Conditions: Healthy
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 26
Healthy volunteers: yes

Brief summary:
The primary objective of the study is to investigate the relative bioavailability of Movalis capsules 15 mg (Test, T) versus Movalis tablets 15 mg (Reference, R).

The secondary objective of the study is to establish bioequivalence of Movalis capsules 15 mg (Test, T) versus Movalis tablets 15 mg (Reference, R).

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: Meloxicam Capsule (Test) intervention 2: Meloxicam Tablet (Reference)
Intervention descriptions: intervention 1: single dose intervention 2: single dose

Protocol document:
Prot_000.pdf: 
001-MCS-40-106-RD-13 (5.0) / Saved on: 15 Jul 2014
Clinical Trial Protocol
TITLE PAGE
Document Number:
c22345272-01
EudraCT No.:
BI Trial No.:
Not applicable
0107-0277
BI Investigational
Product:
UHAC 62 XX, Meloxicam, Movalis®
Title:
An open-label, randomised, single-dose, two-way crossover study in 
healthy male and female volunteers to evaluate the relative 
bioavailability of a new oral formulation of meloxicam, Movalis®
capsules 15 mg, versus Movalis® tablets 15 mg, after administration 
under fasting state.
Clinical Phase:
Bioequivalence study
Lay Title 
A study to compare the amount of meloxicam in the blood when it is 
taken as capsules or as tablets.
Trial Clinical Monitor:
Phone: 
   Fax: 
 
Principal Investigator:
Address:
. Phone number:
 
Fax:
Status:
Final Protocol
Version and Date:
Version: 1.0 
Date: 28 May 2018
Page 1 of 89
Proprietary confidential information
© 2018 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission


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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Movalis® capsules 15 mg
Name of active ingredient:
UHAC 62 XX, meloxicam, Movalis®
Protocol date:
Trial number:
Revision date:
Not applicable
28 May 2018
0107-0277
Title of trial:
An open-label, randomised, single-dose, two-way crossover study in healthy male and 
female volunteers to evaluate the relative bioavailability of a new oral formulation of 
meloxicam, Movalis® capsules 15 mg, versus Movalis® tablets 15 mg, after 
administration under fasting state.
Principal Investigator:
Adress: 
Phone number:
Fax:
Trial site(s):
Address: 
Clinical phase:
Bioequivalence study
Objectives:
Primary objective:
To investigate the relative bioavailability of Movalis® capsules 15 mg versus
Movalis® tablets 15 mg.
Secondary objectives:
1. To establish bioequivalence of Movalis® capsules 15 mg versus Movalis® tablets 15 
mg.
2. The assessment of safety and tolerability will be an additional objective of this trial.
Methodology:
This will be an open-label, randomised, single-dose, two-way crossover study in
healthy male and female volunteers conducted in one clinical trial site in Russian
Federation.
No. of subjects: 
total entered:
26
each treatment:
Movalis®  capsules 15 mg (Test formulation , T) – 26,
Movalis®  tablets 15 mg (Reference formulation, R) – 26
Diagnosis:
Not applicable
Main criteria
for inclusion:
Male and female subjects aged 18-45, inclusive.
Body mass index by Quetelet between 18.50 -29.99 kg/m2, inclusive.
Test product:
Movalis® capsules (T)
dose:
15 mg
mode of admin.:
Oral with 200 mL of water after an overnight fast of at least 10 h 


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Name of company:
Tabulated
Trial Protocol
Boehringer Ingelheim
Name of finished product:
Movalis® capsules 15 mg
Name of active ingredient:
UHAC 62 XX, meloxicam, Movalis®
Protocol date:
Trial number:
Revision date:
Not applicable
28 May 2018
0107-0277
Comparator product:
Movalis tablets (R)
dose:
15 mg
mode of admin.:
Oral with 200 mL of water after an overnight fast of at least 10 h
Duration of treatment: One day (single dose) for each treatment
Criteria for
pharmacokinetics:
Primary endpoints: AUC0-t and Cmax.
Secondary endpoints: AUC0-∞.
Criteria for safety:
Vital signs (blood pressure, pulse rate, temperature, respiratory rate), global assessment, 
physical examination, 12-lead ECG, laboratory tests, adverse events.
Statistical methods:
Two-sided 90% CIs for the intra-subject ratio (as estimated by the ratio of geometric
means) of each of AUC0-t, AUC0-∞and Cmax will be calculated to determine whether the 
CIs are contained in the acceptance range for bioequivalence (80-125% for AUC0-t; 80-
125% for Cmax). 
The drugs will be considered bioequivalent if:

the limits of the estimated confidence interval for AUC0-t are within 80.00–125.00%;

the limits of the estimated confidence interval for Cmax are within 80.00–125.00%:
The statistical model will be ANOVA on log-transformed parameters including effects 
for "sequence", "subjects nested within sequences", "period" and "treatment". CIs will 
be based on the residual error from ANOVA. The effect ‘subjects within sequences’ 
will be considered as random, whereas the other effects will be considered as fixed.
Descriptive statistics for all other parameters will be calculated.


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FLOW CHART
Phase
Visit
Day
(time window)
Planned Time after drug 
administration
[h:min]1
Time window for 
PK blood sampling 
[h:min]
Hospitalization
Randomisation
Drug administration
Routine laboratory tests2
Exclusionary testing
Blood sampling for PK
Physical examination
12-lead ECG
Vital signs 3
Global assessment
Adverse events
Meals
Concomitant medication
Screening4
1
-14 to -1
x
x5
x
x
x
x
x
Period I
2
-1
-16:00 – -10:00
x
x
x6
x
x7
x
x
x
x
1
-2:00
-2:00 – 0:01
x
x
x
x
0:00
x
0:30
±0:02
x
1:00
±0:02
x
2:00
±0:02
x
3:00
±0:05
x
4:00
±0:05
x
x
5:00
±0:05
x
6:00
±0:05
x
x
x
x
x
7:00
±0:10
x
8:00
±0:10
x
9:00
x
10:00
±0:10
x
11:00
x
12:00
±0:10
x
x
x
x
2
24:00
±0:15
x
x
x
x
x
x
32:00
±0:15
x
                                                          
1 The time points are strict for the T/R drug administration and PK blood sampling.
2 Routine laboratory tests include haematology, clinical chemistry and urinalysis. 
   Hematology:           erythrocyte sedimentation rate (ESR), hematocrit (Hct), haemoglobin (Hb), erythrocytes/ red blood 
cells (RBC), platelet count, leucocytes/white blood cells (WBC), differential WBC (neutrophils, 
eosinophils, basophils, monocytes, lymphocytes). Test is performed at fasted state.
   Clinical chemistry: total protein, glucose, total cholesterol, total bilirubin, creatinine, aspartate transaminase (AST), alanine 
transaminase (ALT), alkaline phosphatase (AP) electrolytes (Na, K, Ca). Test is performed at fasted 
state.
   Urinalysis:           pH, protein, glucose, ketone, bilirubin, urobilinogen, RBC, nitrite, WBC. Urine-Sediment: bacteria; 
epith cells; RBC/erythrocytes; WBC/leucocytes.
If clinical chemistry analysis revealed ALT and/or AST values ≥3 fold ULN in conjunction with an elevation of total 
bilirubin of ≥2 fold ULN, following laboratory tests should be repeated: ALT, AST, and bilirubin (total and direct) - within 
48 to 72 h. If it is confirmed that ALT and/or AST values ≥3 fold ULN occur in conjunction with an elevation of total 
bilirubin of ≥2 fold ULN, hematology, serology and clinical chemistry analysis must be performed and made available to 
the investigator and to BI as soon as possible
3 Vital signs: systolic and diastolic blood pressure (BP), pulse rate (PR), body temperature, respiratory rate.
4 In addition to procedures specified in the Flow Chart at screening the following procedures are also performed: providing 
volunteer with subject information, receiving signed informed consent, collection data about demographics, smoking and 
alcoholic history, relevant medical history, concomitant medication, measuring body weight, height and calculation of 
body-mass-index (BMI).
5At screening exclusionary testing includes: infectious serology (qualitative HbsAg test, qualitative test for anti-HCV total, 
qualitative test for anti-HIV1/2, test for syphilis); urine test for β-HCG (test strips for women); urine drug screening (test 
strips for cannabis, benzodiazepine, barbiturates, opiates, cocaine, amphetamines); breath test for alcohol.
6 On Day -1 of period I to confirm subject’s eligibility the following exclusionary testing is achieved: urine test for β-HCG 
(test strips for women); urine drug screening (test strips for cannabis, benzodiazepine, barbiturates, opiates, cocaine, 
amphetamines); breath test for alcohol. 
7 If 12-lead ECG is taken on Day -7-1 at screening, the results can be used on Day 1 in Period I.


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Phase
Visit
Day
(time window)
Planned Time after drug 
administration
[h:min]1
Time window for 
PK blood sampling 
[h:min]
Hospitalization
Randomisation
Drug administration
Routine laboratory tests2
Exclusionary testing
Blood sampling for PK
Physical examination
12-lead ECG
Vital signs 3
Global assessment
Adverse events
Meals
Concomitant medication
3
48:00
±0:15
x
x
x
x
x
x
4
72:00
±0:15
x
x
x
x
x
x
x
Wash-out8
7 days
Period II
3
7
-16:00 – -10:00
x
x9
x
x
x
x
x
8
-2:00
-2:00 – 0:00
x
x
x
x
x
0:00
x
0:30
±0:02
x
1:00
±0:02
x
2:00
±0:02
x
3:00
±0:05
x
4:00
±0:05
x
x
5:00
±0:05
x
6:00
±0:05
x
x
x
x
x
x
7:00
±0:10
x
8:00
±0:10
x
9:00
x
10:00
±0:10
x
11:00
x
12:00
±0:10
x
x
x
x
x
9
24:00
±0:15
x
x
x
x
x
x
32:00
±0:15
x
10
48:00
±0:15
x
x
x
x
x
x
11
72:00
±0:15
x
x
x
x
x
x
x
x
Follow-up
4
18 
x10
x
x
x
x
                                                          
8 The duration of the wash-out period is calculated from the time of administration of the study drug in the first study period 
to the time of administration of the study drug in the second study period. The interval between the discharge of the study 
subject from the hospital in the first period and the hospitalization of the study subject in the second study period is about 
3.5 days
9 On Day 7 in period II to confirm subject’s eligibility the following exclusionary testing is achieved: urine test for β-HCG 
(test strips for women); urine drug screening (test strips for cannabis, benzodiazepine, barbiturates, opiates, cocaine, 
amphetamines); breath test for alcohol.
10 Only urine test for β-HCG (test strips for women).


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TABLE OF CONTENTS
TITLE PAGE ......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS ................................................2
FLOW CHART...................................................................................................4
TABLE OF CONTENTS ...................................................................................6
ABBREVIATIONS.......................................................................................... 10
1.
INTRODUCTION.................................................................................... 13
1.1
MEDICAL BACKGROUND............................................................................13
1.2
DRUG PROFILE...............................................................................................13
1.2.1
Composition of Movalisoral formulations.......................................13
1.2.2
Pharmacodynamics...............................................................................14
1.2.3
Pharmacokinetics..................................................................................15
1.2.4
Indications .............................................................................................16
1.2.5
Contraindications..................................................................................16
1.2.6
Special warning and precautions.........................................................17
1.2.7
Dosage and administration...................................................................18
1.2.8
Interactions............................................................................................19
1.2.9
Pregnancy and lactation.......................................................................20
1.2.10 Effects on ability to drive and use machines ......................................20
1.2.11 Non-clinical studies...............................................................................21
1.2.12 Clinical studies ......................................................................................21
1.2.13 Side effects .............................................................................................23
1.2.14 Special instructions...............................................................................24
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT ......................................................................................... 27
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................27
2.2
TRIAL OBJECTIVES.......................................................................................28
2.2.1
Primary objective..................................................................................28
2.2.2
Primary endpoints ................................................................................28
2.2.3
Secondary objectives.............................................................................28
2.2.4
Secondary endpoints.............................................................................28
.................................................................................29
2.2.6
Other endpoints.....................................................................................29
2.3
BENEFIT - RISK ASSESSMENT ...................................................................29
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION.............. 31
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................31
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP..........................................................................................32
3.3
SELECTION OF TRIAL POPULATION ......................................................32


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3.3.1
Main diagnosis for study entry............................................................33
3.3.2
Inclusion criteria...................................................................................33
3.3.3
Exclusion criteria ..................................................................................33
3.3.4
Removal of subjects from therapy or assessments.............................35
3.3.4.1
Removal of individual subjects................................................35
3.3.4.2
Discontinuation of the trial by the sponsor..............................37
3.3.5
Replacement of subjects .......................................................................37
4.
TREATMENTS........................................................................................ 38
4.1
TREATMENTS TO BE ADMINISTERED....................................................38
4.1.1
Identity of BI investigational product and comparator product......38
4.1.2
Method of assigning subjects to treatment groups ............................39
4.1.3
Selection of doses in the trial................................................................39
4.1.4
Drug assignment and administration of doses for each subject .......39
4.1.5
Blinding and procedures for unblinding ............................................40
4.1.6
Packaging, labelling, and re-supply ....................................................40
4.1.7
Storage conditions.................................................................................40
4.1.8
Drug accountability ..............................................................................41
4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT....................................................................................................42
4.2.1
Rescue medication, emergency procedures, and additional 
treatments ..............................................................................................42
4.2.2
Restrictions............................................................................................42
4.2.2.1
Restrictions regarding concomitant treatment .........................42
4.2.2.2
Restrictions on diet and life style.............................................42
4.3
TREATMENT COMPLIANCE.......................................................................43
5.
VARIABLES AND THEIR ASSESSMENT ......................................... 44
5.1
EFFICACY - CLINICAL PHARMACOLOGY.............................................44
5.1.1
Endpoints of efficacy.............................................................................44
5.2
SAFETY..............................................................................................................44
5.2.1
Endpoints of safety................................................................................44
5.2.2
Assessment of adverse events...............................................................44
5.2.2.1
Definitions of adverse events...................................................44
5.2.2.2
Adverse event collection and reporting ...................................47
5.2.3
Assessment of safety laboratory parameters......................................49
5.2.4
Electrocardiogram................................................................................52
5.2.5
Assessment of other safety parameters...............................................52
5.2.5.1
Vital signs ................................................................................52
5.2.5.2
Medical examinations..............................................................52
5.2.5.3
Local tolerability......................................................................53
5.3
OTHER...............................................................................................................53
5.3.1
Pharmacogenomic evaluation..............................................................53
5.4
APPROPRIATENESS OF MEASUREMENTS.............................................53


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5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................53
5.5.1
Pharmacokinetic endpoints..................................................................53
5.5.1.1
Primary endpoints....................................................................53
5.5.1.2
Secondary endpoints................................................................54
5.5.2
Methods of sample collection...............................................................54
5.5.2.1
Plasma sampling for pharmacokinetic analysis.......................54
5.5.2.2
Urine sampling for pharmacokinetic analysis..........................55
5.5.3
Analytical determinations ....................................................................55
5.5.3.1
Analytical determination of analyte plasma concentration......55
5.5.3.2
The bioanalytical method will be documented before the start 
of the study (preliminary validation) for the subsequent 
development of the validation report.......................................55
5.5.3.3
Analytical determination of analyte urine concentration.........58
5.6
BIOMARKER(S) ...............................................................................................58
5.6.1
Biochemical and cellular biomarker(s)...............................................58
5.6.2
Pharmacogenomic biomarker(s) .........................................................58
5.6.3
Methods of sample collection...............................................................58
5.6.4
Analytical determinations ....................................................................59
5.7
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP .....59
6.
INVESTIGATIONAL PLAN.................................................................. 60
6.1
VISIT SCHEDULE............................................................................................60
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................60
6.2.1
Screening and run-in period ................................................................60
6.2.2
Treatment period ..................................................................................61
6.2.3
End of trial and follow-up period........................................................67
7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE......................................................................................... 68
7.1
STATISTICAL DESIGN – MODEL ...............................................................68
7.1.1
Objectives...............................................................................................68
7.1.2
Endpoints...............................................................................................68
7.1.3
Model......................................................................................................69
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................71
7.3
PLANNED ANALYSES....................................................................................72
7.3.1
Primary analyses...................................................................................72
7.3.2
Secondary analyses ...............................................................................72
7.3.3
Safety analyses.......................................................................................73
7.3.4
Interim analyses ....................................................................................73
7.3.5
Pharmacokinetic analyses ....................................................................73
7.3.6
Biomarker analysis ...............................................................................74
7.3.6.1
Analysis of cellular and biochemical biomarkers....................74


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7.3.6.2
Pharmacogenomic analyses .....................................................74
7.4
HANDLING OF MISSING DATA ..................................................................74
7.4.1
Safety......................................................................................................74
7.4.2
Plasma drug concentration - time profiles..........................................75
7.4.3
Pharmacokinetic parameters...............................................................75
7.5
RANDOMISATION ..........................................................................................75
7.6
DETERMINATION OF SAMPLE SIZE ........................................................76
8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS ................................................................................................ 78
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT ..........................................................................................................78
8.2
DATA QUALITY ASSURANCE .....................................................................79
8.3
RECORDS..........................................................................................................79
8.3.1
Source documents .................................................................................79
8.3.2
Direct access to source data and documents.......................................79
8.3.3
Storage of records .................................................................................79
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................80
8.5
STATEMENT OF CONFIDENTIALITY.......................................................80
8.6
TRIAL MILESTONES .....................................................................................80
8.7
COMPENSATION AVAILABLE TO THE SUBJECT  IN THE EVENT 
OF TRIAL RELATED INJURY......................................................................81
9.
REFERENCES......................................................................................... 82
9.1
PUBLISHED REFERENCES...........................................................................82
9.2
UNPUBLISHED REFERENCES.....................................................................82
10. APPENDICES .......................................................................................... 86
10.1
CLINICAL EVALUATION OF LIVER INJURY .........................................86
10.1.1 Introduction...........................................................................................86
10.1.2 Procedures .............................................................................................86
10.2
CONTACT INFORMATION OF THE CRO AND THE CENTRAL 
LABORATURY .................................................................................................87
10.2.1 Clinical research organization.............................................................87
10.2.2 Local Clinical Laboratory....................................................................88
10.2.3 Central Clinical Laboratory ................................................................88
11. DESCRIPTION OF GLOBAL AMENDMENT(S).............................. 89


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ABBREVIATIONS
AE
ACR20
Adverse event
20% improvement according to American College of Rheumatology 
(ACR) response criteria
AESI
Adverse events of special interest
ALT
Alanine transaminase 
ANOVA
Analysis of variance
AST
Aspartate transaminase 
AUC0-∞
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 extrapolated to infinity
AUCt1-t2
Area under the concentration-time curve of the analyte in plasma over 
the time interval t1 to t2
AUC0-t
Area under the concentration-time curve of the analyte in plasma over 
the time interval from 0 to the last quantifiable data point
BA
Bioavailability
BI
Boehringer Ingelheim
BMI
Body Mass Index (weight divided by height squared)
BLQ
Below limit of quantification
ß-HCG
Beta-human chorionic gonadotrophin
BP
Blood pressure
CA
Competent authority
CK
Creatinine kinase
CI
Confidence interval
CL
Total clearance of the analyte in plasma after intravascular 
administration
CL/F
Apparent clearance of the analyte in plasma after extravascular 
administration
Cmax
Maximum measured concentration of the analyte in plasma
Cmin
Minimum measured concentration of the analyte in plasma
C(')t
Measured (predicted) concentration of the analyte in plasma at the last 
time t at which quantification of the analyte in plasma was still 
possible
COX-1
COX-2
Cyclooxygenase-1
Cyclooxygenase-2
CRO
Contact research organisation
CRF
Case report form
CTMF
Clinical trial master file
CTP
Clinical trial protocol
CTR
Clinical trial report
CTCAE
Common Terminology Criteria for Adverse Events
CV
Arithmetic coefficient of variation
CYP
Cytochrome 
DILI
Drug induced liver impairment

Bioequivalence margin
ECG
Electrocardiogram


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EDTA
Ethylendiaminetetraacetic acid
EDC
Electronic data capture 
EOT
End of trial
F
Absolute bioavailability factor
FAS
Full Analysis Set
eCRF
Electronic case report form
GCP
Good clinical practice
GI
Gastro-intestinal
gMean
Geometric mean
h
hours
HBsAg
Hepatitis B surface antigen
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
HPLC
High performance liquid chromatography
HPC
Human Pharmacology Centre
HR
Heart rate
IB
Investigator's Brochure
ICH
International committee on harmonisation
IEC
Independent ethics committee
IRB
Institutional review board
ISF
Investigator site file
kg
Kilograms
HPLC-MS/MS
High performance liquid chromatography, tandem mass spectrometry
Ln
Natural logarithm
LOQ
Limit of quantification
MedDRA
Medical dictionary for drug regulatory affairs
mg
Milligrams
ml
Milliliters
NOA
Not analysed
NOAEL
No observed adverse effect level
NOTEL
No toxic effect level
NOP
No peak detectable
NOR
No valid result
NOS
No sample available
NSAID
Non-steroid anti-inflammatory drug
PK
Pharmacokinetics
PD
Pharmacodynamic(s)
PR
Pulse rate
p.o.
Oral
PR
Pulse rate
R
RA
Reference treatment
Rheumatoid arthritis
SAE
Serious adverse event
SmPC
Summary of Product Characteristics
SCR
Screening


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SOP
Standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
T
Test treatment
q.d.
Quaque die, once daily
QT
Time between start of the Q-wave and the end of the T-wave in an 
electrocardiogram


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
The active ingredient of Movalis® formulations is meloxicam. Meloxicam is a non-steroidal 
anti-inflammatory drug (NSAID) of the enolic acid class, which has shown anti-
inflammatory, analgesic and antipyretic properties, ATC: M01AC06. 
In clinical trials meloxicam was shown to be safe and effective in the treatment of symptoms 
of osteoarthritis, rheumatoid arthritis and ankylosing spondylitis.  
Meloxicam was first registered as tablets (7.5 mg, 15 mg), capsules (7.5 mg, 15 mg) and 
suppositories (15 mg) with the trademark Mobicin France on 8 May 1995. This date was 
defined as the international birthdate of meloxicam. Since then, registrations have been 
obtained worldwide for the dosage forms and strengths mentioned above and further 
formulations (oral suspension 7.5 mg/5ml, solution for injection 15 mg/1.5ml, capsule 7.5 
mg, table 10 mg, suppository 7.5 mg). These registrations were granted not only as Mobic, 
but also with further trademarks, e.g. Movalis, Hexaphlogin, Mobicox, and Movatec. 
Meloxicam is currently authorised and marketed in more than 100 European and non-
European countries. 
1.2
DRUG PROFILE
The drug profile of meloxicam is presented briefly in this section. For details refer to 
Meloxicam Investigator’s Brochure, section “Guidance for the investigator” [c22930410].
1.2.1
Composition of Movalisoral formulations
Composition of Test formulation: Movaliscapsules 15 mg, Boehringer Ingelheim Ellas A.E, 
Greece.
INN
Meloxicam
Brand name
Movalis
Chemical name
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-
carboxamide-1,1-dioxide
Formulation
Capsule
Active substance
meloxicam15 mg
Excipients
Capsule content: sodium citrate, lactose monohydrate, maize starch, 
magnesium stearate.
Capsule shell: gelatin, indigo carmine, yellow iron oxide, titanium dioxide 
Pharmaco-therapeutic group
Non-steroidal anti-inflammatory drug
ATC
M01AC06


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Composition of Reference formulation: Movalistablets 15 mg, Boehringer Ingelheim Ellas 
A.E., Greece and Boehringer Ingelheim Pharma GmbH & Co. KG, Germany.
INN
Meloxicam
Brand name
Movalis
Chemical name
4-hydroxy-2-methyl-N-(5-methyl-2-thiazolyl)-2H-1,2-benzothiazine-3-
carboxamide-1,1-dioxide
Formulation
Tablet
Active substance
meloxicam15 mg
Excipients
sodium citrate, lactose monohydrate, microcrystalline cellulose, povidone 
K25, colloidal anhydrous silica, crospovidone, magnesium stearate
Pharmaco-therapeutic group
Non-steroidal anti-inflammatory drug
ATC
M01AC06
The choice of the drug Movalis(Boehringer Ingelheim Ellas A.E., Greece and Boehringer 
Ingelheim Pharma GmbH & Co. KG, Germany.) tablets 15 mg as a comparator is due to the 
following reasons:

Movalisis an original medicinal product, the quality, safety and efficacy of which were 
established during registration in the territory of the Russian Federation, which 
corresponds to the requirements of the Guidelines "Evaluation of bioequivalence of 
medicines" (2008) and Decision of the Eurasian Economic Commission No. 85 of 
03.11.2016 "On Approval of the Rules for Conducting studies of bioequivalence of drugs 
in the framework of the Eurasian Economic Union"[Decision of the Eurasian Economic 
Commission No. 85].

Compared drugs are produced in comparable dosage forms-tablets and capsules [Decision 
of the Eurasian Economic Commission No. 85].

Compared preparations contain the active substance in an equal amount, which is the 
largest dosage of the study drug and the reference preparation: 15 mg.

The excipients included in the composition of the drugs are well known and should not 
influence the pharmacokinetics of the drugs being compared.
The choice of the reference drug batch will be made taking into account the results of 
quantitative determination of the active substance content and data on its dissolution
[Decision of the Eurasian Economic Commission No. 85].
1.2.2
Pharmacodynamics
Meloxicam is a non-steroidal anti-inflammatory drug, a derivative of enolic acid, and has 
anti-inflammatory, analgesic and antipyretic effects. The pronounced anti-inflammatory 
effect of meloxicam is established on all standard models of inflammation. The mechanism of 
action of meloxicam is its ability to inhibit the synthesis of prostaglandins - known 
inflammatory mediators.


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Meloxicam in vivo inhibits the synthesis of prostaglandins at the site of inflammation to a 
greater extent than in the mucous membrane of the stomach or kidneys. These differences are 
associated with a more selective inhibition of cyclooxygenase-2 (COX-2) compared to 
cyclooxygenase-1 (COX-1). In clinical trials, the frequency of perforations in the upper 
gastrointestinal tract, ulcers and bleeding that were associated with the use of meloxicam was 
low and depended on the magnitude of the dose of the drug.
1.2.3
Pharmacokinetics
Absorption
Meloxicam is well absorbed from the gastrointestinal tract, which is reflected by a high 
absolute bioavailability of about 90% following oral administration. After a single application 
of meloxicam maximum concentration of drug in plasma is achieved within 5-6 hours.
Simultaneous intake of food and inorganic antacids does not alter absorption. When given 
orally (in doses of 7.5 and 15 mg), meloxicam concentrations are proportional to the doses.
Steady state of pharmacokinetics is achieved within 3-5 days The range of differences 
between the maximum and basal concentrations of the drug after its administration once a 
day is relatively small and when using a dose of 7.5 mg 0.4-1.0 μg / ml, and when using a 
dose of 15 mg - 0.8-2.0 μg / ml (given respectively, the values of Cmin and Cmax during the 
steady state of pharmacokinetics), although values outside this range were also noted. The 
maximum concentration of meloxicam in plasma during the steady state of pharmacokinetics 
is reached 5-6 hours after ingestion.
Distribution
Meloxicam is strongly bound to plasma proteins, mainly with albumin (99%).  It penetrates 
into the synovial fluid, the concentration in the synovial fluid is approximately 50% of the 
concentration in the plasma. The volume of distribution after multiple oral doses of 
meloxicam (in doses from 7.5 mg to 15 mg) is about 16 liters, with a coefficient of variation 
of 11 to 32%. 
Biotransformation
Meloxicam is almost completely metabolized in the liver with the formation of 4 
pharmacologically inactive derivatives.  The main metabolite, 5'-carboxymeloxicam (60% of 
the dose value), is formed by oxidation of the intermediate metabolite, 5'-
hydroxymethylmeloxicam, which is also excreted, but to a lesser degree (9% of the dose 
value).  In vitro studies have shown that CYP2C9 plays an important role in this metabolic 
transformation, the CYP3A4 isoenzyme plays an additional role.  In the formation of the 
other two metabolites (which constitute, respectively, 16% and 4% of the dose value), 
peroxidase takes part, the activity of which, probably, varies individually. 
Elimination
Meloxicam is excreted through the intestines and kidneys, mainly in the form of metabolites.  
In unchanged form with feces less than 5% of the daily dose is excreted, in the urine in 


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unchanged form the drug is found only in trace amounts.  The average half-life of meloxicam 
varies from 13 to 25 hours. 
Plasma clearance is an average of 7 - 12 ml/min after a single dose of meloxicam. 
Patients with hepatic/renal insufficiency
Lack of liver function, as well as mild renal failure, does not significantly affect the 
pharmacokinetics of meloxicam. The rate of excretion of meloxicam from the body is much 
higher in patients with moderate renal insufficiency. Meloxicam binds less strongly to plasma 
proteins in patients with terminal renal insufficiency. With terminal renal failure, an increase 
in volume distribution can lead to higher concentrations of free meloxicam, so in these 
patients the daily dose should not exceed 7.5 mg. 
Elderly
Older patients have similar pharmacokinetic parameters in comparison with young patients.  
In elderly patients, the average plasma clearance during the equilibrium state of 
pharmacokinetics is slightly lower than in young patients.  Older women have higher AUC
values (area under the concentration-time curve) and a longer half-life, compared to young 
patients of both sexes.
1.2.4
Indications
The information is based on the current version of the instructions for the use of the reference 
drug in Russian Federation.

