 and 2. intervention 2: Participants received placebo matched to cladribine once-daily for 5 consecutive days in treatment period 1 and 2. intervention 3: Participants received Microgynon® tablet once daily for 21 days in treatment period 1 and 2. Participants received Microgynon® for 21 days, starting on the first day of the menstrual cycle in Run-in period.

Protocol document:
Prot_000.pdf: 






Cladribine tablets
Effects of cladribine tablets on the pharmacokinetics of Microgynon®
MS700568-0031
C O N F I D E N T I A L
I N F O R M A T I O N
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This document is the property of Merck KGaA, Darmstadt, Germany, or one of its subsidiaries. It is intended for 
restricted use only and may not – in full or part – be passed on, reproduced, published or used without express 
permission of Merck KGaA, Darmstadt, Germany, or its subsidiary. Copyright © 2021 by Merck KGaA, 
Darmstadt, Germany, or its subsidiary. All rights reserved.
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Table of Contents
Title Page
..............................................................................................................1
Table of Contents
..............................................................................................................5
1
Protocol Summary ................................................................................9
1.1
Synopsis................................................................................................9
1.2
Schema................................................................................................11
1.3
Schedule of Activities.........................................................................12
2
Introduction.........................................................................................18
2.1
Study Rationale...................................................................................18
2.2
Background.........................................................................................18
2.3
Benefit/Risk Assessment ....................................................................18
3
Objectives and Endpoints ...................................................................20
4
Study Design.......................................................................................21
4.1
Overall Design....................................................................................21
4.2
Scientific Rationale for Study Design ................................................23
4.3
Justification for Dose..........................................................................24
4.4
End of Study Definition......................................................................25
5
Study Population.................................................................................25
5.1
Inclusion Criteria ................................................................................25
5.2
Exclusion Criteria...............................................................................26
5.3
Lifestyle Considerations .....................................................................30
5.3.1
Meals and Dietary Restrictions...........................................................30
5.3.2
Caffeine, Alcohol, and Tobacco .........................................................30
5.3.3
Activity ...............................................................................................30
5.3.4
COVID-19 Vaccination Considerations.............................................30
5.4
Screen Failures....................................................................................31
6
Study Intervention(s) ..........................................................................31
6.1
Study Intervention(s) Administration.................................................32
6.1.1
Medical Device(s) Use .......................................................................32
6.2
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability.....................................................................................33
6.3
Measures to Minimize Bias: Study Intervention Assignment 
and Blinding........................................................................................34
6.3.1
Study Intervention Assignment ..........................................................34
6.3.2
Blinding ..............................................................................................34
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6.3.3
Emergency Unblinding.......................................................................35
6.4
Study Intervention Compliance..........................................................35
6.5
Concomitant Therapy .........................................................................36
6.5.1
Rescue Medicine.................................................................................36
6.5.2
Permitted Medicines ...........................................................................36
6.5.3
Prohibited Medicines..........................................................................36
6.5.4
Other Interventions.............................................................................38
6.6
Dose Selection and Modification........................................................38
6.6.1
Cladribine ...........................................................................................38
6.6.2
Matching Placebo Tablets...................................................................40
6.6.3
Microgynon.........................................................................................40
6.7
Study Intervention after the End of the Study ....................................40
6.8
Special Precautions.............................................................................41
6.9
Management of Adverse Events of Interest........................................41
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal...............................................................42
7.1
Discontinuation of Study Intervention................................................42
7.1.1
Temporary Discontinuation................................................................42
7.1.2
Rechallenge.........................................................................................42
7.2
Participant Discontinuation/Withdrawal from the Study ...................43
7.3
Lost to Follow Up...............................................................................44
8
Study Assessments and Procedures....................................................44
8.1
Efficacy Assessments and Procedures................................................45
8.2
Safety Assessments and Procedures ...................................................45
8.2.1
Physical Examinations........................................................................46
8.2.2
Vital Signs ..........................................................................................47
8.2.3
Electrocardiograms.............................................................................47
8.2.4
Clinical Safety Laboratory Assessments ............................................47
8.2.5
Suicidal Risk Monitoring....................................................................48
8.3
Adverse Events and Serious Adverse Events.....................................48
8.3.1
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information....................................................48
8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events .................................................................................................49
8.3.3
Follow-up of Adverse Events and Serious Adverse Events ...............49
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8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events .................................................................................................49
8.3.5
Pregnancy ...........................................................................................50
8.4
Treatment of Overdose .......................................................................50
8.5
Pharmacokinetics................................................................................51
8.7
Genetics ..............................................................................................53
8.8
Biomarkers..........................................................................................53
8.9
Health Economics...............................................................................53
8.10
Immunogenicity Assessments ............................................................53
9.3
Populations for Analyses ....................................................................55
9.4
Statistical Analyses.............................................................................56
9.4.1
Efficacy Analyses ...............................................................................56
9.4.2
Safety Analyses ..................................................................................56
9.4.3
Other Analyses....................................................................................57
9.4.4
Analysis of Primary Endpoints...........................................................58
9.4.5
Analysis of Secondary Endpoints.......................................................58
9.4.6
Sequence of Analyses.........................................................................58
10
References...........................................................................................59
11
Appendices .........................................................................................60
Appendix 1
Abbreviations......................................................................................61
Appendix 2
Study Governance...............................................................................64
Appendix 3
Contraception......................................................................................72
Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting................................................74
Appendix 5
Clinical Laboratory Tests ...................................................................78
Appendix 6
Pharmacokinetic Parameters...............................................................80
Appendix 7
Protocol Amendment History.............................................................81
Appendix 8
Sponsor Signature Page......................................................................83
Appendix 9
Coordinating Investigator Signature Page..........................................84
Appendix 10
Principal Investigator Signature Page.................................................85
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Table of In-Text Tables
Table 1
Study Objectives and Endpoints.........................................................20
Table 2
Dose of cladribine per treatment week by participant weight in 
each treatment Year ............................................................................39
Table 3
Cladribine 10 mg tablets per week day for study days.......................39
Table 4
Accepted Time Deviations From Planned PK Sampling Times ........52
Table 5
PK Parameters of EE and LNG ..........................................................52
Table 6
PK Parameters of Cladribinea.............................................................53
Table 7
Analysis Populations ..........................................................................56
Table 8
Protocol-Required Clinical Laboratory Assessments.........................78
Table of In-Text Figures
Figure 1
Study Design Diagram........................................................................11
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Effects of cladribine tablets on the pharmacokinetics of Microgynon®
MS700568-0031
C O N F I D E N T I A L
I N F O R M A T I O N
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1.2
Schema
Figure 1
Study Design Diagram
CLA=Cladribine tablets, 10 mg; MGY=Microgynon tablets (Ethinylestradiol 30 µg, Levonogestrel 150 µg); PLC=Cladribine Placebo tablets; D=day; PK=blood sampling for 
pharmacokinetics. 
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1.3
Schedule of Activities
The Schedule of Activities (SoA) is provided below.
Schedule of Activities – Screening, Run-in-Period and Study Period 1
Assessments & Procedures
Screening
(up to 21
days before 
Day 1)b
Run-in-
Period
Intervention Study Period 1 (Days)
Notes
D
1 to 28
D
8
D
9
D
10
D
11
D
12
D
13
D
14
D
15
D
21
Residency
X
X
X
X
X
X
X
X
In individual cases Investigator may 
allow participants to stay overnight at 
home from Day 8 to Day 12.
In-patient stay is required from the 
evening of Day 13 until discharge on 
Day 15 after completion of all planned 
study assessments.
Ambulatory Visit
X
X
X
Run-in-Period: ambulatory visits on 
Days 7, 14 and 21
Written Informed Consent
X
Prior to any screening procedures
Inclusion and Exclusion Criteria 
review
X
Xa
a Re-check before administration on: 
contraception method, blood loss and 
lifestyle considerations. 
Results of safety laboratory on Day 21
of Run-in-Period (Baseline).
Demographic Data
X
Physical Examination 
X
Herpes Zoster Serology
X
Serology diagnosis, if ABS negative 
vaccination and at least 4 weeks
before cladribine administration
Medical History / Concomitant 
Disease
X
Prior and Concomitant Treatment
X
X
X
X
X
X
X
X
X
X
X
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Assessments & Procedures
(cont’d, Study Period 1)
Screening
(up to 21 
days before 
Day 1)b
Run-in-
Period
Intervention Study Period 1 (Days)
Notes
D
1 to 28
D
8
D
9
D
10
D
11
D
12
D
13
D
14
D
15
D
21
Hematology, Clinical Chemistry & 
Urine Analysis
X
X
X
Run-in-Period on Day 21 (Baseline)
QuantiFERON®-TB Test
X
Done in local laboratory
Serum Pregnancy Test
X
Urine Pregnancy Test
X
X
A negative urine pregnancy test must 
be in place at Day 7 of Run-in-Period
and on Day 8 of Study Period 1.
Alcohol Breath Test / Drugs of 
Abuse
X
X
See Appendix 5.
On Day 8 urine drug screen is done 
locally
Height / Weight / Body Mass Index 
(BMI)
X
X
X
Additional weight control: Run-in-
Period on Day 21 and on Day 21 
Study Period 1
Vital Signs
X
X
X
X
X
X
X
X
Run-in-Period on Days 7, 14 and 21. 
Days 9-13 predose and 1 h postdose; 
on Day 14 at 24 h and 25.5 h 
postdose (Day 13) of 
cladr bine/placebo administration
12-lead ECG
X
X
X
On Day 9 predose and 1.5 h postdose; 
on Day 14 at 24 h and 25.5 h 
postdose (Day 13) of 
cladr bine/placebo administration
Randomization
X
Within 10 days after Run-in-Period 
Day 21
Participant Diary Delivery
X
X
X
Microgynon Delivery
X
X
X
During Screening a second 
appointment needs to be scheduled to 
deliver Microgynon after lab values for 
inclusion have been assessed.
Participant Diary Collection
X
X
Run-in-Period on Day 21
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Cladribine tablets
Effects of cladribine tablets on the pharmacokinetics of Microgynon®
MS700568-0031
C O N F I D E N T I A L
I N F O R M A T I O N
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a
See information given in the ‘notes column’ for line ‘inclusion and exclusion criteria review.
b
In case the Screening period lasts > 21 days and ≤60 days due to a delayed menstrual cycle of the participant (Run-in Day 1), the participant can start with a 
delayed  Run-in-Period without having re-performed the Screening assessments. In case of the requirement to re-assess one or more Screening laboratory value(s), 
the Screening period may be prolonged for up to 8 weeks after the last Screening laboratory assessment and the participant can start with a delayed Run-in-Period 
without re-assessing the complete set of Screening laboratory assessments.
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Effects of cladribine tablets on the pharmacokinetics of Microgynon®
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Schedule of Activities – Study Period 2 and End of Study
Assessments & Procedures
Intervention Study Period 2 (Days)
End of Study
Notes
D
8
D
9
D
10
D
11
D
12
D
13
D
14
D
15
D
21
4-7 days after completion 
of D21
Residency
X
X
X
X
X
X
X
X
In individual cases Investigator may 
allow participants to stay overnight at 
home from Day 8 to Day 12.
In-patient stay is required from the 
evening of Day 13 until discharge on 
Day 15 after completion of all planned 
study assessments.
Ambulatory Visit
X
X
Physical Examination
X
Prior and Concomitant Treatment 
Review
X
X
X
X
X
X
X
X
X
X
Hematology, Clinical Chemistry & 
Urine Analysis
X
X
X
Urine Pregnancy Test
X
X
A negative urine pregnancy test is 
required prior to cladribine 
administration on Day 9.
Alcohol Breath Test / Drugs of 
Abuse
X
See Appendix 5
Urine drug screen is done locally
Weight / BMI
X
X
Vital Signs
X
X
X
X
X
X
X
On Days 9-13 predose and 1 h 
postdose; on Day 14 at 24 and 25.5 h 
postdose (Day 13) of 
cladribine/placebo administration
12-lead ECG
X
X
X
On Day 9 predose and 1.5 h postdose; 
on Day 14 at 24 h and 25.5 h 
postdose (Day 13) of 
cladribine/placebo administration
Participant Diary Collection
X
Document No. 
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*OREDO9HUVLRQ,'
CCI


Cladribine tablets
Effects of cladribine tablets on the pharmacokinetics of Microgynon®
MS700568-0031
C O N F I D E N T I A L
I N F O R M A T I O N
18/85
2
Introduction
Cladribine is a prodrug, which is activated after intracellular phosphorylation to 
2-chlorodeoxy-adenosinetriphosphate (CdATP). Cladribine through its active metabolite 
exerts reversible selective depletion of lymphocytes, which are thought to underlie the 
autoimmune processes involved in multiple sclerosis (MS) pathophysiology. 
In August 2017, cladribine tablets were granted marketing authorization by the European 
Commission (EC) for the treatment of highly active relapsing multiple sclerosis (RMS) in the 
28 countries of the European Union (EU) and additionally in several further countries.
Complete information on the chemistry, pharmacology, efficacy, and safety of cladribine is in 
the Investigator’s Brochure and Package Insert and Summary of Product Characteristics 
(Merck Serono Europe Ltd., 2017).
2.1
Study Rationale
The primary study rationale is to evaluate the potential effects of cladribine tablets on the 
pharmacokinetics of an oral contraceptive (Microgynon tablets [EE 30 µg, LNG 150 µg]).
2.2
Background
Cladribine is an innovative treatment approach for patients with highly active relapsing 
multiple sclerosis (RMS). It is the only disease-modifying drug that can deliver and sustain 
long-standing disease control with a maximum of 20 days of oral treatment in the first 2 years 
in patients with highly active RMS (Giovannoni G. 2010, Giovannoni G. 2017a, Giovannoni 
G. 2017b).
The existing in vitro data in cultured human hepatocytes on the induction potential of cladribine 
towards cytochrome P450 3A4 (CYP3A4) was considered not entirely conclusive. Based on 
that, the European Medicines Agency (EMA) requested the conduct of a drug-drug interaction 
(DDI) study with an oral contraceptive as a post approval commitment of the Marketing 
Authorization Holder (MAH). 
2.3
Benefit/Risk Assessment
Both interventions employed in this study (i.e., cladribine tablets and Microgynon tablets) are 
approved medications in Europe with established efficacy and safety profiles. The patients
enrolled into this study have an established diagnosis of RMS and have been determined by 
the Investigator to require a disease modifying RMS treatment such as cladribine tablets. The 
employed cladribine dose in this study is consistent with their labeled use. By application of 
the inclusion and exclusion criteria of this protocol, it is also ensured that none of the 
participants enrolled will have any contraindications for the use of cladribine tablets. 
Essentially similar considerations apply for the use of Microgynon tablets in the present study: 
The employed Microgynon dose and dose regimen is consistent with the labeled use of the 
product, and by observation of the inclusion and exclusion criteria of this protocol, it is ensured 
that none of the participants enrolled will have any contraindications for the use of Microgynon. 
There are also no known contraindications or warnings established for the concomitant use of 
both products, and there are no medically important drug-interactions to be expected. 
The study is conducted under conditions that ensure a close monitoring and early detection of 
adverse events (AEs) and adequate medical intervention or study withdrawal (if required). 
Document No. 
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Global Version ID: 