Osteoarthritis (arthrosis, degenerative diseases of joint), including those with pain 
component; 

Rheumatoid arthritis; 

Ankylosing spondylitis; 

Other inflammatory and degenerative musculoskeletal
system
diseases, such as 
arthropathy, dorsopathy (e.g., sciatica, lower back pain, shoulder-related tendinitis and 
other) accompanied by pain.
1.2.5
Contraindications
The information is based on the current version of the instructions for the use of the reference 
drug in Russian Federation.

Hypersensitivity to the active ingredient or excipients of the product;

Complete or incomplete combination of bronchial asthma, recurrent polyposis of the nose 
and paranasal sinuses, angioedema or urticaria caused by intolerance to acetylsalicylic 
acid or other nonsteroidal anti-inflammatory drugs due to the existing probability of cross 
sensitivity (including history of these conditions);


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
Erosive-ulcerative lesions of the stomach and duodenum at the stage of exacerbation or 
recent lesions;

Inflammatory diseases of the intestine – Crohn's disease or ulcerative colitis at the stage 
of exacerbation;

Severe hepatic insufficiency;

Severe renal insufficiency (if hemodialysis is not conducted, creatinine clearance is less 
than

30 mL/min, and also in confirmed hyperkalemia), a progressive kidney disease;

Active gastrointestinal bleeding, recent cerebrovascular diseases or the established 
diagnosis of systemic hemorrhagic diseases;

Pronounced uncontrolled heart failure;

Pregnancy;

Breast feeding;

Therapy of perioperative pains during coronary artery bypass grafting (CABG);

Children aged less than 12 years;

Rare hereditary intolerance of galactose (the maximum daily dose of the product with the 
meloxicam dosage of 7.5 mg and 15 mg contains 47 mg and 20 mg of lactose, 
respectively).
1.2.6
Special warning and precautions
The information is based on the current version of the instructions for the use of the reference 
drug in Russian Federation. Due to increased risk of adverse reactions caution should be 
exercised when treating patients with following conditions:

a history of gastrointestinal diseases (peptic ulcer of the stomach and duodenum, diseases 
of the liver);

congestive heart failure;

renal insufficiency (creatinine clearance 30-60 mL/min);

coronary artery disease;

cerebrovascular diseases;

dyslipidemia/hyperlipidemia;

diabetes mellitus;

concomitant therapy with the following agents: oral glucocorticosteroids, anticoagulants 
(including warfarin), antiaggregants, selective inhibitors of serotonin reuptake (including 
citalopram, fluoxetine, paroxetine, sertraline);

diseases of the peripheral arteries;

elderly age;

a prolonged use of NSAIDs;

smoking;

frequent consumption of alcohol.


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1.2.7
Dosage and administration
The information is based on the current version of the instructions for the use of the reference 
drug in Russian Federation.
Osteoarthritis with pain syndrome: 7.5 mg a day. When necessary, the dose may be increased 
to 15 mg a day.
Rheumatoid arthritis: 15 mg a day. Depending on the therapeutic effect, the dose may be 
reduced to 7.5 mg a day.
Ankylosing spondylitis: 15 mg a day. Depending on the therapeutic effect, the dose may be 
reduced to 7.5 mg a day.
In patients with the increased risk of side reactions (history of diseases of the gastrointestinal 
tract, risk factors of cardiovascular diseases) it is recommended to begin treatment with the 
dose of 7.5 mg a day. (see Special warnings and precautions).
In patients with pronounced renal insufficiency receiving hemodialysis the dose should not 
exceed 7.5 mg a day.
General recommendations
As the potential risk of side reactions depends on the dose and duration of treatment, the 
maximum possible low doses and duration of treatment should be used.
The maximum recommended daily dose is 15 mg.
Combined use
The product should not be used concomitantly with other NSAIDs.
The total daily dose of MOVALIS used as different pharmaceutical forms should not exceed 
15 mg.
Adolescents
The maximum dose in adolescents (12-18 years) is 0.25 mg/kg and should not exceed 15 mg.
Use of tablets
The product is contraindicated for children less than 12 years due to impossibility of 
adjustment of appropriate dosage for this age group.
The total daily dose should be taken as a single dose with food and water or other liquid. 


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1.2.8
Interactions
The information is based on the current version of the instructions for the use of the reference 
drug in Russian Federation.

Other inhibitors of prostaglandin synthesis including glucocorticoids and salicylates – the 
concomitant administration with meloxicam increases the risk of formation of ulcers in 
the gastrointestinal tract and gastrointestinal bleedings (due to synergism of action). The 
concomitant administration with other NSAIDs is not recommended.

Anticoagulants for oral administration, heparin for systemic use, thrombolytic agents –
the concomitant administration with meloxicam increases the risk of bleeding. Thorough 
control of the coagulation system is necessary in case of the concomitant administration.

Antithrombocytic agents, inhibitors of serotonin reuptake – the concomitant 
administration with meloxicam increases the risk of bleeding due to inhibition of 
thrombocyte function. Thorough control of the coagulation system is necessary in case of 
the concomitant administration.

Preparations of lithium – NSAIDs increase the plasma level of lithium by decreasing its 
renal excretion. The concomitant use of meloxicam with lithium preparations is not 
recommended. If the concomitant administration is necessary, it is recommended to 
perform thorough control of the plasma concentration of lithium throughout the course of 
use of lithium preparations.

Methotrexate – NSAIDs decrease renal secretion of methotrexate, thereby increasing its 
concentration plasma. The concomitant use of meloxicam and methotrexate (in the 
dosage of more than 15 mg a week) is not recommended. During the concomitant use 
thorough control of renal function and blood count is recommended. Meloxicam may 
enhance hematological toxicity of methotrexate, particularly in patients with renal 
impairment. The concomitant use of meloxicam and methotrexate for 3 days increases the 
risk of increasing toxicity of the latter.

Contraception – the data are available that NSAIDs may decrease effectiveness of 
contraceptive devices, however, this has not been proved.

Diuretics – the use of NSAIDs at dehydration of patients is associated with the risk of 
developing acute renal insufficiency.

Antihypertensive agents (beta-adrenoblockers, inhibitors of angiotensin converting 
enzyme, vasodilating agents, diuretics). NSAIDs reduce the effect of antihypertensive 
agents by inhibition of prostaglandins which possess vasodilating properties.

Angiotensin-II receptor antagonists, as well as inhibitors of angiotensin converting 
enzyme, at the concomitant use with NSAIDs enhance a decrease of glomerular filtration 
and that may result in development of acute renal insufficiency, particularly in patients 
with renal impairment.

Cholestyramine, by binding meloxicam in the gastrointestinal tract, causes its more rapid 
elimination.

NSAIDs may enhance nephrotoxicity of cyclosporin due to the effect on renal 
prostaglandins.

Pemetrexed – at concomitant use of meloxicam and pemetrexed in patients with 
creatinine clearance from 45 to 79 mL/min the use of meloxicam should be stopped at 5 
days before a patient begins to take pemetrexed and may be resumed 2 days after 


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discontinuation of pemetrexed. If concomitant use of meloxicam and pemetrexed is 
needed, such patients should be under strict control, particularly with respect to 
myelosuppression and occurrence of side effects of the gastrointestinal tract. The
concomitant use of meloxicam and pemetrexed is not recommended in patients with 
creatinine clearance less than 45 mL/min.
At the concomitant use of meloxicam with the medications possessing the known capacity to 
inhibit CYP 2C9 and/or CYP 3А4 (or are metabolized with participation of these enzymes), 
such as sulfonylureas or probenecid, the possibility of pharmacokinetic interaction should be 
considered. 
At concomitant use with oral antidiabetic agents (e.g. sulphonylureas, nateglinide), CYP 
2C9-mediated interactions are possible which may result in an increase of the blood 
concentration of both these agents and meloxicam. Patients who take meloxicam 
concomitantly with sulphonylureas or nateglinide should carefully control sugar level in 
blood due to the possibility of hypoglycemia developing.
No significant pharmacokinetic interactions were revealed during concomitant administration 
of antacids, cimetidine, digoxin and furosemide.
1.2.9
Pregnancy and lactation
The use of MOVALIS is contraindicated during pregnancy.
NSAIDs are known to pass into mother's milk, therefore the use of MOVALIS is 
contraindicated during breast feeding.
As an inhibitor of cyclooxygenase/prostaglandin synthesis, MOVALIS may influence 
fertility, and therefore it is not recommended for women who are planning pregnancy. 
Meloxicam may cause delay of ovulation. In view of this it is recommended to withdraw 
MOVALIS in women who have problems with conception and are undergoing examination 
for such problems.
1.2.10
Effects on ability to drive and use machines
The information is based on the current version of the instructions for the use of the reference 
drug in Russian Federation.
Special clinical trials of the effect of the product on the ability to drive cars and operate 
machines have not been conducted. However, when driving a car and operating machines the 
possibility of developing dizziness, drowsiness, visual disorder or other disorders of the 
central nervous system should be taken into consideration. Patients should be cautious while 
driving a car and operating machines.


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1.2.11
Non-clinical studies
An extensive toxicological program confirmed that meloxicam has an acceptable safety 
profile.
Oral LD50 values ranged from about 98 mg/kg in female rats up to >800 mg/kg in mini-pigs. 
Intravenous values ranged from about 52 mg/kg in rats to 100 - 200 mg/kg in mini-pigs. Main 
signs of toxicity included reduced motor activity, anaemia, and cyanosis. Most deaths 
occurred as a consequence of gastric ulcers and subsequent perforation leading to peritonitis.
Repeated dose toxicity studies in rats and mini-pigs showed characteristic changes reported 
with other NSAIDs e.g. gastro-intestinal ulceration and erosions, and in the long term studies, 
renal papillary necrosis. Gastro-intestinal side effects were observed at oral doses of 1mg/kg 
and higher in rats, and of 3 mg/kg and above in mini-pigs. After intravenous administration 
doses of 0.4 mg/kg in rats and 9 mg/kg in mini-pigs caused gastro-intestinal lesions. Renal 
papillary necrosis occurred only in rats at doses of 0.6 mg/kg or higher doses after lifetime 
exposure to meloxicam.
Studies of toxicity on reproduction in rats and rabbits did not reveal teratogenicity up to oral 
doses of 4 mg/kg in rats and 80 mg/kg in rabbits. Oral reproductive studies in the rat have 
shown a decrease of ovulations and inhibition of implantations and embryotoxic effects 
(increase of resorptions) at maternotoxic dose levels at 1 mg/kg and higher.
The affected dose levels exceeded the clinical dose (7.5-15 mg) by a factor of 10 to 5-fold on 
an mg/kg dose basis (75 kg person). Fetotoxic effects at the end of gestation, shared by all 
prostaglandin synthesis inhibitors, have been described.
Meloxicam was not mutagenic in the Ames test, the host-mediated assay, and a mammalian 
gene mutation assay (V79/HPRT), nor is it clastogenic in the chromosomal aberration assay 
in human lymphocytes and the mouse bone marrow micronucleus test.
Carcinogenicity studies in rats and mice did not show a carcinogenic potential up to dose 
levels of 0.8 mg/kg in rats and 8 mg/kg in mice. In these studies meloxicam was chondro-
neutral, i.e. it did not damage the articular cartilage following long-term exposure.
Meloxicam did not induce immunogenic reactions in tests on mice and guinea pigs. In several 
tests it was shown that meloxicam was less phototoxic than older NSAIDs but similar in this 
respect to both piroxicam and tenoxicam.
In local tolerance studies meloxicam was well tolerated by all tested routes of administration; 
intravenous, intramuscular, rectal, dermal, and ocular administration.
For further details see ‘Investigator’s Brochure’[c22930410].
1.2.12
Clinical studies
Osteoarthritis 
The primary evidence for efficacy of meloxicam for the treatment of the signs and symptoms 
of osteoarthritis of the knee and hip was evaluated in two randomised placebo-controlled 


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trials (EU trial 107.42, U.S. trial 107.181) [U92-0541; U98-3221] and four randomised 
active-controlled trials conducted in E.U. (E.U trials 107.43, 107.44, 107.45, 107.63) [U93-
2036; U93-2016; U93-2037; U93-2015].
The data both from 3-week, double-blind, placebo-controlled study and 3-months, double-
blind, placebo-controlled study showed that meloxicam in doses of 7.5 mg and 15 mg was 
consistently superior to placebo, and the lowest effective dose was 7.5 mg once daily.
Data available from the four double-blind, active-controlled trials ranging from 6 weeks’ to 6 
months’ duration demonstrated that the efficacy of meloxicam, in doses of 7.5 mg/day, 15 
mg/day and 30 mg/day, was comparable to traditional NSAIDs piroxicam 20 mg/day and 
diclofenac SR 100 mg/day. The dose 30 mg/day was discontinued during the trials. The data 
suggested a dose response when comparing all trials.
Rheumatoid Arthritis
The primary evidence for use of meloxicam for the treatment of the signs and symptoms of 
rheumatoid arthritis was evaluated in two randomised placebo-controlled trials (Trial 107.35 
and 107.183) [U93-2066; U99-3147] and three randomised active-controlled trials (Trial 
107.14, 107.36, 107.61) [U93-2021; U92-0311; U93-2054]. 
In a 3-week, double-blind E.U. trial 107.35 meloxicam (7.5 mg and 15 mg daily) was 
compared to placebo. In a 12-week, double-blind, controlled U.S. trial107.183 meloxicam 
(7.5 mg, 15 mg, and 22.5 mg daily) was compared to placebo and diclofenac 2x75 mg daily. 
The primary endpoint in the studies was the ACR20 response rate, a composite measure of 
clinical, laboratory, and functional measures of rheumatoid arthritis (RA)-response. Patients 
receiving meloxicam 7.5 mg and 15 mg daily showed significant improvement in the primary 
endpoint compared with placebo. The lowest effective dose of meloxicam was 7.5 mg. No 
incremental benefit was observed with the 22.5 mg dose compared to the 15 mg 
dose.Meloxicam 7.5 mg, 15 mg and 22.5 mg were comparable to the active control drugs. 
Since efficacy of 7.5 mg may be low for the initial treatment of acute flares of RA, 15 mg is 
considered a more appropriate starting dose. The data suggest evidence for a dose response.
Data from the active-controlled trials (Trial 107.14, 107.36, 107.61) ranging from 3 weeks’ to 
6 months’ duration showed that meloxicam 15 mg/day was as effective as piroxicam 
20mg/day or naproxen 750 mg/day. 
Ankylosing spondylitis
The primary evidence for use of meloxicam for the treatment of ankylosing spondylitis was 
established in one randomised controlled trial (Trial 107.98) [U98-0090; U97-0033]. In this 
6-week, double-blind, controlled study meloxicam (15 mg and 22.5 mg daily) was superior to 
placebo in treating the signs and symptoms of ankylosing spondylitis. The lowest dose 
investigated is meloxicam 15 mg once daily. Both doses, meloxicam 15 mg and 22.5 mg, 
were comparable with regard to efficacy with no further increase in efficacy for the dose 
above 15 mg. Meloxicam 15 mg and 22.5 mg once daily were both comparable to piroxicam 
20 mg daily. Effective symptom relief was maintained during long-term therapy (extension 
phase of the trial till one year).
In all clinical trials, gastro-intestinal adverse events overall were reported less frequently with 
meloxicam 7.5 mg and 15 mg than with the NSAIDs with which it has been compared, due 


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predominantly to a lower reporting incidence of events such as dyspepsia, vomiting, nausea 
and abdominal pain. The incidence of upper gastro-intestinal perforation, ulcers, and bleeds 
reported in association with meloxicam is low and dose dependent.
For further details see ‘Investigator’s Brochure’ [c22930410].
1.2.13
Side effects
Below there are described side effects the relation of which with the use of MOVALIS was 
regarded as possible.
The side effects registered in the period of post-marketing use, the relation of which with the 
product use was evaluated as possible are asterisked (*).
Inside the system organ classes by the frequency of occurrence of side effects the following 
categories are used: very common (≥ 1/10); common (≥ 1/100, < 1/10); uncommon (≥ /1,000, 
< 1/100); rare (≥ 1/10,000, < 1/1,000); very rare (< 1/10,000); not established.
Blood and lymphatic system
Uncommon – anemia;
Rare – changes of blood count including changes of the differential white cell count, 
leukopenia, thrombocytopenia.
Immune system
Uncommon – other immediate hypersensitivity reactions*;
Not established – anaphylactic shock*, anaphylactoid reaction*.
Nervous system
Common – headache;
Uncommon – dizziness, drowsiness.
Psychiatric disorders
Common – altered mood*;
Not established – mental confusion*, disorientation*.
Sense organs
Uncommon – vertigo;
Rare – conjunctivitis*, disorders of vision including blurred vision*, tinnitus.
Gastrointestinal tract
Common – abdominal pain, dyspepsia, diarrhea, nausea, vomiting;
Uncommon – latent or overt gastrointestinal bleeding, gastritis*, stomatitis, constipation, 
abdominal distension, belching;
Rare – gastroduodenal ulcers, colitis, esophagitis;


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Very rare – perforation of the gastrointestinal tract.
Liver
Uncommon – transient changes of liver function parameters (e.g., increased activity of 
transaminases or bilirubin);
Very rare – hepatitis*.
Skin and subcutaneous tissues
Uncommon – angioedema*, itching, skin rash;
Rare – toxic epidermal necrolysis*, Stevens-Johnson syndrome*, urticaria;
Very rare – bullous dermatitis*, multiform erythema*;
Not established – photosensitization.
Respiratory system
Rare – bronchial asthma in patients with allergy to acetylsalicylic acid or other NSAIDs.
Cardiovascular system
Uncommon – increased blood pressure, feeling of facial flushing;
Rare – palpitation.
Urinary system
Uncommon – changes of kidney function parameters (increased level of creatinine and/or 
urea in serum), disorders of urination including acute urine retention*;
Very rare – acute renal insufficiency*.
Reproductive system and breast
Uncommon – ovulation delayed*;
Not established – infertility female*.
The concomitant use with medications suppressing the bone marrow (e.g., methotrexate) may 
induce cytopenia.
Gastrointestinal bleeding, ulcer or perforation may lead to fatal outcome.
As with other NSAIDs, the possibility of occurrence of interstitial nephritis, 
glomerulonephritis, renal medullary necrosis, nephrotic syndrome is not excluded. 
1.2.14
Special instructions
Patients with diseases of the gastrointestinal tract should be under regular observation. 
MOVALIS should be discontinued at the occurrence of an ulcerative lesion of the 
gastrointestinal tract or gastrointestinal bleeding.
Ulcers of the gastrointestinal tract, perforation or bleedings may occur during the use of 
NSAIDs at any time both in the presence of alerting symptoms or information about a history 


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of serious gastrointestinal complications and in the absence of these signs. The consequences 
of these complications on the whole are more serious in elderly persons.
The use of MOVALIS may be associated with the development of such serious reactions of 
the skin as exfoliative dermatitis, Stevens-Johnson syndrome, toxic epidermal necrolysis. 
Therefore particular emphasis should be given to the patients who report the development 
adverse events with respect to the skin and mucosae as well as reactions of hypersensitivity to 
the product, especially if such reactions were observed during the previous courses of 
treatment. The development of such reactions is as a rule observed within the first month of 
treatment. When the first signs of skin rash, changes of mucosae or other signs of 
hypersensitivity appear, the discontinuation of MOVALIS should be considered.
Cases of an increase of the risk of developing serious cardiovascular thromboses, myocardial 
infarction, an attack of angina pectoris, possibly with fatal outcome are described during the 
use of NSAIDs. Such risk increases during a long-term use of the product, and also in 
patients with a history of the above diseases and predisposed to such diseases.
NSAIDs inhibit in the kidneys synthesis of prostaglandins which participate in maintenance 
of renal perfusion. The use of NSAIDs in patients with decreased renal blood flow or reduced 
volume of the circulating blood may lead to decompensation of latent renal insufficiency. 
After discontinuation of NSAID the renal function usually recovers to the initial level. At the 
greatest risk of developing such reaction there may be elderly patients, patients with 
dehydration, congestive heart failure, liver cirrhosis, nephrotic syndrome or acute renal 
impairment, who concomitantly take diuretics, ACE inhibitors, angiotensin-II receptor 
antagonists, and also patients who previously had serious surgical interventions leading to
hypovolemia. Thorough monitoring of diuresis and renal function should be performed in 
such patients at the beginning of therapy.
The use of NSAIDs concomitantly with diuretics may result in retention of sodium, 
potassium and water, and also in a reduction of the natriuretic action of diuretic agents. As a 
result, the predisposed patients may have an enhancement of symptoms of heart failure or 
hypertension. Therefore thorough control of the condition of such patients should be 
performed, and also adequate hydration should be maintained. The study of renal function 
before the beginning of treatment is necessary. In case of conduction of combined therapy 
renal function should be also monitored.
An episodic increase of the activity of transaminases in serum or other parameters of renal 
function may occur during the use of MOVALIS (as well as other NSAIDs). In most cases 
this increase was slight and transient. If the revealed changes are significant or do not 
decrease with time, MOVALIS should be discontinued, and the revealed laboratory changes 
should be monitored.
The weakened or emaciated patients may tolerate worse the adverse events, and for this 
reason such patients should be under thorough observation.
As with other NSAIDs, MOVALIS may mask symptoms of the basic infectious disease.
As an agent inhibiting cyclooxygenase/prostaglandin synthesis, MOVALIS may influence 
fertility, and therefore it is not recommended to women with difficulties in conception. In this 
connection, the women undergoing examination for this reason are recommended to 
discontinue MOVALIS.


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In patients with weak or moderate renal insufficiency (creatinine clearance more than 25 
mL/min) no dose adjustment is required.
In patients with liver cirrhosis (compensated) no dose adjustment is required. 


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
The following formulations of Movaliswere previously approved for clinical use in Russian 
Federation: tablet, suppository, oral suspension, solution for injections. To allow the 
registration of Movalis capsules, and interchangeability of the safety and efficacy data 
between Movalistablets 15 mg and capsules 15 mg, a local bioequivalence study to assess 
bioavailability/bioequivalence is deemed to be necessary. If this local trial is successful, 
marketing authorisation for Movaliscapsules 15 mg will be sought.
Data obtained from phase I trials in healthy male subjects (Trial 107.074 [U93-0094] 107.082
[U93-2038]) 
conducted 
in 
Germany 
and 
local 
regulatory 
requirements 
to 
bioavailability/bioequivalence studies indicate that it is rational to conduct an open-label, 
single-dose, 2x2 crossover study  in general population (healthy male and female volunteers). 
Although previous bioavailability/bioequivalence studies on meloxicam were conducted 
under fed state, it is planned to assess the bioavailability/bioequivalence of Movaliscapsules 
15 mg compared to Movalistablets 15 mg under fasting state based on these grounds:

Local bioequivalence studies are conducted at fasting state according to regulatory 
requirements in Russian Federation [Decision of the Eurasian Economic Commission No. 
85, Methodical Guidelines for Conduction of Bioequivalence Studies].

Pharmacokinetics of meloxicam is not altered by food effect [U88-0771; U93-0260; U98-
2348].

The safety profile of meloxicam is well-known.

FDA guidance on meloxicam: recommends for conducting bioequivalence studies either 
under fed state or under fasting state [P12-09147].
The dose (Movaliscapsules 15 mg) selected for the trial is the maximum dose and the same
as applied for marketing authorisation in Russian Federation. In accordance the Decision of 
the Eurasian Economic Commission No. 85 of 03.11.2016 "On Approval of the Rules for 
Conducting studies of bioequivalence of drugs in the framework of the Eurasian Economic 
Union"[Decision of the Eurasian Economic Commission No. 85], blood sampling for 
pharmacokinetics is achieved during 72 hours of each treatment period, separated by wash-
out phase of 7 days (about eight half-lives).


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2.2
TRIAL OBJECTIVES
2.2.1
Primary objective
The primary objective of the study is to investigate the relative bioavailability of Movalis
capsules 15 mg (Test, T) versus Movalistablets 15 mg (Reference, R).
2.2.2
Primary endpoints
Relative bioavailability is primarily to be investigated on the basis of the following 
pharmacokinetic parameters:

AUC0-t (area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 to t, the last blood sampling).
Time frame for the primary endpoint: Baseline (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 
24, 32, 48, 72 hours post-dose.

Cmax (maximum measured concentration of the analyte in plasma)Time frame for the 
primary endpoint: Baseline (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 12, 24, 32, 48, 72 
hours post-dose.
2.2.3
Secondary objectives
The secondary objectives of the study are:

To establish bioequivalence of Movaliscapsules 15 mg (Test, T) versus Movalis
tablets 15 mg (Reference, R).

The assessment of safety and tolerability will be an additional objective of this trial.
2.2.4
Secondary endpoints
The following secondary endpoints will be evaluated.
Pharmacokinetic parameters:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 extrapolated to infinity).
Time frame for the secondary endpoint: Baseline (pre-dose), 0.5, 1, 2, 3, 4, 5, 6, 7, 8, 10, 
12, 24, 32, 48, 72 hours post-dose.