Cladribine tablets
Effects of cladribine tablets on the pharmacokinetics of Microgynon®
MS700568-0031
C O N F I D E N T I A L
I N F O R M A T I O N
19/85
The total amount of blood taken will be about 400 ml over a period of more than 3 months 
(with a typical blood donation there will be drawn up to 500 ml of blood at a single occasion).
The use of Microgynon in the present study serves scientific purposes with the aim to provide 
group ethical benefits by establishing simplified contraception recommendations for women 
requiring a treatment with cladribine tablets (currently cumbersome non-hormonal, but 
effective methods of contraception need to be applied for at least 6 months, see Appendix 3).
More detailed information about the known and expected benefits and risks and reasonably 
expected adverse events of cladribine may be found in Section 4.2 (Scientific Rationale for 
Study Design), the Package Insert and Summary of Product Characteristics (Merck Serono 
Europe Ltd., 2017).
After careful consideration of the benefits and risks, the performance of the clinical study in 
women with RMS is considered ethically and medically justified because of the anticipated 
therapeutic benefit of the product for participants and the group-ethical benefits that are
associated with simplified contraception recommendations that are expected to also include 
hormonal contraceptives based on the results from the present study.
This clinical study will be conducted in compliance with the clinical study protocol, guideline 
of Good Clinical Practice of the International Conference on Harmonization (ICH Topic E6, 
GCP) and the applicable regulatory requirements. 
Based on the available nonclinical and clinical data to date, the conduct of the study, as 
specified in this protocol, is considered justifiable.
Document No. 
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Cladribine tablets
Effects of cladribine tablets on the pharmacokinetics of Microgynon®
MS700568-0031
C O N F I D E N T I A L
I N F O R M A T I O N
21/85
4
Study Design
4.1
Overall Design
This is a randomized, double-blind, 2-period, 2-sequence crossover study with a 1 month Run-
in-Period in pre-menopausal women with active relapsing multiple sclerosis (RMS) requiring 
a disease-modifying RMS treatment. The overall study design is shown in Section 1.2, 
Figure 1.
The study design will comprise a ≤21-day Screening period followed by a Microgynon Run-
in-Period, followed by 2 sequential treatment periods (Study Periods 1 and 2) of 28 days each. 
In case the Screening period lasts > 21 days and ≤60 days due to a delayed menstrual cycle of 
the participant (Run-in Day 1), it is acceptable that the participant starts with a delayed Run-
in-Period without having re-performed the Screening assessments (in order to minimize 
unnecessary investigational burden for the participant). In case of the requirement to re-assess 
one or more Screening laboratory value(s), the Screening period may be prolonged for up to 
8 weeks after the last Screening laboratory assessment and it is acceptable that the participant
starts with a delayed Run-in-Period without re-assessing the complete set of Screening
laboratory assessments. In both cases, the participant does not need to sign a new Informed 
Consent Form (ICF).
In the Run-in-Period as well as during both treatment periods, Microgynon (1 tablet/day 
containing 30 µg ethinyl estradiol [EE] and 150 µg levonorgestrel [LNG]) will be administered 
for 21 days, followed by 7 days off-treatment. In Study Periods 1 and 2 Microgynon will 
continue to be administered together with randomized treatment sequences of a 5-day once-
daily cladribine 10 mg tablet treatment (Day 9 to Day 13 of Study Period 1) followed by a 
5-day once-daily matched placebo treatment (Day 9 to Day 13 of Study Period 2) or vice versa; 
i.e., participants will be randomized to 1 of 2 double-blind treatment sequences, either 
cladribine-placebo or placebo-cladribine. Additionally, matched placebo treatment (Day 15 to 
Day 19) will be given in order to protect the blind for the cladribine-placebo sequence, that 
will receive their second weekly dose of cladribine on Day 15 to Day 19 in Study Period 2. In 
turn, the placebo-cladribine sequence will receive the second weekly dose of cladribine after 
the End of Study Visit as part of standard medical care.
An End of Study examination will be performed within 4-7 days after the last visit of Study 
Period 2. To the extent possible, an Early Termination (ET) visit will be conducted for 
participants who withdraw prematurely. The same assessments as for the End of Study Visit 
will be conducted at the ET visit as far as feasible.
During the Run-in-Period participants will take Microgynon on an ambulatory basis and 
document daily drug intake in a participant diary. Participants will be requested to come to 
weekly visits in the mornings of Day 7, 14 and 21 for documentation of adverse events, 
participant diary check, and therapeutic drug monitoring (i.e., pharmacokinetic (PK) sampling 
for EE and LNG trough levels). 
For Study Periods 1 and 2, participants will continue to take Microgynon on an ambulatory 
basis of Days 1 to 7 and to document drug intake in a participant diary. On Day 8 they will be 
hospitalized until discharge in the morning of Day 15 after completion of all in-house study-
related assessments. At some study sites the hospitalization periods need to be conducted in 
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Cladribine tablets
Effects of cladribine tablets on the pharmacokinetics of Microgynon®
MS700568-0031
C O N F I D E N T I A L
I N F O R M A T I O N
23/85
4.2
Scientific Rationale for Study Design
This study will investigate the potential effects of cladribine treatment on the pharmacokinetics 
of the frequently prescribed monophasic oral contraceptive Microgynon. The outcome of the 
study is expected to be generalizable also to other hormonal oral contraceptives containing EE 
as estrogen component and LNG or other progestin components metabolized by CYP3A4 (e.g.
norethindrone, norelgestromin, etc.), as the available published evidence suggests that LNG is 
a highly sensitive substrate for the assessment of CYP3A4 induction, and that the effect of 
CYP3A4 induction (in terms of AUC reduction) on other CYP3A4-metabolized progestins is 
qualitatively comparable. The study addresses a recent request by the EMA for the conduct of 
a cladribine DDI study with an oral contraceptive as a post approval commitment. 
Cladribine has been shown to have teratogenic effects in preclinical studies, consistent with its 
pharmacologic mechanisms of action. This study will provide additional important information 
on the safety of cladribine and the most suitable contraceptive methods to be used with 
cladribine. 
The study design is consistent with DDI studies examining the perpetrator effects of 
investigational medicinal products (IMPs) on the pharmacokinetics (PK) of hormonal 
contraceptives. Accordingly, the study aims to compare the effect of repeat-dose cladribine 10 
mg tablets and matched placebo on the repeat-dose PK of the monophasic oral contraceptive 
Microgynon. The study objective is to show that both treatments will have an equivalent effect 
on the PK of both Microgynon components (EE/LNG). As the dose and posology of cladribine 
treatment is based on body weight, and participants with a very low body weight (i.e., < 50 kg) 
would receive only a 4-day treatment per treatment week instead of a 5-day treatment, the study
will only enroll participants with a body weight of ≥50 kg to allow for a standardized 5-day 
repeat-dose cladribine treatment of all study participants. This approach will standardize the 
cladribine treatment duration, thereby reducing the complexity of the study design.
Participants randomized to the treatment sequence placebo-cladribine, will receive their first 
5-day cladribine treatment in Study Period 2 (Days 9 to 13), and will receive their second 5-day 
cladribine treatment between 28 to 35 days thereafter, which conforms to the approved 
cladribine posology. It is important to note, that this second cladribine treatment week will not 
be part of the study itself but provided as standard medical care of participants in the following 
month after end of the study (see Section 6.7).
Participants randomized to the treatment sequence cladribine-placebo, will receive their first 
5-day cladribine treatment in Study Period 1 (Days 9 to 13). Since, according to the study 
design, they will have to receive Placebo treatment 4 weeks thereafter (i.e., Study Period 2, 
Days 9 to 13), their second 5-day cladribine treatment will have to be deferred by 6 days (i.e.,
Study Period 2, Days 15 to 19). Accordingly, participants will receive their second 5-day 
cladribine treatment 34 days after having received their first cladribine 5-day treatment in Study 
Period 1. This schedule will only marginally deviate from the approved cladribine posology. 
In view of the long-lasting duration of action of cladribine, this modest deferral of the second 
cladribine treatment week is unlikely to affect the overall efficacy of cladribine treatment. 
Document No. 
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Cladribine tablets
Effects of cladribine tablets on the pharmacokinetics of Microgynon®
MS700568-0031
C O N F I D E N T I A L
I N F O R M A T I O N
25/85
4.4
End of Study Definition
A participant has completed the study if she has completed all study parts, including the End 
of Study Visit, and the following review of all End of Study safety assessments, including the 
blood sample results have been completed by the Investigator. In case of ongoing adverse 
events or safety laboratory deviations requiring follow-up activities, the end-of study will be 
defined for those subjects as the date of the last follow-up visit.
The end of the study is defined as the date when the last End of Study visit of the last study 
participant globally has been performed and the following review of all safety assessments, 
including the blood sample results have been completed by the Investigator 
Routine standard of care activities (e.g., blood drawing) should only be initiated once the site 
was unblinded to the patient treatment sequence.
5
Study Population
The criteria in Sections 5.1 (Inclusion Criteria) and 5.2 (Exclusion Criteria) are designed to 
enroll only participants, who are appropriate for the study, thereby ensuring the study fulfills 
its objectives. All relevant medical and nonmedical conditions should be taken into 
consideration when deciding whether a participant is suitable for this study.
Prospective approval of protocol deviations to inclusion and exclusion criteria, also known as 
protocol waivers or exemptions, is not permitted.
Before performing any study assessments that are not part of the participant’s routine medical 
care, the Investigator will confirm that the participant or the participant’s legal representative 
has provided written informed consent, as indicated in Appendix 2 (Study Governance).
5.1
Inclusion Criteria
Participants are eligible to be included in the study only if all the following criteria apply:
Age
1. Are 18 to 45 Years of age inclusive, at the time of signing the informed consent.
Type of Participant and Disease Characteristics
2. Have a diagnosis of clinically stable and definite RMS by either McDonald MS or Poser
criteria.
3. Apart from their underlying primary disease condition (i.e., RMS) are in good health as 
determined by medical history, physical examination, 12-lead ECG, vital signs, clinical 
biochemistry, hematology and urinalysis.
4. Have white blood cell counts, absolute lymphocyte counts and absolute neutrophil 
counts within normal ranges (applies for patients in Year 1) at Screening and on Day 21 
of the Run-in-Period (Baseline), respectively. Platelets should not be below 100 x 109/L.
In case of second year cladribine treatment, lymphocyte counts must be at least 
800 cells/mm³ at Screening and on Day 21 of the Run-in-Period (Baseline).
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5. Have other safety laboratory values within normal ranges at Screening, or modestly out 
of range which are assessed by the Investigator as not clinically relevant. 
6. Are able and willing to accept dietary restrictions and restrictions regarding the use of 
concomitant medications (incl. over-the-counter (OTC)) products, herbal medicines and 
dietary supplements) over the course of the study as further specified in the Exclusion 
Criteria. 
7. Are able and willing to undergo serial venous blood sampling for pharmacokinetic 
evaluation.
8. Are able to comply with all of the study requirements.
Weight
9. Have a body weight within ≥50 kg and ≤100 kg and body mass index (BMI) within the 
range ≥18 kg/m2 and ≤30 kg/m2 (inclusive) at Screening.
Sex
10. Are non-pregnant, non-breast feeding women of any ethnic origin.
11. Are pre-menopausal women with or without child-bearing potential with a negative 
serum pregnancy test, and women with child-bearing potential receiving adequate birth 
control. Women with childbearing potential must be willing to avoid pregnancy by using 
a highly effective method of birth control in addition to the hormonal contraceptive 
(Microgynon) that is employed in the study. According to World Health Organization
(WHO) definition highly effective methods of birth control are those resulting in a less 
than 1% per Year failure rate when used consistently and correctly, such as intrauterine 
devices (IUDs). Highly effective contraception should be maintained throughout the 
study (starting from enrollment), and for at least 4 weeks after the last dose of study 
intervention. An effective contraceptive method (e.g., by taking a hormonal oral 
contraceptive or applying another effective birth control method) must be used starting 
1 month after last dose of study intervention and continue for at least 5 months (see also 
Appendix 3). Women without childbearing potential are defined as surgically or 
medically sterile.
Informed Consent
12. Can give signed informed consent, as indicated in Appendix 2 (Study Governance), 
which includes compliance with the requirements and restrictions listed in the ICF and 
this protocol.
5.2
Exclusion Criteria
Participants are excluded from the study if any of the following criteria apply:
Medical Conditions
1. History of clinically relevant allergy or known hypersensitivity to the active substance 
or to any of the excipients (e.g., fructose) of cladribine tablets or hypersensitivity to 
drugs with a similar chemical structure to cladribine.
2. History of clinically relevant allergy or known hypersensitivity to 1 of the active 
substances levonorgestrel (LNG) or ethinylestradiol (EE) or to any excipients (e.g.,
lactose and sucrose) of Microgynon tablets. 
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3. Presence or history of any serious allergy (requiring hospitalization or prolonged 
systemic treatment).
4. Positive results from serology examination for Hepatitis B surface antigen (HbsAg) not 
due to vaccination, hepatitis B core antibody (HbcAb), Hepatitis C virus antibody (anti-
HCV) or Human Immunodeficiency virus 1 and 2 antibody (anti-HIV1/2).
5. Active chronic infection (tuberculosis or hepatitis).
6. History or current evidence of any significantly immunocompromising comorbidities.
7. Current diagnosis or personal history of cancer.
8. Moderate or severe renal impairment (creatinine clearance < 60 mL/min).
9. Moderate or severe hepatic impairment (Child Pugh B and C). 
10. Presence or risk of venous thromboembolism (VTE), e.g., history of deep venous 
thrombosis (DVT); pulmonary embolism (PE); known hereditary or acquired 
predisposition for venous thromboembolism, such as APC-resistance, including Factor 
V Leiden, antithrombin-III-deficiency, protein C deficiency, protein S deficiency; major 
surgery with prolonged immobilization; high VTE risk due to the presence of multiple 
risk factors.
11. Presence or risk of arterial thromboembolism (ATE), e.g., current arterial thrombo-
embolism; history of arterial thromboembolism (e.g., myocardial infarction) or 
prodromal condition (e.g., angina pectoris, diagnosis of coronary artery disease); 
cerebrovascular disease, e.g., current stroke, history of stroke or prodromal condition 
such as transient ischemic attack (TIA); history of migraine with focal neurological 
symptoms; known hereditary or acquired predisposition for arterial thromboembolism, 
such as hyperhomocysteinemia and antiphospholipid antibodies (anticardiolipin-
antibodies, lupus anticoagulant); a high risk of arterial thromboembolism due to multiple 
risk factors.
12. Diabetes mellitus (Type 1 or Type 2) with vascular manifestations (e.g., diabetic foot 
syndrome, retinopathy or arteriosclerosis).
13. Poorly controlled arterial hypertension, i.e., systolic blood pressure ≥160 mm, or 
diastolic blood pressure ≥100 mm Hg).
14. Severe hyperlipoproteinemia, i.e., total cholesterol ≥240 mg/dL or hypertriglyceridemia 
≥200 mg/dL in combination with low density lipoprotein (LDL) cholesterol ranging 
between 160 to 190 mg/dL.
15. Signs and symptoms of Transmissible Spongiform Encephalopathy or Progressive 
Multifocal Leukencephalopathy (PML) at Screening.
16. Presence of chronic or recurrent infection or any acute infection within the last 2 weeks 
before first dosing in treatment periods employing cladribine.
17. Signs or symptoms of neurological disease other than MS that could explain the 
symptoms of the participant.
18. Presence of gastrointestinal (GI) disease or history of gastrointestinal -tract surgery that, 
in the opinion of the Investigator, may affect the absorption of the study drugs, i.e., the 
pharmacokinetic outcome of the study.
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Prior/Concomitant Therapy
19. Current immune-suppressive or myelosuppressive therapies (e.g., methotrexate, cyclo-
phosphamide, cyclosporine or azathioprine, or chronic use of corticosteroids) or prior 
treatment with immunomodulatory or immunosuppressive medicinal products within 
the last year prior to the planned first study intervention, with the exception of the 
following therapies and application of the specified wash-out criteria below:
a) Interferon b, Dimethylfumarate, and Glatirameracetate (Copaxone): until remission 
of treatment-specific effects as indicated by a lymphocyte count not below the lower 
limit of normal range of central lab (1.000 - 1.200 cells/mm3) and at least 1 month,
b) Azathioprine, Cyclosporine A, Mitoxantrone, Methotrexate:  until remission of 
treatment-specific effects as indicated by a lymphocyte count not below the lower 
limit of normal range of central lab (1.000 - 1.200 cells/mm3) and at least 3 months,
c) Alemtuzumab, Rituximab, until remission of treatment-specific effects as indicated 
by a lymphocyte count not below the lower limit of normal range of central lab 
(1.000 - 1.200 cells/mm3) and at least 6 months.
d) Elimination of teriflunomide and other medications may be accelerated by the 
administration of cholestyramine or activated charcoal (accelerated elimination 
procedure [AEP]). In cases where AEP is approved and was carried out according 
to the summary of product characteristics before Screening, including confirmation 
by therapeutic drug monitoring, Exclusion Criterion # 19 is therefore not applicable.
Note: The AEP is an established procedure if pregnancy is desired or if the 
immune-suppressive or myelosuppressive therapy is to be changed and the 
previously given medication is to be removed from the body within a short time. 
Even in the case of a medication with a very long half-life, by means of AEP it is 
possible to reduce blood levels below the detection limit within a short period of 
time.
20. Vaccination with live or attenuated live vaccines within 4 weeks prior to 
cladribine/placebo administration, and participants who are expected to require 
vaccination with live or attenuated live vaccines throughout the study.
21. Regular use of any medications that can directly influence gastrointestinal motility and 
absorption of cladribine (e.g., use of histamine receptor antagonists (H2), proton pump 
inhibitors, or antacids), and participants who are expected to use such products 
throughout the study.
22. Participants who have used potent or moderate inducers of CYP3A4 or other 
cytochrome P450 enzymes or of the drug transporters P-gp and BCRP, such as 
carbamazepine, dexamethasone, phenytoin, rifabutin, rifampin and pioglitazone within 
the last 4 weeks prior to the planned first study intervention and participants who are 
expected to use such products throughout the study.
23. Participants who have used strong or moderate inhibitors of CYP3A4 or other 
cytochrome P450 enzymes including oral/systemic ketoconazole, itraconazole, 
miconazole, clotrimazole, fluconazole, posaconazole, voriconazole, clarithromycin, 
erythromycin, ciprofloxacin, verapamil, diltiazem, indinavir, nelfinavir, saquinavir, 
ritonavir, amprenavir, lopinavir, atazanavir, darunavir and cyclosporine within the last 
4 weeks prior to the planned first study intervention, and participants who are expected 
to use such products throughout the study.
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24. Participants who have used equilibrative nucleoside (ENT1) and concentrative 
nucleoside (CNT3) transport proteins inhibitors such as dilazep, nifedipine, nimodipine, 
cilostazol, sulindac or reserpine within 2 weeks prior to the first scheduled study 
intervention, and participants who are expected to use such products throughout the 
study.
25. Use of any herbal medications such as St John's Wort, milk thistle/silymarin, goldenseal/ 
berberine and Echinacea, or any dietary supplements (including vitamins and minerals) 
within 2 weeks prior to the first scheduled study intervention, and participants who are 
expected to use such products throughout the study.
26. Participants reporting consumption of any drug metabolizing enzyme (e.g., CYP3A4 or 
other cytochrome P450 enzymes) inducing or inhibiting aliments, beverages or food 
supplements, e.g., broccoli, Brussels sprouts, grapefruit, grapefruit juice, Seville orange, 
star fruit, and products containing such fruit components (e.g., juices, marmalade, jam, 
etc.) within 2 weeks prior to the first scheduled study intervention, and participants who 
are expected to use such products throughout the study.
Prior/Concurrent Clinical Study Experience
27. Exposure to another investigational drug within the last 2 months or within last 6 month 
if agent is known to be immunosuppressive.
28. Participant has previously received at least 1 dose of study intervention in the current 
study.
Diagnostic Assessments
29. Clinically significant abnormal finding in the 12-lead ECG recording at the Screening 
examination, including QTc > 450 ms (Fridericia's formula) or participants with 
congenital long QT syndrome, or other clinically significant abnormal ECG findings 
that in the opinion of the Investigator may increase the safety risk to the participant.
Other Exclusions
30. Current history or presence of drug or alcohol abuse, confirmed by positive test results 
for drugs of abuse and/or alcohol or have a history of drug or alcohol abuse. Alcohol 
abuse is defined as: an average daily intake of more than 3 units or a weekly intake of 
more than 14 units for females where 1 unit equals 8-10 g alcohol (1 unit equals 340 mL 
of beer, 115 mL of wine or 43 mL of spirits).
31. Smoking of > 10 cigarettes per day or equivalent.
32. Loss or donation of more than 400 mL of blood in the 12 weeks prior to first dose.
33. Participant plans to donate oocytes for medically assisted reproduction techniques 
(ART) within 6 months after the last cladribine dose.
34. Participant is a "vulnerable" individual (e.g., person is kept in detention).
35. Participant is Investigator in the current study, or a first-degree relative of a study 
Investigator, or is an employee of the sponsor or study centers.
36. Participant is considered unable or unwilling to co-operate adequately, i.e., to follow 
study procedures and Investigator instructions adequately (e.g., language difficulties, 
etc.).
37. Participant is anticipated to be unavailable for scheduled study visits/procedures.
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6.1
Study Intervention(s) Administration
Study intervention administration details are provided in the table below. 
Study Intervention 
Name:
Cladribine Tablets 
Cladribine Placebo 
Tablets
Microgynon
Dose Formulation:
White, round, biconvex 
tablets of 8.5 mm 
diameter, engraved with 'C' 
on 1 side and '10' on the 
other side. 
White, round, biconvex 
tablets of 8.5 mm 
diameter, engraved with 'C' 
on 1 side and '10' on the 
other side 
Beige, sugar-coated 
tablets
Unit Dose 
Strength(s)/
Dosage Level(s):
10 mg / tablet
N/A (placebo)
Levonorgestrel (LNG) 
150 µg and ethinyl
estradiol (EE) 30 µg
Route of 
Administration:
Oral
Oral
Oral
Dosing 
Instructions:
Each treatment week 
consists of 5 consecutive 
days on which a participant 
receives 10 mg or 20 mg 
(one or 2 tablets) taken 
with water in the morning 
as a single daily dose, 
depending on body weight. 
For details, see Section
6.6
As for cladribine. For 
details, see Section 6.6
1 tablet daily for 21 days, 
starting on the first day of 
the menstrual cycle 
followed by 7 treatment-
free days. Subsequent 
cycles (Study Periods 1 
and 2): Tablet-taking from 
the next pack of 
Microgynon is continued 
after a 7-day treatment-
free interval, beginning on 
the same day of the week 
as the Run-in-Period. For 
details, see Section 6.6
Supplier:
Merck KGaA
Merck KGaA
From commercially 
available sources; 
provided by Merck KGaA
Packaging and 
Labeling
Cladribine will be supplied 
in blister packages, 
containing 1, 4 and 
6 tablets.
Packages with 1 tablet for 
the study and the medical 
care treatment of the first 
year will be used. 
All IMPs will be packaged 
and labeled in accordance 
with all applicable 
regulatory requirements 
and Good Manufacturing 
Practice Guidelines.
Placebo will be supplied in 
blister packages, 
containing 1, 4 and 
6 tablets.
All IMPs will be packaged 
and labeled in accordance 
with all applicable 
regulatory requirements 
and
Good Manufacturing 
Practice Guidelines.
Microgynon 21 will be 
supplied and packaged 
and labeled in accordance 
with all applicable 
regulatory requirements 
and Good Manufacturing 
Practice Guidelines.
EE=ethinyl estradiol; IMP=investigational medicinal product; LNG=levonorgestrel; N/A=not applicable; 
µg=microgram; mg= milligram; mm= millimeter
6.1.1
Medical Device(s) Use
Not applicable.
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6.2
Study Intervention(s) Preparation, Handling, Storage, and 
Accountability
The Investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance (i.e., 
receipt, reconciliation, and final disposition records).
Upon receipt of the study intervention(s), the Investigator or designee must confirm 
appropriate temperature conditions have been maintained during transit and any 
discrepancies are reported and resolved before use. Also, the responsible person will check 
for accurate delivery and acknowledge receipt by signing or initialing and dating the 
appropriate document and returning it to the location specified. A copy will be archived for 
the Investigator Site File.
Only participants enrolled in the study may receive study intervention(s) and only 
authorized site staff may supply or administer it (where enrolled is defined as a participant 
who has started the Run-in-Period, see Table 7). All study intervention(s) must be stored in 
a secure, environmentally-controlled, and monitored (manual or automated) area, in 
accordance with the labeled storage conditions, and with access limited to the Investigator 
and authorized site staff.
Dispensing will be recorded on the appropriate accountability forms so that accurate records 
will be available for verification at each monitoring visit.
Study intervention(s) accountability records at the study site will include the following:
Confirmation of receipt, in good condition and in the defined temperature range
The inventory provided for the clinical study and prepared at the site
The dose(s) each participant used during the study
The disposition (including return, if applicable) of any unused study intervention(s)
Dates, quantities, batch numbers, container numbers, expiry dates, formulations for 
study interventions prepared at the site, and the participant numbers
The Investigator site will maintain records, which adequately documents that participants 
were provided the doses specified in this protocol, and all study intervention(s) provided 
were fully reconciled
Unused study intervention(s) must not be discarded or used for any purpose other than the 
present study. No study intervention that is dispensed to a participant may be re-dispensed 
to a different participant
A Study Monitor will periodically collect the study intervention(s) accountability forms and 
check all returns (both unused and used containers) before authorizing their destruction by 
the study site or arranging for their return to the Sponsor or designee. In the event the site is 
unable to destroy unused and used containers, it is recommended local or regional 
destruction is organized by the CRO. Unused and used containers must only be returned to 
the Sponsor CMO depot, if required by the local law
Further guidance and information for the final disposition of unused study interventions are 
provided in the Operations Manual.
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6.3.3
Emergency Unblinding
In an emergency, the Investigator is solely responsible for determining if unblinding of a 
participant’s study intervention assignment is warranted. Participant safety must always be the 
first consideration in this decision. If the Investigator decides that unblinding is warranted, the 
Investigator should make every effort to contact the Sponsor prior to the unblinding, unless this 
could delay emergency treatment. The Sponsor must be notified within 24 hours after 
unblinding. The Investigator must provide the Sponsor the reason for unblinding without 
revealing the study intervention, except to the designated drug safety representative via the 
Emergency Unblinding Notification Form. The date of and reason for unblinding must be 
recorded in the source documents. Contact information for unblinding in an emergency is given 
on the participant emergency card provided to each participant, as noted in Appendix 2 (Study 
Governance Considerations).
The Sponsor’s Global Patient Safety department will submit any Suspected Unexpected 
Serious Adverse Reactions (SUSAR) reports to regulatory authorities and ethics committees 
with unblinded information, per applicable regulations. Only blinded information will be 
provided to the study team.
Under certain circumstances, Global Patient Safety may be required to unblind the treatment 
assignment for an individual participant following a serious adverse event (SAE) or other 
serious event; for example, if an expedited regulatory report is required. See Section 8.3.4 for 
further details on expedited reporting and SAEs. 
Unblinding of the period assignment of an individual participant due to emergency will not per 
se render this participant unevaluable for PK and 
 assessments, provided the unblinding or 
related emergency procedure will not alter the planned per-protocol study interventions (see
Section 9.3).
6.4
Study Intervention Compliance
During the 2 cladribine treatment periods, while participants are hospitalized, administrations 
of cladribine tablets will be performed by dedicated site staff in accordance with the protocol 
requirements and specifications of the Investigator. This includes checking the oral and buccal 
cavity with the aid of a flashlight and tongue depressor. The proper administration of the study
medication will be documented on the individual eCRF.
Participants will be provided with a pack of Microgynon for 1 cycle during the Screening Visit 
and a diary for recording daily Microgynon intake. The diary entries are checked for 
compliance of Microgynon intake during ambulatory visits on Day 7, 14 and 21 of the first 
cycle (Run-in-Period). On Day 21 of the first cycle (Run-in-Period) and Day 21 of Study 
Period 1, participant diary and empty Microgynon packing is collected, and a new diary and 
Microgynon pack is delivered. Additionally, therapeutic drug monitoring (PK sampling for EE 
and LNG) is performed on Days 7, 14 and 21 of the first cycle (Run-in-Period), and on Days 
13, 14 and 15 of each period.
Participants must be 100% compliant to cladribine and placebo intake to be eligible for 
Pharmacokinetic and 
 evaluation (see Populations for Analysis, Section 9.3).
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Assessment of compliance with respect to Microgynon intake will be based on participant 
reports (diary) and pill counts during the study, and at the end of the study on retrospective 
analysis of EE/LNG blood levels of all samples collected. Deviations from compliance to 
Microgynon for each of the 21 days of intake per cycle, if any, will be judged by the 
Investigator whether such protocol non-compliance is considered significant. In case of 
significant non-compliance, the participant would be withdrawn from further therapy or the 
study (see Section 7.1 and 7.2).  
6.5
Concomitant Therapy
Record in the eCRF all concomitant interventions (e.g., medicines or nondrug interventions) 
used from the time the participant signs the informed consent until completion of the study, 
including any changes. For prescription and over-the-counter medicines, vaccines, vitamins, 
and herbal supplements, record the name, reason for use, dates administered, and dosing 
information.
Contact the Medical Monitor for any questions on concomitant or prior therapy.
6.5.1
Rescue Medicine
Not applicable.
6.5.2
Permitted Medicines
The only permitted medications are the following:
Acetaminophen (Paracetamol) up to 1 g per day, at the discretion of the Investigator
Established treatments for chronic stable concomitant diseases (e.g., for hypertension, 
hyperlipidemia, etc.) are allowed, when kept stable throughout the study. 
Any medicines that are considered necessary to protect the participant’s welfare in emergencies
may be given at the Investigator’s discretion, regardless if it results in a protocol deviation.
Cladribine pretreatment is permitted, provided 
the participant has completed a full first year course of treatment, and
the second year treatment initiated during this study (Day 8 of Study Period 1) is initiated 
within 12-18 months after the first dose of cladribine in Year one, and
lymphocyte count is at least 800 cells/mm3 at Screening and on Day 21 of the Run-in-Period 
(Baseline) before initiating treatment in year 2.  
6.5.3
Prohibited Medicines
During intake of Microgynon and Cladribine (Day 9 – Day 13 and Day 15 – Day 19), intake 
of concomitant oral medication, including medicines as permitted in Section 6.5.2, is not 
allowed from 3 hours before to 3 hours after cladribine intake except of Microgynon.
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On Day 14 until the last PK sample is drawn on Day 15 concomitant medications, including 
medicines as permitted in Section 6.5.2, have to be paused, unless interruption of a specific 
chronic concomitant medication for one day would be considered to pose a medical risk to a 
subject. 
Prohibited medicines include:
Previous immune-suppressive or myelosuppressive therapies or prior treatment with 
immunomodulatory or immunosuppressive medicinal products within the last year prior to the 
planned first study intervention or expected use of such products throughout the study with the 
exception of the therapies and application of the specified wash-out criteria described in
Exclusion Criterion #19.
Previous use of potent or moderate inducers of CYP3A4 or other cytochrome P450 enzymes 
or of the drug transporters P-gp and BCRP, such as carbamazepine, dexamethasone, phenytoin, 
rifabutin, rifampin, pioglitazone, oral/systemic ketoconazole, itraconazole, miconazole, 
clotrimazole, fluconazole, posaconazole, voriconazole, clarithromycin, erythromycin, 
ciprofloxacin, verapamil, diltiazem, indinavir, nelfinavir, saquinavir, ritonavir, amprenavir, 
lopinavir, atazanavir, darunavir and cyclosporine within the last 4 weeks prior to the planned 
first study intervention, or use of such products throughout the study (see Exclusion Criteria 
#22 and #23)
Regular previous and expected concomitant use of any medications that can directly influence 
GI motility and absorption of cladribine (e.g., use of histamine receptor antagonists (H2), proton 
pump inhibitors, or antacids), and expected use of such products throughout the study (see 
Exclusion Criterion #21)
Previous use of equilibrative nucleoside (ENT1) and concentrative nucleoside (CNT3) 
transport proteins inhibitors such as dilazep, nifedipine, nimodipine, cilostazol, sulindac or 
reserpine within 2 weeks prior to the first scheduled study intervention, and expected use of 
such products throughout the study (see Exclusion Criterion #24).
Use of any herbal medications such as St John's Wort, milk thistle/silymarin, goldenseal/ 
berberine and Echinacea, or any dietary supplements (including vitamins and minerals) within 
2 weeks prior to the first scheduled study intervention, and expected use such products 
throughout the study (see Exclusion Criterion #25).
Participants that had undergone a previous 1 year cycle of cladribine may be considered for 
inclusion into this study as their second year treatment course. Therefore, previous cladribine 
treatment is permitted, provided the participant has completed a full first year course of 
treatment and that the second year treatment initiated during this study (Day 9 of Study Period 1
or 2, respectively depending on treatment group) is initiated within 12 to 18 months after the 
first dose of cladribine in year one. Note that lymphocyte counts for these participants needs to 
be at least 800 cells/mm³ before initiating cladribine treatment in year 2 (see Section 6.7) rather 
than within normal ranges (see Inclusion Criterion #4)
The participants are prohibited from using prescription or over-the-counter medications, herbal 
medicines and dietary supplements (e.g., vitamins and minerals) as detailed in the Exclusion 
Criteria (see Section 5.2), apart from acetaminophen up to 1 g per day, as judged appropriate 
by the Investigator, within the specified time-periods prior to the first study intervention during 
the study, and until after the End of Study Visit. 
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6.5.4
Other Interventions
Study participants should adhere to the following restrictions from Day -1 (screening phase) 
until the End of Study Visit, if periods of prohibition are not specified otherwise:
Women of childbearing potential must agree to comply with the requirements of reliable 
contraception as specified in Inclusion Criterion #11. 
Vaccination with live or life attenuated vaccines as specified in Exclusion Criterion #20
Alcohol intake beyond the limits as specified in Exclusion Criterion #30
Smoking beyond the limits as specified in Exclusion Criterion #31