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2.2.6
Other endpoints
Safety parameters:

Vital signs (BP, PR, body temperature, respiratory rate)

Global assessment

Physical examination

Clinical laboratory tests (haematology, clinical chemistry and urinalysis)

12-lead ECG

Adverse events
These parameters will be evaluated in a descriptive way only, and are therefore considered to
be ‘other endpoints’. A confirmatory analysis is not planned (see Section 7.3).
2.3
BENEFIT - RISK ASSESSMENT
Due to the fact that the study is conducted with the participation of healthy volunteers, there 
is no benefit of drug administration to the state of their health. Volunteers who took part in 
the study will be provided with monetary compensation for the inconvenience.  
However, volunteers as a result of the survey will receive reliable information about their 
health status (as part of the surveys), as well as information on the individual tolerability of 
the drugs compared, which may be useful to them in the future
The safety profile of meloxicam is well established from clinical trials and post-marketing 
surveillance. Eventual adverse events and related cautions and warnings are well known.
Procedure-related risks
The use of an indwelling venous catheter for the purpose of blood sampling may be 
accompanied by mild bruising and also, in rare cases, by transient inflammation of the wall of 
the vein. In addition, in rare cases a nerve might be injured while inserting the venous 
catheter, potentially resulting in paresthesia, reduced sensibility, and/or pain for an indefinite 
period. The same risks apply to veinipuncture for blood sampling.
The total volume of blood, including blood tests for detecting laboratory abnormalities 
(general blood analysis, biochemical blood analysis and blood tests for infections (HIV, 


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hepatitis B, hepatitis C, syphilis)) withdrawn during the entire study per subject will be not 
more than 253 ml. It does not exceed the volume of a normal blood donation (450 mL). No 
health-related risk to healthy subjects is expected from this blood withdrawal.
Procedure
Quantity
Volume (ml)
Total volume (ml)
Blood chemistry
3
5,0
15,0
General blood analysis
3
5,0
15,0
Serological examination
1
5,0
5,0
PK of meloxicam
32
6,0
192,0
Blood sampling to prevent the heparinized 
solution from entering the sample
26
1,0
26,0
Total volume, ml
253,0
Drug-related risks and safety measures
A total of 50 926 patients were treated with meloxicam during the period Aug 1993 – Jun 
2010 with a total exposure of 7 932.1 patient-years [U02-0061; U10-2374-01; U09-0192-01; 
U07-0105; U04-0230; c22930410]. The cumulative estimated exposure of patients to 
marketed meloxicam during the 1995 – Jun 2010 is estimated at 22 828x103 patient years 
[U10-2374-01]. The review of post-marketing reports for meloxicam till 2011 did not 
indicate a previously unrecognised medical finding [U02-0061; U10-2374-01; U09-0192-01; 
U07-0105; U04-0230, U11-1340-01].
The safety data from multiple-dose phase I studies on meloxicam showed a good tolerability 
at oral doses up to 15 mg in healthy volunteers [U93-0094; U93-2038; U97-2327; U95-
2126]. 
In view of the extensive experience with oral meloxicam in clinical studies and its wide use 
in therapeutic practice, single oral treatment with meloxicam during each treatment period in 
the current trial can be accepted to have a highly favourable benefit: risk-profile with a broad 
safety margin.  The available literature data on the clinical use of meloxicam allow one to 
expect that two single doses of compared drugs do not pose a threat to the life and health of 
volunteers. For more information please refer to the IB and to the local label.
Possible side effects of meloxicam are described in the Instruction for use of the Movalis
tablets and the Investigator’s Brochure, and the investigator will be ready to take all 
necessary measures to stop them from volunteers. During the study, careful monitoring of 
volunteers should be made to avoid side effects. In the event that significant clinical 
symptoms appear in the study, suspicion of their occurrence, it is necessary to urgently 
conduct a clinical blood test and other necessary studies, as well as take the necessary 
measures to eliminate.
Although rare, a potential for drug-induced liver injury is under constant surveillance by 
sponsors and regulators. Therefore, this study requires timely detection, evaluation, and 
follow-up of alterations in selected liver laboratory parameters to ensure subjects´ safety.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as an open-label, randomised, single-dose, two-way crossover 
trial. The two treatment sequences will be randomly allocated to the subjects (Table 3.1: 1).
Table 3.1:1
Summary of treatment sequences
The treatments will be one Movaliscapsule 15 mg administered under fasting state for T (Test) 
and one Movalistablet 15 mg administered under fasting state for R (Reference). The overall 
trial scheme is presented in Figure 3.1: 1.
Movalis® capsule 15 mg (T)
Movalis® capsule 15 mg
(R)
Screening
max 14
days
Movalis® tablet 15 mg 
(R)
Period I
4 days 
Wash-out10
7 days
Movalis® tablet 15 mg
(T)
Period II
4 days
Follow-up
phase
7 days
Figure 3.1:1
Trial scheme
                                                          
10 The duration of the wash-out period is calculated from the time of administration of the study drug in the first study period 
to the time of administration of the study drug in the second study period. The interval between the discharge of the study 
subject from the hospital in the first period and the hospitalization of the study subject in the second study period is about 
3.5 days.
Treatment 
sequence
Number of 
subjects per 
period
Treatment phase
Period I
Period II
TR
13
one Movaliscapsule 15 mg (T)
one Movalistablet 15 mg (R)
RT
13
one Movalistablet 15 mg (R)
one Movaliscapsule 15 mg (T)
Total number of subjects
26


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Administrative structure of the trial
The trial will be conducted at State budgetary institution of public health in 
 
 under the 
supervision of the Principal Investigator.
On-site monitoring will be performed by a contract research organisation appointed by BI.
Safety laboratory tests will be performed by the local laboratory of the trial site.
The trial is sponsored by Boehringer Ingelheim LLC, Russia
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP
For bioavailability/bioequivalence study, the crossover design is viewed favourably due to its 
efficiency: since each subject serves as his/her own control, the comparison between 
formulations is based on a comparison within subjects rather than between subjects. This 
means that the inter-subject variability is removed from the comparison between 
formulations.
3.3
SELECTION OF TRIAL POPULATION
The sample size for this trial was determined assuming an intra-subject coefficient of 
variation (CV) of 18% for AUC and 23% for Cmax considering the data reported in the trial 
107.074 [U93-0094]. Although intra-subject CV was reported 12.9% for AUC and 17.9% for 
Cmax, the data were obtained exclusively from male subjects. Therefore, intra-subject CV 
assumed for this trial (including male and female subjects) was supposed at least 5% higher 
than reported previously. Using these CVs and the sample size of 24, the power to conclude 
bioequivalence is achieved at least 80% if the ratio (both for AUC and Cmax) is as much as 
5% different from the ratio that reflects perfect equivalence (i.e., 100%).  Accounting for up 
to 2 dropouts, 26 subjects will be included in the study.
It is planned that 26 healthy male and female volunteers will be enrolled in the study. 
Volunteers will be recruited from the volunteers' database of the trial site.
A log of all subjects enrolled into the study (i.e. having given informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.


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3.3.1
Main diagnosis for study entry
The study will be performed in healthy subjects.
3.3.2
Inclusion criteria
Subjects will only be included into the trial, if they meet the following criteria:
1. Male and female subjects aged 18-45, inclusive.
2. Body mass index by Quetelet between 18.50 -29.99 kg/m2, inclusive.
3. The verified diagnosis is "healthy" according to the conclusion investigator according to 
the information in the anamnesis, the results of the physical examination, the ECG, the 
results of measurement of vital signs of the body (blood pressure, heart rate, breathing 
rate and body temperature), and laboratory indicators.
4. Preconducting standard clinical and laboratory and instrumental studies did not reveal the 
presence of any diseases and abnormalities.
5. Systolic blood pressure not less than 100 mm Hg. and not higher than 139 mm Hg.
diastolic blood pressure not less than 70 mm Hg. and not more than 90 mm Hg. the heart 
rate is not less than 60 beats per minute and not more than 90 beats per minute, the 
frequency of respiratory movements is within the range of 12-20 per minute.
6. Ability to understand and accept the explanation of the study; the written informed 
consent of the volunteer to participate in the study in accordance with applicable law.
7. Female subjects of childbearing potential who agree on using double-barrier 
contraception from a screening visit to 30 days after the last administration of the study 
drug, inclusive. If a female is postmenopausal (no menses for at least 1 year) or surgically 
sterile (bilateral tubal ligation, bilateral oophorectomy, or hysterectomy) she will be 
exempt from the requirement. In case of using oral contraceptives, these should be 
withdrawn at least 2 months before the study. 
8. Male subjects who agree on using effective contraception (barrier contraceptive methods)
from a screening visit to 30 days after the last administration of the study drug, inclusive.
3.3.3
Exclusion criteria
Subjects will not be allowed to participate if any of the following general criteria apply:
1. Drug intolerance of any drug.
2. Allergic history.
3. Acute infectious diseases or allergic reactions requiring treatment (including drug 
allergy), less than 4 weeks before the screening.


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4. Surgical interventions on the gastrointestinal tract (with the exception of appendectomy), 
which can have a significant effect on the absorption or metabolism of study drugs.
5. Known hypersensitivity to meloxicam or any excipient of the test and reference products.
6. Known hypersensitivity to other NSAIDs: subjects who have developed signs of asthma, 
nasal polyps, angio-oedema or urticarial following the administration of acetylsalicylic 
acid or other NSAIDs.
7. Chronic diseases of the cardiovascular, bronchopulmonary, neuroendocrine system, as 
well as diseases of the gastrointestinal tract, liver, kidneys, blood, or other conditions that 
make it impossible for the volunteer to participate in the study according to the 
investigator opinion.
8. The results of standard laboratory and instrumental methods of examination, obtained 
during the screening, go beyond normal values.
9. History of gastro-intestinal ulceration/ perforation or bleeding; history of malignancy 
within 5 years before the screening.
10. Positive results of blood tests for infections (HIV, syphilis, hepatitis B or C) at screening.
11. A positive alcohol test at screening.
12. A positive urine drug test (cannabis, benzodiazepines, barbiturates, opiates, cocaine, and 
amphetamines) at screening. 
13. Pregnancy or breastfeeding. 
14. Any diet, for example, vegetarian, for 2 weeks before the first day of screening.
15. Alcohol intake more than 10 units. alcohol per week (1 unit of alcohol is equivalent to ½ 
liter of beer, 200 ml of wine or 50 ml of alcohol) or anamnestic information about 
alcoholism, drug addiction, abuse of medicines.
16. The inability to be without food for at least 12 hours and the inability to take the drug on 
an empty stomach.
17. Blood donation (≥ 450 ml) within 3 months before screening.
18. Depot injections, the installation of intrauterine hormonal therapy systems or implants of 
any drugs for 6 months before the screening;
19. For women: use of hormonal contraceptives less than 2 months before the screening.
20. Regular drug intake within 2 weeks before the screening.
21. Intake of systemic drugs known to alter liver function (barbiturates, omeprazole, 
cimetidine) within 4 weeks before the screening.
22. For women: volunteers with preserved reproductive potential who had unprotected 
intercourse with an unsterilized male partner for 30 days before the screening
23. Participation in another clinical trial within 3 months before the screening.
24. Difficult access to the vein, complicating or making it impossible to install a catheter and 
frequent blood sampling.


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25. Smoker (≥10 cigarettes or ≥ 3 pipes per day).
26. Inability to refrain from smoking on study days.
27. Volunteers who do not want or are unable to give up alcohol and excessive physical 
exertion from the first day of screening and before the visit of follow-up.
28. Volunteers who are unwilling or unable to refuse drinks and food containing 
methylxanthines (coffee, tea, cola, energy drinks, chocolate, etc.) and grapefruit / 
grapefruit juice, Seville oranges (sour or bitter oranges) and their juices, and dietary 
supplements and products including St. John's wort (Hypericum perforatum) from the 
first day of screening and until a follow-up visit.
29. Volunteers who lead a lifestyle (including night work and extreme physical activities such 
as sports or weight lifting), which can make it difficult to interpret the laboratory data 
obtained during the study.
30. Volunteers who do not intend to comply with the study regime.
31. Volunteers who are obviously or probably, in the opinion of the investigator, are not able 
to understand and evaluate the information on this study in the process of signing the ICF, 
in particular regarding the expected risks and possible discomfort.
32. The presence of volunteers dehydration due to diarrhea, vomiting or other cause within 
the last 24 hours before the first day of screening.
33. The presence of volunteers attacks of seizures, epilepsy and any other neurological 
disorders in the anamnesis
34. Recent cerebrovascular bleeding or established systemic bleeding disorders.
35. Known lactose intolerance.
36. Reports difficulty for swallowing tablets or capsules.
For study restrictions, refer to Section 4.2.2.
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
An individual subject is to be removed from the trial if:
1. The subject withdraws consent, without the need to justify the decision
2. The investigator decided that the volunteer should be excluded in the interests of the 
volunteer himself.
3. Non-compliance with the requirements of exclusion criteria, revealed during the study. 
Deviations of vital signs, as well as standard laboratory and instrumental indicators from 
the normal values, revealed after the Test or Reference drug intake, are considered as AE.
4. The emergence of AE / SAE, when the continuation of volunteer participation in the 
study is undesirable or impossible (according to the sponsor or investigator opinion).


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5. Vomiting or diarrhea within 12 hours after taking the drug.
6. The subject needs to take concomitant drugs that interfere with the investigational product 
or other trial medication or unauthorized concomitant treatment (protocol violation).
7. Failure to comply with the protocol requirements: the sampling schedule of biosamples (2 
times or more), the regime throughout the entire study, including during the washout
period, (alcohol consumption, prohibited products, etc.).
8. Non-compliance with the rules of the volunteer stay on a clinical basis.
9. Volunteer receives additional treatment (or needs additional treatment), which can affect 
the pharmacokinetics of the study drug.
10. The volunteer needs treatment in the hospital during the study.
11. Volunteers enter the hospital after the appointed time (delay more than 1 hour), which 
violates the protocol requirements.
12. Volunteer has a positive alcohol breath test.
13. Volunteer has a positive pregnancy test.
14. Volunteer has a positive urine drug test (cannabis, benzodiazepines, barbiturates, opiates, 
cocaine, and amphetamines)
15. Arising side effects of the drug are so serious that the continuation of the study is 
unacceptable.
16. The subject shows an elevation of AST and/or ALT ≥3-fold ULN combined with an 
elevation of total bilirubin ≥2-fold ULN (measured in the same blood sample) and/or 
needs to be followed up according to Section 10.1 of this clinical trial protocol and the 
‘DILI checklist’ provided in the ISF.
If a subject is removed from or withdraws from the trial prior to first administration of trial 
medication, the data of this subject will not be entered in the case report form (CRF) or trial 
database and will not be reported in the clinical trial report (CTR). The only exception to this 
rule is when the subject had an AESI and/or SAE that the investigator considers related to the 
screening procedure. If a subject is removed from or withdraws from the trial after first 
administration of trial medication, this will be documented and the reason for discontinuation
must be recorded in the CRF. In this case, the data will be included in the CRF/trial database 
and will be reported in the CTR. At the time of discontinuation a complete end of trial 
examination will be performed if possible and the information will be recorded in the CRFs. 
These discontinuations will be discussed in the CTR.
If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication has to be stopped immediately, and the subject has to be removed from the trial. 
The subject is to be followed until she has given birth or until the end of pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the clinical trial report. For reporting of pregnancy and all related events refer to 
Section 5.2.2.2.


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3.3.4.2
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial 
site at any time for any of the following reasons:
1. New toxicological findings or serious adverse events invalidate the earlier positive 
benefit-risk-assessment. More specifically, the trial will be terminated if more than 50% 
of the subjects show drug-related and clinically relevant adverse events of moderate or 
severe intensity, or if at least one drug-related serious adverse event is reported that is
considered to be unacceptable.
2. The expected enrolment goals overall or at a particular trial site are not met
3. Violation of GCP, or the CTP or the contract with BI by a trial site or investigator, 
disturbing the appropriate conduct of the trial
4. The sponsor decides to discontinue the further development of the investigational 
product.
3.3.5
Replacement of subjects
Subjects who are enrolled in the trial and do not fulfil the inclusion/exclusion criteria will be
replaced and will not receive a randomization number. 
In case more than 2 subjects do not complete the trial, the trial clinical monitor together with 
the trial pharmacokineticist and the trial statistician are to decide if and how many subjects 
will be replaced. A replacement subject will be assigned a unique study subject number and
will be assigned to the same treatment as the subject he or she replaces.


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4.
TREATMENTS
4.1
TREATMENTS TO BE ADMINISTERED
The study medication is produced by Boehringer Ingelheim. Unit strength of each 
formulation is based on amount of meloxicam.
4.1.1
Identity of BI investigational product and comparator product
The characteristics of the test product are given below:
Name:
Movalis
Substance:
Meloxicam
Pharmaceutical formulation: Capsule
Pharmaceutical code:
UHAC 62 XX
Source:
            Boehringer Ingelheim Ellas A.E., 5th km Paiania – Markopoulo,
                                   Koropi Attiki, 19400, Greece.
Unit strength:
15 mg
Posology:
1-0-0
Route of administration:
p.o.
Duration of use:
single dose
The characteristics of the reference product are given below:
Name:
Movalis
Substance:
Meloxicam
Pharmaceutical formulation: Tablet
Pharmaceutical code:
UHAC 62 XX
Source:
Boehringer Ingelheim Ellas A.E., 5th km Paiania – Markopoulo,
                                   Koropi Attiki, 19400, Greece.
Unit strength:
15 mg
Posology:
1-0-0
Route of administration:
p.o.
Duration of use:
single dose


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4.1.2
Method of assigning subjects to treatment groups
The randomisation list of study subject numbers and assigned treatment sequences will be 
provided to the trial site in advance.
This trial is an open-label study. The allocation of subjects to one of the two treatment 
sequences (TR or RT) as per randomisation list will be performed prior to the first study drug 
administration. For this purpose the subject will be assigned a randomisation number (= 
random number indicating the treatment sequence) by drawing lots. Once a subject number 
has been assigned, it cannot be reassigned to any other subject. The randomisation procedure 
is described in Section 7.5.
4.1.3
Selection of doses in the trial
The dose selected for this trial reflects standard clinical doses.
4.1.4
Drug assignment and administration of doses for each subject
This trial is a two-way crossover study. All subjects will receive the two treatments in
randomised order. The treatments to be evaluated are outlined in Table 4.1.4: 1 below.
Table 4.1.4:1
Treatments in a single administration
Treatment
Substance
Formulation
Test or 
Reference
Total dose [mg]
1
meloxicam
capsule 
T
15
2
meloxicam
tablet 
R
15
Following an overnight fast of at least 8 hours, the medication will be administered under 
fasting state as a single oral dose with about 200 mL of ambient boiled water in the 
sitting/standing position under supervision of two study team members. Subjects will be kept 
under close medical surveillance until 72 hours following drug administration and are not 
allowed to lie down during the 2 hours following drug administration. Water is allowed ad 
libitum except for one hour before drug administration and four hours after drug 
administration. Standardised meals will be served only at 4, 6, 9 and 11 hours after drug 
administration.
This trial is a two-way crossover study. All subjects will receive the two treatments in 
randomised order. The treatments will be separated by a wash-out phase of about eight half-
lives (>6 t1/2).
The dosage and the method of drug intake is identical to the approved instructions for the use 
of the original drug Movalistablets, as well as to the draft instruction on the use of the 
reproduced drug Movaliscapsules . Each drug will be taken orally once a day on an empty 


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stomach by 15 mg (1 tablet/capsule) with an interval between doses (washout period) of at 
least 7 days (≥6T1 / 2). The dose of drugs does not exceed the average therapeutic dose.
The order of taking the drugs will be determined by the randomization scheme.
Subjects will be kept under close medical surveillance from 10 h before drug administration 
until 72 h following drug administration. During the first 2 h after drug administration, they 
are not allowed to lie down (i.e. no declination of the upper body of more than 45 degrees 
from upright posture). For restrictions with regard to diet see Section 4.2.2.2.
4.1.5
Blinding and procedures for unblinding
Not applicable
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by Boehringer Ingelheim. The clinical trial supply consists of 
containers with trial- and centre identification that hold the trial medication.
Smaller boxes in the clinical trial supply containers will be labelled in Russian according to 
the legal requirements in Russian Federation. 
No re-supply is planned.
Before each dosing, the Test and the Reference drugs will be packed into individual 
containers for each volunteer to receive in each study period in accordance with the 
randomization scheme.
Individual containers will be marked with labels that contain the following information:

Protocol number;

Name of the test preparation (T / R);

Study period number;

Randomization number.
The label composition for labelling individual doses of the study drug and the reference 
preparation can be supplemented after agreement with the research sponsor.
Label examples are given in the Investigator Site File (ISF).
4.1.7
Storage conditions
Keep drug supplies in their original packaging. Do not store drug supplies at temperature 
above 25°C. 


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The trial medication must be stored securely, e.g. in a locked cupboard or at a pharmacy. It 
may only be dispensed to trial subjects according to the protocol by authorised personnel as 
documented in the form "Study personal responsibility log".
4.1.8
Drug accountability
The investigator / pharmacist / investigational drug storage manager will receive the 
investigational drugs delivered by the sponsor when the following requirements are fulfilled:

Approval of the study protocol by the IRB / ethics committee 

Availability of a signed and dated clinical trial contract between the sponsor and the CRO

Approval/notification of the regulatory authority, e.g. competent authority

Availability of the curriculum vitae of the principal investigator

Availability of a signed and dated clinical trial protocol or immediately imminent signing 
of the clinical trial protocol 
Only authorised personnel as documented in the form ‘Study personal responsibility log’ may 
dispense medication to trial subjects. The trial medication must be administered in the 
manner specified in the CTP. All unused trial medication must be returned to the sponsor or 
to the CRO. Receipt, usage and return and disposal must be documented on the respective 
forms. Account must be given for any discrepancies. 
The investigator / pharmacist / investigational drug storage manager must maintain records of 
the product’s delivery to the trial site, the inventory at the site, the use by each subject, and 
the return to the sponsor or alternative disposal of unused products. 
These records will include dates, quantities, batch / serial numbers, expiry (‘use-by’) dates. 
The investigator / pharmacist / investigational drug storage manager will maintain records 
that document adequately that the subjects were provided the doses specified by the CTP, and
that reconcile all investigational products received from the sponsor. At the time of disposal
or return to the sponsor (and/or) appointed CRO, the investigator / pharmacist / must verify 
that all unused or partially used drug supplies have been returned by the clinical trial subject
and that no remaining supplies are in the investigator’s possession.


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4.2
CONCOMITANT THERAPY, RESTRICTIONS, AND RESCUE 
TREATMENT
4.2.1
Rescue medication, emergency procedures, and additional treatments
There are no specific rescue drugs foreseen for the treatment of AEs. No special emergency 
procedures are to be followed. No additional treatment is planned. However, in case of 
adverse events in need of treatment, the investigator can authorise symptomatic therapy. In 
those cases, subjects will be treated as necessary and, if required, kept under supervision at 
the trial site or transferred to a hospital until all medical evaluation results have returned to an 
acceptable level.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
In principle, no concomitant therapy is allowed. All concomitant or rescue therapies will be 
recorded (including time of intake on study days) on the appropriate pages of the CRF.
4.2.2.2
Restrictions on diet and life style
While admitted to the trial site the subjects are restricted from consuming any other foods or 
drinks than those provided by the staff. 
Standardised meals will be served at the time points described in the Flow Chart.
No food is allowed from 8 h before drug intake until 4 h after drug intake.
No water is allowed from 1 h before drug intake until 4 h after drug intake, except the water 
administered with the drug and additional 200 mL at 2 h post-dose (mandatory for all 
subjects). After 4 h post-dose water is allowed ad libitum.
Alcoholic beverages, grapefruits, Seville oranges (sour or bitter oranges) and their juices, and 
dietary supplements and products including St. John's wort (Hypericum perforatum) are not 
permitted starting 7 days before the first administration of trial medication until after the last 
PK sample of each study period is collected.
Excessive physical activity (such as competitive sport) should be avoided starting 7 days 
before the first administration of trial medication until the end of trial examination.
Direct exposure to the sun or exposure to solarium radiation should be avoided during the 
entire study.


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Subjects must abstain from smoking and alcoholic beverages for 24 hours prior 
administration of the study medication and during the treatment phase (Period I and II). 
Methylxanthine-containing drinks or foods (coffee, tea, cola, energy drinks, chocolate, etc.), 
juices of certain fruits (e.g. apples, oranges, grapefruits) are not permitted 24 hours 
preceeding the administration of study medication and during the treatment phase (Period I 
and II). 
During the treatment phase the subject will receive balanced food of high quality. The 
standard menu usually includes dietary course without fat and fried food. Meals intake will 
be controlled and standardised during the treatment phase (Period I and II). 
Subjects must use effective methods of contraception (i.e., double-barrier) over the trial 
period and to 30 days after the last administration of the study drug, inclusive. Women of 
childbearing potential should practice sexual continence or using barrier contraception 
methods (non-hormone intrauterine device, condom with intravaginal spermicide, cervical 
cap with spermicide, diaphragm with spermicide). Women enrolled in the trial are free from 
obligation to use contraception if they are postmenopausal (absence of menstrual period for at 
least a year), underwent hysterectomy or tubal ligation, or are confirmed to be infertile.
If a woman becomes pregnant during participation in the trial, she withdraws immediately 
from the trial. Investigator will fill in a Pregnancy Report Form. 
Male subjects participating in the trial must also use effective contraception (barrier 
contraceptive methods) over the trial period and to 30 days after the last administration of the 
study drug, inclusive. If a partner of the male subject becomes pregnant, the investigator must 
be informed about and fill in a Pregnancy Report Form.
4.3
TREATMENT COMPLIANCE
Compliance will be assured by administration of all trial medication in the study centre under 
supervision of the investigating physician or a designee. The measured plasma concentrations 
will provide additional confirmation of compliance.
Subjects who are non-compliant (for instance, who do not appear for scheduled visits or 
violate trial restrictions) may be removed from the trial and the CRF will be completed 
accordingly (for further procedures, please see Section 3.3.4.1).


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
EFFICACY - CLINICAL PHARMACOLOGY
5.1.1
Endpoints of efficacy
No efficacy endpoints will be evaluated in this trial.
5.2
SAFETY
5.2.1
Endpoints of safety
Safety and tolerability of the investigational drug will be assessed based on:

Vital signs (BP, PR, body temperature, breathing rate)

Global assessment

Physical examination

Clinical laboratory tests (haematology, clinical chemistry and urinalysis)

12-lead ECG

Adverse events (including clinically relevant findings from the physical examination)
These parameters will be evaluated in a descriptive way only, and are therefore considered to 
be ‘further parameters of interest’. A confirmatory analysis is not planned (see Section 7.3).
5.2.2
Assessment of adverse events
5.2.2.1
Definitions of adverse events
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
investigation subject administered a medicinal product and which does not necessarily have 
to have a causal relationship with this treatment.
An AE can therefore be any unfavourable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
product, whether or not considered related to the medicinal product.


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The following should also be recorded as an AE in the CRF and BI SAE form (if applicable):

Worsening of the underlying disease or of other pre-existing conditions 

Changes in vital signs, ECG, physical examination and laboratory test results, if they are 
judged clinically relevant by the investigator.
If such abnormalities already exist prior to trial inclusion, they will be considered as baseline 
conditions and should be collected in the eCRF only.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which fulfils at least one of the 
following criteria:

results in death, 

is life-threatening, which refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused death 
if more severe, 

requires inpatient hospitalisation or 

requires prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, 

is a congenital anomaly/birth defect, 

is deemed serious for any other reason if it is an important medical event when based on 
appropriate medical judgment which may jeopardise the patient and may require medical 
or surgical intervention to prevent one of the other outcomes listed in the above 
definitions. Examples of such events are intensive treatment in an emergency room or at 
home for allergic bronchospasm, blood dyscrasias or convulsions that do not result in 
hospitalisation or development of dependency or abuse.
AEs considered ‘Always Serious’
Every new occurrence of cancer of new histology must be classified as a serious event 
regardless of the time since the discontinuation of the trial medication and must be reported 
as described in Section 5.2.2.1 subsections “AE Collection” and “AE reporting to sponsor 
and timelines”.
Cancers of new histology and exacerbations of existing cancer must be classified as a serious 
event regardless of the time since discontinuation of the drug and must be reported as 
described in Section 5.2.2.1 subsections “AE Collection” and “AE reporting to sponsor and 
timelines”.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which, by their nature, can always be 
considered to be ‘serious’ even though they may not have met the criteria of an SAE as 
defined above.


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A copy of the latest list of ‘Always Serious AEs’ will be provided upon request. These events 
should always be reported as SAEs as described above.
Adverse events of special interest (AESIs)
The term adverse events of special interest (AESI) relates to any specific AE that has been 
identified at the project level as being of particular concern for prospective safety monitoring 
and safety assessment within this trial, e.g. the potential for AEs based on knowledge from 
other compounds in the same class. AESIs need to be reported to the sponsor’s 
Pharmacovigilance Department within the same timeframe that applies to SAEs, please see 
Section 5.2.2.2.
The following are considered as AESIs:

Hepatic injury
A hepatic injury is defined by the following alterations of hepatic laboratory parameters: 
o
an elevation of AST and/or ALT ≥3-fold ULN combined with an elevation of 
total 
bilirubin ≥2-fold ULN measured in the same blood sample, or
o
aminotransferase (ALT, and/or AST) elevations ≥10 fold ULN
These lab findings constitute a hepatic injury alert and the subjects showing these lab 
abnormalities need to be followed up according to the ‘DILI checklist’ provided in the ISF. In 
case of clinical symptoms of hepatic injury (icterus,
unexplained encephalopathy, 
unexplained coagulopathy, right upper quadrant abdominal pain, etc.) without lab results 
(ALT, AST, total bilirubin) available, the Investigator should make sure that these parameters 
are analysed, if necessary in an unscheduled blood test. Should the results meet the criteria of 
hepatic injury alert, the procedures described in the DILI checklist should be followed.
Intensity of AEs
The intensity (severity) of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Sufficient discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
Medical judgment should be used to determine the relationship, considering all relevant 
factors, including pattern of reaction, temporal relationship, de-challenge or re-challenge, 
confounding factors such as concomitant medication, concomitant diseases and relevant 
history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship 
could be:


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
The event is consistent with the known pharmacology of the drug 

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-existing 
or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is reduced).
Arguments that may suggest that there is no reasonable possibility of a causal relationship 
could be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives). Of note, this 
criterion may not be applicable to events whose time course is prolonged despite 
removing the original trigger. 

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the trial drug treatment continues or remains 
unchanged. 
5.2.2.2
Adverse event collection and reporting
AEs collection
Upon enrolment into a trial, the subject’s baseline condition is assessed (for instance, by 
documentation of medical history/concomitant diagnoses), and relevant changes from 
baseline are noted subsequently. 
Subjects will be required to report spontaneously any AEs as well as the time of onset, end, 
and intensity of these events. In addition, each subject will be regularly assessed by the 
medical staff throughout the clinical trial and whenever the investigator deems necessary. As 
a minimum, subjects will be questioned for AEs (and concomitant therapies) at the time 
points indicated in the Flow Chart. Assessment will be made using non-specific questions 
such as ‘How do you feel?’. Specific questions will be asked wherever necessary in order to 
more precisely describe an AE.
A carefully written record of all AEs shall be kept by the investigator in charge of the trial. 
Records of AEs shall include data on the time of onset, end time, intensity of the event, and
any treatment or action required for the event and its outcome.


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The following must be collected and documented on the appropriate CRF(s) by the 
investigator:

From signing the informed consent onwards until an individual subject’s end of trial: 
o
All AEs (serious and non-serious) and all AESIs 
o
The only exception to this rule are AEs (serious and non-serious) and AESIs in Phase 
I trials in healthy volunteers, when subjects discontinue from the trial due to screening 
failures prior to administration of any trial medication. In these cases, the subjects’ 
data must be collected at trial site but will not be entered in the eCRF or trial database 
and will not be reported in the CTR.

After the individual subject’s end of trial: 
o
The investigator does not need to actively monitor the subject for new AEs but should 
only report any occurrence of cancer and related SAEs and related AESIs of which the 
investigator may become aware of by any means of communication, e.g. phone call. 
Those AEs should, however, not be reported in the CRF.
The REP for 7 days, when measurable drug levels or PD effects are still likely to be present, 
is defined as 7 days after the last administration of Meloxicam. Therefore, all AEs that occur
through the treatment phase and throughout the REP will be considered as on treatment; 
please see Section 7.3.3. Events that occur after the REP will be considered to be follow-up 
events.
The follow-up period is the time from the last administration of trial medication, including 
the REP, until the end of trial examination (last per protocol contact).
AE reporting to sponsor and timelines
The Investigator must report SAEs, AESIs, and non-serious AEs that are relevant for the 
reported SAE or AESI, on the BI SAE form via fax immediately (within 24 hours) to the 
sponsor’s unique entry point (country specific contact details will be provided in the ISF). 
The same timeline applies if follow-up information becomes available. In specific occasions 
the Investigator could inform the sponsor upfront via telephone. This does not replace the 
requirement to complete and fax the BI SAE form. 
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timelines apply as for the initial 
information.
Information required
All (S)AEs, including those persisting after individual patient’s end of trial must be followed 
up until they have resolved, have been assessed as “chronic” or “stable” , or no further 
information can be obtained.
Pregnancy
In rare cases, pregnancy might occur in a clinical trial. Once a subject has been enrolled in 
the clinical trial and has taken trial medication, the investigator must report any drug 


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exposure during pregnancy in a trial participant immediately (within 24 hours) by means of 
Part A of the Pregnancy Monitoring Form to the sponsor’s unique entry point.
Similarly, potential drug exposure during pregnancy must be reported if a partner of a male 
trial participant becomes pregnant. This requires a written consent of the pregnant partner.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring 
Form for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and Part B)
as well as non-trial specific information and consent for the pregnant partner.
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE 
and/or AESI, only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form 
is to be completed. If there is an SAE and/or AESI associated with the pregnancy an SAE 
form must be completed in addition.
5.2.3
Assessment of safety laboratory parameters
For the assessment of laboratory parameters, blood and urine samples will be collected by the 
trial site at the time points indicated in the Flow Chart after the subjects have fasted for at 
least 10 h. Overnight fasting is not required at the discretion of the investigator or designate 
for retests.
The parameters that will be determined are listed in Tables 5.2.3: 1 and 5.2.3: 2. Reference 
ranges will be provided in the ISF, Section 10.


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Table 5.2.3: 1
Routine laboratory tests
Category
Test name 
Haematology
Erythrocyte sedimentation rate (ESR)
Haematocrit (Hct)
Haemoglobin (Hb)
Red Blood Cell Count / Erythrocytes
Platelet Count / Thrombocytes
White Blood Cells / Leucocytes
Diff Automatic
Neutrophiles (Relative Count)
Eosinophils (Relative  Count)
Basophils (Relative  Count)
Monocytes (Relative  Count)
Lymphocytes (Relative Count)
Diff Manual (if Diff Automatic is not available)
Neutrophils, Bands (Stabs) 
Neutrophils, Polymorphonuclear (PMN)
Eosinophils
Basophils 
Monocytes 
Lymphocytes 
Clinical Chemistry
Aspartate transaminase (AST)
Alanine transaminase (ALT)
Alkaline Phosphatase (AP)
Glucose 
Creatinine
Bilirubin Total 
Protein, Total
Cholesterol, total 
Electrolytes: Calcium, Sodium, Potassium
For haematology and clinical chemistry, 5 ml of blood will be taken per test. A total amount 
of 35 ml blood will be taken per subject during the trial for safety routine laboratory tests 
(haematology and clinical chemistry).
Haematology and clinical chemistry is assessed at screening and at 72 h post dose in first and 
second period.


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Table 5.2.3: 2
Routine urinalysis
Category
Test name 
Urinalysis (test strips)
Urine Protein
Urine Glucose
Urine Ketone
Urobilinogen
Urine Bilirubin
Urine RBC/Erythrocyte
Urine WBC/Leukocytes
Urine pH
Urine-Sediment
(microscopic examination) :
Urine Sediment Bacteria 
Urine Squamous Epith Cells
Urine Sediment RBC/Erythrocytes  
Urine Sediment WBC/Leucocytes
Urinalysis and Urine-Sediment (microscopic examination) will be assessed at screening and 
at 72 h post dose in first and second period.
The tests listed in Table 5.2.3: 3 constitute exclusionary lab safety tests. These tests will be 
performed for eligibility control. The results will not be part of the report. 
Table 5.2.3: 3
Exclusionary laboratory tests
Category
Test name 
Infectious Serology
Hepatitis B Surface Antigen (qualitative HbsAg test)
Hepatitis C Antibodies (qualitative anti-HCV total)
HIV-1 and HIV -2 Antibody (qualitative anti-HIV1/2)
RPR test for syphilis (Rapid plasma reagin test) 
Pregnancy testing (women)
Urine test for ß-HCG (test strips)
Drug Screening (Urine test strips)
Cannabis
Benzodiazepines
Barbiturates
Opiates
Cocaine
Amphetamines
Alcohol testing
Alcohol breath test (using Alcotester) 
Testing for infections (infectious serology) is done at screening.
Pregnancy testing, urine drug tests and alcohol testing will be assessed using express tests at 
screening and on the hospitalization day of each treatment period.


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5.2.4
Electrocardiogram
Twelve-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded at screening and the 
time points given in the Flow Chart.
All ECGs will be recorded for a 10-sec duration after the subjects have rested for at least 10
min in a supine position. ECG assessment will always precede all other study procedures of 
the same time point (except blood drawing from an intravenous cannula which is already in 
place) to avoid impact of sampling on the ECG quality. 
All locally printed ECGs will be evaluated by the investigator or a designee. ECGs may be 
repeated for quality reasons (like alternating current artefacts, muscle movements, electrode 
dislocation) and the repeated ECG will be used for analysis. Additional (unscheduled) ECGs
may be collected by the investigator for safety reasons. 
Abnormal findings will be reported as AEs (during the trial) or baseline conditions (at 
screening) if judged clinically relevant by the investigator. Any ECG abnormalities will be 
monitored carefully and, if necessary, the subject will be removed from the trial and will 
receive the appropriate medical treatment. 
5.2.5
Assessment of other safety parameters
5.2.5.1
Vital signs
Vital signs will be measured at screening and the time points given in the Flow Chart.
Systolic and diastolic blood pressure as well as pulse rate (by palpation, count for 1 minute) 
will be measured after 10 minutes of rest in the supine/sitting position. All recordings shall be 
made on the same arm.
Additional vital sign to be recorded is body temperature and breathing rate.
5.2.5.2
Medical examinations
The subject will undergo an assessment of major body systems at screening and the time 
points given in the Flow Chart.
Body system and site
Skin, hear, nails
Endocrine system
Ear, nose, throat
Cardiovascular system
Gastrointestinal system
Neurological system
Musculoskeletal system
Reproductive system
Renal system


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5.2.5.3
Local tolerability
Not applicable
5.3
OTHER
5.3.1
Pharmacogenomic evaluation
Not applicable.
5.4
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are standard measurements and will be 
performed in order to monitor safety aspects and to determine pharmacokinetic parameters in 
an appropriate way.
The pharmacokinetic parameters and measurements are generally used as measurements to 
assess drug exposure.
The scheduled measurements are appropriate to see drug induced changes in vital signs and 
standard laboratory values. These primary and secondary endpoints are standard and accepted 
for evaluation of safety and tolerability of an oral drug, and they are widely used in this kind 
of studies.
Therefore, the appropriateness of all measurements applied in this trial is given.
5.5
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
Date and exact clock time of administration as well as of pharmacokinetic sampling times 
have to be recorded. These actual sampling times will be used for determination of 
pharmacokinetic parameters.
5.5.1
Pharmacokinetic endpoints
5.5.1.1
Primary endpoints
The following primary endpoints will be determined for meloxicam:

AUC0-t (area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 to the last quantifiable data point)

Cmax (maximum measured concentration of the analyte in plasma)


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5.5.1.2
Secondary endpoints
The following secondary endpoints will be evaluated for meloxicam:

AUC0-∞(area under the concentration-time curve of the analyte in plasma over the time 
interval from 0 extrapolated to infinity)
5.5.2
Methods of sample collection
5.5.2.1
Plasma sampling for pharmacokinetic analysis
A total amount of 192 ml blood will be taken per subject during the whole course of the study 
for pharmacokinetic purposes.
For quantification of analyte plasma concentrations, 6 mL of blood will be taken from a 
forearm vein in an K2EDTA (K2-ethylendiaminetetraacetic acid)-anticoagulant blood-
drawing tube at the following time points:
Table 5.5.2.1: 1
Plasma sampling schedule
Day
Planned Time points in period I
1
-2:00, 0:30, 1:00, 2:00, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00 h after dosing
2-4
24:00, 32:00, 48:00 and 72:00h after dosing on Day 1
Day
Planned Time points period II
8
-2:00, 0:30, 1:00, 2:00, 3:00, 4:00, 5:00, 6:00, 7:00, 8:00, 10:00, 12:00 h after dosing
9-11
24:00, 32:00, 48:00 and 72:00h after dosing on Day 8
The K2 EDTA-anticoagulated blood samples will be centrifuged no later than 30 minutes 
after blood sampling. Centrifugation will last for about 10 minutes at 2000g at temperature
+4Cо. Two aliquots of K2 EDTA plasma samples will be obtained. Both aliquots should 
contain at least 1.0 ml plasma. Both aliquots should be frozen no later than 30 minutes after 
the aliquoting. Until shipment on dry ice to the analytical laboratory, the plasma samples will 
be stored at –20C or below at the clinical site and at the analytical laboratory until analysis. 
The second aliquot will be stored at –20C or below at the trial site until the clinical trial 
report is final or shipment is requested by the analytical laboratory. 


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5.5.2.2
Urine sampling for pharmacokinetic analysis
Not applicable
5.5.3
Analytical determinations
5.5.3.1
Analytical determination of analyte plasma concentration
Plasma levels of meloxicam will be determined by a validated HPLC-MS/MS assay (high 
performance liquid chromatography, tandem mass spectrometry).
5.5.3.2
The bioanalytical method will be documented before the start of the study 
(preliminary validation) for the subsequent development of the validation report.
The lower limit of quantification (LLQ, LLOQ) of meloxicam will be no more than 0.05
ng/mL, with meeting the condition that the lower limit of quantification will not exceed 5% 
of the maximum concentration (Cmax). [P07-08427, P07-07106]
The upper limit of quantification (ULQ, ULOQ) meloxicam will be set up to the linearity of 
the LC/MS/MS method. Dilution integrity will be validated if necessary to cover the 
concentration range in the Study samples. Evaluation of dilution integrity may be covered by 
partial validation.
The validation of HPLC-MS/MS method includes the following parameters:
selectivity;
linearity;
lower limit of quantification (LLQ);
calibration range;
inter-run and intra-run precision and accuracy;
effect of previous sample transfer;
extraction degree;
effect of the matrix;
stability.
Test procedure
The samples will be analyzed in analytical runs. In one run, the following set of samples will 
be analyzed:
a) Zero (blank) sample, zero sample with the internal standard, not less than 8 points of the 
calibration curve with a concentration different from zero.
b) Quality control (QC) samples at three concentrations (low, medium, and high), in two 
replicates for each concentration.
c) Plasma samples of one or more volunteers obtained in two periods.


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Determination of analyte concentrations
The analyte concentration in plasma will be calculated using the following equation: 
x = (y – a)/b
and using the following calibration curve: y = a + b x, where:
y is the ratio of the analyte peak to the internal standard peak,
x is the concentration of the analyte in plasma,
a is the intersection point,
b is the slope corresponding to the calibration curve of each analytical run.
The a and b values will be obtained by weighted regression of the calibration curve of each 
run. The weighted linear regression method will be used because of the wide calibration 
range.
Values beyond the lower limit of quantification (LLQ) will be considered as zero values.
The calculated concentrations of the calibration samples, quality control (QC) samples, the 
intersection point, the slope, the correlation coefficient for each analytical run will be 
presented in the study report in the form of a table.
Acceptability/unacceptability criteria
To assess the acceptability of each analytical run, criteria will be used meeting the following 
regulatory standards:
Guidelines on Expertise of Medicinal Products/edited by 
 of Medicine, 
 
. Federal State Budgetary Institution “National Center for Expertise of Medicinal 
Products”, 2014;
Guidance for Industry: Bioanalytical Method Validation (FDA, 2001);
Guideline on bioanalytical method validation (EMEA, 2011).
Unacceptability of the entire analytical run
All samples will be analyzed once. The analytical run will be analyzed again if at least one of 
the below criteria is not met: 
The calibration curve should include at least 6 points with a non-zero concentration.
At least 75% of the calibration samples should meet the following criteria: the 
concentration of the LLQ sample should be within ±20% of the nominal value, the 
concentration of the remaining calibration samples should be within ±15% of the nominal 
value.
The concentration values of the control (QC) samples should be within ±15% of the 
nominal value for at least 67% of the samples (4 of 6). The control samples beyond this 
interval should not have the same concentration. 


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Repeated analysis of samples 
Some samples will be analyzed again if at least one of the following criteria is met: 
The concentration of the test sample exceeds the upper limit of quantification (ULOQ). 
Such sample will be diluted with intact plasma and analyzed again.
Insufficient signal from the internal standard.
Error during the sample preparation.
Inaccurate injection of the sample into the chromatographic system or malfunction of the 
equipment.
Low-quality chromatography.
Quantification of the analyte level in a plasma sample obtained before taking the drug by 
a volunteer.
Some samples collected for repeated analysis and obtained after taking the drug, will be 
analyzed once. The values obtained during the repeated analysis will be considered the first 
valid values.
In case of quantitative determination of the analyte level in a plasma sample obtained before 
taking the drug, the samples will be analyzed twice. A report will be provided on the baseline 
values, results of the repeated tests, the final result and a conclusion on the acceptability or 
unacceptability for inclusion in the statistical analysis.
Samples collected for repeated analysis will be analyzed in one analytical run, including 
samples for constructing a calibration curve and control (QC) samples.
Repeated analysis due to pharmacokinetic reasons is generally not performed; however, 
repeated analysis can be performed as part of the laboratory study to clarify the possible 
reasons for obtaining the results assessed as incorrect.
All repeated tests will be performed in accordance with the standard operating procedures of 
the laboratory. Detailed information on the analysis procedure and validation of results will 
be included in the final study report. 
Incurred Sample Reanalysis (ISR) demonstrates the repeatability and stability of the 
analytical method in the matrix of real samples. If the number of samples is less than 1,000, 
about 10% of the samples will be analyzed again; if the number of samples is more than 
1,000, the number of re-analyzed samples will be 10% of 1,000 samples and 5% of the 
number of samples exceeding 1,000. The total number of ISR samples planned for the 
bioequivalence study will be selected from each volunteer included in the bioequivalence 
assessment. The ISR will contain samples in the Cmax range and in the elimination phase. 
If the ISR results for a sample are invalid for analytical reasons (a low internal standard zone, 
sample processing errors, malfunctioning of the measuring equipment), this sample will be 
excluded from the statistical ISR evaluation and will not be analyzed again. If the number of 
ISR samples with an invalid analytical result exceeds 5% of all ISR samples, the samples will 
be analyzed again.


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Criterion for the ISR results acceptance: the concentrations obtained from the initial analysis 
and from the repeated analysis should be within 20% of the average value, for at least 67% of 
the repeats. If the ISR results are unsatisfactory, the Study Director will decide to investigate 
the cause of the differences and take adequate measures to minimize the error (and 
inaccuracy). The ISR results will be presented in the analytical report; they will not be used 
for any correction of the concentration results for the pharmacokinetic and statistical 
evaluation of the study
Based on the data on the analyte concentration in the blood plasma of volunteers at discrete 
time intervals, pharmacokinetic curves (of the concentration dependence on time) will be 
constructed and pharmacokinetic parameters calculated.
Detailed information on the analysis procedure and validation of results will be included in 
the final study report.
The analytical work and its documentation can be evaluated by the Sponsor during the 
monitoring activities. During sample analysis, the bioanalyst will be blinded to subject 
allocation and will have no access to the random code.
5.5.3.3
Analytical determination of analyte urine concentration
Not applicable
5.6
BIOMARKER(S) 
Not applicable
5.6.1
Biochemical and cellular biomarker(s)
Not applicable
5.6.2
Pharmacogenomic biomarker(s) 
Not applicable
5.6.3
Methods of sample collection
Not applicable


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5.6.4
Analytical determinations
Not applicable
5.7
PHARMACOKINETIC - PHARMACODYNAMIC RELATIONSHIP
Not applicable


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Time windows are permitted as follows:
Procedures at screening: 
within 14 days prior to the first study day.
Wash-out phase: 
7 days starting from the first drug intake. 
End-of-study evaluation: 
7 days following the last trial procedure.
For planned individual plasma concentration sampling times refer to the Flow Chart.
Sampling time is related to the time of drug administration. The actual sampling times will be 
recorded and used for determination of pharmacokinetic parameters.
Deviations from time of sampling are permitted for pharmacokinetic blood sampling as 
follows:
0 – 2 h: 
  2 minutes
3 – 6 h: 
  5 minutes
7 – 12 h: 
10 minutes
>12 h: 
15 minutes
For other parameters (vital signs, ECG, haematology, clinical chemistry), a time window of 
±1 hour is permitted. 
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period
After the volunteers have been informed on the trial, volunteers will sign the written 
informed consent in accordance with GCP and the local legislation prior to admission to the 
study.
The subjects will be assigned a screening number and undergo screening. The screening 
investigations must be completed within 14 days preceding the first study drug 
administration.
The screening procedures are necessary to determine the subject eligibility to the trial and are 
outlined in the Flow Chart. The screening includes the following procedures:

Questioning on demography;

Questioning on medical history (including lifestyle and bad habits);

Questioning on prior medication;

Body weight, height, calculation of body mass index (BMI);


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
Assessment of vital signs: blood pressure (BP), pulse rate (PR), body temperature,
respiratory rate;

Physical examination;

Assessment of exclusionary testing: infectious serology, urine pregnancy test, urine drug 
screening, alcohol breath test;

Assessment of routine laboratory tests at fasted state (haematology, clinical chemistry, 
urinalysis);

12-lead ECG (If 12-lead ECG is taken on Day -7-1 at screening, the results can be also 
used on Day 1 in Period I);

Evaluation of inclusion / exclusion criteria in the study;

Assessment of adverse events.
A screening log, including screening number, initials, date of birth and subsequent reason(s) 
for exclusion from the study, will be completed for all subjects who have given written 
informed consent.
6.2.2
Treatment period
Each subject will have two periods of 4 days in the treatment phase. Test and reference drug 
administration will be separated by 7 days (about eight half-lives). For each period the 
subjects will come to the trial site no later than 10 hours before the planned time the study 
drug administration and will be confined there at least 72 hours after the study drug 
administration (Day -1 to 3 in period I and Day 7 to 10 in period II). 
The procedures and measurements performed during each treatment period are outlined in the 
Flow Chart.
In general, if several measurements including venepuncture are scheduled for the same point 
of time, venepuncture should be the last of the measurements due to its inconvenience to the 
subject and possible influence on physiologic parameters.
Period I/ Visit 2
Day -1 
Hospitalization of the study subjects will be performed not less than 10 hours before the 
planned time of study drug administration.
After completion of hospitalization, but before randomization, the following procedures will 
be done:

Physical examination

Assessment of adverse events.

Accounting for concomitant medications

Evaluation of the change in anamnestic data.

Evaluation of adherence to the study restrictions.


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
Assessment of exclusionary testing using express tests: urine pregnancy test (women), 
urine drug screening, alcohol breath test.

Assessment of vital signs: BP, PR, body temperature and respiratory rate;

12-lead ECG (If 12-lead ECG is taken on Day -7-1 at screening, the results can be also 
used on Day 1 in Period I)

Global assessment 

Evaluation of inclusion / exclusion criteria.
The randomization will be conducted on day -1, after completion of all planned procedures. 
The randomization numbers will be assigned sequentially in ascending order. The 
randomization number is assigned to the study subjects for the entire study.
Day 1 
Time point from 2 hours before administration to 1 minute before administration:

Pre-dose blood sampling for PK;

Assessment of vital signs (BP, PR, body temperature, respiratory rate);

Assessment of adverse events;

Accounting for concomitant medications.
Time point 00:00:

The study drug (capsule or tablet) will be taken with 200 ml ambient boiled water in a 
sitting/standing position under fasting state.
Time point 00:30±0:02 minutes:

Blood sampling for PK.
Time point 01:00±0:02 minutes:

Blood sampling for PK.
Time point 02:00±0:02 minutes:

Blood sampling for PK.
Time point 03:00±0:05 minutes:

Blood sampling for PK.
Time point 04:00±0:05 minutes:

Blood sampling for PK;

Breakfast.
Time point 05:00±0:05 minutes:

Blood sampling for PK.


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Time point 06:00±0:05 minutes:

Blood sampling for PK;

Assessment of vital signs (BP, PR, body temperature, respiratory rate);

Assessment of adverse events;

Dinner;

Accounting for concomitant medications.
Time point 07:00±0:10 minutes:

Blood sampling for PK.
Time point 08:00±0:10 minutes:

Blood sampling for PK.
Time point 09:00:

Afternoon snack.
Time point 10:00±0:10 minutes:

Blood sampling for PK.
Time point 11:00:

Dinner.
Time point 12:00±0:10 minutes:

Blood sampling for PK;

Assessment of vital signs (BP, PR, body temperature, respiratory rate);

Assessment of adverse events;

Accounting for concomitant medications.
Day 2 
Time point 24:00±0:15 minutes:

Blood sampling for PK;

Physical examination;

Assessment of vital signs (BP, PR, body temperature, respiratory rate);

Global assessment;

Assessment of adverse events;

Accounting for concomitant medications.
Time point 32:00±0:15 minutes:

Blood sampling for PK;


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Day 3
Time point 48:00±0:15 minutes:

Blood sampling for PK;

Physical examination;

Assessment of vital signs (BP, PR, body temperature, respiratory rate);

Global assessment;

Assessment of adverse events;

Accounting for concomitant medications.
Day 4
Time point 72:00±0:15 minutes:

Blood sampling for PK;

Physical examination;

Assessment of vital signs (BP, PR, body temperature, respiratory rate);

Global assessment;

Assessment of adverse events;

Accounting for concomitant medications.

Routine laboratory tests (haematology, clinical chemistry, urinalysis);
Standardised meals (breakfast) will be given to subjects at appointed time at the trial site.
All abnormal values (including laboratory parameters) will be registered as AE. 
Period II/ Visit 3
Day 7
Hospitalization of the study subjects will be performed not less than 10 hours before the 
planned time of study drug administration.
After completion of hospitalization, the following procedures will be done:

Physical examination

Assessment of adverse events.

Accounting for concomitant medications

Evaluation of the change in anamnestic data.

Evaluation of adherence to the study restrictions.

Assessment of exclusionary testing using express tests: urine pregnancy test (women), 
urine drug screening, alcohol breath test.

Assessment of vital signs: BP, PR, body temperature and respiratory rate;

12-lead ECG (If 12-lead ECG is taken on Day -7-1 at screening, the results can be also 
used on Day 1 in Period I)

Global assessment 


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Day 8
Time point from 2 hours before administration to 1 minute before administration:

Pre-dose blood sampling for PK;

Assessment of vital signs (BP, PR, body temperature, respiratory rate);

Assessment of adverse events;

Accounting for concomitant medications.
Time point 00:00:

The study drug (capsule or tablet) will be taken with 200 ml ambient boiled water in a 
sitting/standing position under fasting state.
Time point 00:30±0:02 minutes:

Blood sampling for PK.
Time point 01:00±0:02 minutes:

Blood sampling for PK.
Time point 02:00±0:02 minutes:

Blood sampling for PK.
Time point 03:00±0:05 minutes:

Blood sampling for PK.
Time point 04:00±0:05 minutes:

Blood sampling for PK;

Breakfast.
Time point 05:00±0:05 minutes:

Blood sampling for PK.
Time point 06:00±0:05 minutes:

Blood sampling for PK;

Assessment of vital signs (BP, PR, body temperature, respiratory rate);

Assessment of adverse events;

Dinner;

Accounting for concomitant medications.
Time point 07:00±0:10 minutes:

Blood sampling for PK.


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Time point 08:00±0:10 minutes:

Blood sampling for PK.
Time point 09:00:

Afternoon snack.
Time point 10:00±0:10 minutes:

Blood sampling for PK.
Time point 11:00:

Dinner.
Time point 12:00±0:10 minutes:

Blood sampling for PK;

Assessment of vital signs (BP, PR, body temperature, respiratory rate);

Assessment of adverse events;

Accounting for concomitant medications.
Day 9
Time point 24:00±0:15 minutes:

Blood sampling for PK;

Physical examination;

Assessment of vital signs (BP, PR, body temperature, respiratory rate);

Global assessment;

Assessment of adverse events;

Accounting for concomitant medications.
Time point 32:00±0:15 minutes:

Blood sampling for PK;
Day10
Time point 48:00±0:15 minutes:

Blood sampling for PK;

Physical examination;

Assessment of vital signs (BP, PR, body temperature, respiratory rate);

Global assessment;

Assessment of adverse events;

Accounting for concomitant medications.


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Day 11
Time point 72:00±0:15 minutes:

Blood sampling for PK;

Physical examination;

Assessment of vital signs (BP, PR, body temperature, respiratory rate);

Global assessment;

Assessment of adverse events;

Accounting for concomitant medications;

Routine laboratory tests (haematology, clinical chemistry, urinalysis).

12-lead ECG
Standardised meals (breakfast) will be given to subjects at appointed time at the trial site.
All abnormal values (including laboratory parameters) will be registered as AE. 
6.2.3
End of trial and follow-up period
Upon completion of the treatment phase, a follow-up phase will be organised for 7 days after 
the last procedure of period II.
During follow-up visit (Day 18) the following procedures will be done:

Physical examination;

Assessment of vital signs (BP, PR, body temperature, respiratory rate);

Assessment of adverse events;

Accounting for concomitant medications.

Urine pregnancy test
In the case of discontinuation, a follow-up will be done 7 days after the last procedure before 
discontinuation.


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7.
STATISTICAL METHODS AND DETERMINATION OF
SAMPLE SIZE
7.1
STATISTICAL DESIGN – MODEL
The study will be conducted according to an open-label, randomised, single-dose, two-way 
crossover design. To show bioequivalence, the crossover design is viewed favourably due to 
its efficiency: since each subject serves as his/her own control, the comparison between 
formulations is based on a comparison within subjects rather than between subjects. This 
means that the inter-subject variability is removed from the comparison between 
formulations.
7.1.1
Objectives
The primary objective is to investigate the relative bioavailability of Movaliscapsules 15 
mg versus Movalis® tablets 15 mg following single oral administration in healthy male and 
female volunteers under fasting state. Movalis® capsule 15 mg is regarded as the test 
treatment (T) while Movalis® tablet 15 mg is the reference treatment (R). This objective is 
accomplished by comparing treatments T and R within each subject.
The secondary objectives of the study are:

To establish bioequivalence of Movalis® capsules 15 mg (Test, T) versus Movalis®
tablets 15 mg (Reference, R).

The assessment of safety and tolerability will be an additional objective of this trial.
7.1.2
Endpoints
Relative bioavailability is primarily to be determined on the basis of the parameters: AUC0-t
and Cmax.
The derivation of these primary parameters is given below.
Additionally, the following PK parameters will also be estimated: AUC0-∞,
The derivation of these other PK parameters is given in Section 7.1.3.
Safety and tolerability will be assessed in a descriptive manner.


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7.1.3
Model
The assessment of safety and tolerability will be an additional objective of this trial, and will 
be evaluated by descriptive statistics.
AUCs: The areas under the curve spanning various time intervals will be calculated using the 
linear up/log down algorithm. If a drug concentration is equal to or higher than the 
preceding concentration, the linear trapezoidal method will be used. If the drug 
concentration is smaller than the preceding concentration, the logarithmic method 
will be used.
Linear trapezoidal rule (t2> t1 and C2C1):
The area of the trapezoid between the two data points (t1, C1) and (t2, C2) will be 
computed by:
Logarithmic trapezoid rule (t2> t1 and C2< C1):
The area of the trapezoid between the two data points (t1, C1) and (t2, C2) will be 
computed by:





1
2
1
2
1
2
t2
t1
C
/
C
ln
C
C
t
t
AUC





AUC0-: The area under the plasma concentration-time curve over the time interval from 0 
extrapolated to infinity will be calculated according to the following equation
   
where C'tz is the predicted concentration at the time tz (last time point with a plasma 
concentration above the quantification limit) at which quantification was still 
possible. The area under the concentration-time curve from the time point 0 until the 
last quantifiable drug plasma concentration (AUC0-t) will be calculated by the linear 
up/log down method as described above.
The pharmacokinetic parameter AUC0-t will be used for testing bioequivalence 
between Test and Reference formulation [Decision of the Eurasian Economic 
Commission No. 85].
AUCres: Residual area under the curve will be calculated according to the following equation
AUC res=
Cmax: Individual Cmax values will be directly determined from the plasma concentration time 
profiles of each subject.