Dietary restrictions as specified regarding CYP enzyme inducing or inhibiting foods and 
beverages as specified in the Exclusion Criterion #26
Oocyte donation as specified in as specified in Exclusion Criterion #33
Planned (i.e., elective) hospital visits or surgical procedures during the course of the study
are not permitted. In case of emergency or other strong medical need arising for such 
procedures, the participant would be withdrawn from the study
Participation in a clinical study with intake of an investigational drug up to 2 months prior 
to inclusion is not permitted (see Exclusion Criterion #27). However, participation in non-
interventional studies or registries in the indication RMS are permitted prior to and during 
the study.
6.6
Dose Selection and Modification
6.6.1
Cladribine
The recommended cumulative dose of cladribine is 3.5 mg/kg body weight over 2 years,
administered as 1 treatment course of 1.75 mg/kg per year. Each treatment course consists of 
2 treatment weeks, 1 at the beginning of the first month and 1 at the beginning of the second 
month of the respective treatment year. Each treatment week consists of 5 days on which a 
participant receives 10 mg or 20 mg (one or 2 tablets) as a single daily dose, depending on 
body weight. The distribution of the total dose over the 2 years of treatment is provided in
Table 3. For some weight ranges the number of tablets may vary from 1 treatment week to the 
next. Only if weight changes drastically (± 10 kg), cladribine dose for the second treatment 
needs to be adapted. Details are described in the IMP Handling Manual.
Note that for participants randomized to the treatment sequence placebo-cladribine only the 
first cladribine 5-day treatment will be part of the study, while the second cladribine 5-day 
treatment will be offered to the study participants as medical care of participants in the month 
after End of Study (see Section 6.7). The same applies for the completion for cladribine 
treatment in year 2 for those participants that receive their first year treatment course under the 
current protocol, in which case the second year treatment will be offered to the study 
participants as continued medical care after end of study (see Section 6.7).
Cladribine or matched placebo tablets must be taken orally with 200 mL non-carbonated tap 
water, and swallowed without chewing in fasted state in the mornings (between 8:00 and 10:00) 
of Days 9, 10, 11, 12, 13, and Days 15, 16, 17, 18, and 19. As the tablets are uncoated, they 
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must be swallowed immediately once removed from the blister and not be left exposed on 
surfaces or handled for any period of time greater than that required for dosing. 
The hands of the participant or study nurses (whoever will handle the tablet for administration) 
must be dry when handling the tablets and washed thoroughly afterwards.
Table 2
Dose of cladribine per treatment week by participant weight in each 
treatment Year
Weight range
Dose in mg (number of 10 mg tablets) per treatment week
Kg
Treatment Week 1
Treatment Week 2
50 to < 60
50 mg (5 tablets)
50 mg (5 tablets)
60 to < 70
60 mg (6 tablets)
60 mg (6 tablets)
70 to < 80
70 mg (7 tablets)
70 mg (7 tablets)
80 to < 90
80 mg (8 tablets)
70 mg (7 tablets)
90 to < 100
90 mg (9 tablets)
80 mg (8 tablets)
100 to < 110
100 mg (10 tablets)
90 mg (9 tablets)
110 and above
100 mg (10 tablets)
100 mg (10 tablets)
kg=kilogram; mg=milligram
Table 2 above shows how the total number of tablets per treatment week is distributed over the 
individual days. The daily cladribine doses in each treatment week are to be taken at intervals 
of 24 hours at approximately the same time each day, i.e., in the morning after an overnight 
fast. If a daily dose consists of 2 tablets, both tablets are taken together as a single dose. Table 3
below shows the number of tablets to be given for each day as a function of the total numbers 
of tablets per week.
Table 3
Cladribine 10 mg tablets per week day for study days
Total number of tablets 
per week
Day 9
Day 10
Day 11
Day 12
Day 13
5
1
1
1
1
1
6
2
1
1
1
1
7
2
2
1
1
1
8
2
2
2
1
1
9
2
2
2
2
1
10
2
2
2
2
2
Days are shown as Study Days as per Schedule of Assessments, where Day 9 of each period is the first day of 
study intervention administration.
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6.6.2
Matching Placebo Tablets
Matching placebo tablets will be handled and administered according to the same methodology 
and posology as described in Section 6.6.1 for the cladribine treatment. Participants will be 
randomized to receive cladribine placebo tablets either in Study Period 1 or 2 on Days 9, 10, 
11, 12, 13 or/and on Days 15, 16, 17, 18, and 19 on top of the ongoing repeat-dose Microgynon
treatment.
6.6.3
Microgynon
Microgynon tablets must be taken orally with 200 mL non-carbonated tap water, and 
swallowed without chewing. Tablets must be taken in the order directed on the blister package 
at about the same time every day between 7:00 and 9:00 in the morning after an overnight fast.
On days with concomitant cladribine/placebo intake, Microgynon tablets need to be taken 
1 hour before cladribine administration with 200 mL non-carbonated tap water.
First treatment cycle (Run-in-Period): 1 tablet daily for 21 days, starting on the first day of 
the menstrual cycle followed by 7 treatment-free days. Contraceptive protection begins 
immediately.
Subsequent cycles (Study Periods 1 and 2): Tablet-taking from the next pack of Microgynon
is continued after a 7-day treatment-free interval, beginning on the same day of the week as 
the Run-in-Period. 
6.7
Study Intervention after the End of the Study
The dose and the posology of both the examined treatments, cladribine tablets and the 
monophasic oral contraceptive Microgynon as per this study protocol will be consistent with 
the labeled use of both products. The study design ensures that participants would be able to 
receive the full dose and dosage regimen as per label with only minimum deviations, as further 
described in Section 4.1 and below.
Study participants will be offered the approved 2-year use of cladribine. Following completion 
of the 2 annual treatment courses, no further cladribine treatment is required in years 3 and 4. 
Participants randomized to the treatment sequence cladribine-placebo will receive their first 
and second 5-day repeat-dose treatments as part of their study participation. 
For participants randomized to the treatment sequence placebo-cladribine, only the first 
cladribine 5-day treatment will be part of the study, while the second cladribine 5-day treatment 
will be offered to the study participants as medical care in the month after end of study provided 
by the Sponsor.
Further on, 1 year after having received the first dose of cladribine of the first 5-day repeat-
dose treatments (as part of the study), participants will embark into treatment course 2 which 
also consists of 2 5-day repeat-dose treatments, 1 at the beginning of the first month and 1 at 
the beginning of the second month of the second treatment year. Cladribine treatment will be 
provided by the Sponsor outside of the study.
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Study participants that enter the study as their second year treatment course (see Section 6.5.3) 
will complete their full 2-year treatment course during or shortly after the End of Study Visit, 
and no further treatment will be provided by the Sponsor.
Principal Investigators will be informed of the treatment sequence of each participant once a 
participant has completed the End of Study Visit, as they need to know whether another dose 
of cladribine needs to be given. Details on this procedure are described in the IMP Handling 
Manual.
Criteria for initiating and continuing cladribine therapy are as follows:
Lymphocyte counts must be
normal before initiating cladribine treatment in Study Period 1 of the study;
at least 800 cells/mm³ before initiating cladribine treatment in year 2.
If necessary, the treatment course in year 2 can be delayed for up to 6 months to allow for 
recovery of lymphocytes. If this recovery takes more than 6 months, the participant should not 
receive cladribine anymore.
With respect to treatment with Microgynon, contraceptive measures may or may not be altered 
after end of the study as per preference of treating physician and participant. In any case, after 
conclusion of the study effective contraception (e.g., by taking a hormonal oral contraceptive 
or applying another highly effective birth control method) starting 1 month after last dose of 
study intervention must be used and continue for at least 5 months (see Inclusion Criterion #11,
and Appendix 3).
6.8
Special Precautions
Not applicable. For details, refer to the Product Information for cladribine tablets and 
Microgynon.
6.9
Management of Adverse Events of Interest
Hematological Monitoring:
Cladribine's mode of action is associated with a reduction in lymphocyte count. The effect 
on lymphocyte count is dose-dependent. Decreases in neutrophil count, red blood cell 
(RBC) count, hematocrit, hemoglobin or platelet count compared to baseline values have 
also been observed in clinical studies, although these parameters usually remain within 
normal limits
Lymphocyte counts should be measured at Screening, on Day 21 of the Run-in-Period
(Baseline), at the end of each treatment period, and 2 and 6 months after start of cladribine 
treatment. If the lymphocyte count is below 500 cells/mm³, it should be actively monitored 
until values increase again.
With exception of the Screening and Run-In-Period Day 21 blood samples, the white blood 
count (WBC), which includes lymphocyte count will not be distributed to the Investigator 
during study conduct but will be forwarded to the Medical Monitor for review and clinical 
judgement. This is to exclude the possibility of unblinding of the Investigator for the 
treatment sequence (i.e., placebo/cladribine or cladribine/placebo). In case of medically 
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significant decreases in lymphocyte counts (Grade 3 to 4 lymphopenia) the Medical Monitor
informs the Investigator directly by e-mail and/or phone (if feasible).
Infections:
Cladribine can reduce the body's immune defense and may increase the likelihood of 
infections. HIV infection, active tuberculosis and active hepatitis must be excluded before 
initiation of cladribine therapy
Latent infections may be activated, including tuberculosis or hepatitis. Therefore, screening 
for latent infections, in particular tuberculosis and hepatitis B and C, must be performed 
prior to initiation of therapy as specified in Exclusion Criterion #5
A delay in initiation of cladribine treatment should also be considered in participants with 
an acute infection until the infection is fully controlled (see Exclusion Criterion #20)
Particular attention is recommended for participants who have no history of exposure to 
varicella zoster virus. Vaccination of antibody-negative participants is recommended prior 
to initiation of cladribine therapy. Initiation of treatment with cladribine must be postponed 
for 4 to 6 weeks to allow for the full effect of vaccination to occur
Blood transfusions:
In participants who require blood transfusion, irradiation of cellular blood components is 
recommended prior to administration to prevent transfusion-related graft-versus-host 
disease. Consultation with a hematologist is advised.
Further details on the monitoring of participants with adverse events, serious adverse events 
and adverse events of special interest are provided in Appendix 4.
7
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal
7.1
Discontinuation of Study Intervention
The Schedule of Activities (SoA, see Section 1.3) specifies the data to collect at study 
intervention discontinuation and follow-up, and any additional evaluations that need to be 
completed.
ECG recordings / potential cardiac changes: If a clinically significant finding is identified
(including, but not limited to changes from baseline in QT interval corrected using Bazett’s 
formula [QTcB] or Fridericia’s formula [QTcF]) after enrollment, the Investigator or qualified 
designee will determine if the participant can continue in the study and if any change in 
participant management is needed. This review of the ECG printed at the time of collection 
must be documented. Any new clinically relevant finding should be reported as an AE.
7.1.1
Temporary Discontinuation
Not applicable. 
7.1.2
Rechallenge
Not applicable. 
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7.2
Participant Discontinuation/Withdrawal from the Study
A participant may withdraw from the study at any time, at her own request (i.e., withdrawal 
of consent), and without giving a reason
The participant may be withdrawn by the Investigator due to participation in another clinical 
study
The participant may be withdrawn at any time at the discretion of the Investigator for safety, 
behavioral, compliance, or administrative reasons
The SoA (see Section 1.3) specifies the data to collect at study discontinuation and follow-
up, and any additional evaluations that need to be completed.
A participant must also be withdrawn if any of the following occur:
Occurrence of pregnancy (for further details in case of pregnancy see Section 8.3.5),
Use of non-permitted concomitant therapy, as defined in Section 6.5). However, any 
medications that are considered necessary for the participant’s wellbeing (e.g.,
Acetaminophen up to 1 g per day) may be given at the discretion of the Investigator,
Protocol non-compliance judged as significant by the Investigator, including 
non-compliance to the required study considerations (e.g., food/diet requirements), as 
defined in Section 6.4,
Participant lost to follow-up (see Section 7.3)
Any events that endanger the safety of the participant.
If a participant has failed to attend scheduled study assessments, the Investigator must 
determine the reasons and the circumstances as completely and accurately as possible.
In case a participant has to be withdrawn from the study, the medical monitor and clinical study 
leader of the Sponsor will be informed immediately.
If there is a medical reason for the withdrawal, the participant will remain under the supervision 
of the Investigator until satisfactory health has returned or care has been transferred to the 
participant’s general practitioner or to a hospital consultant.
In case of premature withdrawal from the study, the assessments scheduled for the End of Study 
Visit should be performed with focus on the most relevant assessments (see Section 1.3). In 
any case, the appropriate electronic case report form (eCRF) section must be completed.
Participants who withdraw from the study for any reason or do not have a full PK dataset will 
not routinely be replaced. If the assumed drop-out rate of 18 % to 30% will be unexpectedly
higher, a discussion should occur between the Investigator and the Sponsor regarding whether 
a replacement may be considered. The number of participants evaluable for BE (16
participants) need to be maintained. Each replacer will be assigned to the treatment sequence 
of the replaced participant. Details on this procedure are described in the Operations Manual.
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7.3
Lost to Follow Up
A participant will be considered lost to follow-up if she repeatedly fails to return for scheduled 
visits and is unable to be contacted by the study site.
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit:
The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible, counsel the participant on the importance of maintaining the assigned visit 
schedule, and ascertain if the participant wants to or should continue in the study
Before a participant is deemed “lost to follow up”, the Investigator or designee must make 
every effort to regain contact with the participant: 1) where possible, make 3 telephone calls; 
2) if necessary, send a certified letter (or an equivalent local method) to the participant’s last 
known mailing address, and 3) if a participant has given the appropriate consent, contact the 
participant’s general practitioner for information. These contact attempts should be 
documented in the participant’s medical record
Should the participant continue to be unreachable, she will be considered to have withdrawn 
from the study.
In any case, the appropriate electronic case report form (eCRF) section must be completed.
8
Study Assessments and Procedures
Study assessments and procedures and their timing are summarized in the SoA, see 
Section 1.3
No protocol waivers or exemptions are allowed
Immediate safety concerns should be discussed with the Sponsor’s Medical Monitor
immediately upon occurrence or awareness to determine if the participant should continue 
or discontinue study intervention
Adherence to the study design requirements, including those specified in the SoA (see
Section 1.3), is essential and required for study conduct
All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The Investigator will maintain a screening log to 
record details of all participants screened, to confirm eligibility, and if applicable, record 
reasons for screening failure
Prior to performing any study assessments that are not part of the participant’s routine 
medical care, the Investigator will obtain written informed consent as specified in 
Appendix 2 (Study Governance)
Procedures conducted as part of the participant’s routine medical care (e.g., blood count) 
and obtained before signing of the ICF may be used for Screening or Baseline purposes 
provided the procedures met the protocol-specified criteria and were performed within the 
time frame defined in the SoA, see Section 1.3.
Participant’s total duration of participation will be 3 cycles of hormonal contraceptive (84 days) 
plus the Screening period of up to 21 days and the End of Study Visit 4 - 7 days after Day 21 
of the second period. Therefore, the total duration of treatment with HC is 63 days (3 cycles of 
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HC of 21 days), treatment duration with cladribine is 5 days for the sequence placebo-
cladribine, and 10 days for sequence cladribine-placebo and the total duration of each 
participant in the study is 82 - 105 days. 
Sites will be visited by the Study Monitor in regular intervals of usually every 4-8 weeks, 
depending on recruitment, for monitoring and source data verification (see also Appendix 2).
8.1
Efficacy Assessments and Procedures
Not applicable, see under Section 8.5 and 8.6.
8.2
Safety Assessments and Procedures
The safety profile of the study intervention will be assessed through the recording, reporting 
and analysis of baseline medical conditions, adverse events (AEs), physical examination 
findings, vital signs, electrocardiograms, and laboratory tests.
Comprehensive assessment of any potential AE experienced by each participant will be 
conducted starting when the participants give informed consent and throughout the study. The 
Investigator will report any AEs, whether observed by the Investigator or reported by the 
participant; the reporting period is specified in Section 8.3.1 (Time Period and Frequency for 
Collecting Adverse Event and Serious Adverse Event Information).
For cladribine tablets an established safety and adverse event (AE) profile is available, which 
is based on a complete clinical development program in RMS participants. Adverse reactions 
described in the list below are derived from pooled data from clinical studies in RMS in which 
oral cladribine was used as monotherapy at a cumulative dose of 3.5 mg/kg. The safety 
database from these studies comprises 923 participants.
The following definitions apply to the frequency terminology used hereafter: 
very common (≥1/10); 
common (≥1/100 to < 1/10); uncommon (≥1/1,000 to < 1/100); 
rare (≥1/10,000 to < 1/1,000); 
very rare (< 1/10,000); 
frequency not known (cannot be estimated from the available data).
Infections and infestations
Common:
Oral herpes, dermatomal herpes zoster
Very rare:
Tuberculosis
Blood and lymphatic system disorders
Very common:
Lymphopenia
Common:
Decrease in neutrophil count
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Skin and subcutaneous tissue disorders
Common:
Rash, alopecia
Safety & Tolerability of Microgynon
The decision to use Microgynon should take into consideration the individual woman's current 
risk factors, particularly those for venous thromboembolism (VTE). This risk is adequately 
managed by application of respective Inclusion and Exclusion Criteria as detailed in Section 5.
However, there are medical reasons for which the Investigator must stop the treatment with 
Microgynon immediately:
Occurrence for the first time, or exacerbation, of migrainous headaches or unusually 
frequent or unusually severe headaches
Sudden disturbances of vision, of hearing or other perceptual disorders
First signs of thrombosis or blood clots (e.g., unusual pains in or swelling of the leg(s), 
stabbing pains on breathing or coughing for no apparent reason). Feeling of pain and 
tightness in the chest
6 weeks before an elective major operation (e.g., abdominal, orthopedic), any surgery to the 
legs, medical treatment for varicose veins or prolonged immobilization, e.g., after accidents 
or surgery. Do not restart until 2 weeks after full ambulation. In case of emergency surgery, 
thrombotic prophylaxis is usually indicated e.g., subcutaneous heparin
Onset of jaundice, hepatitis, itching of the whole body
Significant rise in blood pressure
Severe upper abdominal pain or liver enlargement
Clear exacerbation of conditions known to be capable of deteriorating during oral 
contraception or pregnancy.
When stopping the oral contraception with Microgynon during the study highly effective non-
hormonal contraception should be used to ensure contraceptive protection is maintained.
8.2.1
Physical Examinations
Physical examination will be performed on the Screening Visit and on the End of Study Visit 
as scheduled in the Schedule of Assessments (see Section 1.3).
A complete physical examination will include, at a minimum assessments of the 
Cardiovascular, Respiratory, Gastrointestinal and Neurological systems. Height (at Screen) 
and weight will also be measured and recorded. In addition, weight will be measured on 
Day 21 of Run-in-Period and Day 21 of Study Period 1 (to be able to calculate/adapt dosage
of study intervention accordingly to actual weight) and Day 8 of Study Period 2.
A brief physical examination will include, at a minimum, assessments of the skin, lungs, 
cardiovascular system, and abdomen (liver and spleen)
Investigators should pay special attention to clinical signs related to previous serious 
illnesses.
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Any relevant findings are to be recorded on the Medical History form in the eCRF (for findings 
from the past that occurred prior to ICF signature) or on the AE form in the eCRF (for findings 
presently occurring; events existing but unresolved prior to study intervention). 
8.2.2
Vital Signs
Vital signs will be measured on the Screening Visit, on Days 7, 14, 21 of the Run-in-Period, in 
Study Periods 1 and 2 on Days 9- 13 predose and 1 hour (h) postdose after cladribine / placebo 
administration, on Day 14 at 24 hours and 25.5 hours after cladribine / placebo administration
(Day 13), and on the End of Study Visit (as scheduled in the Schedule of Assessments, see 
Section 1.3). 
Vital signs will be measured in a semi-supine position after 5 minutes rest and will 
include temperature, systolic and diastolic blood pressure, pulse and respiratory rate:
Tympanic temperature will be measured,
Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available.
8.2.3
Electrocardiograms
For safety evaluation, 12-lead ECGs will be recorded on the Screening Visit, in Study Periods 
1 and 2 on Day 9 at predose and at 1.5 hours postdose after cladribine / placebo administration, 
on Day 14 at 24 hours and 25.5 hours after cladribine / placebo administration (Day 13) and at 
the End of Study Visit as scheduled in the Schedule of Assessments (see Section 1.3). 
Single 12-lead ECG will be obtained as outlined in the SoA (see Section 1.3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and QTc
intervals. See Section 7 (Discontinuation of Study Intervention and Participant/Withdrawal) 
for QTc withdrawal criteria and any additional QTc readings that may be necessary
The ECGs will be recorded in supine position after at least 5 minutes rest
The ECG should be interpreted by the Investigator (normal/abnormal). For abnormal ECGs 
the clinical significance (yes/no) should be judged by the Investigator and the abnormality 
is to be specified
Local safety ECGs for real-time monitoring will be used.
8.2.4
Clinical Safety Laboratory Assessments
Blood and urine samples will be collected for the clinical laboratory tests listed in 
Appendix 5, at the time points listed in the SoA (see Section 1.3). All samples should be 
clearly identified
Additional tests may be performed at any time during the study, as determined necessary by 
the Investigator or required by local regulations
The tests will be performed by the central laboratory with exception of the following tests 
done locally: Urine test for pregnancy and drug screening, QuantiFERON®-TB test
The Sponsor must receive a list of the central laboratory normal ranges before shipment of 
study intervention(s). Any changes to the ranges during the study must be forwarded to the 
Sponsor or designated organization
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The Investigator must review each laboratory report, document their review, and record any 
clinically relevant changes occurring during the study in the AE section of the eCRF. The 
laboratory reports must be filed with the source documents
Laboratory/analyte results that could potentially unblind the study will not be reported to 
investigative sites or other blinded personnel. Instead the medical monitor will review
lymphocyte counts. Details are described in Section 6.9.
Any abnormalities in any of the laboratory parameters will be judged by a physician 
individually in relation to the reference ranges from the laboratory. For all findings of 
clinical relevance, follow-up examinations will be carried out until the deviation returns to 
normal or the absence of pathological relevance can be confirmed
For specific laboratory parameters such as lymphocyte count, however, that are reflecting a 
direct
and long-lasting
cladribine treatment effect, monitoring will follow the 
recommendations in the SmPC (Merck Serono Europe Ltd., 2017)
In case of the requirement to re-assess one or more Screening laboratory value(s), the 
Screening period may be prolonged for up to 8 weeks after the last Screening laboratory
assessment. From a participant safety perspective and in order to minimize unnecessary 
investigational burden for the participant it is acceptable that the participant starts with a 
delayed Run-in-Period of the study without re-assessing the complete set of Screening
laboratory assessments. The participant does not need to sign a new ICF. 
The laboratory parameters to be determined are provided in detail in Appendix 5.
8.2.5
Suicidal Risk Monitoring
Not applicable.
8.3
Adverse Events and Serious Adverse Events
The definitions of an adverse event (AE), a serious adverse event (SAE), and adverse event of 
special interest (AESI) are in Appendix 4.
8.3.1
Time Period and Frequency for Collecting Adverse Event 
and Serious Adverse Event Information
The AE reporting period for safety surveillance begins when the participant is initially included 
in the study (date of first signature of first informed consent) and continues until the End of
Study Visit.
Any SAE assessed as related to study intervention must be recorded and reported, as indicated 
in Appendix 4, whenever it occurs, irrespective of the time elapsed since the last administration 
of study intervention.
The method of recording, evaluating, and assessing causality of AEs (including SAEs) and the 
procedures for completing and transmitting SAE reports are presented in Appendix 4.
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8.3.2
Method of Detecting Adverse Events and Serious Adverse 
Events
At each study visit, the participant will be queried on changes in her condition. During the 
reporting period, any unfavorable changes in the participant’s condition will be recorded as 
AEs, regardless if reported by the participant, observed by the Investigator or evidenced by 
diagnostic procedures (e.g., safety laboratory, ECG, etc.).
Complete, accurate and consistent data on all AEs experienced for the duration of the reporting 
period (defined below) will be reported on an ongoing basis in the appropriate section of the 
eCRF. All SAEs and all nonserious AEs of special interest must be additionally documented 
and reported using the appropriate Report Form as specified in Appendix 4.
8.3.3
Follow-up of Adverse Events and Serious Adverse Events
AEs are recorded and assessed continuously throughout the study, as specified in Section 8.3.1
(Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event 
Information) and are assessed for their outcome at the End of Study Visit. All SAEs ongoing 
at the End of Study Visit as well as any nonserious AEs of special interest must be monitored 
and followed up by the Investigator until stabilization or until the outcome is known, unless 
the participant is documented as “lost to follow-up”. Reasonable best efforts to obtain this 
information must be made and documented. It is also the responsibility of the Investigator to 
ensure that any necessary additional therapeutic measures and follow-up procedures are 
performed. Further information on follow-up procedures is given in Appendix 4 (Adverse 
Events: Definitions and Procedures for Recording, Evaluating, Follow-up, and Reports).
Monitoring of Specific Adverse Events is further detailed in Section 9.
8.3.4
Regulatory Reporting Requirements for Serious Adverse 
Events
The Sponsor will send appropriate safety notifications to Health Authorities in accordance with 
applicable laws and regulations.
The Investigator must comply with any applicable site-specific requirements related to the 
reporting of SAEs (particularly deaths) involving study participants to the Independent Ethics 
Committee/Institutional Review Board (IEC/IRB) that approved the study.
In accordance with ICH GCP, the Sponsor/designee will inform the Investigator of findings 
that could adversely affect the safety of participants, impact the conduct of the study or alter 
the IEC’s/IRB’s approval/favorable opinion to continue the study. In line with respective 
regulations, the Sponsor/designee will inform the Investigator of AEs that are both serious and 
unexpected and considered to be related to the administered product (“suspected unexpected 
serious adverse reactions” or SUSARs). The Investigator should place copies of Safety Reports 
in the Investigator Site File. National regulations regarding Safety Report notifications to 
Investigators will be considered.
When specifically required by regulations and guidelines, the Sponsor/designee will provide 
appropriate Safety Reports directly to the concerned lead IEC/IRB and will maintain records 
of these notifications. When direct reporting is not clearly defined by national or site-specific 
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regulations, the Investigator will be responsible for promptly notifying the concerned IEC/IRB 
of any Safety Reports provided by the Sponsor/designee and of filing copies of all related 
correspondence in the Investigator Site File.
For studies covered by the European Directive 2001/20/EC, the Sponsor’s responsibilities 
regarding the reporting of SAEs/SUSARs/Safety Issues will be carried out in accordance with 
that Directive and with the related Detailed Guidance documents.
8.3.5
Pregnancy
In the event of a pregnancy in a participant occurring during the study, the participant must be 
discontinued from study intervention. The Sponsor/designee must be notified without delay 
and the participant must be followed as indicated above.
Only pregnancies the Investigator considers to be related to the study intervention (e.g., 
resulting from a drug interaction with a contraceptive method) are AEs. However, all 
pregnancies with an estimated conception date during the period defined in Section 8.3.1 (Time 
Period and Frequency for Collecting Adverse Event and Serious Adverse Event Information) 
must be recorded in the AE page/section of the eCRF for pregnancies in female participants. 
The Investigator must notify the Sponsor/designee in an expedited manner of any pregnancy 
using the Pregnancy Report Form, which must be transmitted by the same process specified 
for SAE reporting in Appendix 4, section on Reporting Serious Adverse Events and Adverse 
Events of Special Interest.
Investigators must actively follow up, document and report on the outcome of all these 
pregnancies, even if the participants are withdrawn from the study.
The participant’s primary care physician or gynecologist should be informed regarding the 
extent of the participant’s participation in the current study with the study intervention. The 
Sponsor will provide to the participant’s primary care physician or gynecologist all information 
pertinent to the risk assessment for the pregnancy outcome and potential fetal harm. 
Accordingly, the primary care physician or gynecologist will counsel the participant regarding 
medical considerations in decision making on continuation or discontinuation of the pregnancy. 
The Investigator must notify the Sponsor/designee of these outcomes using the Pregnancy 
Report Form. If an abnormal outcome occurs, the SAE Report Form will be used if the 
participant sustains an event and the Parent-Child/Fetus Adverse Event Report Form if the 
child/fetus sustains an event. Any abnormal outcome (e.g., spontaneous abortion, fetal death, 
stillbirth, congenital anomalies, ectopic pregnancy) must be reported in an expedited manner, 
as specified in Section 8.3.1, while normal outcomes must be reported within 45 days after 
delivery.
8.4
Treatment of Overdose
For this study, any dose of cladribine greater than the dose specified in the protocol according 
to participants’ body weight (see Table 2) within a 24-hour time period (for definition of daily 
doses by body weight see Table 3) will be considered an overdose.
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References 
Giovannoni G, et al (a). Safety and efficacy of cladribine tablets in patients with relapsing–
remitting multiple sclerosis: Results from the randomized extension trial of the CLARITY 
study. Mult Scler 2017;1:1352458517727603.
Giovannoni G, et al (b). EAN 2017:P0542.
Giovannoni G, Comi G, Cook S, Rammohan K, Rieckmann P, Soelberg Sørensen P, et al. A 
placebo-controlled trial of oral cladribine for relapsing multiple sclerosis. N Engl J Med 
2010;362:416-26.
Martin P, et al. Effects of Fostamatinib on the Pharmacokinetics of Oral Contraceptive, 
Warfarin, and the Statins Rosuvastatin and Simvastatin: Results From Phase I Clinical Studies.
Drugs RD 2016;16:93-107.
MAVENCLAD® (Cladribine) SmPC, 2017.
McDonald WI, et al. Recommended diagnostic criteria for multiple sclerosis: guidelines from 
the International Panel on the diagnosis of multiple sclerosis. Ann Neurol 2001;50(1):121-7.
Poser CM. Diagnostic criteria for multiple sclerosis. Clin Neurol Neurosurg 2001;103(1):1-11.
Song I, et al. Dolutegravir Has No Effect on the Pharmacokinetics of Oral Contraceptives With 
Norgestimate and Ethinyl Estradiol. Ann Pharmacother 2015;49(7):784-9.
Zhu B, et al. Evaluation of Potential Drug–Drug Interaction Between Delayed-Release 
Dimethyl Fumarate and a Commonly Used Oral Contraceptive (Norgestimate/Ethinyl 
Estradiol) in Healthy Women. Clin Pharmacol Drug Dev 2017;6(6):604-13.
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Appendices
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Appendix 1
Abbreviations 
ABS
Antibody serum
AE
Adverse Event
AEP
Accelerated elimination procedure
AESI
Adverse Event of special interest
ALT
Alanine aminotransferase
a.m.
ante meridiem
ANOVA
Analysis of variance
Anti-HCV
Hepatitis C virus antibody
Anti-HIV1/2
Human Immunodeficiency virus 1 and 2 antibody
ART
Assisted reproduction techniques
AST
Aspartate aminotransferase
ATE
Arterial thromboembolism
AUC
Area under the curve
BE
Bioequivalence
BMI
Body mass index
BUN
Blood urea nitrogen
CdATP
2-chlorodeoxy-adenosinetriphosphate
CI
Confidence interval
CRO
Contract Research Organization
CTFG
Clinical Trial Facilitation Group
CV
Coefficient of variation
CYP
Cytochrome P450
DBP
Diastolic blood pressure
DDI
Drug-drug interaction
DVT
Deep venous thrombosis
ECG
Electrocardiogram
(e)CRF
Electronic Case Report Form
EE
Ethinyl estradiol
EMA
European Medicines Agency
ET
Early termination (visit)
GCP
Good Clinical Practice
GI
Gastro-intestinal
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h
Hour(s)
HbcAb
Hepatitis B core antibody
HbsAg
Hepatitis B surface antigen
HC
Hormonal contraceptives/contraception
hCG
Human Chorionic Gonadotropin 
HCV
Hepatitis C virus
HDL
High density lipoprotein
HIV
Human immunodeficiency virus
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IMP
Investigational Medicinal Product
IRB
Institutional Review Board
IUD
Intrauterine device
LDL
Low density lipoprotein
LNG
Levonorgestrel
MAH
Marketing Authorization Holder
MCH
Mean Corpuscular Hemoglobin
MCV
Mean Corpuscular Volume 
MS
Multiple sclerosis
OTC
Over-the-counter
PE
Pulmonary embolism
PK
Pharmacokinetics
PML
Progressive multifocal leukencephalopathy
RBC
Red Blood Cell
RMS
Relapsing Multiple Sclerosis
SAE
Serious Adverse Event
SBP
Systolic blood pressure
SD
Standard deviation
SGOT
Serum Glutamic-Oxaloacetic Transaminase
SGPT
Serum Glutamic-Pyruvic Transaminase
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SoA
Schedule of Activities
SUSAR
Suspected unexpected serious adverse reactions
TB
Tuberculosis
TIA
Transient ischemic attack
VTE
Venous thromboembolism 
WBC
White Blood Cell
WHO
World Health Organization
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Appendix 2
Study Governance
Financial Disclosure
Investigators and Sub-Investigators will provide the Sponsor with sufficient, accurate financial 
information, as requested, for the Sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. 
Informed Consent Process
The Investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions on the study
Participants must be informed that their participation is voluntary
Participants or their legally-authorized representative will be required to sign a statement of 
informed consent that meets the requirements of 21 CFR 50; local regulations; ICH 
guidelines; Health Insurance Portability and Accountability Act (HIPAA) requirements, 
where applicable; and the IRB/IEC or study center
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF
If the ICF is 
 during their participation in the study, participants must be re-
consented to the most current, approved version
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative
The original signed and dated consent will remain at the Investigator’s site and must be 
safely archived so that it can be retrieved at any time for monitoring, auditing and inspection 
purposes