2
1
1
2
t2
-
t1
C
C
t
t
0.5
AUC







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The statistical model used for the analysis of AUC0-t , AUC0-and Cmax will be an ANOVA 
(analysis of variance) model on the logarithmic scale. This model will include effects 
accounting for the following sources of variation: ‘sequence’, ‘subjects nested within 
sequences’, ‘period’ and ‘treatment’. The effect ‘subjects within sequences’ will be 
considered as random, whereas the other effects will be considered as fixed. The model is 
described by the following equation:
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response (AUC0-t, Cmax, AUC0-) measured on subject m in 
sequence i receiving treatment k in period j,
= the overall mean,
i = the ith sequence effect, i = 1, 2,
sim = the effect associated with the mth subject in the ith sequence,
m = 1, 2, ..., ni
j = the jth period effect, j = 1, 2,
k = the kth treatment effect, k = 1, 2,
eijkm = the random error associated with the mth subject in sequence i who received 
treatment k in period j.
tmax: Individual tmax values will be directly determined from the plasma concentration time
profiles of each subject. If the same Cmax concentration occurs at different time points, 
tmax is assigned to the first occurrence of Cmax.
t1/2: The terminal half-life will be calculated from the terminal rate constant using the
equation.
       
Estimation of kel: The apparent terminal rate constant kel will be estimated from a regression
of ln(C) versus time over the terminal log-linear drug disposition portion 
of the concentration-time profiles. The log-linear profiles, which include 
the regression line through the terminal points, will be checked via visual 
inspection, and it will be determined whether the regression appropriately 
represents the terminal slope. Only data points that describe the terminal 
log-linear decline will be included in the regression. A minimum of three 
points will be used in the determination of kel. If the last concentration-
time point increases, this time point may be included if the t1/2estimate is 
reasonable. If kel is not determinable then consequently only parameters 
not requiring kel will be reported. In addition, the lower (tkz,start) and upper 
(tkz,end) limit on time for values to be included in the calculation of kel will 
be listed.


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7.2
NULL AND ALTERNATIVE HYPOTHESES
The relative bioavailability of Movalis® capsules 15 mg compared to Movalis® tablets 15 mg 
will be investigated by applying the average bioequivalence method to the ratio between PK 
parameters AUC0-t and Cmax.
Bioequivalence of Movalis® capsules 15 mg compared to Movalis® tablets 15 mg is 
established by using the average bioequivalence method to assess whether the ratio of PK 
parameters (AUC0-t and Cmax) of the two treatments (T/R) is contained within a pre-specified 
acceptance range. Acceptance range for the ratio of geometric means is 80-125% for AUC0-t
and 80-125% for Cmax [Decision of the Eurasian Economic Commission No. 85].
In general, the hypothesis of inequivalence is tested: Null hypothesis H0 (Inequivalence):











R
T
R
T
or
(i.e. the difference of the population average responses is either less than or equal to the 
lower bound or greater than or equal to the upper bound of the acceptance range),
Alternative hypothesis Ha (Equivalence):








R
T
(i.e. the difference of the population average responses is both greater than the lower 
bound and less than the upper bound of the acceptance range),where
T

and 
R

are the population average responses of the log-transformed measures for 
the formulations Test (Movalis® capsules 15 mg) and Reference (Movalis® tablets 15 
mg),
Andis the bioequivalence limit that defines the acceptance range for AUC0-t and Cmax
on the logarithmic scale.
In this trial, for example, is taken to be ln(1.25) for AUC comparison. This translates to an 
acceptance range of 80 to 125% for the geometric mean of the ratio of the parameters on the 
original scale.
This hypothesis and its alternative can be decomposed into two one-sided null hypotheses, 
H01 and H02, with their accompanying alternatives:
H01:






R
T
vs.
Ha1:
δ
μ
μ
R
T



H02:
δ
μ
μ
R
T


vs.
Ha2:
δ
μ
μ
R
T


Due to the nature of normal-theory confidence intervals, the test of the null hypothesis at the 
= 0.05 level is equivalent to carrying out two one-sided tests of the above null hypotheses 
each at the = 0.05 level of significance. The rejection of both null hypotheses H01 and H02 at 
the = 0.05 level is equivalent to the inclusion of the 90% confidence interval for 
R
T



in 
the acceptance range.


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7.3
PLANNED ANALYSES
7.3.1
Primary analyses
The primary pharmacokinetic parameters will be obtained by non-compartmental analysis 
using WinNonlin software (Pharsight, USA).
The pharmacokinetic parameters (AUC0-t, AUC0-∞and Cmax) will be log transformed (natural 
logarithm) prior to fitting the ANOVA model. The difference between the expected means 
for log(T)-log(R) will be estimated by the difference in the corresponding Least Square 
Means (point estimate) and two-sided 90% confidence intervals based on the t-distribution 
will be computed. These quantities will then be back-transformed to the original scale to give 
the point estimate and 90% confidence interval for each endpoint.
All evaluable subjects for both treatment periods will be included in the analysis of the 
relative bioavailability.
A subject is considered to be not evaluable, if:

The subject has a protocol deviation relevant to the evaluation of relative bioavailability. 
(Whether a protocol deviation is relevant, will be decided no later than the Report 
Planning Meeting) or

The subject experiences emesis and vomiting occurs at or before two times median tmax, 
namely, within 12 hours after study drug administration.
7.3.2
Secondary analyses
Concentrations will be used for graphs and calculations in the format that is reported in the 
bioanalytical report.
Plasma concentrations will be plotted graphically versus time for all subjects as listed in the 
drug plasma concentration-time tables. For the presentation of the mean profiles, the 
arithmetic mean and the planned blood sampling times will be used.
The following descriptive statistics will be calculated for plasma concentrations as well as for 
all primary, secondary and further pharmacokinetic parameters: N, arithmetic mean, standard 
deviation, minimum, median, maximum, arithmetic coefficient of variation, geometric mean
and geometric coefficient of variation. The data format for descriptive statistics of 
concentrations will be identical with the data format of the respective concentrations. The 
descriptive statistics of pharmacokinetic parameters will be calculated using the individual 
values with the number of decimal places as provided by the evaluation program. Then the 
individual values as well as the descriptive statistics will be reported with three significant 
digits in the clinical trial report.


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7.3.3
Safety analyses
All subjects who received at least one dose of study drug will be included in the safety 
evaluation. Safety analyses will be performed in accordance with BI standards.
Adverse events will be coded using the Medical Dictionary for Drug Regulatory Affairs 
(MedDRA). Adverse events occurring prior to drug administration will be assigned to the 
screening period while all other adverse events will be assigned to the treatment periods for 
evaluation.
Independent of this rule, the relationship of an adverse event to the study drugs treatments 
will be assessed by the investigator. Adverse event information as reported in the CRFs will 
be aggregated in a two-step process. The evaluation of adverse events will comprise various 
frequency tabulations.
Descriptive statistics of laboratory values over time for the difference from baseline will be 
provided. Frequency tables of changes with respect to the reference range between baseline 
and last value on treatment will also be presented.
Safety will also be assessed by evaluation of vital signs (BP, PR, temperature and breathing 
rate), physical examination, and ECG.
7.3.4
Interim analyses
No interim analysis is planned.
7.3.5
Pharmacokinetic analyses
All randomized volunteers who followed the Protocol requirements, e.g. the volunteers who 
met the inclusion/exclusion criteria and completed the planned periods of the study drug 
administration in accordance with all Protocol requirements (except for minor deviations that 
are not clear grounds for exclusion) constitute a data set “without deviations from Protocol” 
for the pharmacokinetic assessment.
Data of the following volunteers will be included in the final pharmacokinetic and statistical 
analysis:

volunteers who have completed all periods of the study;

volunteers with missing samples (fewer than two samples).
Calculations will be made on the basis of data on the real, not planned, sampling time of each 
sample.
The decision to exclude the results of measuring the analyte concentrations in the volunteer 
samples from analysis will be taken before the final analysis of the samples.


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If before taking the test or reference product, a volunteer has a concentration of less than or 
equal to 5% of the Cmax value, then the data of this volunteer can be included without any 
calculations into all pharmacokinetic measurements and calculations. If the concentration 
value before taking the test or reference product is more than 5% of the Cmax value, then the 
data of this volunteer will be excluded from the pharmacokinetic and statistical analysis.
Data of volunteers excluded from the analysis due to the concentration value before the drug 
dosing higher than 5% of the Cmax value will be included in a separate appendix of the final 
study report.
Volunteers, in whose plasma the reference product concentration cannot be determined or is 
determined in small amounts only, will be excluded from pharmacokinetic and statistical 
analysis. Concentrations of the analyte in the volunteer are considered very low if his AUC 
does not exceed 5 percent of the geometrical mean AUC of the reference product (calculated 
without inclusion of volunteer data with outlying values). 
If the LLQ (lower limit of quantification) value is more than 5% of the Cmax value of an 
individual volunteer, then the data of this volunteer will be excluded from pharmacokinetic 
and statistical analysis. The volunteer data are included in a separate appendix of the final 
study report. During pharmacokinetic and statistical analysis, the drug concentrations below 
the lower limit of quantification (BLQ) will be counted as zero. Missing samples and non-
detectable concentrations (e.g. insufficient amount) from the analytical laboratory will be 
interpreted in pharmacokinetic analysis as if they were not collected.
7.3.6
Biomarker analysis
Not applicable
7.3.6.1
Analysis of cellular and biochemical biomarkers
Not applicable
7.3.6.2
Pharmacogenomic analyses
Not applicable
7.4
HANDLING OF MISSING DATA
7.4.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.


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7.4.2
Plasma drug concentration - time profiles
Drug concentration data identified with NOS (no sample available), NOR (no valid result), 
NOA (not analyzed), BLQ (below the lower limit of quantification), or NOP (no peak 
detectable) will be displayed as such and not replaced by zero at any time point (this rule also 
applies also to the lag phase, including the predose values). 
7.4.3
Pharmacokinetic parameters
In the non-compartmental analysis, concentration data identified with NOS, NOR, and NOA 
will not be considered. BLQ and NOP values in the lag phase will be set to zero. The lag 
phase is defined as the period between time zero and the first time point with a concentration 
above the quantification limit. All other BLQ/NOP values of the profile will be ignored.
Every effort will be made to include all concentration data in an analysis. If not possible, a 
case to case decision is required whether the value should only be excluded from half-life 
estimation or the complete analysis.
If a concentration is only excluded from half-life determination, it will be used for all other 
calculations (e.g. descriptive statistics) and for graphical presentation.
If a concentration value is excluded from all calculations, it will not be presented graphically 
or used for the calculation of descriptive statistics and parameter determination. However the 
excluded concentration itself will be listed in the tables of the clinical trial report associated 
with an appropriate flag.
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual 
parameter estimates of a certain parameter are available. If the actual sampling time will not 
be recorded or will be missing for a certain time point, the planned time will generally be 
used for this time point instead. Pharmacokinetic parameters which cannot be determined will 
be identified by "not calculated" (NC).
7.5
RANDOMISATION
Subjects will be randomised to one of the two treatment sequences in a 1:1 ratio. The CRO
will arrange for the randomisation scheme (randomization list). The randomisation list will 
be generated using a validated system, which involves a pseudo-random number generator 
and a supplied seed number so that the resulting allocation of medication numbers to 
treatment is both reproducible and non-predictable. See Section 4.1.2 for the method of 
assigning subjects to treatment sequences.
Study Sponsor is responsible for the quality of the study drugs, as well as the import into the 
Russian Federation and the delivery of the IMP in the clinical site.


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7.6
DETERMINATION OF SAMPLE SIZE
A sample size for this trial was determined independently using the parameters AUC and 
Cmax as a basis for sizing the study.
The sample size for this trial was determined assuming an intra-subject coefficient of 
variation (CV) of 18% for AUC and 23% for Cmax considering the data reported in the trial 
107.074 [U93-0094]. Although intra-subject CV was reported 12.9% for AUC and 17.9% for 
Cmax, the data were obtained exclusively from male subjects. Therefore, intra-subject CV 
assumed for this trial (including male and female subjects) was considered at least 5% higher 
than reported previously.
Using CV of 18% for AUC and CV of 23% for Cmax, and a sample size of 24, the power to 
reject the null hypothesis of bio-inequivalence for both parameters (AUC and Cmax) in favour 
of equivalence at the 5% level of significance is displayed in Tables 7.6: 1 and 7.6: 2 under 
various assumptions for the intra-subject ratio.
Table 7.6: 1
Probability of concluding equivalence based on AUC (i.e., acceptance 
range of 80-125%) assuming a coefficient of variation of 18% and 
various values for the intra-subject ratio, for a two-way crossover 
(N=24)
Ratio1
90%
95%
100%
105%
110%
Power
72%
94%
99%
95%
78%
1) This ratio reflects the median intra-subject ratio defined by exp(µT)/exp(µR) and is estimated by the geometric mean
of the intra-subject ratios
Table 7.6: 2
Probability of concluding equivalence based on Cmax (i.e., acceptance 
range of 80-125%) assuming a coefficient of variation of 23% and 
various values for the intra-subject ratio, for a two-way crossover 
(N=24)
Ratio1
90%
95%
100%
105%
110%
Power
54%
81 %
90%
82%
60%
1) This ratio reflects the median intra-subject ratio defined by exp(µT)/exp(µR) and is estimated by the geometric mean 
of the intra-subject ratios
In accordance with guidelines on conduction of BA/BE studies in Russian Federation, the 
minimum required number of volunteers is 18 [Methodical Guidelines for Conduction of 
Bioequivalence Studies]. Assuming 18 participants in the trial, the illustration of probability 
of concluding equivalence based on AUC and Cmax is given below (Tables 7.6: 3 and 7.6: 4).


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Table 7.6: 3
Probability of concluding equivalence based on AUC (i.e., acceptance 
range of 80-125%) assuming a coefficient of variation of 18% and 
various values for the intra-subject ratio, for a two-way crossover 
(N=18)
Ratio1
90%
95%
100%
105%
110%
Power
60%
87%
95%
87%
66%
1) This ratio reflects the median intra-subject ratio defined by exp(µT)/exp(µR) and is estimated by the geometric mean 
of the intra-subject ratios
Table 7.6: 4
Probability of concluding equivalence based on Cmax (i.e., acceptance 
range of 80-125%) assuming a coefficient of variation of 23% and 
various values for the intra-subject ratio, for a two-way crossover 
(N=18)
Ratio1
90%
95%
100%
105%
110%
Power
43%
67%
76%
68%
48%
1) This ratio reflects the median intra-subject ratio defined by exp(µT)/exp(µR) and is estimated by the geometric mean 
of the intra-subject ratios
From the above tables (Tables 7.6: 1 and 7.6: 2), a sample size of 24 will have at least 80% 
power to conclude bioequivalence if the ratio (both for AUC and Cmax) is as much as 5%
different from the ratio that reflects perfect equivalence (i.e., 100%).  Accounting for up to 2
dropouts, 26 subjects will be included in the study.
The calculations for single comparisons were performed as described by Diletti et al [R94-
1445] using the function power. TOST() of the package PowerTOST Version 1.2-03 in R
Version 3.0.3.


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8.
INFORMED CONSENT, DATA PROTECTION, TRIAL
RECORDS
The trial will be carried out in compliance with the protocol, the principles laid down in the 
Declaration of Helsinki [R10-1167], in accordance with the ICH Harmonised Tripartite 
Guideline for Good Clinical Practice (GCP) and relevant BI SOPs. Investigators and site staff 
must adhere to these principles.
The investigator should inform the sponsor immediately of any urgent safety measures taken 
to protect the study subjects against any immediate hazard, and also of any serious breaches 
of the protocol or of ICH GCP.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the investigator and of the sponsor 
with regard to publication of the results of this trial are described in the investigator contract. 
As a rule, no trial results should be published prior to finalization of the Clinical Trial Report. 
The certificate of insurance cover is made available to the investigator and the patients, and is 
stored in the ISF. 
8.1
STUDY APPROVAL, SUBJECT INFORMATION, AND INFORMED 
CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to a subject’s participation in the trial, written informed consent must be obtained from 
each subject (or the subject’s legally accepted representative) according to ICH GCP and to 
the regulatory and legal requirements of the participating country. Each signature must be 
personally dated by each signatory and the informed consent and any additional subject 
information form are to be retained by the investigator as part of the trial records. A copy of 
the signed and dated written informed consent and any additional subject information must be 
given to each subject or the subject’s legally accepted representative.
The subject must be informed that his/her personal trial-related data will be used by 
Boehringer Ingelheim in accordance with the local data protection law. The level of 
disclosure must also be explained to the subject.
The subject must be informed that his or her medical records may be examined by authorised 
monitors (Clinical Monitor Local/Clinical Research Associate) or Clinical Quality Assurance 
auditors appointed by Boehringer Ingelheim, by appropriate IRB/IEC members, and by 
inspectors from regulatory authorities.


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8.2
DATA QUALITY ASSURANCE
A quality assurance audit/inspection of this trial may be conducted by the sponsor or 
sponsor’s designees, by IRBs/IECs, or by regulatory authorities. The quality assurance 
auditor will have access to all medical records, the investigator’s trial-related files and 
correspondence, and the informed consent documentation of this clinical trial.
The data management procedures to ensure the quality of the data are described in detail in 
the trial data management and analysis plan (TDMAP) available in the CTMF.
8.3
RECORDS
CRF will be approved by the sponsor. For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
All data reported in the CRFs must be consistent with the source data or the discrepancies 
must be explained.
The investigator may need to request previous medical records or transfer records, depending 
on the trial.
8.3.2
Direct access to source data and documents
The investigator/institution will permit trial-related monitoring, audits, IRB/IEC review and 
regulatory inspection, providing direct access to all related source data/documents. CRFs and 
all source documents, including progress notes (if applicable) and copies of laboratory and 
medical test results must be available at all times for review by the sponsor’s clinical trial 
monitor, auditor and inspection by health authorities (e.g. FDA). The Clinical Research 
Associate/on site monitor and auditor may review all CRFs, and written informed consents. 
The accuracy of the data will be verified by reviewing the documents described in Section 
8.3.1.
8.3.3
Storage of records
The investigator must retain a comprehensive and centralised filing system of all study
related documentation that is suitable for inspection by the sponsor and representatives of


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regulatory authorities until notified by the sponsor, and at least for fifteen years after study
completion. Documents should be stored in such a way that they can be accessed/data
retrieved at a later date. Consideration should be given to security and environmental risks.
/Clinical site will keep archived documents for at least 15 years after the 
study completion. No study document will be destroyed without prior written agreement 
between the sponsor and the investigator. Should the investigator wish to assign the study 
records to another party or move them to another location, written agreement must be 
obtained from the sponsor.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements. 
8.5
STATEMENT OF CONFIDENTIALITY
Individual subject medical information obtained as a result of this trial is considered 
confidential and disclosure to third parties is prohibited with the exceptions noted below. 
Subject confidentiality will be ensured by using subject identification code numbers.
Treatment data may be provided to the subject’s personal physician or to other appropriate 
medical personnel responsible for the subject’s welfare. Data generated as a result of the trial 
need to be available for inspection on request by the participating physicians, the sponsor’s 
representatives, by the IRB/IEC and the regulatory authorities.
8.6
TRIAL MILESTONES
When the trial is completed or terminated, the investigator should inform the IRB, regulatory.
The start of the trial is defined as site initiation visit.
The end of the trial is defined as site close out visit.
The “Last Patient Last Treatment” (LPLT) date is defined as the date on which the last 
patient in the whole trial is administered the last dose of trial treatment. Individual 
investigators will be notified of SUSARs occurring with the trial medication until 30 days 
after LPLT at their site.
Early termination of the trial is defined as the premature termination of the trial due to any 
reason before the end of the trial as specified in this protocol.


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Temporary halt of the trial is defined as any unplanned interruption of the trial by the 
sponsor with the intention to resume it.
Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
8.7
COMPENSATION AVAILABLE TO THE SUBJECT IN THE EVENT OF 
TRIAL RELATED INJURY
In accordance with the requirements of the Russian Federation legislation, insurance against
the risk of life and health injury is guaranteed to the volunteers participating in the study. The
investigator should inform the volunteer about the insurance cover. 
The volunteer should be informed that he/she is not allowed to undergo other forms of 
treatment without the permission of the investigator (except emergency care), and must 
inform the investigator about any changes in his/her state during participation in the study. 
The terms and conditions of this insurance covered in detail are made available to the
investigator and the subjects in the ISF.


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9.
REFERENCES 
9.1
PUBLISHED REFERENCES
Decision of the 
Eurasian Economic 
Commission No. 85
"On approval of the rules for conducting studies on the bioequivalence 
of medicinal products within the framework of the Eurasian Economic 
Union.”
website.eurasiancommission.org/ru/act/texnreg/deptexreg/LS1/Docum
ents/32.pdf
Methodical 
guidelines for 
conduction of 
bioequivalence 
studies
Ministry of Healthcare and Social Development, Russian Federation, 
2008,
website.rdg-cro.com/wp-content/uploads/2012/07/Guidelines-for-
conducting-bioequivalence-studies-in-Russia.pdf
P12-09147
FDA guidance on meloxicam: recommended bioequivalence studies. 2008.
P07-07106
Yuan Y, Chen X, Zhong D. Determination of meloxicam in human plasma 
by liquid chromatography-tandem mass spectrometry following transdermal 
administration. J Chromatogr (B) - Anal Technol Biomed Life Sci 852 
(1/2), 650 - 654 (2007)
P07-08427
Gschwend MH, Erenmemisoglu A, Martin W, Tamur U, Kanzik I, Hincal 
AA. Pharmacokinetic and bioequivalence study of meloxicam tablets in 
healthy male subjects. Arzneimittelforschung 57 (5), 264 - 268 (2007)
R94-1445       
Sample size determination for bioequivalence assessment using a
multiplicative model. Authors; Authors and affiliations. Dieter Hauschke; 
Volker W. Steinijans; Edgar Diletti; Martin Burke.
R10-1167
WMA Declaration of Helsinki - Ethical Principles for Medical Research 
Involving Human Subjects. 59th WMA General Assembly, Seoul, Korea, 
October 2008.
9.2
UNPUBLISHED REFERENCES
c22930410
Investigator's Brochure: Meloxicam, 107.P0.
U88-0771
 et al. Effect of food and antacid (Maalox 70) on pharmacokinetics 
following single oral administration of UH-AC-62-XX (meloxicam) in 
healthy volunteers. Trial no. 107.022. Internal study report. 1989-01-31.
U92-0311
 and 
 UHAC 62 XX: Efficacy and tolerance of UHAC 
62 XX in daily doses of 15, 30 and 60 mg p.o. and piroxicam in a daily 
dose of 20 mg p.o. in patients with rheumatoid arthritis. Trial no. 107.14. 
Internal study report. 1991-05-06.


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U92-0541
 and 
 A three weeks, double-blind, 
placebo-controlled study to compare the efficacy and safety of three 
different doses of Meloxicam (7,5 mg, 15 mg, and 30 mg) given once daily 
in patients with osteoarthritis of the knee. Trial no. 107.42. Internal study 
report. 1992-04-03.
U93-2016
 and 
 A six weeks, double-blind, controlled study to 
compare the efficacy and safety of two different doses of Meloxicam (15 
mg and 30 mg) with Diclofenac sodium sustained release (100 mg) in 
patients with osteoarthritis of the knee. Trial no. 107.44. Internal study 
report. 1993-05-28.
U93-2036
 and 
 A six months double-blind study to 
compare the efficacy, safety and tolerance of meloxicam (UHAC-62) and 
piroxicam in patients with osteoarthritis of the hip or the knee. Trial no. 
107.45. Internal study report. 1993-07-26.
U93-0260
 et al. Examination of the effect of high fat food on the bio-
availability of 15 mg UH-AC 62 XX capsules administered orally to 
healthy volunteers. Trial no. 107.071. Internal study report. 1992-
December.
U93-2066
and 
 A double-blind, placebo-controlled trial to
evaluate the efficacy and safety of 15 mg Meloxicam (UH AC 62 XX) once 
daily per os and 7.5 mg Meloxicam once daily per os in patients with 
rheumatoid arthritis. Trial no. 107.35. Internal study report. 1993-08-25.
U93-0094
 et al. Determination of the relative bioavailability of 15 mg UH-
AC 62 XX tablets compared with 15 mg UH-AC 62 XX capsules after oral 
administration over 7 days to healthy volunteers. Trial no. 107.74. Internal 
study report. 1992-07-06.
U93-2021
 and 
 A six month study to compare the efficacy and 
tolerance of 15 mg Meloxicam (UHAC 62 XX) capsules and 20 mg 
Piroxicam capsules in patients with rheumatic arthritis. Trial no. 107.36. 
Internal study report. 1993-05-28.
U93-2038
 et al. Determination of the relative bioavailability of 7.5 mg
UH-AC 62 XX tablets q.d. compared with 7.5 mg UH-AC 62 XX capsules 
q.d. and dose-proportionality between 7.5 mg and 15 mg UH-AC 62 XX 
capsules q.d. after oral administration over 7 days to healthy volunteers in a 
three-way cross-over design. Trial no. 107.82. Internal study report. 1993-
07-27.
U93-2054
 and 
 A six month double-blind trial to 
compare the efficacy and safety of Meloxicam (UHAC 62 XX) 7.5 mg and 
Naproxen 750 mg daily p.o. in patients with rheumatoid arthritis. Trial no. 
107.61. Internal study report. 1993-07-30.
U95-2126
 et al. Relative bioavailability of the 7.5 mg meloxicam suppository 
in comparison with the 7.5 mg meloxicam capsule in steady state in healthy 
volunteers. Open, randomized two-way crossover trial. Trial no. 107.116. 
1995-06-20.


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U97-0033
 and 
 Comparative assessment of the efficacy and
safety of orally administered meloxicam (15 mg daily), meloxicam (22.5 
mg daily), piroxicam (20 mg daily) and placebo in patients with ankylosing 
spondylitis. A one year double-blind phase III trial. Trial no. 107.98. First 
six weeks report. 1997-01-24.
U97-2327
 et al. Relative bioavailability of 15 mg meloxicam syrup p.o. in 
comparison to 15 mg meloxicam capsule p.o. after steady state in healthy 
subjects. Open, randomised, two-way cross-over trial. Trial no. 107.172. 
1997-04-29.
U98-0090
 and 
 Comparative assessment of the efficacy and 
safety of orally administered meloxicam (15 mg daily), meloxicam (22.5 
mg daily), piroxicam (20 mg daily) and placebo in patients with ankylosing 
spondylitis. A one year double-blind phase III trial. Trial no. 107.98. One 
year report. 1997-12-19. 
U98-2348
 et al. Influence of a 40 g fat breakfast on the single oral dose
pharmacokinetics of the 7.5 mg meloxicam tablet (American type) in 
healthy subjects: a two-way cross over randomized open study. Trial no. 
107.178. Internal study report. 1998-07-02.
U98-3221
 et al. A multicenter, double- blind, double-dummy, randomized, 
parallel-group trial to compare the efficacy and safety of three doses of 
Meloxicam (3.75, 7.5, and 15 mg) with placebo in patients with 
osteoarthritis of the knee or hip; and diclofenac (100 mg) as an active 
control to assess trial sensitivity. Trial no. 107.181. Internal study report. 
1998-11-07.
U99-3147
 et al. A multicenter, double-blind, double-dummy, randomized, 
parallel-group trial to compare the efficacy and safety of three doses of 
meloxicam (7.5, 15 and 22.5 mg) with placebo in patients with rheumatoid 
arthritis; and with diclofenac (150 mg) as an active control to assess trial 
sensitivity. Trial no. 107.183. Internal study report. 1999-10-04.
U02-0061
9th Periodic Safety Update report: Meloxicam tablets 7.5 mg, 15 mg,
Meloxicam capsules 7.5 mg, 15 mg, Meloxicam suppositories 7.5 mg, 15 
mg, Meloxicam capsules 7.5 mg/1.5 mL, 15 mg/1.5 mL, Meloxicam oral 
suspension 7.5 mg/5 mL (period covered: 14 January 2001 to 13 January 
2002). 2002-03-14.
U04-0230
10th Periodic Safety Update report: Meloxicam tablets 7.5 mg, 15 mg,
Meloxicam capsules 7.5 mg, 15 mg, Meloxicam suppositories 7.5 mg, 15 
mg, Meloxicam capsules 7.5 mg/1.5 mL, 15 mg/1.5 mL, Meloxicam oral 
suspension 7.5 mg/5 mL (period covered: 14 January 2002 to 8 November 
2004). 2004-12-30.
U07-0105
11th Periodic Safety Update report: Meloxicam tablets 7.5 mg, 15 mg,
Meloxicam capsules 7.5 mg, 15 mg, Meloxicam suppositories 7.5 mg, 15 
mg, Meloxicam capsules 7.5 mg/1.5 mL, 15 mg/1.5 mL, Meloxicam oral 
suspension 7.5 mg/5 mL (period covered: 9 November 2004 to 9 July 
2007). 2007-09-05.


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U09-0192-01  
12th Periodic Safety Update report: Meloxicam tablets 7.5 mg, 15 mg,
Meloxicam capsules 7.5 mg, 15 mg, Meloxicam suppositories 7.5 mg, 15 
mg, Meloxicam capsules 7.5 mg/1.5 mL, 15 mg/1.5 mL, Meloxicam oral 
suspension 7.5 mg/5 mL (period covered: 10 July 2007 to 9 September 
2009). 2009.
U10-2374-01
13th Periodic Safety Update report: Meloxicam tablets 7.5 mg, 15 mg,
Meloxicam capsules 7.5 mg, 15 mg, Meloxicam suppositories 7.5 mg, 15 
mg, Meloxicam capsules 7.5 mg/1.5 mL, 15 mg/1.5 mL, Meloxicam oral 
suspension 7.5 mg/5 mL (period covered: 10 September 2009 to 9 July 
2010). 2010.
U11-1340-01
. Report: Interim safety report on Meloxicam (during period Jul 
2010 - Jan 2011). 2011-03-07.


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10.
APPENDICES
10.1
CLINICAL EVALUATION OF LIVER INJURY
10.1.1
Introduction
Alterations of liver laboratory parameters, as described in Section 5.2.2.1 (Protocol-specified 
AESIs), are to be further evaluated using the following procedures:
10.1.2
Procedures
Repeat the following laboratory tests: ALT, AST, and bilirubin (total and direct) - within 48 
to 72 h. If it is confirmed that ALT and/or AST values ≥3 fold ULN occur in conjunction 
with an elevation of total bilirubin of ≥2 fold ULN, the laboratory parameters listed below 
(clinical chemistry, serology, hormones, haematology) must be determined and made 
available to the investigator and to BI as soon as possible.
In addition,

obtain a detailed history of current symptoms and concurrent diagnoses and medical 
history according to the ‘DILI checklist’ provided in the ISF

obtain history of concomitant drug use (including non-prescription medications, herbal 
and dietary supplement preparations), alcohol use, recreational drug use, and special diets 
according to the ‘DILI checklist’ provided in the ISF;

obtain a history of exposure to environmental chemical agents (consider home and work 
place exposure) according to the ‘DILI checklist’ provided in the ISF;
and report these via the CRF.
Clinical chemistry
Total protein, glucose, total cholesterol, total bilirubin, creatinine, aspartate transaminase 
(AST), alanine transaminase (ALT), alkaline phosphatase (AP) electrolytes (Na, K, Ca).
Serology
Hepatitis B Surface Antigen (qualitative HbsAg test); hepatitis C Antibodies (qualitative anti-
HCV total); HIV-1 and HIV -2 Antibody (qualitative anti-HIV1/2); RPR test for syphilis 
(Rapid plasma reagin test).


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Haematology
Erythrocyte sedimentation rate (ESR), hematocrit (Hct), haemoglobin (Hb), erythrocytes/ red 
blood cells (RBC), platelet count, leucocytes/white blood cells (WBC), differential WBC 
(neutrophils, eosinophils, basophils, monocytes, lymphocytes).

Provide abdominal ultrasound to rule out biliary tract, pancreatic or intrahepatic 
pathology, e.g. bile duct stones or neoplasm.

Initiate close observation of subjects by repeat testing of ALT, AST, and total bilirubin 
(total and direct) at least weekly until the laboratory ALT and/or AST abnormalities 
stabilize or return to normal, then monitor further as specified in the CTP. Depending on 
further laboratory changes, additional parameters identified e.g. by reflex testing will be 
followed up based on medical judgement and Good Clinical Practices (GCP).
10.2
CONTACT INFORMATION OF THE CRO AND THE CENTRAL 
LABORATURY
10.2.1
Clinical research organization
Name: 
Address: 
Study staff: 
Full name
Title
Address and contact information
Address: 
 
Telephone: 
Mobile: 
E-mail: 
 
Address: 
 
Telephone: 
Mobile: 
E-mail:


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10.2.2
Local Clinical Laboratory
Name:
 
Address:
Study staff: 
Full name
Title
Address and contact information
 
 
Telephone: 
Mobile: 
E-mail:
This laboratory will be used to conduct complete blood count, blood chemistry tests, 
urinalysis, and urine sediment.
10.2.3
Central Clinical Laboratory
Name:
Address:
Study staff: 
Full name
Title
Contact information
Telephone: 
This laboratory will be used to conduct serological tests for HIV, hepatites and syphilis.


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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the original protocol.
Number of global amendment
Date of CTP revision
EudraCT number
BI Trial number
BI Investigational Product(s)
Title of protocol
To be implemented only after 
approval of the IRB / IEC /
Competent Authorities
To be implemented 
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for 
approval
Can be implemented without 
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
Section to be changed
Description of change
Rationale for change


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c22345272
1.0
clinical-trial-protocol-version-01
An open-label, randomised, single-dose, two-way crossover study in healthy male
and female volunteers to evaluate the relative bioavailability of a new oral
formulation of meloxicam, Movalis capsules 15 mg, versus Movalis tablets 15 mg,
after administration under fasting state.
Author-Clinical Monitor
28 May 2018 13:36 CEST
Approval-
 Established Core
Products
28 May 2018 13:55 CEST
Approval-Team Member Medical
Affairs
30 May 2018 13:40 CEST
Author-Trial Statistician
04 Jun 2018 08:38 CEST
Verification-Paper Signature
Completion
04 Jun 2018 08:46 CEST


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c22345272
1.0

SAP_001.pdf: 
Confidential
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Statistical Analysis Plan
BI trial Number:
 project code:
Protocol Title:
Effective date:
Version No.:
0107-0277
17BI01
An open-label, randomised, single-dose, two-way crossover study in 
healthy male and female volunteers to evaluate the relative 
bioavailability of a new oral formulation of meloxicam, Movalis® 
capsules 15 mg, versus Movalis® tablets 15 mg, after administration 
under fasting state.
06 May 2019 
1.0 dated 06 May 2019 
CONFIDENTIAL PROPERTY OF 
 
This document contains confidential information of 
, which is not to be disclosed.  
Persons for whom are these data, taking the document, undertake not to publish or distribute the 
information in any other way without written consent of the 
. 


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СHANGE HISTORY
Version
Date
Description
Author
1.0
06 May 2019
New version


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SIGNATURES 
Author:
______________________________________
____________
Signature
Date
Name: ___________________________________________________
Position:
Data manager 
Approved:
______________________________________
____________
Signature
Date
Name:____________________________________________________
Position:
Head of the Data Management Department 
Approved:
______________________________________
____________
Signature
Date
Name:____________________________________________________
Position:
Bioequivalence studies Project Manager 
Approved (Sponsor):
______________________________________
____________
Signature
Date 
Name: ____________________________________________________
Position:
Project Manager 


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TABLE OF CONTENTS
SIGNATURES........................................................................................................................................................ 3
1.
Study Rationale.............................................................................................................................................. 6
1.1.
Introduction................................................................................................................................................ 6
1.2.
Study Hypothesis and Preliminary Data.................................................................................................... 6
1.3.
Protocol Synopsis ...................................................................................................................................... 6
2.
Study Goals.................................................................................................................................................... 8
3.
Study Endpoints ............................................................................................................................................. 8
3.1.
Primary Endpoints ..................................................................................................................................... 8
3.2.
Secondary endpoints.................................................................................................................................. 8
4.
Study Design.................................................................................................................................................. 9
4.1.
Number of comparison groups................................................................................................................... 9
4.2.
Number of centers...................................................................................................................................... 9
4.3.
Masking type.............................................................................................................................................. 9
4.4.
Randomization........................................................................................................................................... 9
4.5.
Control method .......................................................................................................................................... 9
4.6.
Inclusion Criteria ....................................................................................................................................... 9
4.7.
Non-inclusion criteria .............................................................................................................................. 10
4.8.
Exclusion criteria..................................................................................................................................... 11
4.9.
Total number of subjects and conditions of distribution to treatment groups.......................................... 12
4.10.
Description of intervention ...................................................................................................................... 12
4.10.1.
The test drug ......................................................................................................................................... 13
4.10.2.
The reference drug................................................................................................................................ 13
4.10.3.
Dosage .................................................................................................................................................. 13
4.10.4.
Method of administration...................................................................................................................... 13
4.10.5.
Duration of administration.................................................................................................................... 13
4.10.6.
Description of study visits and procedures during each visit................................................................ 13
4.10.6.1.
Screening and introductory period.................................................................................................... 13
4.10.6.2.
Treatment period............................................................................................................................... 14
4.10.6.2.1.
Period I/Visit 2.............................................................................................................................. 14
4.10.6.2.2.
Period II/Visit 3............................................................................................................................. 15
4.10.6.2.3.
Completion of the study and follow-up period ............................................................................. 17
5.
Power and Sample Size................................................................................................................................ 17
6.
Data Management Procedures...................................................................................................................... 19
6.1.
Study Database ........................................................................................................................................ 19
6.2.
Study Datasets.......................................................................................................................................... 19


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6.3.
Data Modifications .................................................................................................................................. 19
6.4.
Blinding and Randomization. .................................................................................................................. 19
6.5.
Unblinding Methods and Procedures....................................................................................................... 19
7.
Study Populations......................................................................................................................................... 19
7.1.
Safety Population (SP)............................................................................................................................. 19
7.2.
Pharmacokinetic population (PKP).......................................................................................................... 19
8.
Subjects Accountability................................................................................................................................ 19
9.
Data and values of indicators obtained during the study.............................................................................. 20
9.1.
Safety data................................................................................................................................................ 20
9.1.1.
Nominal data............................................................................................................................................ 20
9.1.2.
Interval (quantitative) data....................................................................................................................... 20
9.1.3.
Handling missing data ............................................................................................................................. 20
9.2.
Pharmacokinetic data............................................................................................................................... 20
9.2.1.
Primary analysis....................................................................................................................................... 21
9.2.2.
Secondary assays ..................................................................................................................................... 21
9.2.3.
Dispersion analysis .................................................................................................................................. 22
9.3.
Safety Analysis ........................................................................................................................................ 23
9.3.1.
Adverse Events ........................................................................................................................................ 23
9.3.2.
Clinical Laboratory Evaluations .............................................................................................................. 23
9.3.3.
Vital Signs................................................................................................................................................ 24
9.3.4.
Physical Examinations............................................................................................................................. 24
9.3.5.
Electrocardiography................................................................................................................................. 25
9.3.6.
General assessment.................................................................................................................................. 25
9.4.
Restrictive laboratory tests....................................................................................................................... 25
9.5.
Other data................................................................................................................................................. 25
10.
References................................................................................................................................................ 26
Appendix 1............................................................................................................................................................ 27
Appendix 2............................................................................................................................................................ 29
Appendix 3............................................................................................................................................................ 56


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1. Study Rationale
1.1. Introduction
This document contains Summary Results Plan (descriptive statistics) and Statistical Analysis 
Results of a clinical bioequivalence study. The clinical report on the results of this clinical study 
will mainly be based on the results of the statistical analysis designed in this document.
1.2. Study Hypothesis and Preliminary Data
The bioequivalence of Movalis® capsules 15 mg versus Movalis® tablets 15 mg, is established 
by average bioequivalence method to make sure that the coefficient of PK parameters (AUC0-t or 
AUC0-∞and Cmax) of both treatments (T/R) is within the specified acceptable range. The 
acceptable range for geometric mean ratio is 80-125% for AUC0-t and 80-125% for Cmax [1].
Check the equivalence hypothesis: 

Null hypothesis on the no equivalence (H0): μT-μR≤-δ or μT-μR≥ δ (i.e. the difference in the
average population responses is less than or equal to the lower limit, or higher than or equal
to the upper limit of the acceptable range).

Alternative hypothesis on the bioequivalence (HА): -δ <μT-μR<δ (i.e., the difference of the
average population responses is higher than the lower limit and less than the upper limit of
the acceptable range), where μT and μR are the average responses of the population of log-
transformed values for dosage forms T (Movalis® capsules 15 mg) and R (Movalis® tablets
15 mg), and δ is the bioequivalence limit that determines the acceptable range for AUC0-t or
AUC0-∞and Cmax on logarithmic scale.
In this study, e.g., δ is taken for ln(1.25) to compare AUC. This corresponds to an acceptable 
range of 80 to 125% for the geometric mean ratio of parameters on the original scale.
This hypothesis and its alternative can be divided into two one-sided null hypotheses, H01 and 
H02, with the concomitant alternatives:
H01: µT-µR≤-δ
versus HA1: µT-µR> -δ 
H02: µT-µR≥ δ
versus HA2: µT-µR <δ
Due to the nature of the confidence intervals obtained under the test of hypothesis on normal 
distribution, the test of null hypothesis at α = 0.05 is equivalent to two one-sided tests of the 
above null hypotheses, each with α = 0.05 significance level. The deviation of both null 
hypotheses H01 and H02 at α = 0.05 is equivalent to the inclusion of 90% confidence interval for 
μT-μR in the acceptable range.
1.3. Protocol Synopsis
Study ID:
0107-0277
Protocol version and 
date:
Version: 1.0 dated May 28, 2018
BI Study ID:
0107-0277
Protocol amendments:
Not applicable
Protocol title:
An open-label, randomised, single-dose, two-way crossover study in healthy male and 
female volunteers to evaluate the relative bioavailability of a new oral formulation of 
meloxicam, Movalis® capsules 15 mg, versus Movalis® tablets 15 mg, after 
administration under fasting state.


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Principal Investigator: 
.
Address: 
Phone: 
Fax: 
Study site:
Address: 
Study phase:
Bioequivalence study
Objectives:
Primary objective:
Study relative bioavailability of Movalis® capsules 15 mg, versus Movalis® tablets 15 
mg.
Secondary objectives:
1.
Establish the bioequivalence of Movalis® capsules 15 mg, and Movalis® tablets
15 mg.
2.
Evaluation of safety and tolerability is an additional study objective.
Methodology:
It will be an open-label, randomised, two-way crossover study with a single dose of 
medicinal products taken by healthy male and female volunteers under fasting state, 
conducted in the clinical study site located in the Russian Federation.
Number of subjects: 
26
Test drug:
Movalis® capsules 15 mg (T)
Reference drug:
Movalis® tablets 15 mg (R)
Number of subjects in 
each group:
Movalis® capsules 15 mg (Test drug, T) – 26,
Movalis® tablets 15 mg (Reference drug, R) – 26
Diagnosis:
Not applicable 
Duration of study 
participation:
Not more than 32 days.
Main inclusion criteria:
Male and female subjects aged 18-45 years old, inclusive.
Body mass index according to the Quetelet index in the range of 18.50 – 29.99 kg/m2, 
inclusive.
Pharmacokinetics 
criteria:
Primary endpoints: AUC0-t and Cmax.
Secondary endpoints: AUC0-∞.
Safety criteria:
Vital signs (blood pressure, pulse
rate, body temperature, respiratory rate), 
performance status, physical examination, 12-lead ECG, laboratory tests, adverse 
events.


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Statistical methods:
Two-sided 90% confidence intervals for the intra-individual ratio (according to 
geometric mean) for each of the AUC0-t, AUC0-∞and Cmax indices will be calculated 
to determine if confidence intervals enter acceptable bioequivalence range (80-125% 
for AUC0-t; 80-125% for Cmax). 
The drugs will be considered bioequivalent:

if the limits of the estimated confidence interval for AUC0-t are within the range of 
80.00–125.00%;

if the limits of the estimated confidence interval for Cmax are within the range of 
80.00–125.00%.
As a statistical model, analysis of variance (ANOVA) for log-transformed parameters 
will be used, including such effects as “sequences”, “study subjects grouped within a 
sequence”, “period” and “type of therapy”. Confidence intervals will be calculated 
according to the residual error obtained in the ANOVA analysis of variance. The 
effect of “study subjects grouped within a sequence” will be considered random, 
while other effects are fixed.
The descriptive statistics values will be calculated for all other parameters.
2. Study Goals
Primary objective:

Study relative bioavailability of Movalis® capsules 15 mg, versus Movalis® tablets 15 mg.
Secondary objectives:

Establish the bioequivalence of Movalis® capsules 15 mg, and Movalis® tablets 15 mg.

Evaluation of safety and tolerability is an additional study objective.
3. Study Endpoints
3.1. Primary Endpoints
Relative bioavailability should be studied primarily under the following pharmacokinetic 
parameters:

AUC0-t (the area under the concentration-time curve of the analyte in plasma over the interval
from 0 to the last quantifiable data point).

Cmax (maximum measured concentration of the analyte in plasma).
3.2. Secondary endpoints
The following secondary endpoints will be evaluated:
Pharmacokinetic parameters:

AUC0-∞(the area under the concentration-time curve of the analyte in plasma over the
interval from 0 with extrapolation to infinity).


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4. Study Design
This is an open-label, single-dose, randomised, two-way crossover study. Study subjects will be 
randomly assigned to one of two treatment sequences
4.1. Number of comparison groups
Two comparison groups: 
• Movalis® capsule 15 mg,
• Movalis® tablet 15 mg
4.2. Number of centers
This clinical study is planned to be conducted in one clinical center: 
 
.
4.3. Masking type
Not applicable.
4.4. Randomization
Subjects will be randomized to one of two treatment sequences at ratio of 1:1. CRO will 
determine the randomization scheme (make a randomization list). A randomization list will be 
created using a validated system that includes a pseudo-random number generator and the 
provision of random numbers so that the number distribution to subjects is reproducible and 
unpredictable.
4.5. Control method
Not applicable.
4.6. Inclusion Criteria
1. Men and women aged 18–45 years old, inclusive.
2. Body mass index according to the Quetelet index in the range of 18.50–29.99 kg/m2,
inclusive.
3. The verified diagnosis “healthy” as concluded by the Investigator according to the medical
history, results of the physical examination, ECG, vital signs (blood pressure, heart rate,
respiratory rate and body temperature), and laboratory parameters.
4. Preliminary standard clinical and laboratory studies and investigations did not reveal any
diseases or abnormalities.
5. Systolic blood pressure is not less than 100 mmHg and not higher than 139 mmHg; diastolic
blood pressure is not less than 70 mmHg and not more than 90 mmHg; heart rate is not less
than 60 bpm and not more than 90 bpm, respiratory rate is within 12-20 per minute.
6. Ability to understand and accept study rationale; available written informed consent of the
volunteer to participate in the study in accordance with the applicable law.


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7. For females with preserved reproductive potential: a negative pregnancy test and consent to
adhere to adequate contraceptive methods from a screening visit to 30 days after the last dose
of the test drug, inclusive. If a woman is postmenopausal (no menstruation for at least 1 year)
or she underwent surgical sterilization (bilateral tubal ligation, bilateral oophorectomy or
hysterectomy), she is not eligible for this requirement. If oral contraceptives are used, they
should be withdrawn at least 2 months before study initiation.
8. For males: consent to adhere to adequate contraceptive methods (barrier methods of
contraception) from a screening visit to 30 days after the last dose of the test drug, inclusive.
4.7. Non-inclusion criteria
1. Drug intolerance to any medicinal product.
2. Positive history of allergies.
3. Acute infectious diseases or allergic reactions that require treatment (including drug allergy),
less than 4 weeks before the first day of screening.
4. Gastrointestinal surgeries (except of appendectomy), which can significantly affect
absorption or metabolism of the investigational products.
5. Volunteers with known hypersensitivity to meloxicam or any excipient of the test drug or
reference drug.
6. Known hypersensitivity to NSAIDs: volunteers who developed signs of bronchial asthma,
nasal polyps, angioedema or urticaria after administration of acetylsalicylic acid or other
NSAIDs.
7. Chronic diseases of cardiovascular, bronchopulmonary, neuroendocrine system, as well as
gastrointestinal, hepatic disorders, kidney diseases, blood disorders or other conditions that
does not allow a volunteer to participate in the study as concluded by the Investigator.
8. Results of standard laboratory tests and investigations obtained during the screening that are
outside the normal limits.
9. History of ulcers/GI perforations or bleeding; history of malignancies within 5 years prior to
the screening period.
10. Positive blood test results for infectious diseases (HIV, syphilis, hepatitis B or C) at
screening.
11. Positive breath alcohol test at screening.
12. Positive urine drug screen for narcotic and potent substances (marijuana, benzodiazepine,
barbiturates, opiates, cocaine and amphetamine) at screening.
13. Pregnancy or breastfeeding.
14. Any diet, e.g., vegetarian within 2 weeks before the first day of screening.
15. Ingestion of more than 10 units of alcohol per week (1 unit of alcohol is equivalent to ½ liter
of beer, 200 mL of wine or 50 mL of alcohol) or history of alcoholism, drug addiction or
abuse of medicinal products.
16. Impossibility to get along without food for at least 12 hours and inability for drug
administration under fasting conditions.
17. Blood donation (450 mL of blood or plasma and more) within 3 months before screening.


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18. Depot injections, installation of intrauterine hormonal therapeutic systems or implants of any
medicinal products 6 months prior to screening.
19. For females: use of hormonal contraceptives less than 2 months before screening.
20. Regular drug administration less than 2 weeks before screening.
21. Administration of medicinal products that have a pronounced effect on liver function, etc.
(barbiturates, omeprazole, cimetidine, etc.), within 4 weeks before screening.
22. For females: volunteers with preserved reproductive potential who had unprotected
intercourse with an unsterilized male partner within 30 days prior to screening.
23. Participation in any other clinical study or administration of investigational products within 3
months before screening.
24. Difficult venous access which complicates or prevents the installation of a catheter and
frequent blood draws.
25. Smoking (≥10 cigarettes or ≥ 3 pipes daily).
26. Inability to refrain from smoking during the study.
27. Volunteers who do not want or are unable to give up alcohol and vigorous exercises from the
first day of screening to the follow-up visit.
28. Volunteers who do not want or are unable to refuse drinks or food containing
methylxanthines (coffee, tea, cola, energy drinks, chocolate, etc.), as well as
grapefruit/grapefruit juice, bitter orange (marmalade) and its juice, food additives and
products, including St. John’s wort (Hypericum perforatum), from the first day of screening
to the follow-up visit.
29. Volunteers with a lifestyle (including night work and extreme physical activities such as
sports or weight lifting), which can interfere the interpretation of the laboratory data obtained
during the study.
30. Volunteers who will not adhere to the study regime.
31. Volunteers who are apparently or likely, as concluded by the Investigator, not able to
understand and evaluate the study-related information during ICF signing, in particular
regarding the expected risks and possible discomfort.
32. Dehydration in volunteers due to diarrhea, vomiting or other cause within the last 24 hours
before the first day of screening.
33. Volunteers with history of seizures, epilepsy and any other neurological disorders.
34. Recent cerebral hemorrhage or proved systemic bleeding disorders.
35. History of lactose intolerance.
36. Reports on difficulty in swallowing tablets or capsules.
4.8. Exclusion criteria
1. A volunteer withdrew the informed consent, and the justification is not required.
2. The Investigator decided that the volunteer should be excluded for the benefit of the
volunteer himself/herself.


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3. Non-compliance with non-inclusion criteria revealed during the study. Abnormalities of vital 
signs, as well as in standard investigations versus normal limits revealed after the volunteer 
administered the investigational product, are defined adverse events.
4. Emerged AE/SAE when the continuation of volunteer’s participation in the study is 
undesirable or impossible (as concluded by the Sponsor/Manufacturer or Investigator).
5. Vomiting or diarrhea within 12 hours after drug administration.
6. A volunteer should administer concomitant drugs which cannot be used with the test drug, 
other investigational products, or if any unauthorized medicinal product is to be used 
concomitantly (Protocol violation).
7. Failure to adhere to the Protocol requirements: the schedule for biosamples collection (2 
times and more), the regime throughout the study, including the “washout” period (drinking 
alcohol, prohibited foods, etc.).
8. A volunteer does not comply with the rules of inpatient stay.
9. A volunteer receives additional treatment (or needs additional treatment), which can affect 
the pharmacokinetics of the investigational product.
10. A volunteer needs hospitalization during the study.
11. Volunteers visit the hospital after the appointed time (more than 1 hour late) which violates 
the Protocol requirements.
12. A volunteer has a positive breath alcohol test.
13. A volunteer has a positive pregnancy test.
14. A volunteer has a positive drug screen for narcotic and potent substances (marijuana, 
benzodiazepine, barbiturates, opiates, cocaine and amphetamines).
15. If the emerged adverse events to the drug are so serious that the continuation of the study is 
unacceptable.
16. A volunteer has ≥3-fold AST and/or ALT level increase versus ULN together with ≥2-fold 
increase in total bilirubin versus ULN (measured in the same blood sample) and/or if follow 
up is required in accordance with section 10.1 of this study Protocol and a “therapeutic and 
prophylactic meals checklist” is provided to the federal study site. 
4.9. Total number of subjects and conditions of distribution to treatment groups
It is planned to enroll 26 healthy male and female volunteers. Volunteers will be randomized 
(see section 4.4) to one of two treatment sequences:

TR (Test drug administration in the first study period and Reference drug administration in
the second study period).

RT (Reference drug administration in the first study period and Test drug administration in
the second study period).
4.10.
Description of intervention
The therapy includes the administration of Movalis®, one capsule 15 mg, under fasting 
condition, as Test drug (T), and Movalis®, one tablet 15 mg, under fasting condition, as 
Reference drug (R).


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4.10.1. The test drug
Movalis® capsules 15 mg.
INN
Meloxicam
Trade name
Movalis®
Dosage form
Capsules
Active ingredient
Meloxicam 15 mg
Manufacturer
Boehringer Ingelheim Ellas A.E., Greece
Pharmacotherapeutic group
Non-steroidal anti-inflammatory drug 
4.10.2. The reference drug
Movalis® tablets 15 mg.
4.10.3. Dosage
Test drug: 1 capsule (15 mg) of Movalis®.
Reference drug: 1 tablet (15 mg) of Movalis®.
4.10.4. Method of administration
Oral administration with 200 mL of water under fasting at night time for at least 10 h.
4.10.5. Duration of administration
Single dose of the test drug and reference drug by each study subject.
4.10.6. Description of study visits and procedures during each visit
Study procedures schedule is described in Appendix 1.
4.10.6.1.
Screening and introductory period
Screening procedures are necessary to determine the eligibility of a subject in terms of study 
inclusion criteria. Screening procedures include the following:

Demographic data collection;

Medical history collection (including lifestyle and pernicious habits);

Medication history collection;

Measurement of body weight and body height, calculation of body mass index (BMI);

Assessment of vital functions: blood pressure, pulse rate, body temperature, respiratory rate;

Physical examination;

Review of tests for exclusion: serological test of blood plasma to detect infectious diseases,
urine pregnancy test, urine drug screen for narcotic and potent substances, breath alcohol
test;
INN
Meloxicam
Trade name
Movalis®
Dosage form
Tablets
Active ingredient
Meloxicam 15 mg
Manufacturer
Boehringer Ingelheim Ellas A.E., Greece and Boehringer Ingelheim 
Pharma GmbH & Co. KG, Germany
Pharmacotherapeutic group
Non-steroidal anti-inflammatory drug


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
Standard laboratory tests under fasting condition (hematology, blood biochemistry and
urinalysis with microscopic examination of urinary sediment);

12-lead ECG (if 12-lead ECG is taken  between Day -7 and Day -1 (inclusive) at the
screening stage, its results can also be used on Day -1, Period I);

Evaluation of study inclusion/non-inclusion criteria;

Evaluation of adverse events.
4.10.6.2.
Treatment period
Each subject will have two 4-day periods during the treatment phase. The administration of the 
test drug and reference drug will be separated by a 7-day washout period (about 8 half-lives). 
4.10.6.2.1.
Period I/Visit 2
Day -1 
The following study procedures will be performed before subjects randomization:

Physical examination.

Evaluation of adverse events.

Documenting concomitant medications.

Assessment of changes in medical history.

Assessment of adherence to study limitations.

Review of tests for exclusion: urine pregnancy test, urine drug screen for narcotic and potent
substances, breath alcohol test.

Assessment of vital functions: blood pressure, pulse rate, body temperature, respiratory rate.

12-lead ECG (If 12-lead ECG is taken between Day -7 and Day -1 (inclusive) at the
screening stage, its results can also be used on Day -1, Period I).

Performance status.