Participants who are rescreened are required to sign a new ICF
Data Protection
The Sponsor will assign a unique identifier to participants after obtaining their informed 
consent. All participant records or datasets transferred to the Sponsor will contain the 
identifier only; participant names or any identifiable information will not be transferred
The Sponsor must inform participants that their personal study-related data will be used per 
local data protection and privacy laws. The level of disclosure must also be explained to the 
participant
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other Sponsor-appointed, authorized personnel, by 
appropriate IRB/IEC members, and by regulatory authority inspectors. All such persons will 
strictly maintain participants’ confidentiality.
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Any protocol amendments (i.e., changes to the protocol) will be documented in writing and 
require IRB/IEC approval before implementation of changes, except for changes necessary 
to eliminate an immediate hazard to study participants. When applicable, amendments will 
be submitted to the appropriate Health Authorities
The Investigator will be responsible for the following:
Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently per the IRB’s/IEC’s requirements, policies, and procedures
Notifying the IRB/IEC of SAEs or other significant safety findings, as required by 
IRB/IEC procedures
Providing oversight of the study conduct at the site and adherence to requirements of 
21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies 
(if applicable), and all other applicable local regulations
The protocol and any applicable documentation will be submitted or notified to the Health 
Authorities in accordance with all local and national regulations for each site.
Emergency Medical Support
The Sponsor or designee will provide Emergency Medical Support cards to participants for 
use during the study. These provide the means for participants to identify themselves as 
participating in a clinical study. Also, these give health care providers access to any 
information about this participation that may be needed to determine the course of medical 
treatment for the participant. The information on the Emergency Medical Support card may 
include the process for emergency unblinding (if applicable)
The first point of contact for all emergencies will be the clinical study Investigator caring 
for the participant. Consequently, the Investigator agrees to provide his or her emergency 
contact information on the card. If the Investigator is available when an event occurs, they 
will answer any questions. Any subsequent action (e.g., unblinding) will follow the standard 
process established for Investigators.
When the Investigator is not available, the Sponsor provides the appropriate means to contact 
a Sponsor physician (i.e., Medical Monitor or deputy). This includes provision of a 24-hour 
contact number, whereby the health care providers will be given access to the appropriate 
Sponsor physician to assist with the medical emergency and to provide support for the potential 
unblinding of the participant concerned.
Clinical Study Insurance and Compensation to Participants
Insurance coverage will be provided for each country participating in the study. Insurance 
conditions shall meet good local standards, as applicable.
Participants will be compensated for travel cost and loss of workdays with respect to the 
hospitalization periods. 
Clinical Study Report
After completion of the study, a clinical study report will be written by 
 on 
behalf of the Sponsor in consultation with the Coordinating Investigator following the guidance 
in ICH Topic E3. 
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Publication
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the Investigator agrees to submit all manuscripts or abstracts to the Sponsor before 
submission. This allows Merck to protect proprietary information and to provide comments
The Sponsor will comply with the requirements for publication of study results. Per standard 
editorial and ethical practice, the Sponsor will generally support publication of multicenter 
studies only in their entirety and not as individual site data. In this case, a coordinating 
Investigator will be designated by agreement
Authorship will be determined by agreement and in line with International Committee of 
Medical Journal Editors authorship requirements.
Dissemination of Clinical Study Data
The first publication will include the results of the analysis of the primary endpoints and 
will include data from all study sites. The Investigator will inform the Sponsor in advance 
about any plans to publish or present data from the study. Any publications and presentations 
of the results (abstracts in journals or newspapers, oral presentations, etc.), either in whole 
or in part, by Investigators or their representatives will require review by the Sponsor before 
submission. The Sponsor will not suppress publication, but maintains the right to delay 
publication in order to protect intellectual property rights
Posting of data on the EU Clinical Trial Register and on ClinicalTrials.gov is planned and 
will occur within 12 months after the last clinic visit of the final study participant or another 
appropriate date to meet applicable requirements
Data Quality Assurance
All participant study data will be recorded on printed or electronic CRFs or transmitted to 
the Sponsor or designee electronically (e.g., laboratory data). The Investigator is responsible 
for verifying that data entries are complete, accurate, legible, and timely by physically or 
electronically signing the CRF. Details for managing CRFs are in the Operations Manual
The Investigator must maintain accurate documentation (source data) that supports the 
information in the CRF
The Investigator must permit study-related monitoring, quality assurance audits, IRB/IEC 
review, and regulatory agency inspections and provide direct access to the study file and 
source data
The Sponsor or designee is responsible for data management of this study, including quality 
checking of the data and maintaining a validated database. Database lock will occur once 
quality control and quality assurance procedures have been completed. 
 files of the 
CRFs will be provided to the Investigators at study completion
Study monitors will perform ongoing source data verification to confirm that data in the 
CRF are accurate, complete, and verifiable; that the safety and rights of participants are 
being protected; and that the study is being conducted per the currently approved protocol 
and any other study agreements, ICH GCP, and all applicable regulatory requirements
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Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the Investigator for 15 years after study completion, unless local regulations, 
institutional policies, or the Sponsor requires a longer retention. No records may be 
destroyed during the retention period without the Sponsor’s written approval. No records 
may be transferred to another location or party without the Sponsor’s written notification
Source Documents
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected
The Investigator must keep a paper or electronic file (medical file and original medical 
records) at the site for each study participant. The file must identify each participant, contain 
the following demographic and medical information for the participant, and should be as 
complete as possible:
Participant’s full name, date of birth, sex, height, and weight
Medical history and concomitant diseases
Prior and concomitant therapies (including changes during the study)
Study identifier (i.e., the Sponsor’s study number) and participant’s study number
Dates of entry into the study (i.e., signature date on the informed consent) and each visit 
to the site
Any medical examinations and clinical findings predefined in the protocol
All AEs
Date that the participant left the study, including any reason for early withdrawal from 
the study or study intervention, if applicable.
All source data must be filed (e.g., CT or MRI scan images, ECG recordings, and laboratory 
results). Each document must have the participant number and the procedure date; ideally, 
printed by the instrument used for the procedure. As necessary, medical evaluation of these 
records should be performed, documented, signed and dated by the Investigator
Data recorded on printed or electronic CRFs that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
Investigator may need to request previous medical records or transfer records, depending on 
the study. Also, current medical records must be available
The study monitors will use printouts of electronic files for source data verification. These 
printouts must be signed and dated by the Investigator, and kept in the study file
Source documents are stored at the site for the longest possible time permitted by the 
applicable regulations, and/or as per ICH GCP guidelines, whichever is longer. The 
Investigator ensures that no destruction of medical records is performed without the 
Sponsor’s written approval
For data that may be recorded directly in the CRF such as a diary, there will be no record in 
the original participant file and therefore the data entered in the CRF will be considered 
source data
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Study and Site Closure
The Sponsor reserves the right to close the study site or terminate the study at any time and 
for any reason. Study sites will be closed upon study completion. A study site is considered 
closed when all required documents and study supplies have been collected and a site 
closure visit has been completed
The Investigator may initiate site closure at any time, provided there is reasonable cause and 
sufficient notice is given in advance of the intended termination
Reasons for the early closure of a study site by the Sponsor or Investigator may include:
Failure of the Investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the Sponsor's procedures, or GCP guidelines
Inadequate recruitment of participants by the Investigator
Discontinuation of further development of the Sponsor’s compound.
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Appendix 3
Contraception
Woman of Childbearing Potential (WOCBP)
A woman is of childbearing potential (i.e., fertile), following menarche and until either:
1)
Becoming postmenopausal; or,
2)
is permanently sterile by means of a hysterectomy, bilateral salpingectomy or bilateral 
oophorectomy.
Postmenopausal is defined as no menses for 12 months without an alternative medical cause. 
A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to 
confirm a postmenopausal state in women not using hormonal contraception or hormonal 
replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH 
measurement is insufficient.
Highly Effective Contraceptive Methods
A highly effective contraceptive method must be applied from enrollment to 1 month after last 
dose of study intervention.
Highly effective methods are those with a failure rate of less than 1% per year when used 
consistently and correctly.
These methods are further classified into user-independent and user-dependent methods.
Because user-independent methods do not depend on the participant’s ability to use them 
consistently and correctly, they are preferred when contraception is introduced as a condition 
for study participation.
Caution should be taken for hormonal contraception, as it may be susceptible to interaction 
with the study intervention(s), which may reduce the efficacy of the contraception method.
Hence, a second highly effective method of contraception should be used from enrollment to 
1 month after last dose of study intervention.
Highly effective contraceptive methods, to be used in addition to the hormonal contraceptive 
(Microgynon) as per this study protocol are listed below:
Permitted:
User-Independent
Intrauterine device (IUD)
Bilateral tubal occlusion
Vasectomized partner: This is a highly effective contraception method only if the partner is 
the sole sexual partner of the WOCBP and he has received medical assessment of the 
surgical success
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Sexual abstinence: This is a highly effective method only if the WOCBP refrains from 
heterosexual 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 and the preferred and usual lifestyle of the participant.
Not permitted, since they would interfere with the study objective:
User-Dependent
Combined (estrogen- and progestogen-containing) hormonal contraception associated with 
inhibition of ovulation
Oral
Intravaginal
Transdermal
Progestogen-only hormonal contraception associated with inhibition of ovulation
Oral
Injectable
User-Independent
Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulation
Intrauterine hormone-releasing system (IUS)
Effective Contraceptive Method
An effective contraceptive method must be used starting 1 month after last dose of study 
intervention and continue for at least 5 months.
Allowed only under certain situations as specified in the Clinical Trial Facilitation Group 
(CTFG) recommendations, because they have a failure rate of more than 1% per year and 
therefore are not considered to be highly effective methods.
Male or female condom with or without spermicide
Cap, diaphragm or sponge with spermicide
Combination of a male condom with cap, diaphragm or sponge with spermicide (i.e., double 
barrier method)
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Appendix 4
Adverse Events: Definitions and Procedures for Recording, 
Evaluating, Follow-up, and Reporting
Definitions
Adverse Event
An AE is any untoward medical occurrence in a participant administered a pharmaceutical 
product, regardless of causal relationship with this treatment. Therefore, an AE can be any 
unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or 
disease temporally associated with the use of a medicinal product, regardless if it is considered 
related to the medicinal product.
For surgical or diagnostic procedures, the condition/illness leading to such a procedure is 
considered as the AE rather than the procedure itself.
The Investigator is required to grade the severity of each AE.
Investigators must assess the severity of AEs per the Qualitative Toxicity Scale, as follows:
Mild:
The participant is aware of the event or symptom, but the event or symptom 
is easily tolerated.
Moderate:
The participant experiences sufficient discomfort to interfere with or reduce 
his or her usual level of activity.
Severe:
Significant impairment of functioning: the participant is unable to carry out 
his or her usual activities.
Investigators must also systematically assess the causal relationship of AEs to study 
intervention (including any other non-study interventions, radiation therapy, etc.) using the 
following definitions. Decisive factors for the assessment of causal relationship of an AE to 
the study intervention include, but may not be limited to, temporal relationship between the AE 
and the study intervention, known side effects of study intervention, medical history, 
concomitant medication, course of the underlying disease, and study procedures.
Unrelated:
Not reasonably related to the study intervention. AE could not medically 
(pharmacologically/clinically) be attributed to the study intervention under 
study in this clinical study protocol. A reasonable alternative explanation 
must be available.
Related:
Reasonably related to the study intervention. AE could medically 
(pharmacologically/clinically) be attributed to the study intervention under 
study in this clinical study protocol. 
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Abnormal Laboratory Findings and Other Abnormal Investigational Findings
Abnormal laboratory findings and other abnormal investigational findings (e.g., on an ECG 
trace) should not be reported as AEs unless they are associated with clinical signs and 
symptoms, lead to study intervention discontinuation or are considered otherwise medically 
important by the Investigator. If a laboratory abnormality fulfills these criteria, the identified 
medical condition (e.g., anemia or increased alanine aminotransferase (ALT)) must be reported 
as the AE rather than the abnormal value itself.
Serious Adverse Events
An SAE is any untoward medical occurrence that at any dose:
Results in death
Is life-threatening. Life-threatening refers to an event in which the participant is at risk of 
death at the time of the event, not an event that hypothetically might have caused death if it 
was more severe.
Requires inpatient hospitalization or prolongs an existing hospitalization
Results in persistent or significant disability or incapacity
Is a congenital anomaly or birth defect
Is otherwise considered to be medically important. Important medical events that may not 
result in death, be life-threatening, or require hospitalization may be considered as SAEs 
when, based upon appropriate medical judgment, they may jeopardize the participant or may 
require medical or surgical intervention to prevent 1 of the outcomes listed above. Examples 
of such events include allergic bronchospasm requiring intensive treatment in an emergency 
room or at home, blood dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug abuse.
For the purposes of reporting, any suspected transmission of an infectious agent via a study 
intervention is also considered an SAE, as specified below for reporting SAEs, AESIs (Adverse 
Event of special interest) and DLTs.
Events that Do Not Meet the Definition of an SAE
Elective hospitalizations to administer, or to simplify study intervention or procedures (e.g., an 
overnight stay to facilitate chemotherapy and related hydration therapy application) are not 
considered SAEs. However, all events leading to unplanned hospitalizations or unplanned 
prolongation of an elective hospitalization (i.e., undesirable effects of any administered 
treatment) must be documented and reported as SAEs.
Events Not to Be Considered as AEs/SAEs
Medical conditions present at the initial study visit that do not worsen in severity or frequency 
during the study are defined as Baseline Medical Conditions, and are not to be considered AEs.
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Adverse Events of Special Interest
Description of selected adverse reactions
Lymphopenia
Only lymphopenia Grade 3 or Grade 4 represents AESIs. In clinical studies, 20% to 25% of 
the participants treated with a cumulative dose of cladribine 3.5 mg/kg over 2 years as 
monotherapy developed transient Grade 3 or 4 lymphopenia. Grade 4 lymphopenia was seen 
in less than 1% of the participants. The largest proportion of participants with grade 3 or 4 
lymphopenia was seen 2 months after the first cladribine dose in each year (4.0% and 11.3% 
of participants with grade 3 lymphopenia in year 1 and year 2, 0% and 0.4% of participants 
with grade 4 lymphopenia in year 1 and year 2). It is expected that most participants recover to 
either normal lymphocyte counts or grade 1 lymphopenia within 9 months. 
To decrease the risk for severe lymphopenia, lymphocyte counts must be determined before, 
during and after cladribine treatment (see Section 1.3) and strict criteria for initiating and 
continuing cladribine treatment must be followed (see Section 6.5).
Malignancies
In clinical studies and long-term follow-up of participants treated with a cumulative dose of 
3.5 mg/kg oral cladribine, events of malignancies were observed more frequently in cladribine-
treated participants (10 events in 3,414 participant-years [0.29 events per 100 participant-
Years]) compared to participants who received placebo (3 events in 2,022 participant-years 
[0.15 events per 100 participant-years]).
Other Adverse Events to be Reported Following a Specialized Procedure 
Not applicable.
Recording and Follow-Up of AE and/or SAE
It is important that each AE report include a description of the event, its duration (onset and 
resolution dates and also onset and resolution times, when it is important to assess the time of 
AE onset relative to the recorded study intervention administration time), its severity, its causal 
relationship with the study intervention, any other potential causal factors, any treatment given 
or other action taken, including dose modification or discontinuation of the study intervention, 
and its outcome. In addition, serious cases should be identified and the appropriate seriousness 
criteria documented. 
Specific guidance is in the CRF Completion and Monitoring Conventions provided by the 
Sponsor or its designee.
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Reporting Serious Adverse Events and Adverse Events of Special Interest 
Serious Adverse Events
In the event of any new SAE occurring during the reporting period, the Investigator must 
immediately (within a maximum of 24 HOURS after becoming aware of the event) inform the 
Sponsor or its designee in writing. All written reports should be transmitted using the SAE 
Report Form, which must be completed by the Investigator following specific completion 
instructions.
In exceptional circumstances, an SAE (or follow-up information) may be reported by 
telephone; in these cases, a written report must be sent immediately thereafter by fax or e-mail. 
Names, addresses, and telephone and fax numbers for SAE reporting will be included in the 
study specific SAE Report Form. 
Relevant pages from the CRF may be provided in parallel (e.g., medical history, concomitant 
drugs). Additional documents may be provided by the Investigator, if available (e.g., laboratory 
results, hospital report, autopsy report). In all cases, the information provided on the SAE 
Report Form must be consistent with the data about the event recorded in the CRF.
The Investigator must respond to any request for follow-up information (e.g., additional 
information, outcome, final evaluation, other records where needed) or to any question the 
Sponsor/designee may have on the AE within the same timelines as those noted above for 
initial reports. This is necessary to ensure prompt assessment of the event by the Sponsor or 
designee and (as applicable) to allow the Sponsor to meet strict regulatory timelines associated 
with expedited safety reporting obligations.
Requests for follow-up will usually be made via the responsible Monitor, although in 
exceptional circumstances the drug safety department may contact the Investigator directly to 
obtain further information or to discuss the event.
Adverse Events of Special Interest
In the event of a nonserious Grade 3 or 4 AESI (lymphopenia), the Investigator will complete 
the AESI Report Form and send it to the Sponsor/designee within 24 hours. Names, addresses, 
and telephone and fax numbers for AESI reporting will be included on the Report Form. 
Serious AESIs must be reported in an expedited manner as SAEs as outlined above.
Dose-Limiting Toxicities
Not applicable.
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Appendix 5
Clinical Laboratory Tests
Clinical laboratory tests utilized for the study are shown in the table below. 
Table 8
Protocol-Required Clinical Laboratory Assessments
Laboratory 
Assessments
Parameters
Hematology
Platelet Count
RBC Indices:

MCV

MCH

%Reticulocytes
WBC Count with 
Differential:

Neutrophils

Lymphocytes

Monocytes

Eosinophils

Basophils
RBC Count
Hemoglobin
Hematocrit
Clinical Chemistry
BUN
Potassium
Aspartate aminotransferase 
(AST) / serum glutamic-
oxaloacetic transaminase
(SGOT)
Total and direct bilirubin
Creatinine
Sodium
Alanine aminotransferase 
(ALT) /serum glutamic-
pyruvic transaminase 
(SGPT)
Total Protein
Glucose (fasting)
Calcium
Alkaline phosphatase
Uric acid
Amylase
Lipase
γ-Glutamyl-transferase
Triglycerides
Lactate 
dehydrogenase
Creatine 
phosphokinase
Urea
LDL-/HDL-cholesterol 
and cholesterol
Urinalysis

Specific gravity

pH, glucose, protein, blood, ketones, bilirubin, urobilinogen, nitrite, leukocyte esterase by 
dipstick

Microscopic examination (if blood or protein is abnormal). Only if blood, protein, nitrite, or 
leukocyte esterase are positive on the dipstick

Urine pregnancy test (as needed for women of childbearing potential)
Other Tests

Serum human chorionic gonadotropin (hCG) pregnancy test (as needed for women of 
childbearing potential). 

Serology (HIV 1 and 2 antibody (anti-HIV1/2), hepatitis B surface antigen (HbsAG), 
hepatitis B core antibody (HbcAb), hepatitis C virus (anti-HCV) and Herpes Zoster 

QuantifFERON®-TB Gold or Gold Plus test 

Alcohol breath test, 

TSH

Urine drug screen: 

Cocaine

Amphetamines

Methamphetamines

Opiates

Barbiturates

Ecstasy

Benzodiazepine

Methadone

Cannabinoids

Phencyclidine

Tricyclic antidepressants
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ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; HbcAB=hepatitis B 
core antibody; HbsAG=hepatitis B surface antigen; hCG=human chorionic gonadotropin; HCV=hepatitis C virus; 
HDL=high density lipoprotein; HIV=human immunodeficiency virus; LDL=low density lipoprotein; MCH=mean 
corpuscular hemoglobin; MCV=mean corpuscular volume; RBC=red blood cell; SGOT=serum glutamic-
oxaloacetic transaminase; SGPT=serum glutamic-pyruvic transaminase; TSH = thyroid stimulating hormone,
WBC=white blood cell
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Appendix 6
Pharmacokinetic Parameters
Symbol
Definition
AUC
The area under the concentration-time curve (AUC) over the dosing interval from T1=0 hours to 
T2=τ h. Calculated using the mixed log linear trapezoidal rule (linear up, log down). For single 
dose, AUCτ is calculated as a partial area with the defined time range. In multiple dose profiles 
AUCis calculated at steady state from 1 predose time point to the dosing interval time. In 
cases where the actual observation time is not equal to the scheduled observation time AUC
will be calculated based on the estimated concentration at τ hours, and not the concentration at 
the actual observation time.
Cav
The average concentration at steady state. Cav = AUC/.
Cpre
Measured concentration at the end of a dosing interval during repeat-dosing (taken directly 
before next administration)
Cmax
Maximum observed concentration 
Cmin
The minimum observed concentration during a complete dosing interval  
Ctrough
The concentration observed immediately before next dosing (corresponding to predose or 
trough concentration for multiple dosing)
PTF%
The peak trough fluctuation within a complete dosing interval at steady state. 
PTF = 100*(Cmax-Cmin)/Cav.
tmax
The time to reach the maximum observed concentration collected during a dosing interval 
(unless otherwise defined, take the first occurrence in case of multiple/identical Cmax values)
tmin
The time to reach the minimum observed concentration collected during a dosing interval

Dosing interval
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Appendix 7
Protocol Amendment History
The information for the current amendment is on the title page.
Non-substantial amendment 3 to the original protocol (CSP v4.0, version date: 
20 November 2020)
Section # and Name
Description of Change
Brief Rationale
5.2 Exclusion Criteria
Specified exclusion criterion #19
Wash-out 
requirements/procedures 
for additional medications 
added
Non-substantial amendment 2 to the original protocol (CSP v3.0, version date: 
06 April 2020):
Section # and Name
Description of Change
Brief Rationale
1.1 Synopsis, Overall Design
1.3 Schedule of Activities
Clarified wording for extended Screening 
period due to a delayed menstrual cycle and 
laboratory value(s) re-testing
Clarification of process
1.2 Schema, 
Figure 1 Study Design 
Diagram
 of study design diagram to clarify 
wording
Clarification of process
1.3 Schedule of Activities
Weight control added on Day 21 of Run-in-
Period and Day 21 of Study Period 1 
Minor formatting revision
Ability to calculate/adapt 
dosage of study 
intervention accordingly to 
actual weight
Minor corrections
4.1 Overall Design
Clarified wording for extended Screening 
period due to a delayed menstrual cycle and 
laboratory value(s) re-testing
Correction of recruitment phase from 
“12 months” to “21 months” and total clinical 
duration of the study from “16 months” to 
“25 months”
Clarification of process
4.2 Scientific Rationale for 
Study Design
Extension of time window to “between 28 to 
35 days” for the second 5-day cladribine 
treatment (medical care) for Sequence 2
(placebo-cladribine)
For Sequence 1 (cladribine-placebo) change 
of wording from “Accordingly, participants will 
receive their second 5-day cladribine treatment 
4 weeks and 6 days after …” to “Accordingly, 
participants will receive their second 5-day 
cladribine treatment 34 days after …”. 
Clarification of study 
rationale
To be in alignment with the 
wording in the section
6.3.2 Blinding
To further detail wording for the unblinding 
process after the End of Study
Clarification of process
6.3.3 Emergency Unblinding
Clarified wording for recording the date and 
reason for unblinding
Clarification of process
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Section # and Name
Description of Change
Brief Rationale
6.4 Study Intervention 
Compliance
Clarified wording for assessment of 
compliance
Clarification of process
6.7 Study Intervention after 
the End of the Study
Clarified wording for informing Principal 
Investigators of the treatment sequences once 
participants have completed the End of Study 
Visit
Clarification of process
8.2.1 Physical Examination
Weight control added on Day 21 of Run-in-
Period, Day 21 of Study Period 1 and Day 8 of 
Study Period 2 
Alignment with Section 1.3 
Schedule of Activities
8.2.4 Clinical Safety 
Laboratory Assessments
Clarified wording for extended Screening 
period due to laboratory value(s) retesting
Clarification of process
9.3 Populations for Analyses
First paragraph rephrased to clarify 
participants of the data review meeting
Clarification of process
Appendix 2 Study 
Governance
Sentence deleted “• Definition of what 
constitutes source data is found in the Data 
Management Plan”
Clarification of which 
definition is given in the 
Data Management Plan
Whole document
Minor editorial and document formatting 
revisions
Minor corrections; 
therefore, have not been 
summarized
Non-substantial amendment 1 to the original protocol (CSP v2.0, version date: 
04 July 2019):
Section# and Name
Description of Change
Brief Rationale
5.1 Inclusion Criteria
The safety blood sample, including hematology 
assessments, was moved from Day 9 of Study 
Period 1 to Day 21 of Run-in-Period. 
This assures that results of the safety laboratory 
including hematology are in place before start of 
IMP treatment for fulfillment of inclusion criterion 
#4. 
Lymphocyte requirements (inclusion criterion #4) 
were differentiated for treatment in year 1 and 
year 2. 
Range definition for white blood cell counts, 
absolute lymphocyte counts and absolute 
neutrophil counts was changed from strictly 
normal range to normal range (applies for 
patients in year 1).
In order to clarify inclusion 
criterion #4 in Section 5.1. 
6.3.1 Study Intervention 
Assignment
The randomization of participants was moved 
from Day 8 of Study Period 1 to Day 21 of Run-
in-Period.
This assures that participant’s assigned study 
intervention is available at site in time.
In order to correct time point 
of randomization in Section 
6.3.1.
Whole document
Minor editorial and document formatting 
revisions
Minor corrections
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Appendix 10
Principal Investigator Signature Page
Study Title:
A randomized, double-blind, 2-period, 2-sequence 
crossover Phase I study with a 1 month run-in-period to 
examine the effect of cladribine tablets on the 
pharmacokinetics of a monophasic oral contraceptive 
containing 
ethinyl 
estradiol 
and 
levonorgestrel 
(Microgynon) in pre-menopausal women with relapsing 
multiple sclerosis (RMS)
Regulatory Agency Identifying 
Numbers:
EudraCT Number: 2018-001015-70
Clinical 
Study 
Protocol 
Version:
29 July 2021 / Version 5.0
Site Number:
I am responsible for the conduct of the study at this site, and understand and will conduct it per 
the clinical study protocol, any approved protocol amendments, International Conference on 
Harmonisation Good Clinical Practice (Topic E6) and all applicable Health Authority 
requirements and national laws.
____________________________________
___________________________
Signature
Date of Signature
Name, academic degree:
Function/Title:
Institution:
Address:
Telephone number:
Fax number:
E-mail address:
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Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
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M er c k
C o nfi de nti al
T his d oc u me nt is t he pr o pert y of Merc k K Ga A, Dar msta dt, Ger ma n y, or o ne of its affiliate d c o m pa nies.
It is i nte n de d f or restricte d use o nl y a n d ma y n ot - i n f ull or part - be passe d o n, re pr o d uce d, p u blis he d or use d wit h o ut 
e x press per missi o n of Merc k K Ga A, Dar msta dt, Ger ma n y or its affiliate. 
C o p yri g ht © 2 0 2 0 b y Merc k K G a A, D ar mst a dt, Ger m a n y or its affili ate. All ri g hts reser ve d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
P P D




Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
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1
T a ble of C o nte nts
I nte grate d A nalys is Pla n ...................................................................................................... 1
Si g nat ure Pa ge
.............................................................................................................. 3
1
Ta ble of C o nte nts .................................................................................. 4
2
List of A b bre viati o ns a n d Defi niti o n of Ter ms .................................... 6
3
M o dificati o n Hist or y
............................................................................ 6
4
P ur p ose of t he I nte grate d A nal y sis Pla n ............................................... 7
5
O bjecti ves a n d E n d p oi nts ..................................................................... 8
6
O ver vie w of Pla n ne d A nal y ses............................................................. 8
7
C h a n ges t o t he Pla n ne d A nal yses i n t he Cli nical Trial Pr ot oc ol.......... 9
8
Pr ot oc ol De viati o ns a n d A nal y sis Sets ................................................. 9
8. 1
Defi niti o n of Pr ot oc ol De viati o ns a n d A nal ys is Sets ........................... 9
8. 2
Defi niti o n of A nal ys is Sets a n d S u b gr o u ps........................................ 1 0
9
Ge neral S pecificati o ns f or Data A nal y ses .......................................... 1 2
1 0
Trial S u bjects ...................................................................................... 1 3
1 0. 1
Dis p ositi o n of S u bjects a n d Disc o nti n uati o ns .................................... 1 3
1 0. 2
Pr ot oc ol De viati o ns ............................................................................ 1 4
1 0. 2. 1
I m p orta nt Pr ot oc ol De viati o ns............................................................ 1 4
1 0. 2. 2
Reas o ns Lea di n g t o t he E xcl usi o n fr o m a n A nal y sis Set ................... 1 4
1 1
De m o gra p hics a n d Ot her Baseli ne C haracteristics ............................. 1 5
1 1. 1
De m o gra p hics ..................................................................................... 1 5
1 1. 2
Me dical Hist or y .................................................................................. 1 5
1 1. 3
Ot her Baseli ne C haracteristics ............................................................ 1 5
1 2
Pre vi o us or C o nc o mita nt Me dicati o ns/ Pr oce d ures ............................. 1 6
1 3
Treat me nt C o m plia nce a n d E x p os ure ................................................. 1 6
1 4
Efficac y  A nalys es ............................................................................... 1 6
1 5
Safet y  A nalys es .................................................................................. 1 6
1 5. 1
A d verse E ve nts ................................................................................... 1 7
1 5. 1. 1
All A d v erse E ve nts ............................................................................. 1 9
1 5. 1. 2
A d verse E ve nts Lea di n g t o Treat me nt Disc o nti n uati o n ..................... 2 1
1 5. 2
Deat hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nifica nt 
A d verse E ve nts ................................................................................... 2 1
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
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1 5. 2. 1
Deat hs ................................................................................................. 2 1
1 5. 2. 2
Seri o us A d verse E ve nts ...................................................................... 2 1
1 5. 2. 3
Ot her Si g nifica nt A d verse E ve nt ........................................................ 2 1
1 5. 2. 3. 1
A d verse E ve nts of S pecial I nterest ..................................................... 2 1
1 5. 3
Cli nical L a b orat or y E val uati o n........................................................... 2 1
1 5. 4
Vital Si g ns .......................................................................................... 2 2
1 5. 5
E C G E val uat i o n.................................................................................. 2 3
1 5. 6
Se nsiti vit y  A nalys is ............................................................................ 2 4
1 6
A nal y ses of Ot her E n d p oi nts .............................................................. 2 5
1 6. 1
P har mac o ki netics ................................................................................ 2 5
Ge neral S pec ificati o ns f or Plas ma C o nce ntrati o n Data..................................................... 2 5
Ge neral S pecificati o ns f or P K Para meter Data .................................................................. 2 5
1 6. 1. 1
Pri mar y  P har mac o ki netic E n d p oi nts .................................................. 2 6
1 6. 1. 2
Sec o n dar y  P har mac o ki netic E n d p oi nts .............................................. 2 6
1 6. 1. 3
Plas ma C o nce ntrati o n Data ................................................................. 2 6
1 6. 1. 4
Esti mati o n of I n di vi d ual P har mac o ki netic Para meters ....................... 2 8
1 6. 1. 5
Se nsiti vit y  A nalys is ............................................................................ 2 9
1 7
Refere nces ........................................................................................... 2 9
1 8
A p pe n dices ......................................................................................... 2 9
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
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2
L ist of A b bre vi atio ns a n d Defi niti o n of Ter ms
A E
A d verse E ve nt
A N O V A
A nal y sis of V A RI A N C E
B MI
B o d y Mass I n de x
C DI S C
Cli nical Data I nterc ha n ge Sta n dar ds C o ns orti u m
C R F
Case Re p ort F or m
C R O
C o ntract Researc h Or ga nizati o n
C S R
Cli nical St u d y Re p ort
E C G
Electr ocar di o gra m
Ge o C V
Ge o metric C oefficie nt of Variati o n
G M
Ge o metric Mea n
I A P
I nte grate d A nalys is Pla n
I C H
I nter nati o nal C o nfere nce o n Har m o nizati o n
M C A R
M issi n g c o m pletely at ra n d o m
Me d D R A
Me dical Dicti o nar y  f or Re g ulat or y Acti vities
P G x
P har mac o ge netics
P K
P har mac o ki netics
S A E
Seri o us A d verse E ve nt
S O C
S y ste m Or ga n Class
T E A E
Treat me nt E mer ge nt A d verse E ve nt
U CI
U p per C o nfi de nce I nter val
U L O Q
U p per Li mit of Q ua ntificati o n 
3
M o dific ati o n Hist or y
U ni q u e
I d e ntifi er f or
V er si o n
D at e of
I A P V er si o n
A ut h or
C h a n g e s fr o m t h e Pr e vi o u s V er si o n
Fi n al 1. 0
1 2 -O ct -2 0 2 0
n. a.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
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4
P ur p ose of t he I nte gr ate d A n al ysis Pl a n
T he p ur p ose of t his I A P is t o d oc u me nt tec h nical a n d detaile d s pecificati o ns f or t he fi nal a nal y sis 
of data c ollecte d f or pr ot oc ol M S 7 0 0 5 6 8 -0 0 3 1. Res ults of t he a nal y ses descri be d i n t his I AP will 
be i ncl u de d i n t he Cli nical St u d y  Re p ort ( C S R). A d diti o nall y, t he pla n ne d a nal ys es i de ntifie d i n 
t his I A P will be i ncl u de d i n re g ulat or y su b missi o ns or f ut ure ma n uscri pts. A n y  post -h oc, or 
u n pla n ne d a nal ys es perf or me d t o pr o vi de res ults f or i ncl usi o n i n t he C S R b ut n ot i de ntifie d i n 
t his pr os pecti ve I A P will be clearl y i de ntifie d i n t he C S R. 
T he I A P is base d u p o n secti o n 9 ( Statistical C o nsi derati o ns ) of t he trial pr ot oc ol a n d pr ot oc ol 
a me n d me nts a n d is pre pare d i n c o m plia nce wit h I C H E 9. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 




Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
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C h a n ges 
t o t he Pl a n ne d A n al yses 
i n t he Cli nic al 
Tri al 
Pr ot oc ol
T he statistical met h o ds as descri be d i n t he pr ot oc ol were a d o pte d. 
8
Pr ot oc ol De vi ati o ns a n d A n al ysis Sets
8. 1
Defi niti o n of Pr ot oc ol De vi ati o ns a n d A n al ysis Sets
I m p orta nt pr ot oc ol de viati o ns are pr ot oc ol de viati o ns t hat mi g ht 
si g nifica ntl y affect t he 
c o m plete ness, acc urac y, a n d/ or relia bilit y of t he st u d y data or t hat mi g ht si g nifica ntl y affect a 
s u bject's ri g hts, safety, o r well-bei n g. 
T he f oll o wi n g de viati o ns will be i de ntifie d a n d c o nfir me d pri or t o or at t he Data Re vie w Meeti n g 
at t he latest. 
I m p orta nt pr ot oc ol de viati o ns i ncl u de b ut are n ot li mite d t o

De viati o ns fr o m t he i ncl usi o n a n d e xcl usi o n criteria

C o nc o mita nt me dicati o n vi olati o ns (see Secti o n 6. 5. 2 of t he pr ot oc ol)

Use of pr o hi bit e d me dici nes (see Secti o n 6. 5. 3 of t he pr ot oc ol)

S u bjects t hat recei ve i nc orrect treat me nt or d ose

Sa m ple pr ocessi n g err ors t hat ma y  lea d t o i nacc urate bi oa nalyt ical res ults

De viati o n f r o m G o o d Cli nical Practice

N o n -c o m plia nce t o st u d y pr oce d ures or de viati o ns fr o m st u d y pr oce d ures li kel y to affect 
t he pri mar y  en d p oi nts (e. g. s u bject de vel o ps wit h dra wal criteria w hilst o n t he st u d y  b ut is 
n ot wit h dra w n)
I n a d diti o n , f or t he defi niti o n of t he P K a nal ysis set (see secti o n 8. 2 ) e ve nts li kel y to affect t he 
c o m para bilit y bet wee n treat me nts of P K res ults will be i de ntifie d. I mp orta nt e ve nts t o be 
c o nsi dere d are:

V o miti n g or diarr hea f oll o wi n g oral d osi n g (t hese i nsta nces will be disc usse d o n a case-
b y -case basis)

De viati o n fr o m st u d y me dicati o n c o m plia nce i n ter ms of me dical c o n diti o ns a n d/ or A Es 
t hat ma y  ha ve i nterfere d wit h dr u g dis p ositi o n or wit h res pect t o fact ors li kel y to affect 
t he pri mar y e n d p oi nts
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 0 /2 9
All i m p orta nt pr ot oc ol de viati o ns will be d oc u me nte d i n Cli nical Data I nterc ha n ge sta n dar d 
c o ns orti u m ( C DI S C) St u d y  Data Ta b ulati o n M o del ( S D T M) dataset w het her i de ntifie d t hr o u g h 
sites m o nit ori n g, me dical re vie w or pr o gra m mi n g.
I n a d diti o n, p re-d ose /tr o u g h sa m ples w hic h ha ve bee n ta ke n after t he s u bse q ue nt d osi n g will be 
re p orte d as pr ot oc ol de viati o n. T he res ulti n g c o nce ntrati o ns will be i ncl u de d i n c o nce ntrati o n 
listi n gs b ut e xcl u de d fr o m descri pti ve statistics of tr o u g h c o nce ntrati o ns.
8. 2
Defi niti o n of A n al ysis Sets a n d S u b gr o u ps
T he a nal ys is p o p ulati o ns are s pecifie d bel o w. T he fi nal decisi o n t o e xcl u de partici pa nts fr o m a ny 
a nal ys is p o p ulati o n will be ma de d uri n g a bli n de d data re vie w meeti n g pri or t o data base l oc k a n d 
u n bli n di n g.
It is i m p orta nt t o n ote t hat o nl y  Da ys 9 t o 1 3 cla dri bi ne a n d place b o treat me nts are ser vi n g t he
p ur p ose of t he pri mar y a n d sec o n dar y st u d y objecti ves (ie, e xa mi ni n g place b o -c o ntr olle d
cla dri bi ne effects o n t he P K a n d 
 of t he acti ve Micr o g y n o n c o m p o ne nts E E a n d L N G), w hile
D a y s 1 5 t o 1 9 cla dri bi ne a n d place b o treat me nts are o nl y fact ore d i nt o t he st u d y desi g n t o all o w
f or a ti mel y initiati o n of t he sec o n d 5- d a y  cla dri bi ne treat me nt f or partici pa nts assi g ne d t o t he
treat me nts se q ue nce cla dri bi ne -place b o, i n a bli n de d fas hi o n.
T a ble 1
A n al ysis P o p ul ati o ns
A n al ysis Set
Descri pti o n
Scree ni n g
T he Scree ni n g A nal ys is Set will i ncl u de all partici pa nts w h o pr o vi de d 
si g ne d i nf or me d c o nse nt, re gar dless of enr oll me nt (start of r u n -i n-
peri o d) or ra n d o mizati o n or treat me nt stat us i n t he st u d y. 
E nr olle d 
All partici pa nts w h o start t he r u n- i n-peri o d
S afet y
T he Safet y A nal ys is Set will i ncl u de all partici pa nts w h o recei ve at 
least 1 d ose of st u dy i nter ve nti o n.
Partici pa nts will be a nal yze d acc or di n g t o t he act ual treat me nt t he y 
recei ve.
P h ar m ac o ki netic
T he e val uati o n of P K data will be base d o n t he P K A nal ys is Set, a 
s u bset of t he Safet y  Anal y sis Set, w hic h is c haracterize d b y  the 
f oll o wi n g criteria:

T he c o m pleti o n of b ot h peri o ds; 

Partici pa nts m ust be 1 0 0 % c o m plia nt t o cla dri bi ne a n d place b o; 

A bse nces
fr o m 
1 0 0 % 
c o m plia nce 
ta ki n g 
Micr o g y n o n
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C C
I






Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 3 /2 9

Rel. D a y  in peri o d = start date of t he e ve nt or meas ure me nt
– date of first ad mi n + 1 of 
micr o g y n o n wit hi n r u n -i n peri o d, peri o d 1 or peri o d 2 (f or e ve nts or meas ur e me nts o n or after 
t he da y of d osi n g) 
Re peate d la b orat or y assess me nts will be fla g ge d as re peats i n t he s u bject data listi n gs a n d n ot 
i ncl u de d i n s u m mar y ta bles statistics ( u nless t he sc he d ule d meas ure me nt 
was c o nsi dere d 
u nrelia ble, e. g. d ue t o tec h nical reas o ns, a n d nee de d t o be re place d b y  an u nsc he d ule d re peat 
meas ure me nt).
I n t his p hase 1 P K st u d y missi n g o bser vati o ns will be ass u me d t o be missi n g c o m pletel y at 
ra n d o m ( M C A R). N o acti o n will be ta ke n t o ha n dle missi n g data. A s u bject w h o wit h dra ws pri or
t o t he last pla n ne d o bser vati o n i n a trial peri o d will be i ncl u de d i n t he a nal yses u p t o t he ti me of 
disc o nti n uati o n.
1 0
Tri al S u bjects
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or re p orti n g s u bject dis p ositi o n a n d 
treat me nt/trial disc o nti n uati o ns. A d diti o nall y , pr oce d ures f or re p orti n g pr ot oc ol de viati o ns are 
pr o vi de d.
1 0. 1
Dis p ositi o n of S u bjects a n d Disc o nti n u ati o ns
T his f oll o wi n g will be prese nte d i n a s u m mar y  ta ble: 

T otal n u m ber of s u bjects scree ne d (ie, s u bjects w h o ga ve i nf or me d c o nse nt)

T ota l n u m ber of s u bjects e nr olle d

T otal n u m ber of s u bjects ra n d o mize d

N u m ber of scree ne d s u bjects w h o disc o nti n ue d fr o m t he trial pri or t o treat me nt o verall a n d 
gr o u pe d b y t he mai n reas o n f or disc o nti n uati o n:
o
S u bject di d n ot meet all eli gi bilit y criteria
o
Wit h dre w c o nse nt
o
Ot her (C O VI D - 1 9-relate d a n d C O VI D- 1 9- n o n-relate d)

N u m ber of treate d s u bjects o verall

N u m ber a n d perce nta ge of treate d s u bjects w h o c o m plete d st u d y  

N u m ber a n d perce nta ge of treate d s u bjects w h o disc o nti n ue d t he st u d y, wit h t he pr i mar y 
reas o n of disc o nti n uati o n:
o
A d verse e ve nt
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 4 /2 9
o
L ost t o f oll o w - u p
o
Pr ot oc ol n o n -c o m plia nce
o
Deat h
o
Wit h dre w c o nse nt
o
Ot her (C O VI D - 1 9-relate d a n d C O VI D- 1 9- n o n-relate d)

N u m ber a n d perce nta ge of treate d s u bjects w h o c o m plete d micr o g y n o n treat me nt

N u m ber a n d perce nta ge o f s u bjects w h o disc o nti n ue d micr o g y n o n treat me nt wit h t he pr i mar y 
reas o n of disc o nti n uati o n