Evaluation of inclusion/non-inclusion criteria.
Randomization will be performed on Day -1, after completion of all study procedures. 
Randomization numbers will be assigned sequentially in ascending order. A randomization 
number is designated to the study subject throughout the study.
Day 1 
Time point from 2 hours before the 
administration of the investigational 
product 
to 
1 
minute 
before 
the 
administration of the investigational 
product:
Blood collection for PK before the administration of the investigational 
product.
Assessment of vital functions: blood pressure, pulse rate, body 
temperature, respiratory rate.
Evaluation of adverse events.
Documenting concomitant medications.
Timepoint 00:00: 
Administration of the investigational product (capsule or tablet) under 
fasting conditions seated/standing with 200 mL of boiled water having 
the room temperature.
Timepoint 00:30±0:02 minutes: 
Blood collection for PK.
Timepoint 01:00±0:02 minutes: 
Blood collection for PK.
Timepoint 02:00±0:02 minutes: 
Blood collection for PK.
Timepoint 03:00±0:05 minutes:
Blood collection for PK.
Timepoint 04:00±0:05 minutes:
Blood collection for PK.
Breakfast.
Timepoint 05:00±0:05 minutes: 
Blood collection for PK.
Timepoint 06:00±0:05 minutes:
Blood collection for PK.
Assessment of vital functions: blood pressure, pulse rate, body 
temperature, respiratory rate.


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Evaluation of adverse events.
Lunch.
Documenting concomitant medications.
Timepoint 07:00±0:10 minutes: 
Blood collection for PK.
Timepoint 08:00±0:10 minutes:
Blood collection for PK.
Timepoint 09:00: 
Snack.
Timepoint 10:00±0:10 minutes: 
Blood collection for PK.
Timepoint 11:00: 
Supper.
Timepoint 12:00±0:10 minutes: 
Blood collection for PK.
Assessment of vital functions: blood pressure, pulse rate, body 
temperature, respiratory rate.
Evaluation of adverse events.
Documenting concomitant medications.
Day 2 
Timepoint 24:00±0:15 minutes: 
Blood collection for PK.
Physical examination.
Assessment of vital functions: blood pressure, pulse rate, body 
temperature, respiratory rate.
Performance status.
Evaluation of adverse events.
Documenting concomitant medications.
Timepoint 32:00±0:15 minutes: 
Blood collection for PK.
Day 3 
Timepoint 48:00±0:15 minutes: 
Blood collection for PK.
Physical examination.
Assessment of vital functions: blood pressure, pulse rate, body 
temperature, respiratory rate.
Performance status.
Evaluation of adverse events.
Documenting concomitant medications.
Day 4
Timepoint 72:00±0:15 minutes: 
Blood collection for PK.
Physical examination.
Assessment of vital functions: blood pressure, pulse rate, body 
temperature, respiratory rate.
Performance status.
Evaluation of adverse events.
Documenting concomitant medications.
Standard laboratory tests (complete blood count, blood biochemistry and 
urinalysis with microscopic examination of urinary sediment).
4.10.6.2.2.
Period II/Visit 3
Day 7 
After the end of hospitalization the following study procedures will be performed:

Physical examination.

Evaluation of adverse events.

Documenting concomitant medications.

Assessment of changes in medical history.


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
Assessment of adherence to study limitations.

Review of tests for exclusion: urine pregnancy test, urine drug screen for narcotic and potent
substances, breath alcohol test.

Assessment of vital functions: blood pressure, pulse rate, body temperature, respiratory rate.

12-lead ECG.

Performance status.
Day 8
Timepoint from 2 hours before the 
administration of the investigational 
product 
to 
1 
minute 
before 
the 
administration of the investigational 
product:
Blood collection for PK before the administration of the investigational 
product.
Assessment of vital functions: blood pressure, pulse rate, body 
temperature, respiratory rate.
Evaluation of adverse events.
Documenting concomitant medications.
Timepoint 00:00: 
Administration of the investigational product (capsule or tablet) under 
fasting conditions seated/standing with 200 mL of boiled water having 
the room temperature.
Timepoint 00:30±0:02 minutes: 
Blood collection for PK.
Timepoint 01:00±0:02 minutes: 
Blood collection for PK.
Timepoint 02:00±0:02 minutes:
Blood collection for PK.
Timepoint 03:00±0:05 minutes:
Blood collection for PK.
Timepoint 04:00±0:05 minutes:
Blood collection for PK.
Breakfast.
Timepoint 05:00±0:05 minutes:
Blood collection for PK.
Timepoint 06:00±0:05 minutes:
Blood collection for PK.
Assessment of vital functions: blood pressure, pulse rate, body 
temperature, respiratory rate.
Evaluation of adverse events.
Lunch.
Documenting concomitant medications.
Timepoint 07:00±0:10 minutes:
Blood collection for PK.
Timepoint 08:00±0:10 minutes:
Blood collection for PK.
Timepoint 09:00:
Snack.
Timepoint 10:00±0:10 minutes:
Blood collection for PK.
Timepoint 11:00:
Supper.
Timepoint 12:00±0:10 minutes:
Blood collection for PK.
Assessment of vital functions: blood pressure, pulse rate, body 
temperature, respiratory rate.
Evaluation of adverse events.
Documenting concomitant medications.
Day 9 
Timepoint 24:00±0:15 minutes: 
Blood collection for PK.
Physical examination.
Assessment of vital functions: blood pressure, pulse rate, body 
temperature, respiratory rate.
Performance status.
Evaluation of adverse events.
Documenting concomitant medications.
Timepoint 32:00±0:15 minutes:
Blood collection for PK.
Day 10 
Timepoint 48:00±0:15 minutes:
Blood collection for PK.


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Physical examination.
Assessment of vital functions: blood pressure, pulse rate, body 
temperature, respiratory rate.
Performance status.
Evaluation of adverse events.
Documenting concomitant medications.
Day 11
Timepoint 72:00±0:15 minutes: 
Blood collection for PK.
Physical examination.
Assessment of vital functions: blood pressure, pulse
rate, body 
temperature, respiratory rate.
Performance status.
Evaluation of adverse events.
Documenting concomitant medications.
Standard laboratory tests (complete blood count, blood biochemistry and 
urinalysis with microscopic examination of urinary sediment).
12-lead ECG.
4.10.6.2.3.
Completion of the study and follow-up period
After the completed treatment phase, a follow-up visit for the study subjects will be carried out 7 
days after the completion of the last procedure in the second study period. 
During the follow-up visit (Day 18) the following procedures will be performed:

Physical examination.

Assessment of vital functions: blood pressure, pulse rate, body temperature, respiratory rate.

Evaluation of adverse events.

Documenting concomitant medications.

Urine pregnancy test.
In case of early study termination by the volunteer, a follow-up visit will be 7 days after the
last study procedure preceding the subject's termination of the study.
5. Power and Sample Size
Sample size for this study was determined independently using AUC and Cmax parameters as the 
basis for study size determination.
The sample size for this study was determined according to 18% intra-individual coefficient of 
variation (CV) for AUC and 23% for Cmax, taking into account the data obtained during the study 
107.074 [2]. Although intra-individual CV was 12.9% for AUC and 17.9% for Cmax according to 
107.074 study, such data were obtained exclusively from male subjects. Therefore, the intra-
individual CV expected under this study (for males and females) will be accepted in the 
calculations at least 5% higher than previously reported.
With a CV of 18% for AUC and 23% for Cmax, and a sample size of 24 subjects, the statistical 
power to reject the null bioequivalence hypothesis for both parameters (AUC and Cmax) in favor 
of equivalence at 5% significance level is described in Table 5.1 and Table 5.2 at various 
acceptable values of the ratio between the geometric mean of the studied parameters.


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Table 5.1. The probability of the drug equivalence according to AUC (with 80-125% acceptable equivalence 
limits), taking into account 18% intra-individual CV and different values of the geometric mean ratio for the 
studied parameter in the two-way crossover study (N=24)
Ratio1
90%
95%
100%
105%
110%
Test power
72%
94%
99%
95%
78%
1) This ratio reflects the median of the intra-subject ratio determined by exp (μT)/exp (μR) and is calculated as the
geometric mean of the intra-subject ratio.
Table 5.2. The probability of the drug equivalence according to Cmax (with 80-125% acceptable equivalence 
limits), taking into account 23% intra-individual CV and different values of the geometric mean ratio for the 
studied parameter in the two-way crossover study (N=24)
1) This ratio reflects the median of the intra-subject ratio determined by exp (μT)/exp (μR) and is calculated as the
geometric mean of the intra-subject ratio.
In accordance with the instructions for bioavailability/bioequivalence studies in the Russian 
Federation, the minimum required number of healthy volunteers is 18 [3]. Below are the tables 
(Tables 5.3 and 5.4) to demonstrate what is the likelihood of equivalence of the test drug and the 
reference drug under AUC and Cmax parameters providing the participation of 18 healthy 
volunteers.
Table 5.3. 
The probability of the drug equivalence according to AUC (with 80-125% acceptable 
equivalence limits), taking into account 18% intra-individual CV and different values of the geometric mean 
ratio for the studied parameter in the two-way crossover study (N=18)
Ratio1
90%
95%
100%
105%
110%
Test 
power
60%
87%
95%
87%
66%
1) This ratio reflects the median of the intra-subject ratio determined by exp (μT)/exp (μR) and is calculated as the
geometric mean of the intra-subject ratio.
Table 5.4.
The probability of the drug equivalence according to Cmax (with 80-125% acceptable
equivalence limits), taking into account 23% intra-individual CV and different values of the geometric mean 
ratio for the studied parameter in the two-way crossover study (N=18)
Ratio1
90%
95%
100%
105%
110%
Test 
power
43%
67%
76%
68%
48%
1) This ratio reflects the median of the intra-subject ratio determined by exp (μT)/exp (μR) and is calculated as the
geometric mean of the intra-subject ratio.
From the above tables (Table 5.1 and Table 5.2), a sample size of 24 subjects will provide at 
least 80% of the test power to conclude bioequivalence of drugs if the geometric mean ratio of 
the studied parameters (AUC and Cmax) at least 5% differs from complete equivalence (i.e. 
100%). Taking into account 2 cases of dropout, it is planned to include 26 subjects in the study.
Calculations have been made for individual comparisons as described by 
 et al [4] using 
the power.TOST () command from the PowerTOST package, version 1.2-03 in R version 3.0.3.
Ratio1
90%
95%
100%
105%
110%
Test power
54%
81%
90%
82%
60%


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______________________________________________________________ 
6. Data Management Procedures
6.1. Study Database
The electronic data collection system Cloud solution EDC2GO will be used for data collection.
Provider: Genae
The database will be developed based on the paper template CRF. The Data Entry Specialist who 
has the appropriate rights in the database will perform data entry in the office of the CRO. All 
study data will be validated according to the Data Validation Plan. Requests for data clarification 
will be created during the data validation. The database will be closed after all the required 
checks are performed and all queries are resolved. A detailed description of the processing steps 
is provided in the Data Management Plan
6.2. Study Datasets
Descriptions of the study data sets are described in Appendix 3 
6.3. Data Modifications
Data modification is not planned (not applicable).
6.4. Blinding and Randomization.
SAS package version 9.3 will be used for randomization schedule creation. Masking data is not 
planned (not applicable).
6.5. Unblinding Methods and Procedures
Not applicable.
7. Study Populations
7.1. Safety Population (SP)
All subjects who received at least one dose of the investigational product will be included in the 
safety assessment. Safety studies will be carried out in accordance with the Boehringer 
Ingelheim standards.
Data from volunteers who were not randomized in the study and who did not take any dose of 
the test drug or the reference drug will be provided separately.
7.2. Pharmacokinetic population (PKP)
Pharmacokinetic population is defined as all volunteers who completed the study in accordance 
with the requirements of the clinical study Protocol for whom the pharmacokinetic profile can be 
adequately described.
8. Subjects Accountability
Subjects accountability will be carried out with the division into the following groups:
1) Volunteers not included in the studied populations. This group includes:

Volunteers who signed an informed consent form, but discontinued before the
randomization.
2) Volunteers included into the safety population. This group includes:

Volunteers who underwent randomization and took the test drug and/or the reference drug.

Volunteers who took at least one dose of trial drug, but early withdrew from the study.

Volunteers who completed their participation in the study in accordance with the
requirements of the clinical study Protocol.


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3) Volunteers included into the Pharmacokinetic population. This group includes:

Volunteers who completed their participation in the study in accordance with the
requirements of the clinical study Protocol.
9. Data and values of indicators obtained during the study
9.1. Safety data
All subjects who received at least one dose of the investigational product will be included in the 
safety assessment. Safety studies will be carried out in accordance with the Boehringer 
Ingelheim standards.
Analyzed safety parameters include:

Vital signs (blood pressure, pulse rate, body temperature, respiratory rate);

Volunteer’s performance status;

Physical examination data;

Clinical laboratory tests data (complete blood count, blood biochemistry and urinalysis);

12-lead ECG data.
9.1.1. Nominal data
Values with a nominative type of the scale will be presented using the total number of 
observations and the number of observations for each category and percentage. The percentage 
will be represented with 1 digit after the decimal point.
9.1.2. Interval (quantitative) data
Interval (quantitative) values will be presented using the following values of descriptive 
statistics: number of observational data except omissions (n), arithmetic mean, standard 
deviation, minimum, median, maximum, arithmetic coefficient of variation, geometric mean and 
geometric coefficient of variation. The arithmetic mean, standard deviation, minimum and 
maximum values, and median will be represented in decimal form with the same level of 
accuracy (the number of digits after the decimal point) as in the initial data.
9.1.3. Handling missing data
Within safety evaluation, no imputation of missing values is planned.
9.2. Pharmacokinetic data 
All randomized volunteers who meet the Protocol requirements, e.g., volunteers who meet the 
inclusion/exclusion criteria and completed the planned periods of investigational product 
administration in accordance with the Protocol requirement (except for minor deviations that are 
not a clear basis for exclusion), form a volunteer population “without Protocol deviations” for 
pharmacokinetic evaluation.
The following volunteers will be included in the pharmacokinetic and statistical analysis:

Volunteers who have completed all study periods with less than two missing samples.
The calculation will be based on the real, not planned, sampling time.
Decision to exclude the results of analyte concentrations in volunteer’s samples will be taken 
before the final analysis of samples.
If the concentration in a volunteer was less than or equal to 5% of Cmax before the test drug or the 
reference drug administration, the data of this volunteer can be included in the pharmacokinetic 
measurements and calculations without any counting. If the concentration value prior to the test 


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drug or the reference drug administration is greater than 5% of Cmax, then this volunteer’s data 
will be excluded from pharmacokinetic and statistical analysis.
Data of volunteers excluded from the analysis due to the concentration value before the drug 
administration above 5% of Cmax will be included in a separate Appendix to the final study 
report.
Volunteers whose reference drug concentration in plasma cannot be determined, or when only a 
small amount of the drug is detected, will be excluded from pharmacokinetic and statistical 
analysis. Analyte concentrations in volunteers are considered to be very low if the AUC value 
does not exceed 5% of the mean geometric AUC of the reference drug (calculated without 
including volunteer’s data with the specified values).
If the value of LLOQ (lower limit of quantification) is more than 5% for Cmax of a single 
volunteer, then this volunteer’s data will be excluded from pharmacokinetic and statistical 
analysis. The volunteer’s data are included in a separate Appendix of the final study report. 
During pharmacokinetic and statistical analysis, drug concentrations below the lower limit of 
quantitation (BLQ) analysis will be counted as zero. Missing samples and non-detectable 
concentrations (e.g., insufficient amount) from the analytical laboratory will be interpreted in the 
pharmacokinetic analysis as if they were not collected.
9.2.1. Primary analysis
Main pharmacokinetic parameters will be obtained by analyzing the non-compartmental model 
using the WinNonlin software (Pharsight, USA).
The pharmacokinetic parameters (AUC0-t, AUC0-and Cmax) will be transformed logarithmically 
(natural logarithm) before selecting the analysis-of-variance model. The difference between the 
expected average for the double logarithm of T-R will be estimated upon the difference in the 
mean values calculated by the least-squares method (point estimation), and also by the difference 
in the values of the two-sided 90% confidence intervals based on t distribution. These data will 
then be converted back under the original scale to obtain a point estimation and 90% confidence 
interval for each endpoint.
All evaluated subjects for both treatment periods will be included in the analysis of relative 
bioavailability.
Subject is not evaluable if:

Subject has a Protocol deviation related to the assessment of relative bioavailability (the
decision on Protocol deviation relevance will be taken no later than the Report planning
meeting) or

Subject has nausea and vomiting at two mean time tmax or less, namely within 12 hours after
the administration of the investigational product.
9.2.2. Secondary assays
Concentrations will be used to build charts and perform calculations in the format specified in 
the analytical report.
Drug concentrations in plasma will be plotted in diagram to a time base for all subjects, as 
indicated in the concentration-time tables. To demonstrate the average profiles, the arithmetic 
mean and the specified sampling time will be used.


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The following descriptive statistics will be calculated for plasma concentration, as well as for all 
primary, secondary and additional pharmacokinetic parameters: N, arithmetic mean, standard 
deviation, minimum, mean, maximum, arithmetic coefficient of variation, geometric mean and 
geometric coefficient of variation. Data format for the descriptive concentration statistics will be 
identical to the data format of the corresponding concentrations. Descriptive statistics of 
pharmacokinetic parameters will be calculated using individual values with the number of 
decimal digits provided by the evaluation program. Individual values, as well as descriptive 
statistics, will then be recorded with three significant figures in the clinical study report.
9.2.3. Dispersion analysis
As a statistical model for AUC0-t, AUC0-and Cmax, the analysis of variance (ANOVA) model 
using the logarithmic scale will be used. This model will include effects taking into account the 
following sources of variation: 

“Sequence”.

“Study subjects grouped within the sequence”.

“Period”.

“Type of therapy”.
The effect of “study subjects grouped within a sequence” will be considered random, while other
effects are fixed.
9.2.4. The profile of plasma concentration in the course of time
Concentration data with the NOS (no sample), NOR (no reasonable result), NOA (no sample 
analyzed), BLQ (below the limit of quantification) and NOP (no peak detectable) label will be 
identified this way and will not be replaced by zero at any time (also applicable to the lag phase, 
including the values prior to drug administration).
9.2.5. Pharmacokinetic parameters
Model-independent analysis will not include concentration data labeled NOS, NOR and NOA. 
BLQ and NOP values in the lag phase will be taken as zero. Lag phase is defined as the period 
between the zero of the time scale and the first time point with a concentration above the limit of 
quantification. Other BLQ/ NOP parameters will be ignored.
All possible attempts will be made to include all the concentration data in the analysis. If this is 
impossible, then it will be necessary to make a decision for each case separately – whether the 
parameter should be excluded from the half-life assessment or should enter the analysis.
If concentration is excluded only from the definition of half-lives, it will be used for all other 
counts (for example, descriptive statistics) and for a graphic image.
If the concentration value is excluded from all calculations, it will not be included in the 
graphical image or used for descriptive statistics calculations, as well as to determine the 
parameters. However, the excluded concentration will be included in the clinical study report 
tables with the appropriate note.
Descriptive statistics of a parameter is calculated only when the evaluation of at least 2/3 of the 
individual values of a particular parameter is available. If the current sampling time is not 
documented or will not be available for a specific time, the planned time will be used for the 
given timepoint. Pharmacokinetic parameters that cannot be determined will be labeled as “not 
calculated” (NC).


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9.3. Safety Analysis
All deviations of the estimated safety parameters from normal values (including laboratory 
parameters) will be recorded as adverse events. Safety evaluation will be based on the incidence 
of adverse events and frequency of subjects with AE There will be summary tables with 
information on AEs and their description for each volunteer.
9.3.1. Adverse Events
Adverse events will be coded using the Medical Dictionary of Regulatory Activities (MedDRA
version 21.1) terminology. For evaluation, adverse events that occur prior to drug administration 
will be attributed to the screening period, and all other adverse events will be attributed to 
treatment periods.
Concomitant medications used to treat adverse events will be coded using WHO Drug 
Dictionary (Version, relevant at the time of encoding).
Adverse events evaluation will include different tables of frequency of events classified by 
severity of adverse events, evaluation of the association with the test drug/reference drug, 
relation to SAE and actions taken to the investigational product (including the need for 
premature study closure for these volunteers).
Descriptive statistics of laboratory findings over a long period of time will be provided to 
determine the difference from the baseline levels. A table of the frequency of changes will also 
be presented, taking into account the range of normal values between the baseline level and on-
treatment last parameter.
9.3.2. Clinical Laboratory Evaluations
The results of the following laboratory research methods will be used as the analyzed safety 
parameters:
1) Complete blood count:

Erythrocyte sedimentation rate (ESR)

Hematocrit (Hct)

Haemoglobin (Hb)

Red blood cells/Erythrocytes

Platelet count/Platelets

White blood cells/Leukocytes
Automatic hematology analyzer

Neutrophils (relative count)

Eosinophils (relative count)

Basophiles (relative count)

Monocytes (relative content)

Lymphocytes (relative content)
Manual count (if automatic hematology analyzer is not available)

Neutrophils, stabs (Stabs)

Neutrophils, polymorphonuclear (PMN)

Eosinophils

Basophils

Monocytes


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
Lymphocytes
2) Blood biochemistry:

Aspartate aminotransferase (AST)

Alanine aminotransferase (ALT)

Alkaline phosphatase (ALP)

Glucose

Creatinine

Total bilirubin

Total protein

Total cholesterol

Electrolytes: calcium, sodium and potassium
3) Urinalysis:

Nitrites in urine

Protein in urine

Glucose in urine

Ketones in urine

Urobilinogen

Bilirubin in urine

RBC/Erythrocytes in urine

WBC/Leukocytes in urine

pH of urine
4) Urine sediment (microscopic examination):

Bacteria in urine sediment

Pavement epithelium in urine

RBC/Erythrocytes in urine sediment

WBC/Leukocytes in urine sediment
9.3.3. Vital Signs
The results of the following vital signs will be used as analyzed safety parameters:

Blood pressure (systolic and diastolic)

Pulse rate

Body temperature

Respiratory rate
9.3.4. Physical Examinations
The results of a physical examination for the following systems and organs will be evaluated as 
analyzed safety parameters:

Skin, hair, nails

Endocrine system

Ears, nose, throat

Cardiovascular system

Gastrointestinal tract

Nervous system

Musculoskeletal system

Reproductive system

Urinary system


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9.3.5. Electrocardiography
The following data obtained during the electrocardiographic study will be evaluated as the 
analyzed safety parameters:

Heart rate

PQ interval duration

QRS interval duration

QT interval duration
9.3.6. General assessment
The results of the overall evaluation will be evaluated as the analyzed safety parameters.
9.4. Restrictive laboratory tests
The results of the below laboratory test methods are not analyzed safety parameters, and are 
conducted only to confirm the compliance of the volunteer with the inclusion criteria and the 
absence of study exclusion/non-inclusion criteria.
Restrictive laboratory tests include:
1) Serological study of blood plasma for detection of infectious diseases:

Hepatitis B surface antigen (qualitative test HbsAg)

Anti-hepatitis C antibodies (qualitative total anti-HCV value)

HIV-1 and HIV-2 (qualitative anti-HIV1/2)

RPR test for syphilis (anticardiolipin test/microprecipitation test).
2) Pregnancy test (for females):

Urine analysis for β-HCG
3) Urine drug screen for narcotic and potent substances:

Marijuana

Benzodiazepines

Barbiturates

Opiates

Cocaine

Amphetamines
4) Alcohol test:

Breath alcohol test (using alcohol tester)
9.5. Other data
Individual volunteer data that is not significant for study endpoints, but necessary for recording 
the proper implementation of study procedures (method of administration data, time and date of 
investigational product administration, nutrition of subjects, visits) will be tabulated.


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10. References
1. Decision of the Council of the Eurasian Economic Commission No. 85. On Approval of
Good Pharmacovigilance Practice of the Eurasian Economic Union. Website
eurasiancommission.org/ru/act/texnreg/deptexreg/LS1/Documents/32.pdf
2.
 et al. Determination of the relative bioavailability of 15 mg UH-AC 62 XX
tablets compared with 15 mg UH-AC 62 XX capsules after oral administration over 7
days to healthy volunteers. Trial no. 107.74 Internal study report. 1992-07-06.
3. Methodical guidelines for bioequivalence studies. Ministry of Healthcare and Social
Development 
of 
the 
Russian 
Federation, 
2008. 
Website: 
rdg-cro.com/wp-
content/uploads/2012/07/Guidelines-for-conducting-bioequivalence-studies-in-Russia.pdf
4. Sample size determination for bioequivalence assessment using a multiplicative model.
Authors; Authors and affiliations. 


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Appendix 1.
Schedule of study procedures
Phase
Visit
Day 
(time interval)
Planned time after drug 
administration
[h:min]1
Time interval for blood 
sampling for PK [h:min]
Hospitalization
Randomization
Drug administration
Standard lab. tests2
Tests for exclusion
Blood sampling for PK
Physical examination
12-lead ECG
Vital 
signs3
Performance status
Adverse events
Food intake
Concomitant therapy
Screening4
1
-14 to -1
x
x5
x
x
x
x
x
Period I 
2
-1
-16:00 to -10:00
x
x
x6
x
x7
x
x
x
x
1
-2:00
-2:00 to
0:01
x
x
x
x
0:00
x
0:30
±0:02
x
1:00
±0:02
x
2:00
±0:02
x
3:00
±0:05
x
4:00
±0:05
x
x
5:00
±0:05
x
6:00
±0:05
x
x
x
x
x
7:00
±0:10
x
8:00
±0:10
x
9:00
x
10:00
±0:10
x
11:00
x
12:00
±0:10
x
x
x
x
2
24:00
±0:15
x
x
x
x
x
x
32:00
±0:15
x
3
48:00
±0:15
x
x
x
x
x
x
4
72:00
±0:15
x
x
x
x
x
x
x
1.
Time points for T/R drugs administration and for blood sampling for PK are strict.
2.
Standard laboratory tests include clinical blood count, blood biochemistry and urinalysis.
Clinical blood count: Erythrocyte sedimentation rate (ESR), Hematocrit (Hct), Haemoglobin (Hb), Erythrocytes/red
blood cells (RBC), Platelet count, Leukocytes/White blood cells (WBC), Leukocyte formula (neutrophils, eosinophils,
basophils, monocytes, lymphocytes). Perform test under fasting conditions.
Blood biochemistry: Total protein, Glucose, Total cholesterol, Total bilirubin, Creatinine, Aspartate aminotransferase
(AST), Alanine aminotransferase (ALT), Alkaline phosphatase (ALP), Electrolytes (Na, K, Ca). Perform test under
fasting conditions.
Urinalysis: pH, Protein, Glucose, Ketone bodies, Bilirubin, Urobilinogen, Erythrocytes, Nitrites, Leukocytes.
Microscopic examination of urinary sediment: bacteria; Pavement epithelium; Erythrocytes; White blood cells.
If ALT and/or AST values in blood biochemistry are ≥3 fold higher than ULN, together with total bilirubin ≥2 fold
higher than ULN, the following laboratory tests should be repeated within 48-72 hours: ALT, AST and bilirubin (total
and direct). If it is confirmed that ALT and/or AST values ≥3 fold higher than ULN together with total bilirubin ≥2 fold
higher than ULN, complete blood count, serological tests and blood biochemistry should be performed and their
findings should be provided to the Investigator and BI as soon as possible.
3.
Vital signs (blood pressure (BP), pulse, body temperature, respiratory rate).
4.
In addition to the procedures indicated in the study design, the following screening procedures are also performed:
providing the volunteer with information about the study, signing an informed consent form, collecting demographic
data, information on smoking and drinking alcohol, collecting medical history, taking concomitant medications,
measuring body weight and height, the calculation of the body mass index (BMI).
5.
At the screening visit the following tests for exclusion are performed: serological analysis of blood plasma for infection
(qualitative analysis for HbsAg, qualitative analysis for total anti-HCV antibodies, qualitative analysis for antibodies to
HIV1/2, test for syphilis); urine analysis for β-HCG (test strips for females); urine drug screen (test strips for the
detection of marijuana, benzodiazepine, barbiturates, opiates, cocaine, amphetamines);breath alcohol test.
6.
During the visit on Day -1, Period 1, the following analyzes for exclusion are performed to confirm that the patients
meet study criteria: urine analysis for β-HCG (test strips for females); urine drug screen (test strips for the detection of
marijuana, benzodiazepine, barbiturates, opiates, cocaine, amphetamines); breath alcohol test.
7.
If the 12-lead ECG is performed on Day -7- -1 at screening, its results can be used on Day -1, Period I.


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Phase
Visit
Day 
(time interval)
Planned time after drug 
administration
[h:min]1
Time interval for blood 
sampling for PK [h:min]
Hospitalization
Randomization
Drug administration
Standard lab. tests2
Tests for exclusion
Blood sampling for PK
Physical examination
12-lead ECG
Vital 
signs3
Performance status
Adverse events
Food intake
Concomitant therapy
Washout 
period8
7 days
Period II
3
7
-16:00 to -10:00
x
x9
x
x
x
x
x
8
-2:00
-2:00 to
0:00
x
x
x
x
x
0:00
x
0:30
±0:02
x
1:00
±0:02
x
2:00
±0:02
x
3:00
±0:05
x
4:00
±0:05
x
x
5:00
±0:05
x
6:00
±0:05
x
x
x
x
x
x
7:00
±0:10
x
8:00
±0:10
x
9:00
x
10:00
±0:10
x
11:00
x
12:00
±0:10
x
x
x
x
x
9
24:00
±0:15
x
x
x
x
x
x
32:00
±0:15
x
10
48:00
±0:15
x
x
x
x
x
x
11
72:00
±0:15
x
x
x
x
x
x
x
x
Follow-up
4
18 
x10
x
x
x
x
8.
Duration of washout period is calculated from the time of investigational product administration in the first study 
period to the time of the investigational product administration in the second study period. Interval between the hospital 
discharge of the volunteer in the first period and the hospitalization of the volunteer in the second study period is 
approximately 3.5 days.
9.
During the visit on Day 7, Period 2, the following analyzes for exclusion are performed to confirm that the patients meet 
study criteria: urine analysis for β-HCG (test strips for females); urine drug screen (test strips for the detection of 
marijuana, benzodiazepine, barbiturates, opiates, cocaine, amphetamines); breath alcohol test.
10. Only urine analysis for β-HCG (test strips for females). 


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Appendix 2. 
Table Templates
Accounting for volunteers
Table 1. Information on completion / early dropout from the study 
Included in the study
Safety population
Pharmacokinetic population
Completed according to the protocol
Prematurely withdrawn (no further participation)
Table 2. Disposition
Index
RT
TR
Total
N
%
N
%
N
%
First Period
Treated Subjects
Completed accordance to Protocol
Early termination
Protocol violation
Withdrawal of consent 
Adverse event
Lost to follow-up
Other
Second Period 
Treated Subjects
Completed accordance to Protocol
Early termination
Protocol violation
Withdrawal of consent 
Adverse event
Lost to follow-up
Other


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Initial characteristics of volunteers
Table 3. Descriptive statistics of demographic data
Index
RT
TR
Total
N
%
N
%
N
%
Sex
Male
Female
Race
Caucasian
Other
Table 4. Descriptive statistics of anthropometric data
Index
TR
N
SD
Mean
Median
Min
Max
Age
Body weight
Height
BMI
Index
RT
N
SD
Mean
Median
Min
Max
Age
Body weight
Height
BMI
Index
Total
N
SD
Mean
Median
Min
Max
Age
Body weight
Height
BMI


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Safety indications - Adverse events
Table 5. Overall summary of Adverse events
Index
The Drug Test (T)
The Drug Reference (R)
Total
N
%
N
%
N
%
AE reported
SAE reported
Subjects with AE
Subjects with SAE
Is Life Threatening
Persist or Significant Disability/Incapacity
Requires or Prolongs Hospitalization
Congenital Anomaly or Birth Defect 
Other Medically Important Serious Event
Subjects with severe AEs
Subjects with investigator defined 
drug−related AEs
Subjects with AEs leading to 
discontinuation of trial drug
Subjects with AEs of special interest
Subjects with serious AEs
Subjects with other significant AEs 
(according to ICH E3)
Table 6. Frequency of subjects with adverse events by treatment, primary system organ class and preferred 
term.
System organ class/
Preferred term.
The Drug Test (T)
The Drug Reference (R)
Total
N
%
N
%
N
%
Total number of subjects
Total with adverse events
System organ class

Preferred term.


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Safety indicators - results of instrumental methods
Table 7. Dynamics of ECG indices during the study (Screening - Second Period)
Index
Relative time
The Drug Test (T)
The Drug Reference (R)
Total
N
SD
Mean
Median
Min
Max
N
SD
Mean
Median
Min
Max
N
SD
Mean
Median
Min
Max
Heart
Rate
Screening Visit
First Period Admission (Day -1)
Second Period Admission (Day 7)
Second Period (Day 11)
PQ
Screening Visit
First Period Admission (Day -1)
Second Period Admission (Day 7)
Second Period (Day 11)
QRS
Screening Visit
First Period Admission (Day -1)
Second Period Admission (Day 7)
Second Period (Day 11)
QT
Screening Visit
First Period Admission (Day -1)
Second Period Admission (Day 7)
Second Period (Day 11)


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Table 8. Assessment of ECG indices during the study (Screening - Second Period).
Index
Relative time
The Drug Test (T)
The Drug Reference (R)
Total
Normal
Abnormal
Normal
Abnormal
Normal
Abnormal
N
%
N
N
N
N
%
N
%
N
%
N
Heart
Rate
Screening Visit
First Period Admission (Day -1)
Second Period Admission (Day 7)
Second Period  (Day 11)
PQ
Screening Visit
First Period Admission (Day -1)
Second Period Admission (Day 7)
Second Period  (Day 11)
QRS
Screening Visit
First Period Admission  (Day -1)
Second Period Admission (Day 7)
Second Period  (Day 11)
QT
Screening Visit
First Period Admission  (Day -1)
Second Period Admission (Day 7)
Second Period  (Day 11)


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Table 9. Dynamics of vital signs during the study (Screening - Period 1 - Period 2 - Visit of follow-up observation)
Index
Visit/Relative time
The Drug Test (T)
The Drug Reference (R)
Total
N
SD
Mean
Media
n
Min
Max
N
SD
Mean
Median
Min
Max
N
SD
Mean
Median
Min
Max
Pulse rate
Screening Visit
First Period Admission (Day -1)
Day 1 (-2:00)
Day 1 (6:00)
Day 1 (12:00)
Day 2 (24:00)
Day 3 (48:00)
Day 4 (72:00)
Second Period Admission (Day 7)
Day 8 (-2:00)
Day 8 (6:00)
Day 8 (12:00)
Day 9 (24:00)
Day 10 (48:00)
Day 11 (72:00)
Follow-Up Visit (Day 18)
Systolic blood pressure
Screening Visit
First Period Admission (Day -1)
Day 1 (-2:00)
Day 1 (6:00)
Day 1 (12:00)
Day 2 (24:00)
Day 3 (48:00)
Day 4 (72:00)
Second Period Admission (Day 7)
Day 8 (-2:00)
Day 8 (6:00)
Day 8 (12:00)
Day 9 (24:00)
Day 10 (48:00)
Day 11 (72:00)
Follow-Up Visit  (Day 18)


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Diastolic blood pressure
Screening Visit
First Period Admission (Day -1)
Day 1 (-2:00)
Day 1 (6:00)
Day 1 (12:00)
Day 2 (24:00)
Day 3 (48:00)
Day 4 (72:00)
Second Period Admission (Day 7)
Day 8 (-2:00)
Day 8 (6:00)
Day 8 (12:00)
Day 9 (24:00)
Day 10 (48:00)
Day 11 (72:00)
Follow-Up Visit (Day 18)
Body temperature
Screening Visit
First Period Admission (Day -1)
Day 1 (-2:00)
Day 1 (6:00)
Day 1 (12:00)
Day 2 (24:00)
Day 3 (48:00)
Day 4 (72:00)
Second Period Admission (Day 7)
Day 8 (-2:00)
Day 8 (6:00)
Day 8 (12:00)
Day 9 (24:00)
Day 10 (48:00)
Day 11 (72:00)
Follow-Up Visit  (Day 18)
Respiratory 
rate
Screening Visit  
First Period Admission (Day -1)
Day 1 (-2:00)
Day 1 (6:00)
Day 1 (12:00)
Day 2 (24:00)


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Day 3 (48:00)
Day 4 (72:00)
Second Period Admission (Day 7)
Day 8 (-2:00)
Day 8 (6:00)
Day 8 (12:00)
Day 9 (24:00)
Day 10 (48:00)
Day 11 (72:00)
Follow-Up Visit (Day 18)


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Table 10. Assessment of vital signs during the study (Screening - Period 1 - Period 2 - Visit of follow-up observation)
Index
Visit/Relative time
The Drug Test (T)
The Drug Reference (R)
Total
Normal
Abnormal
Normal
Abnormal
Normal
Abnormal
N
%
N
N
N
%
N
%
N
%
N
%
Pulse rate
Screening Visit
First Period Admission (Day -1)
Day 1 (-2:00)
Day 1 (6:00)
Day 1 (12:00)
Day 2 (24:00)
Day 3 (48:00)
Day 4 (72:00)
Second Period Admission (Day 7)
Day 8 (-2:00)
Day 8 (6:00)
Day 8 (12:00)
Day 9 (24:00)
Day 10 (48:00)
Day 11 (72:00)
Follow-Up Visit (Day 18)
Systolic blood pressure
Screening Visit
First Period Admission (Day -1)
Day 1 (-2:00)
Day 1 (6:00)
Day 1 (12:00)
Day 2 (24:00)
Day 3 (48:00)
Day 4 (72:00)
Second Period Admission (Day 7)
Day 8 (-2:00)
Day 8 (6:00)
Day 8 (12:00)
Day 9 (24:00)
Day 10 (48:00)
Day 11 (72:00)
Follow-Up Visit  (Day 18)
b
l
o
Screening Visit


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First Period Admission (Day -1)
Day 1 (-2:00)
Day 1 (6:00)
Day 1 (12:00)
Day 2 (24:00)
Day 3 (48:00)
Day 4 (72:00)
Second Period Admission (Day 7)
Day 8 (-2:00)
Day 8 (6:00)
Day 8 (12:00)
Day 9 (24:00)
Day 10 (48:00)
Day 11 (72:00)
Follow-Up Visit (Day 18)
Body temperature
Screening Visit
First Period Admission (Day -1)
Day 1 (-2:00)
Day 1 (6:00)
Day 1 (12:00)
Day 2 (24:00)
Day 3 (48:00)
Day 4 (72:00)
Second Period Admission (Day 7)
Day 8 (-2:00)
Day 8 (6:00)
Day 8 (12:00)
Day 9 (24:00)
Day 10 (48:00)
Day 11 (72:00)
Follow-Up Visit  (Day 18)
Respiratory rate
Screening Visit  (Day 18)
First Period Admission (Day -1)
Day 1 (-2:00)
Day 1 (6:00)
Day 1 (12:00)
Day 2 (24:00)
Day 3 (48:00)


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Day 4 (72:00)
Second Period Admission (Day 7)
Day 8 (-2:00)
Day 8 (6:00)
Day 8 (12:00)
Day 9 (24:00)
Day 10 (48:00)
Day 11 (72:00)
Follow-Up Visit (Day 18)


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____Table 11. Assessment of Physical examination by time (Screening- Follow 
up)_____________________________________________________________________________________________________________________
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Relative 
time
Body system and site
The Drug Test (T)
The Drug Reference (R)
Total
Normal
Abnormal
Normal
Abnormal
Normal
Abnormal
N
%
N
%
N
%
N
%
N
%
N
%
Screening
Day -14 to -1
Skin, hair, nails
Endocrine system
Ear, nose, throat
Cardiovascular system
Gastrointestinal system
Nervous system
Musculoskeletal system
Reproductive system
Renal system
First Period
Day -1, 
-10:00 - -16:00
Skin, hair, nails
Endocrine system
Ear, nose, throat
Cardiovascular system
Gastrointestinal system
Nervous system
Musculoskeletal system
Reproductive system
Renal system
Day 2,
+ 24:00
Skin, hair, nails
Endocrine system
Ear, nose, throat
Cardiovascular system
Gastrointestinal system
Nervous system
Musculoskeletal system
Reproductive system
Renal system
Day 3, 
+ 48:00
Skin, hair, nails
Endocrine system
Ear, nose, throat
Cardiovascular system
Gastrointestinal system
Nervous system
Musculoskeletal system


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Reproductive system
Renal system
Day 4, 
+ 72:00
Skin, hair, nails
Endocrine system
Ear, nose, throat
Cardiovascular system
Gastrointestinal system
Nervous system
Musculoskeletal system
Reproductive system
Renal system
Second Period
-10:00 - -16:00
Skin, hair, nails
Endocrine system
Ear, nose, throat
Cardiovascular system
Gastrointestinal system
Nervous system
Musculoskeletal system
Reproductive system
Renal system
+ 24:00
Skin, hair, nails
Endocrine system
Ear, nose, throat
Cardiovascular system
Gastrointestinal system
Nervous system
Musculoskeletal system
Reproductive system
Renal system
+ 48:00
Skin, hair, nails
Endocrine system
Ear, nose, throat
Cardiovascular system
Gastrointestinal system
Nervous system
Musculoskeletal system
Reproductive system
Renal system


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+ 72:00
Skin, hair, nails
Endocrine system
Ear, nose, throat
Cardiovascular system
Gastrointestinal system
Nervous system
Musculoskeletal system
Reproductive system
Renal system
Follow up
Not applicable
Skin, hair, nails
Endocrine system
Ear, nose, throat
Cardiovascular system
Gastrointestinal system
Nervous system
Musculoskeletal system
Reproductive system
Renal system
First and Second Period
-10:00 - -16:00
Skin, hair, nails
Endocrine system
Ear, nose, throat
Cardiovascular system
Gastrointestinal system
Nervous system
Musculoskeletal system
Reproductive system
Renal system
+ 24:00
Skin, hair, nails
Endocrine system
Ear, nose, throat
Cardiovascular system
Gastrointestinal system
Nervous system
Musculoskeletal system
Reproductive system
Renal system
4
8
:
0
Skin, hair, nails


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Endocrine system
Ear, nose, throat
Cardiovascular system
Gastrointestinal system
Nervous system
Musculoskeletal system
Reproductive system
Renal system
+ 72:00
Skin, hair, nails
Endocrine system
Ear, nose, throat
Cardiovascular system
Gastrointestinal system
Nervous system
Musculoskeletal system
Reproductive system
Renal system


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Safety indicators - laboratory results
Table 12 Dynamics of biochemical blood test parameters during the study (Screening-Second period)
Visit
Index
The Drug Test (T)
The Drug Reference (R)
Total
N
SD
Mean
Median
Min
Max
N
SD
Mean
Median
Min
Max
N
SD
Mean
Median
Min
Max
Screening
Total protein (g/l)
Alkaline phosphatase (U/l)
ALT (U/l)
AST (U/l)
Glucose (Mmol/l)
Total cholesterol (Mmol/l)
Total bilirubin (Mcmol/l)
Creatinine (Mcmol/l)
Potassium (Mmol/l)
Sodium (Mmol/l)
Calcium (Mmol/l)
First Period (72:00)
Total protein (g/l)
Alkaline phosphatase (U/l)
ALT (U/l)
AST (U/l)
Glucose (Mmol/l)
Total cholesterol (Mmol/l)
Total bilirubin (Mcmol/l)
Creatinine (Mcmol/l)
Potassium (Mmol/l)
Sodium (Mmol/l)
Calcium (Mmol/l)
Second Period (72:00)
Total protein (g/l)
Alkaline phosphatase (U/l)
ALT (U/l)
AST (U/l)
Glucose (Mmol/l)
Total cholesterol (Mmol/l)
Total bilirubin (Mcmol/l)
Creatinine (Mcmol/l)
Potassium (Mmol/l)
Sodium (Mmol/l)
Calcium (Mmol/l)


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First and Second Periods
(72:00)
Total protein (g/l)
Alkaline phosphatase (U/l)
ALT (U/l)
AST (U/l)
Glucose (Mmol/l)
Total cholesterol (Mmol/l)
Total bilirubin (Mcmol/l)
Creatinine (Mcmol/l)
Potassium (Mmol/l)
Sodium (Mmol/l)
Calcium (Mmol/l)


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Table 13. Assessment of biochemical blood test parameters during the study (Screening-Second period)
Visit
Index
The Drug Test (T)
The Drug Reference (R)
Total
Normal
Abnormal
Normal
Abnormal
Normal
Abnormal
N
%
N
N
N
%
N
%
N
%
N
%
Screening
Total protein (g/l)
Alkaline phosphatase (U/l)
ALT (U/l)
AST (U/l)
Glucose (Mmol/l)
Total cholesterol (Mmol/l)
Total bilirubin (Mcmol/l)
Creatinine (Mcmol/l)
Potassium (Mmol/l)
Sodium (Mmol/l)
Calcium (Mmol/l)
First Period (72:00)
Total protein (g/l)
Alkaline phosphatase (U/l)
ALT (U/l)
AST (U/l)
Glucose (Mmol/l)
Total cholesterol (Mmol/l)
Total bilirubin (Mcmol/l)
Creatinine (Mcmol/l)
Potassium (Mmol/l)
Sodium (Mmol/l)
Calcium (Mmol/l)
Second Period (72:00)
Total protein (g/l)
Alkaline phosphatase (U/l)
ALT (U/l)
AST (U/l)
Glucose (Mmol/l)
Total cholesterol (Mmol/l)
Total bilirubin (Mcmol/l)
Creatinine (Mcmol/l)
Potassium (Mmol/l)
Sodium (Mmol/l)
Calcium (Mmol/l)
n
d
P
Total protein (g/l)


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Visit
Index
The Drug Test (T)
The Drug Reference (R)
Total
Normal
Abnormal
Normal
Abnormal
Normal
Abnormal
N
%
N
N
N
%
N
%
N
%
N
%
Alkaline phosphatase (U/l)
ALT (U/l)
AST (U/l)
Glucose (Mmol/l)
Total cholesterol (Mmol/l)
Total bilirubin (Mcmol/l)
Creatinine (Mcmol/l)
Potassium (Mmol/l)
Sodium (Mmol/l)
Calcium (Mmol/l)


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Table 14 Dynamics of the parameters of the general blood test during the study (Screening- Second Period)
Visit
Index
The Drug Test (T)
The Drug Reference (R)
Total
N
SD
Mean
Median
Min
Max
N
SD
Mean
Median
Min
Max
N
SD
Mean
Median
Min
Max
Screening
Red blood cells (х1012/l)
White blood cells (х109/l)
Neutrophils (%)
Eosinophils (%)
Basophils (%)
Monocytes (%)
Lymphocytes (%)
Hematocrit (%)
Hemoglobin (g/l)
Platelet count (х109/l)
ESR (mm/h)
First Period (72:00)
Red blood cells (х1012/l)
White blood cells (х109/l)
Neutrophils (%)
Eosinophils (%)
Basophils (%)
Monocytes (%)
Lymphocytes (%)
Hematocrit (%)
Hemoglobin (g/l)
Platelet count (х109/l)
ESR (mm/h)
Second Period (72:00)
Red blood cells (х1012/l)
White blood cells (х109/l)
Neutrophils (%)
Eosinophils (%)
Basophils (%)
Monocytes (%)
Lymphocytes (%)
Hematocrit (%)
Hemoglobin (g/l)
Platelet count (х109/l)
ESR (mm/h)
n
d
P
Red blood cells (х1012/l)


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Visit
Index
The Drug Test (T)
The Drug Reference (R)
Total
N
SD
Mean
Median
Min
Max
N
SD
Mean
Median
Min
Max
N
SD
Mean
Median
Min
Max
White blood cells (х109/l)
Neutrophils (%)
Eosinophils (%)
Basophils (%)
Monocytes (%)
Lymphocytes (%)
Hematocrit (%)
Hemoglobin (g/l)
Platelet count (х109/l)
ESR (mm/h)


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Table 15. Assessment of the parameters of the general blood test during the study (Screening- Second Period)
Visit
Index
The Drug Test (T)
The Drug Reference (R)
Total
Normal
Abnormal
Normal
Abnormal
Normal
Abnormal
N
%
N
N
N
%
N
%
N
%
N
%
Screening
Red blood cells (х1012/l)
White blood cells (х109/l)
Neutrophils (%)
Eosinophils (%)
Basophils (%)
Monocytes (%)
Lymphocytes (%)
Hematocrit (%)
Hemoglobin (g/l)
Platelet count (х109/l)
ESR (mm/h)
First Period (72:00)
Red blood cells (х1012/l)
White blood cells (х109/l)
Neutrophils (%)
Eosinophils (%)
Basophils (%)
Monocytes (%)
Lymphocytes (%)
Hematocrit (%)
Hemoglobin (g/l)
Platelet count (х109/l)
ESR (mm/h)
Second Period (72:00)
Red blood cells (х1012/l)
White blood cells (х109/l)
Neutrophils (%)
Eosinophils (%)
Basophils (%)
Monocytes (%)
Lymphocytes (%)
Hematocrit (%)
Hemoglobin (g/l)
Platelet count (х109/l)
ESR (mm/h)
co
nd 
Pe
rio
Red blood cells (х1012/l)
White blood cells (х109/l)


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Visit
Index
The Drug Test (T)
The Drug Reference (R)
Total
Normal
Abnormal
Normal
Abnormal
Normal
Abnormal
N
%
N
N
N
%
N
%
N
%
N
%
Neutrophils (%)
Eosinophils (%)
Basophils (%)
Monocytes (%)
Lymphocytes (%)
Hematocrit (%)
Hemoglobin (g/l)
Platelet count (х109/l)
ESR (mm/h)


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Table 16. Evaluation of the results of the general analysis of urine (norm, pathology) (Screening- Second Period).
Visit
Index
The Drug Test (T)
The Drug Reference (R)
Total
Normal
Abnormal
Normal
Abnormal
Normal
Abnormal
N
%
N
%
N
%
N
%
N
%
N
%
Screening
pH
Protein (g/l)
Urobilinogen (Mcmol/l)
Glucose (Negative/Positive)
Ketones (Negative/Positive)
Bilirubin (Negative/Positive)
Nitrites (Negative/Positive)
Red blood cells (in a field of view)
White blood cells (in a field of view)
First Period (72:00)
pH
Protein (g/l)
Urobilinogen (Mcmol/l)
Glucose (Negative/Positive)
Ketones (Negative/Positive)
Bilirubin (Negative/Positive)
Nitrites (Negative/Positive)
Red blood cells (in a field of view)
White blood cells (in a field of view)
Second Period (72:00)
pH
Protein (g/l)
Urobilinogen (Mcmol/l)
Glucose (Negative/Positive)
Ketones (Negative/Positive)
Bilirubin (Negative/Positive)
Nitrites (Negative/Positive)
Red blood cells (in a field of view)
White blood cells (in a field of view)
First and Second Periods
(72:00)
pH
Protein (g/l)
Urobilinogen (Mcmol/l)
Glucose (Negative/Positive)
Ketones (Negative/Positive)
Bilirubin (Negative/Positive)
Nitrites (Negative/Positive)
Red blood cells (in a field of view)
White blood cells (in a field of view)


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Table 17. Dynamics of the microscopy of urinary sediment (Screening- Second Period)
Visit
Index
The Drug Test (T)
The Drug Reference (R)
Total
N
SD
Mean
Median
Min
Max
N
SD
Mean
Median
Min
Max
N
SD
Mean
Median
Min
Max
Screening
Red blood cells 
(in a field of view)
White blood cells 
(in a field of view)
Epith Cells 
(in a field of view)
Bacteria 
(in a field of view)
First Period (72:00)
Red blood cells 
(in a field of view)
White blood cells 
(in a field of view)
Epith Cells 
(in a field of view)
Bacteria 
(in a field of view)
Second Period 
(72:00)
Red blood cells 
(in a field of view)
White blood cells 
(in a field of view)
Epith Cells 
(in a field of view)
Bacteria 
(in a field of view)
First and Second 
Periods (72:00)
Red blood cells 
(in a field of view)
White blood cells 
(in a field of view)
Epith Cells 
(in a field of view)
Bacteria 
(in a field of view)


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Table 18. Evaluation of the results of microscopy of urinary sediment (Screening- Second Period)
Visit
Index
The Drug Test (T)
The Drug Reference (R)
Total
Normal
Abnormal
Normal
Abnormal
Normal
Abnormal
N
%
N
%
N
%
N
%
N
%
N
%
Screening
Red blood cells 
(in a field of view)
White blood cells 
(in a field of view)
Epith Cells 
(in a field of view)
Bacteria 
(in a field of view)
First Period (72:00)
Red blood cells 
(in a field of view)
White blood cells 
(in a field of view)
Epith Cells 
(in a field of view)
Bacteria 
(in a field of view)
Second Period 
(72:00)
Red blood cells 
(in a field of view)
White blood cells 
(in a field of view)
Epith Cells 
(in a field of view)
Bacteria 
(in a field of view)
First and Second 
Periods (72:00)
Red blood cells 
(in a field of view)
White blood cells 
(in a field of view)
Epith Cells 
(in a field of view)
Bacteria 
(in a field of view)


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Table 19. Bioequivalence evaluation using Least Square Means by Formulation ratios and their 90% confidence intervals after single oral administration of Movalis®
capsules 15 mg (T) and Movalis® tablets 15 mg (R) under fasting state
PK parameter
NT 
NR
GeoLSMT
GeoLSMR
GeoLSM T/R ratio, %
90% Confidence interval, %
CVintra, %
Power, %
AUC0-t
Cmax
AUC0-∞
Table 20. Main statistics (Number of observations, Geometric means and GeoCVs) of PK parameters by formulation and Geometric Means (T/R) ratios after single oral 
administration of Movalis® capsules 15 mg (T) and Movalis® tablets 15 mg (R) under fasting state
PK parameter
The Drug Test (T)
The Drug Reference (R)
Geo Means T/R 
Ratio (%)
N
Geo Mean
Geo CV (%)
N
GeoMean
Geo CV (%)
AUC0-t
(ng∙h/ml)
AUC0-∞
(ng∙h/ml)
Cmax
(ng/ml)


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Appendix 3.  
List of the study datasets
Name of form
Code of form
Screening
First period, 
admission
First period
Second period, 
admission
Second period
Follow-up visit
Unschedul- ed 
visit
Main forms
Screenfailure 
data
Inclusion
F_ENRL
X
-
-
-
-
-
-
-
-
Demographic information
F_DMGR
X
-
-
-
-
-
-
-
X
Bad habits
F_BADHB
X
-
-
-
-
-
-
-
X
Past and concomitant deseases (repeat form)
F_DIS
X
-
-
-
-
-
-
-
X
Pharmacological history over last 3 months (repeat form)
F_MHIST
X
-
-
-
-
-
-
-
X
Allergic history
F_ALERG
X
-
-
-
-
-
-
-
X
Physical examination
F_PHIS
X
X
-
X
-
X
X
-
X
Anthropometric parameters
F_ANTHR
X
-
-
-
-
-
-
-
X
Vital signs
F_MAIN
X
X
X
X
X
-
X
Electrocardiography
F_ECG
X
X
X
X
-
X
-
X
Complete blood count
F_BLOOD
X
-
X
-
X
-
X
-
X
Blood serum chemistry
F_BBLOOD
X
-
X
-
X
-
X
-
X
Serology
F_SERO
X
-
-
-
-
-
-
-
X
Urinalysis
F_URINA
X
-
X
-
X
-
X
-
X
Microscopic examination of urine sediment
F_MICRO
X
-
X
-
X
-
X
-
X
Pregnancy test
F_TEST
X
X
-
X
-
X
-
-
X
Urine drug screen
F_DRUG
X
X
-
X
-
-
-
-
X
Alcohol breath test
F_ALCO
X
X
-
X
-
-
-
-
X
Inclusion criteria
F_CRIT
X
-
-
-
-
-
-
-
X
Visit comments
F_COMM
X
X
X
X
X
X
X
-
X
Visit information
F_INFO
X
X
X
X
X
X
-
-
Randomization
F_RAND
-
X
-
-
-
-
-
-
-
Global assessment
F_GLOB
-
X
-
X
-
-
X
-
-
Physical examination (repeat form)
F_PHIST
-
-
X
-
X
-
-
-
-
Vital signs (repeat form)
F_MAINT
-
-
X
-
X
-
-
-
-
AE/SAE evaluation and cncomitant therapy (repeat form)
F_AE_TH
-
-
X
-
X
-
-
-
-
Global assessment (repeat form)
F_GLOBT
-
-
X
-
X
-
-
-
-
Administration of the study drug
F_DRUGT
-
-
X
-
X
-
-
-
-
Collection of PK blood samples (repeat form)
F_FARM
-
-
X
-
X
-
-
-
-


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DMSP03_TMPL01_V.01_16.05.2016
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Name of form
Code of form
Screening
First period, 
admission
First period
Second period, 
admission
Second period
Follow-up visit
Unschedul- ed 
visit
Main forms
Screenfailure 
data
Meals
F_EAT
-
-
X
-
X
-
-
-
-
End of participation
F_END
-
-
-
-
-
-
-
X
-
Adverse event Form (repeat form)
F_AE
-
-
-
-
-
-
-
X
-
Concomitant therapy (repeat form)
F_TREAT
-
-
-
-
-
-
-
X
-
Main screen failure information
F_SF
-
-
-
-
-
-
-
X