N u m ber a n d perce nta ge of treate d s u bjects w h o c o m plete d M S treat me nt
N u m ber a n d perce nta ge of s u bjects w h o disc o nti n ue d M S treat me nt wit h t he pr i mar y reas o n of 
disc o nti n uati o n .
A listi n g of disc o nti n ue d s u bjects will be pr o vi de d.
A listi n g of partici pa nts affecte d b y  the C O VI D - 1 9 relate d st u d y disr u pti o n b y  uni q ue s u bject 
n u m ber i de ntifier will als o be pr o vi de d.
1 0. 2
Pr ot oc ol De vi ati o ns
1 0. 2. 1
I m p ort a nt Pr ot oc ol De vi ati o ns
Listi n gs of i m p orta nt pr ot oc ol de viati o ns will be pr o vi de d i ncl u di n g t he date a n d relati ve d a y  in 
relati o n t o d osi n g i n t he rele va nt peri o d.
1 0. 2. 2
Re as o ns Le a di n g t o t he E xcl usi o n fr o m a n A n al ysis Set
All criteria/reas o ns lea di n g t o t he e xcl usi o n of a s u bject fro m a n a nal ys is set will be liste d base d 
o n t he safet y set. 
Reas o ns f or e xcl u di n g i n di vi d ual P K c o nce ntrati o ns will als o be liste d se parately a n d fla g ge d i n 
t he mai n listi n g base d o n t he safety a nal ys is set.
A n y  PK c o nce ntrati o ns a n d/or P K para meters e xcl ude d fr o m P K a nal ysis set or s u m mar y 
statistics will be i ncl u de d i n s u bject listi n gs a n d fla g ge d; a reas o n f or e xcl usi o n will be detaile d 
i n t he C S R (e. g. a f o ot n ote or a ta ble of e xcl usi o ns). A n y fla gs s h o ul d be i ncl u de d i n t he st u d y 
s pecific A Da M data sets.     
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 5 /2 9
1 1
De m o gr a p hics a n d Ot her B aseli ne C h ar acteristics
1 1. 1
De m o gr a p hics
S u m maries will be gi ve n f or t he safet y, t he p har mac o ki netic set, a n d p har mac o d y n a mic set, if 
differe nt.
De m o gra p hic c haracteristics will be liste d b y  su bject a n d s u m marize d usi n g t he f oll o wi n g 
i nf or mati o n fr o m t he Scree ni n g/ Baseli ne Visit C R F pa ges. 
De m o gra p hic c haracteristics:

Se x: fe male ( o nl y fe males i ncl u de d i n t his trial)

Race: Blac k or Africa n A merica n, A merica n I ndia n or Alas ka Nati ve, Asia n, Nati ve 
Ha waiia n or ot her Pacific Isla n der, W hite, Ot her

Et h nic ori gi n - His pa nic or Lati n o: y es, n o 

Et h nic ori gi n - Ja pa nese: yes, n o 

A ge ( y ears): s u m mar y statistics

Hei g ht (c m) at Baseli ne: s u m mar y  statistics

Wei g ht ( k g) at Baseli ne: s u m mar y  statistics

B MI ( k g/ m²) at Baseli ne: s u m mar y  statistics
A ge will be ta ke n fr o m t he C R F a n d ca n n ot be deri ve d fr o m t he data beca use o nl y t he ye ar of 
birt h is c ollecte d i n t he C R F.
B MI will be r e-deri ve d (ie, n ot ta ke n directl y fr o m t he data base) acc or di n g t o t he f oll o wi n g 
f or m ula:

B MI ( k g/ m²) = wei g ht ( k g) / ( hei g ht ( m) * hei g ht ( m))
1 1. 2
Me dic al Hist or y
T he me dical hist or y  will be liste d b y  su bject i ncl u di n g t he preferre d ter m a n d Me d D R A s yste m 
or ga n class ( S O C) b o d y usi n g Me d D R A, c urre nt versi o n.
1 1. 3
Ot her B aseli ne C h ar acteristics
Ot her baseli ne c haracteristics will be liste d b y  su bject a n d s u m marize d usi n g t he f oll o wi n g 
i nf or mati o n fr o m t he Scree ni n g/ Baseli ne Visit C R F pa ges. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 6 /2 9
Ot her baseli ne c haracteristics:

S m o ki n g stat us

Alc o h ol c o ns u m pti o n
1 2
P re vi o us or C o nc o mit a nt Me dic ati o ns/ Pr oce d ures
Pre vi o us me dic ati o ns
are me dicati o ns, ot her t ha n trial me dicati o ns a n d pre -me dicati o ns f or trial 
dr u g, w hic h starte d a n d st o p pe d bef ore first a d mi nistrati o n of trial dr u g. 
C o nc o mit a nt tre at me nts are me dicati o ns, ot her t ha n trial me dicati o ns, w hic h are ta ke n b y  
s u bjects a ny ti me o n -trial ( o n or after t he first da y of trial dr u g treat me nt f or eac h s u bject). 
I n case t he date val ues will n ot all o w t o u ne q ui v ocall y all ocati n g a me dicati o n t o pre vi o us o r 
c o nc o mita nt me dicati o n t he me dicati o n will be c o nsi dere d as c o nc o mita nt me dicati o n
A n y  pre vi o us a n d c o nc o mita nt me dicati o n will be e nc o de d wit h W H O -D D, latest versi o n. Pri or 
a n d c o nc o mita nt me dicati o ns will be liste d b y  s u bject (all s u bjects).
T he f oll o wi n g i nf or mati o n will be dis pla y e d i n a listi n g: ge neric or tra de na me (as re p orte d i n 
C R F), W H O dr u g na me (i ncl u di n g c o di n g), d ose/ u nit, r o ute, fre q ue nc y, reas o n f or use, start/e n d 
date a n d ti me.
C o nc o mita nt pr oce d ures will be prese nte d i n a data listi n g.
1 3
Tre at me nt C o m pli a nce a n d E x p os ure
A listi n g of date a n d ti me of eac h dr u g a d mi nistrati o n a n d eac h bl o o d sa m pli n g i ncl u di n g ti me 
de viati o ns will be pr o vi de d s orte d b y s u bject.
1 4
Effic ac y A n al yses
N ot a p plica ble.
1 5
S afet y A n al yses
T he s u bsecti o ns i n t his secti o n i ncl u de s pecificati o ns f or s u m marizi n g safet y en d p oi nts t hat are 
c o m m o n acr oss cli nical trials s uc h as a d verse e ve nts, la b orat or y  tests a n d vital si g ns.
Safet y  data a nalys is will be c o n d ucte d o n t he Safet y A nalys is Set. 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 7 /2 9
1 5. 1
A d verse E ve nts
All a d verse e ve nts will be s u m marize d o verall as well as b y R u n -i n peri o d a n d per treat me nt 
se q ue nce b y  peri o d, Micr o g y n o n al o ne, Micr o g y n o n
+ Cla dri bi ne, Micr o g y n o n + Place b o a n d 
o verall.
F or s u bjects assi g ne d t o treat me nt se q ue nce 1, cla dri bi ne-place b o (see als o Sec ti o n 1. 2 of t he 
st u d y pr ot oc ol), t he f oll o wi n g treat me nt la bels will be use d i n ta bles a n d listi n gs:

R u n -i n Peri o d: Fr o m r u n-i n peri o d u ntil Da y 1 of peri o d 1, pre-d ose t o Micr o g y n o n
o
I n case of missi n g A E ti me o n Da y  1 of r u n-i n peri o d, t he A E will be assig ne d t o 
R u n -i n Peri o d.

Micr o g y n o n al o ne: Fr o m Da y  1 of peri o d 1, p ost-d ose t o Micr o g yn o n u ntil Da y  9 of peri o d 1, 
pre -d ose of Cla dri bi ne
o
I n case of missi n g A E ti me o n Da y  1 of peri o d 1, t he A E will be assi g ne d t o 
Micr o g y n o n al o ne

Micr o g y n o n + Cla dri bi ne: Fr o m D a y  9 of peri o d 1, p ost -d ose t o Cla dri bi ne u ntil Da y  1 of 
peri o d 2, pre -d ose of Micr o g y n o n
o
I n case of missi n g A E ti me o n Da y  9 of peri o d 1, t he A E will be assi g ne d t o 
Micr o g y n o n + Cla dri bi ne
o
I n case of missi n g A E ti me o n Da y  1 of peri o d 2, t he A E will
be assi g ne d t o 
Micr o g y n o n + Cla dri bi ne

Micr o g y n o n al o ne: Fr o m Da y  1 of peri o d 2, p ost-d ose t o Micr o g yn o n u ntil Da y  9 of peri o d 2, 
pre -d ose of Place b o

Micr o g y n o n + Place b o: Fr o m D a y  9 of peri o d 2, p ost -d ose t o Place b o u ntil Da y  15 of peri o d 
2, pre -d ose of Cla dri bi ne
o
I n case of missi n g A E ti me o n Da y  9 of peri o d 2, t he A E will be assi g ne d t o 
Micr o g y n o n + Place b o

Micr o g y n o n + Cla dri bi ne: Fr o m Da y  15 of peri o d 2, p ost -d ose t o Cla dri bi ne u ntil e n d of 
st u d y.
o
I n case of missi n g A E ti me o n Da y  15 of peri o d 2, t he A E will be assi g ne d t o 
Micr o g y n o n + Cla dri bi ne
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 8 /2 9
F or s u bjects assi g ne d t o treat me nt se q ue nce 2, place b o -cla dri bi ne, t he f oll o wi n g treat me nt la bels 
will be use d i n ta bles a n d listi n gs:

R u n -i n Peri o d: Fr o m r u n-i n peri o d u ntil Da y 1 of peri o d 1, pre- d ose t o Micr o g yn o n
o
I n case of missi n g A E ti me o n Da y  1 of r u n-i n peri o d, t he A E will be assi g ne d t o 
R u n -i n Peri o d.

Micr o g y n o n al o ne: Fr o m Da y  1 of peri o d 1, p ost-d ose t o Micr o g yn o n u ntil Da y  9 of peri o d 1, 
pre -d ose of Place b o
o
I n case of missi n g A E ti me o n Da y  1 of p eri o d 1, t he A E will be assi g ne d t o 
Micr o g y n o n al o ne

Micr o g y n o n + Place b o: Fr o m D a y  9 of peri o d 1, p ost-d ose t o Place b o u ntil Da y  1 of peri o d 2, 
pre -d ose of Micr o g y n o n
o
I n case of missi n g A E ti me o n Da y  9 of peri o d 1, t he A E will be assi g ne d t o 
Micr o g y n o n + Place b o
o
I n case of missi n g A E ti me o n Da y  1 of peri o d 2, t he A E will be assi g ne d t o 
Micr o g y n o n + Place b o

Micr o g y n o n al o ne: Fr o m Da y  1 of peri o d 2, p ost-d ose t o Micr o g yn o n u ntil Da y  9 of peri o d 2, 
pre -d ose of Cla dri bi ne
o
Micr o g y n o n + Cla dri bi ne: Fr o m Da y  9 of peri o d 2, p ost -d ose t o Cla dri bi ne u ntil 
e n d of st u d y.I n case of missi n g A E ti me o n Da y  9 of peri o d 2, t he A E will be 
assi g ne d t o Micr o g yn o n + Cla dri bi ne
T he n u m ber a n d perce nta ge of s u bjects e x perie nci n g at least o ne T E A E will be s u m marize d b y  
treat me nt as well as t he n u m ber of e ve nts. A T E A E is a n A E wit h o nset after start of treat me nt.
Start of treat me nt defi nes t he mi ni m u m date of first i nta ke of micr o g y n o n or cla dri bi ne or 
place b o . Ta bles b y  relati o ns hi p t o trial dr u g a n d b y se verit y will be ge nerate d. A Es will be c o de d 
usi n g Me dical Dicti o nar y f or Re g ulat or y  Acti vities ter mi n ol o g y, latest versi o n. 
If a n e ve nt was re p orte d m ore t ha n o nce, t he w orst se verit y will be ta b ulate d.
I nc o m plete T E A E -relate d dates will be ha n dle d as f oll o ws:

I n case t he o nset date is missi n g c o m pletely or missi n g partiall y  b ut t he o nset m o nt h a n d ye ar, 
or t he o nset year are e q ual t o t he start of trial treat me nt t he n t he o nset date will be re place d b y 
t he mi ni m u m of start of trial treat me nt a n d T E A E res ol uti o n date. 

I n all ot her cases t he missi n g o nset da y or missi n g o nset m o nt h will be re place d b y 1.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
1 9 /2 9

I nc o m plete st o p dates will be re place d b y t he last da y  of t he m o nt h (if da y is missi n g o nl y), if 
n ot res ulti n g i n a date later t ha n t he date of s u bject's deat h. In t he latter case, t he date of deat h 
will be use d t o i m p ute t he i nc o m plete st o p date. 

I n all ot her cases t he i nc o m plete st o p date will n ot be i m p ute d. 
1 5. 1. 1
All A d verse E ve nts
All A Es rec or de d d uri n g t he c o urse of t he trial (ie, assesse d fr o m si g nat ure of i nf or me d c o nse nt 
u ntil t he e n d of t he F oll o w -u p/ E n d of Trial visit) will be c o de d acc or di n g t o Me d D R A latest 
versi o n a n d assi g ne d t o a S O C a n d P T.
T E A Es will be s u m marize d b y  se verit y, usi n g Me d D R A latest versi o n preferre d ter m as e ve nt 
cate g or y a n d Me d D R A pri mar y s yste m or ga n class ( S O C) b o d y ter m as B o d y Sys te m cate g or y. 
T he s e verit y of A Es is assesse d b y t he i n vesti gat or per t he Q ualitati ve T o xicit y  Scale, as f oll o ws:
Mil d:
T he partici pa nt is a ware of t he e ve nt or s ym pt o m, b ut t he e ve nt or s ym pt o m is 
easil y t olerate d.
M o der ate:
T he partici pa nt e x perie nces s ufficie nt disc o mf ort t o i nterfere wit h or re d uce his or 
her us ual le vel of acti vit y.
Se vere:
Si g nifica nt i m pair me nt of f u ncti o ni n g: t he partici pa nt is u na ble t o carr y o ut his or 
her us ual acti vities.
T E A Es relate d t o trial treat me nt are t h ose e ve nts wit h relati o ns hi p missi n g, u n k n o w n or relate d.
T he f oll o wi n g will be s u m marize d i n a n o ver vie w ta ble wit h t he n u m ber a n d perce nta ge of 
s u bjects (a n d t he n u m ber of e ve nts).

A n y T E A E 

T E A Es of s pecial i nterest

Trial treat me nt (eit her M S treat me nt or micr o g yn o n) relate d T E A Es 

M S treat me nt relate d T E A Es

Micr o g y n o n relate d T E A Es

A n y  seri o us T E A Es 

Trial treat me nt (eit her M S treat me nt or micr o g yn o n) relate d seri o us T E A Es 

M S
treat me nt relate d seri o us T E A Es 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 0 /2 9

Micr o g y n o n relate d seri o us T E A Es 

A n y  se vere T E A E

Trial treat me nt (eit her M S treat me nt or micr o g yn o n) related se vere T E A E 

M S
treat me nt related se vere T E A E 

Micr o g y n o n related se vere T E A E 

T E A Es lea di n g t o deat h

Trial treat me nt (eit her M S treat me nt or micr o g yn o n) relate d T E A Es lea di n g t o deat h

M S
treat me nt relate d T E A Es lea di n g t o deat h

Micr o g y n o n relate d T E A Es lea di n g t o deat h
T E A Es will be s u m marize d i n ta bles wit h:

T he n u m ber a n d perce nta ge of s u bjects b y  treatme nt wit h at least o ne T E A E a n d t he n u m ber 
of e ve nts o verall a n d b y  S O C a n d P T. Gr o u p/ S O C ter ms will be s orte d al p ha betically a n d P Ts 
wit hi n eac h gr o u p/ S O C ter m will be s orte d b y desce n di n g fre q ue nc y. 

T he n u m ber a n d perce nta ge of s u bjects b y  treat me nt wit h at least o ne n o n- seri o us T E A E a n d 
t he n u m ber of n o n- seri o us T E A E a p pl yi n g fre q ue nc y thres h ol d of 5 %. Gr o u p/ S O C ter ms will 
be s orte d al p ha beticall y a n d P Ts wit hi n eac h gr o u p/ S O C ter m will be s orte d b y  desce n di n g 
fre q ue nc y.
I n a d diti o n, t he f oll o wi n g ta bles will be pr o vi de d. Gr o u p/ S O C ter ms will be s orte d al p ha beticall y 
a n d P Ts wit hi n eac h gr o u p/ S O C ter m will be s orte d b y  desce n di n g fre q ue nc y (base d o n all 
treat me nt gr o u ps c o m bi ne d): 

A ta ble b y se verit y of T E A Es wit h t he n u m ber a n d perce nta ge of s u bjects by treat me nt wit h at 
least o ne T E A E a n d t he n u m ber of e ve nts b y S O C a n d P T. 

A ta ble b y  relati o ns hi p t o trial treat me nt (eit her M S 
treat me nt or micr o g y n o n) wit h t he 
n u m ber a n d perce nta ge of s u bjects b y  treat me nt wit h at least o ne T E A E a n d t he n u m ber of 
e ve nts b y S O C a n d P T. 

A ta ble b y  relati o ns hi p t o M S 
treat me nt wit h t he n u m ber a n d perce nta ge of s u bjects b y  
treat me nt wit h at least o ne T E A E a n d t he n u m ber of e ve nts by S O C a n d P T. 

A ta ble b y  relati o ns hi p t o micr o g y n o n wit h t he n u m ber a n d perce nta ge of s u bjects b y  
treat me nt wit h at least o ne T E A E a n d t he n u m ber of e ve nts by S O C a n d P T .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 1 /2 9
Pre -treat me nt A Es ( A Es wit h o nset after i nf or me d c o nse nt b ut bef ore start of treat me nt) a n d 
T E A Es will be liste d se paratel y.
1 5. 1. 2
A d verse E ve nts Le a di n g t o Tre at me nt Disc o nti n u ati o n
T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of trial treat me nt will be s u m marize d i ncl u di n g 
n u m ber of s u bjects, perce nta ge a n d n u m ber of e ve nts.
A listi n g of T E A Es lea di n g t o per ma ne nt disc o nti n uati o n of a trial treat me nt will a d diti o nall y be 
pr o vi de d.
1 5. 2
De a t hs, Ot her Seri o us A d verse E ve nts, a n d Ot her Si g nific a nt 
A d verse E ve nts
1 5. 2. 1
De at hs
All deat hs as well as reas o n f or deat h will be base d o n i nf or mati o n fr o m t he “ Re p ort of S u bject 
Deat h” C R Fs. 
Listi n g of deat hs, if a n y,  will be pr o vi de d dis pla y i n g date a n d ca use of deat h (i ncl u di n g T E A E 
lea di n g t o deat h a n d relate d ness t o trial treat me nt, w he n a p plica ble), a n d date a n d ti me of 
treat me nt a d mi nistrati o n.
1 5. 2. 2
Seri o us A d verse E ve nts
A s u m mar y ta ble of S A Es, if a n y, b y  treat me nt a n d o verall will be pr o vi de d dis pla y i ng t he 
n u m ber a n d perce nta ge of s u bjects b y  treat me nt wit h at least o ne S A E a n d t he n u m ber of S A E 
o verall a n d b y  sys te m or ga n class a n d preferre d ter m. Gr o u p/ S O C ter ms a n d P Ts wit hi n eac h 
gr o u p/ S O C ter m will be s orte d al p ha beticall y .
Listi n g of S A Es, if a n y , will be pr o vi de d i n a d diti o n.
1 5. 2. 3
Ot her Si g nific a nt A d verse E ve nt
1 5. 2. 3. 1
A d verse E ve nts of S peci al I nterest
A Es t hat were i de ntifie d as A Es of s pecial i nterest (see A p pe n di x 4 of t he cli nical st u d y pr ot oc ol) 
will be prese n te d i n a se parate data listi n g.
1 5. 3
Cli nic al L a b or at or y E v al u ati o n
T he f oll o wi n g tre at me nt la bels will be use d i n ta bles a n d listi n gs:

Scree ni n g: D uri n g t he scree ni n g peri o d

R u n -i n Peri o d: D uri n g r u n -i n peri o d 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 2 /2 9

Micr o g y n o n + Place b o or Micr o g y n o n + Cla dri bi ne: F or t he meas ure me nt o n Da y  8, Da y  9 
a n d D a y 1 4  

F oll o w -u p: D uri n g f oll o w -u p/e n d of st u d y peri o d
All la b orat or y  data will be re p orte d wit h SI u nits. La b orat or y para meters will be liste d b y s u bject 
a n d ti me-p oi nt a n d s u m marize d i n dicati n g t he treat me nt at t he res pecti ve ti me-p oi nt usi n g 
descri pti ve statistics a n d B o x a n d W his ker pl ot f or a bs ol ute val ues a n d c ha n ge fr o m baseli ne 
o ver ti me b y  treat me nt se q ue nce, peri o d a n d treat me nt. 
La b orat or y  val ues t hat are o utsi de t he n or mal ra n ge will als o be fla g ge d i n t he data listi n gs, 
al o n g wit h c orres p o n di n g n or mal ra n ges. Cli nicall y si gnifica nt a b n or malities/ o utliers as per t he 
T o xicit y  Gra di n g Scale f or Healt h y  Ad ult a n d A d olesce nt V ol u ntee rs E nr olle d i n Pre ve nti ve 
Vacci ne Cli nical Trials will a d diti o nall y be liste d se paratel y. Cli nicall y  si gnifica nt val ues will be 
defi ne d as val ues wit h t o xicit y gra di n g of gra de 2 or hi g her .
‘ Baseli ne’ refers t o t he last sc he d ule d meas ure me nt bef ore a d mi nistrati o n of cla dri bi ne or 
place b o o n D a y  9 of eac h peri o d. I.e. ‘ baseli ne’ f or peri o d 1 refers t o assess me nts o n Da y  21 of 
t he r u n-i n peri o d.
S hift ta bles f or p ost -d ose s hift ( L o w, N or mal, Hi g h, Missi n g)
will als o be prese nte d . T he s hift 
ta bles will be prese nte d f or f oll o w- u p vers us scree ni n g.
See A p pe n di x 5 of t he cli nical st u d y  pr ot oc ol f or a ta ble of t he safet y la b orat or y e val uati o ns.
Safet y  la b orat or y val ues are se parate d i nt o:

He mat ol o g y

Bi oc he mistr y

Uri nal y sis

Ot her tests
Descri pti ve statistics s hift ta bles a n d b o x pl ots will be create d o nl y f or he mat ol o g y  an d 
bi oc he mistr y  res ults.
1 5. 4
Vit al Si g ns
T he f oll o wi n g treat me nt la bels will be use d i n ta bles a n d listi n gs:

Scree ni n g: D uri n g t he scree ni n g peri o d

R u n -i n Peri o d: D uri n g r u n-i n peri o d 
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 3 /2 9

Micr o g y n o n + Place b o or Micr o g y n o n + Cla dri bi ne : F or eac h meas ure me nt
fr o m Da y  9 on 
u ntil Da y  1 4

F oll o w -u p: D uri n g f oll o w -u p/e n d of st u d y peri o d
Vital si g ns will be liste d b y  su bject a n d ti me-p oi nt a n d s u m marize d f or a bs ol ute val ues a n d 
c han ges -fr o m-baseli ne b y treat me nt se q ue nce, peri o d, treat me nt a n d visit usi n g descri pti ve 
statistics. Descri pti ve statistics ta bles will start at baseli ne.
1 5. 5
E C G E v al u ati o n
T he f oll o wi n g treat me nt la bels will be use d i n ta bles a n d listi n gs:

Scree ni n g: D uri n g t he scree ni n g peri o d

Micr o g y n o n + Place b o or Micr o g y n o n + C la dri bi ne: F or eac h meas ure me nt
o n Da y  9 an d 
D a y  1 4

F oll o w -u p: D uri n g f oll o w -u p/e n d of st u d y peri o d
E C G data will be s u m marize d f or a bs ol ute val ues a n d c ha n ges -fr o m-baseli ne b y  treat me nt 
se q ue nce, peri o d, treat me nt, a n d visit usi n g descri pti ve statistics. Descri pti ve statistics ta bles will 
start at baseli ne. Cli nicall y  si gnifica nt E C G fi n di n gs f or i n di vi d ual s u bjects will be liste d a n d 
s u m marize d.
T he ti me i nter vals ( P R, Q R S, R R, Q T a n d c orrecte d Q T i nter vals [ base d o n Fri dericia’s f or m ula, 
Q Tc F]) will be s u m marize d descri pti vel y b y treat me nt se q ue nce, peri o d, treat me nt a n d visit .
T he Fri dericia’s C orrecti o n ( Q Tc F) is deri ve d as f oll o ws: 
Fri dericia’s C orrecti o n ( Q Tc F) 
3 R R
Q T
Q Tc
f 
w here: R R = R R -i nter val meas ure d i n sec o n ds.
Baseli ne f or E C G is defi ne d as D a y  9 pre- d ose (f or eac h peri o d).
O bser ve d Q Tc F val ues will be cate g orize d acc or di n g t o t heir a bs o l ute val ues i nt o t he cate g ories

≤4 3 0 ms,

> 4 3 0 a n d ≤ 4 5 0 ms,
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 4 /2 9

> 4 5 0 a n d ≤ 4 7 0 ms,

> 4 7 0 a n d ≤ 5 0 0 ms, a n d

> 5 0 0 ms,
a n d cate g orize d acc or di n g t o t heir a bs ol ute c ha n ge fr o m baseli ne i nt o t he cate g ories

≤3 0 ms,

> 3 0 a n d ≤ 6 0 ms, a n d

> 6 0 ms.
T he n u m ber a n d perce nta ge of s u bjects b y  these cate g ories at a n y p ost -d ose assess me nt ( p ost-
d ose t o i nta ke of place b o or cla dri bi n e) will be ta b ulate d b y  treat me nt se q ue nce, peri o d a n d 
treat me nt. 
All E C G meas ure me nts will be liste d , wit h i n vesti gat or re p orte d a b n or malities i n dicate d.
I n vesti gat or re p orte d i nter pretati o n res ults will als o be liste d a n d ta b ulate d b y  treat me nt 
se q ue nce, peri o d a n d treat me nt usi n g t he n u m ber a n d perce nta ge of s u bjects f or eac h 
i nter pretati o n cate g or y ( N or mal, A b n or mal 
N ot 
Cli nicall y  Si g nifica nt [ N C S], A b n or mal 
Cli nicall y  Si g nifica nt [ C S].
1 5. 6
Se nsiti vit y A n al ysis
D ue t o a dis pe nsati o n err or at t he st u d y site, t he treat me nt se q ue nce f or patie nt 
nee de d 
t o be u n bli n de d ( o nly S p o ns or Me dical Res p o nsi ble a n d Me dical M o nit or were u n bli n de d) s o 
t hat a p pr o priate f urt her s u bject treat me nt c o ul d be e ns ure d.
T his ha p p e ne d d uri n g t he 
de vel o p me nt of t he i A P. 
F oll o wi n g t he “f or ca use” u n bli n di n g, i n a st u d y t ea m call bet wee n ve n d or a n d C R O o n 
, t he act ual assi g n me nt of t he patie nt was re veale d, t o a v oi d c o m m u nicati o n err ors re gar di n g 
t he treat me nt se q ue nce t o w hic h t his patie nt was i nitiall y ra n d o mise d, a n d w hic h treat me nt 
se q ue nce t he patie nt act uall y recei ve d. T his disc ussi o n t o o k place after t he patie nt had c o m plete d 
her last treat me nt as per pr ot oc ol a n d her treat me nt assi g n me nt was u n bli n de d acc or di n g t o s t u d y 
pr ot oc ol, t o deter mi ne w het her or n ot s he ma y  re q uire a sec o n d cla dri bi ne treat me nt c o urse after 
c o ncl usi o n of t he st u d y.  
T he s p o ns or statisticia n at t he ti me, w h o s h o ul d n ot ha ve bee n i nf or me d of t he treat me nt 
assi g n me nt, was prese nt a n d c o nse q ue ntl y u n bli n de d re gar di n g t he treat me nt se q ue nce of a 
si n gle patie nt.
T o this e n d, a se nsiti vit y anal y sis will be perf or me d b y  excl u di n g t he affecte d patie nt fr o m t he 
a nal ys is. T his a d diti o nal a n al ys is will be d o ne f or A Es. A n o ver vie w ta ble of treat me nt e mer ge nt 
A Es as me nti o ne d Secti o n 1 5. 1 will be pr o vi de d .
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 
C CI


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 5 /2 9
1 6
A n al yses of Ot her E n d p oi nts
1 6. 1
P h ar m ac o ki netics
T he f oll o wi n g treat me nt la bels will be use d i n ta bles a n d listi n gs:
R u n -i n Peri o d: D uri n g r u n-i n peri o d (f or E E a n d L N G o nl y)
Micr o g y n o n + Place b o or Micr o g y n o n + Cla dri bi ne. 
Ge ner al S pecific ati o ns f or Pl as m a C o nce ntr ati o n D at a
P K c o nce ntrati o n data will be prese nte d i n ta bles a n d descri pti vel y  s u m marize d b y treat me nt a n d 
n o mi nal ti me p oi nt u si n g n, arit h metic mea n, S D , me dia n, mi ni m u m, ma xi m u m, a n d C V %. 
Val ues bel o w t he L L O Q will be ta ke n as zer o f or descri pti ve statistics of P K c o nce ntrati o ns.
Descri pti ve statistics of P K c o nce ntrati o n data will be calc ulate d usi n g val ues wit h t he sa me 
precisi o n as t he s o urce data, a n d r o u n de d f or re p orti n g p ur p oses o nl y. T he f oll o wi n g c o n ve nti o ns 
will be a p plie d w he n re p orti n g descri pti ve statis tics of P K c o nce ntrati o n data:
Mea n, Mi n, Me dia n, Ma x: 
3 si g nifica nt di gits
S D:      
            4 si g nifica nt di gits
C V %:
1 deci mal place 
F or fi nal e val uati o ns val ues greater t ha n t he u p per li mit of q ua ntificati o n ( U LO Q) are n ot 
acce pte d a n d s h o ul d be re place d b y  vali d n u meric val ues fr o m dil uti o n meas ure me nt. Missi n g 
c o nce ntrati o ns (e. g. n o sa m ple, i ns ufficie nt sa m ple v ol u me f or a nal ys is, n o res ult or res ult n ot 
vali d) will be re p orte d a n d use d ge nerall y as “ N. R.”. Pre -d ose sa m ples t hat oc c ur bef ore t he first 
dr u g a d mi nistrati o n will be assi g ne d a ti me of 0 h o urs, as if t he sa m ple ha d bee n ta ke n 
si m ulta ne o usl y wit h t he st u d y dr u g a d mi nistrati o n.
Ge ner al S pecific ati o ns f or P K P ar a meter D at a
P K para meter data will be descri pti vel y  s u m marize d: n, arit h metic mea n, S D , me dia n, mi ni m u m, 
ma xi m u m, C V %, ge o metric mea n ( Ge o Mea n), t he ge o metric c oefficie nt of variati o n ( Ge o C V %), 
a n d t he 9 5 % CI f or t he Ge o Mea n.
P K para meter C ma x will be re p orte d wit h t he sa me precisi o n as t he s o urce data. All ot her P K 
p ara meters will be re p orte d t o 3 si g nifica nt fi g ures. I n e x p ort datasets, as well as i n t he S D T M 
P P d o mai n, P K para meters will be pr o vi de d wit h f ull precisi o n, a n d will n ot be r o u n de d. 
Descri pti ve statistics of P K para meter data will be calc ulate d usi n g f ull precisi o n val ues, a n d 
r o u n de d f or re p orti n g p ur p oses o nl y. 
T he f oll o wi n g c o n ve nti o ns will be a p plie d w he n re p orti n g descri pti ve statistics of P K para meter 
data:
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 6 /2 9
Mea n, Mi n, Me dia n, Ma x, Ge o Mea n, 9 5 % CI : 
3 si g nifica nt di gits
S D:
            4 si g nif ica nt di gits
C V %, Ge o C V %:
1 deci mal place 
Rati o of Ge o Mea n a n d 9 0 % CI
4 deci mal places
All statistical a nal yses a n d descri pti ve s u m maries of p har mac o ki netic data will be perf or me d o n 
t he P K A nal y sis Set. All a vaila ble c o nce ntrati o n/ P K data will be liste d. Data of s u bjects n ot i n 
t he P K a nal ysis set or i n vali d data will be fla g ge d acc or di n gl y ; a reas o n f or e xcl usi o n will be 
detaile d i n t he C S R (e. g. a f o ot n ote or a ta ble of e xcl usi o ns). A n y fla gs s h o ul d be i ncl u de d i n t he 
st u d y s pecific A Da M data sets.
1 6. 1. 1
Pri m ar y P h ar m ac o ki netic E n d p oi nts
T he P K e val uati o n will be base d u p o n t he P K A nal y sis Set. T he statistical a nal ys is of pri mar y 
P K para meters A U C ,ss a n d C ma x,ss of E E a n d L N G (t he acti ve i n gre die nts of t he Micr o g y n o n
treat me nt) will 
be perf or me d usi n g a n a nal ys is of varia nce ( A N O V A) m o del 
i ncl u di n g 
T R E A T M E N T, 
P E RI O D, 
S E Q U E N C E 
a n d S U BJ E C T( S E Q U E N C E) 
as fi xe d effects. 
Para meters will be l o g-tra nsf or me d bef ore t he y are pr ocesse d. L S M E A N S f or Test – Refere nce 
differe nces wi ll be esti mate d f or all 4 pri mar y en d p oi nts t o get her wit h 9 0 % c o nfi de nce i nter vals, 
res ulti n g i n Test/ Refere nce rati os a n d c orres p o n di n g 9 0 % c o nfi de nce i nter vals f oll o wi n g bac k -
tra nsf or mati o n. 
Bi oe q ui vale nce ( w hic h mea ns a bse nce of dr u g -dr u g i nteracti o n) will be c o ncl u de d, if all f o ur
9 0 % CI s f or t he T E S T/ R E F E R E N C E rati os are f ull y co ntai ne d wit hi n t he [ 0. 8 0 0 0 t o 1. 2 5 0 0] 
acce pta nce ra n ge.
Scatter pl ots will be pr o d uce d f or t he i n di vi d ual pri mar y  P K para meters b y  treat me nt i n dicati n g 
t he ge o metric mea ns wit hi n eac h treat me nt. B o x pl ots f or pri mar y  P K para meters b y  treat me nt 
will als o be pr o vi de d.
1 6. 1. 2
Sec o n d ar y P h ar m ac o ki netic E n d p oi nts 
Sec o n dar y  PK para meters calc ulate d f or E E a n d L N G: C mi n,ss ; C tr o u g h; tma x,ss ; C a v,ss; a n d pea k -t o-
tr o u g h fl uct uati o n ( P T F %). Sec o n d ar y P K para meters calc ulate d f or Cla dri bi ne : Cma x a n d t ma x .
Sec o n dar y  para meters will be liste d.
S u m mar y  statistics will be pr o vi de d f or all sec o n dar y P K para meters f or E E, LN G a n d cla dri bi ne 
i n plas ma b y a nal yt e, treat me nt a n d da y, if a p plica ble.
1 6. 1. 3
Pl as m a C o nce ntr ati o n D at a
C o nce ntrati o ns of E E , L N G a n d cla dri bi ne will be ta b ulate d a n d dis pla y e d gra p hicall y. S u m mar y 
statistics will be pr o vi de d b y a nal yt e, treat me nt a n d n o mi nal ti me p oi nt a n d da y.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 7 /2 9
T he f oll o wi n g fi g ures will be pr o d uce d f or t he E E a n d L N G plas ma c o nce ntrati o ns o n Da y  1 4:

Arit h metic mea n plas ma c o nce ntrati o n-ti me pr ofiles o verla y i n g all treat me nts o n li near a n d 
se mi-l o garit h mic scale

Arit h metic mea n plas ma c o nce ntrati o n -ti me pr ofiles o verla y i n g all treat me nts o n li near scale 
i ncl u di n g S D err or bars

I n di vi d ual plas ma c o nce ntrati o n -ti me pr ofiles o verla y i n g s u bjects, f or eac h treat me nt 
se paratel y o n li near a n d se mi-l o garit h mic scale

I n di vi d ual plas ma c o nce ntrati o n-ti me pr ofiles o verla y i n g all treat me nts, se paratel y for eac h 
s u bject o n li near a n d se mi-l o garit h mic scale
T he f oll o wi n g fi g ures will be pr o d uce d f or t he cla dri bi ne plas ma c o nce ntrati o ns o n Da y s 1 0, 1 1, 
1 2 a n d 1 3 se paratel y:

I n di vi d ual plas ma c o nce ntrati o n -ti me pr ofiles o n li near a n d se mi-l o garit h mic scale o verla y i n g 
s u bjects, f or each treat me nt se parately o n li near a n d se mi-l o garit h mic scale ( x-scale: relati ve 
act ual ti me relate d t o c orres p o n di n g cla dri bi ne a d mi nistrati o n)

I n di vi d ual plas ma c o nce ntrati o n -ti me pr ofiles o n li near a n d se mi-l o garit h mic scale o verla y i n g 
all treat me nts, se paratel y f or eac h s u bjects o n li near a n d se mi-l o garit h mic scale ( x-scale: 
relati ve act ual ti me relate d t o c orres p o n di n g cla dri bi ne a d mi nistrati o n)
T he f oll o wi n g fi g ures will be pr o d uce d f or t he cla dri bi ne plas ma c o nce ntrati o ns o verla y i n g Da ys 
1 0, 1 1, 1 2 a n d 1 3 :

I n di vi d ual plas ma c o nce ntrati o n-ti me pr ofiles o n li near a n d se mi-l o garit h mic scale
se paratel y for eac h treat me nt a n d s u bjects o n li near a n d se mi-l o garit h mic scale ( x-scale: 
relati ve act ual ti me relate d t o c orres p o n di n g cla dri bi ne a d mi nistrati o n)

Arit h metic mea n plas ma c o nce ntrati o n-ti me pr ofiles f or eac h treat me nt se paratel y on 
li near a n d se mi-l o garit h mic scale

Arit h metic mea n plas ma c o nce ntrati o n-ti me pr ofiles f or eac h treat me nt se paratel y on 
li near scale i ncl u di n g err or bars
T he f oll o wi n g listi n g will be pr o d uce d:

Plas ma c o nce ntrati o ns will be liste d f or eac h a nal yte b y  treat me nt, s u bject, a n d n o mi nal 
ti me a n d da y. E xcl u de d plas ma c o nce ntrati o ns will be fla g ge d.
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: 


Cl a dri bi ne t a blets 
Effects of cl a dri bi ne t a blets o n t he p h ar m ac o ki netics of Micr o g y n o n ®
M S 7 0 0 5 6 8- 0 0 3 1
Fi n al v 1 . 0
C O N F I D E N T I A L
I N F O R M A T I O N
2 8 /2 9
1 6. 1. 4
Esti m ati o n of I n di vi d u al P h ar m ac o ki netic P ar a meters
T he co m p uter pr o gra m P h oe ni x ®
Wi n N o nli n ® 
versi o n 6. 4, or hi g her ( Certara, L. P., 1 6 9 9 S 
Ha nle y  Roa d, St L o uis, M O 6 3 1 4 4, U S A) will be use d t o deri ve P K para meters a p pl yi n g N o n -
c o m part me ntal a nal ysis ( N C A). T he statistical s oft ware S A S ® ( Statistical A nal ysis Sys te m, S A S-
I nstit ute, Car y  NC, U S A, wi n d o ws versi o n 9. 1 or hi g her) m a y  be use d t o ge nerate a d diti o nal P K 
para meters, pr o d uce ta bles, listi n gs a n d fi g ures. 
T he f oll o wi n g P K para meters will be calc ulate d f or Da y 1 4, w he n a p pr o priate:
T a ble 2
P K P ar a meters of E E a n d L N G
S y m b ol
Defi niti o n
C ma x,ss
Ma xi m u m o bser ve d c o nce ntrati o n i n stea d y state
C mi n,ss
Mi ni m u m o bser ve d c o nce ntrati o n i n stea d y state d uri n g a c o m plete d osi n g 
i nter val ()
C tr o u g h
Meas ure d c o nce ntrati o n at t he e n d of a d osi n g i nter val at stea d y  state (ta ke n 
directl y  bef ore ne xt a d mi nistrati o n)
tma x,ss
Ti me t o reac h t he o bser ve d ma xi m u m ( pea k) c o nce ntrati o n at stea d y state
A U C ,ss
Area u n der t he plas ma c o nce ntrati o n-ti me c ur ve i n stea d y state d uri n g a 
c o m plete d osi n g i nter val ()
C a v,ss
A vera ge plas ma c o nce ntrati o n at stea dy state d uri n g a c o m plete d osi n g 
i nter val (); Ca v,ss= A U C ,ss / 
P T F %
Pea k -t o-tr o u g h fl uct uati o n o ver 1 c o m plete d osi n g i nter val at stea dy state
T he f oll o wi n g P K para meters will be calc ulate d f or Da ys 9, 1 0, 1 1, 1 2 a n d 1 3, w he n a p pr o priate:
T a ble 3
P K P ar a meters of cl a dri bi ne a
P ar a meter
F ull descri pti o n
C ma x
Ma xi m u m o bser ve d c o nce ntrati o n ( Da ys 1 0- 1 3 o nl y )
tma x
Ti me t o reac h t he o bser ve d ma xi m u m ( pea k) c o nce ntrati o n ( Da ys 1 0- 1 3
o nl y )
C pre
Meas ure d 
c o nce ntrati o n d uri n g re peat-d osi n g ta ke n directl y  bef ore dr u g 
a d mi nistrati o n ( o n Da y 1 0- 1 3).
D oc u me nt N o. 
O bject N o. 
Gl o bal Versi o n I D: