Clinical trial NCT02350296
Conditions: Pain Disorders
Keywords: headache dental pain neuralgia dysmenorrhoea muscular and osteoarticular pain
Sponsor: Dompé Farmaceutici S.p.A
Start date: 2014-11-26; Completion date: 2015-04-22
Enrollment: 30 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
Objectives:

The objective of the study was to investigate the bioequivalence between two formulations containing ketoprofen lysine salt (KLS) when administered as single oral doses in two consecutive study periods to healthy male and female volunteers under fasting conditions.

Primary end-point: to evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of absorption of ketoprofen after single dose administration of test and reference products.

Secondary end-points:

* to describe the pharmacokinetic (PK) profile of ketoprofen after single dose administration of test and reference products;
* to collect safety and tolerability data after single dose administration of test and reference products.

Detailed description:
This was a single centre, single dose, open, randomised, two-way cross-over, two-stage bioequivalence study. According to the two-stage design of the study, an initial group of subjects was treated in study stage 1 and data were analysed. Since bioequivalence was demonstrated, according to the protocol the study was terminated after stage 1, and stage 2 was not performed.

The study was conducted as planned and consisted of a screening visit, a treatment phase of 2 study periods separated by a wash-out interval of at least 4 days and a final visit / early termination visit (ETV).

Considering the lack of information about the PK profile of the new formulation, it was decided to use a "two stage" bioequivalence study design, that allows a re-calculation of the sample size in case the number of subjects initially enrolled in the study is not large enough to provide a reliable answer to the questions addressed, due to a possible underestimation of the variability or misleading estimation of the point estimate for the test/reference ratio of the geometric means.

The sequence of treatments in the two study periods was assigned to each randomised subject according to a computer generated randomisation list.

A wash-out period of at least 4 days between the two administrations is justified by the elimination half-life of the ketoprofen (1-2 h).

Arms: arm 1: In this arm, a single dose of the test product (1 tablet; 40 mg KLS) was orally administered, under fasting conditions, in the first study period (day 1, 08:00±1h), and, after a wash-out period of at least 4 days, a single dose of the reference product OKi® 80 mg (half a sachet, 40 mg KLS) was orally administered, under fasting conditions, in the second study period (day 1, Visit 5, 08:00 ±1h). arm 2: In this arm, a single dose of the reference product OKi® 80 mg (half a sachet, 40 mg KLS) was orally administered, under fasting conditions, in the first study period (day 1, Visit 3, 08:00 ±1h) and, after a wash-out period of at least 4 days, a single dose of the test product (1 tablet; 40 mg KLS) was orally administered, under fasting conditions, in the second study period (day 1, Visit 5, 08:00±1h).
Interventions: intervention 1: KSL 40 mg intervention 2: OKi® 80 mg
Intervention descriptions: intervention 1: Ketoprofen lysine salt (KLS) immediate release oral tablets 40 mg, corresponding to 25 mg of ketoprofen free acid. Ketoprofen lysine salt was administered according to the randomisation list and the cross-over design. One (1) tablet of test formulation was administered to the subjects in the morning with 240 mL of still mineral water. Afterwards, no fluid intake was permitted for 2 h. All subjects were under fasting conditions from the evening before investigational product administration (i.e. for at least 10 h, overnight). intervention 2: OKi® 80 mg granules for oral solution (bipartite sachets: each half sachet containing 40 mg of KLS corresponding to 25 mg of ketoprofen free acid). Ketoprofen lysine salt was administered according to the randomisation list and the cross-over design.

The content of half sachet of the reference formulation was dissolved in 190 mL of still mineral water. The subject drank the entire solution immediately. Then the glass was rinsed with 50 mL of still mineral water and the subject drank the rinse immediately. Afterwards, no fluid intake was permitted for 2 h. All subjects were under fasting conditions from the evening before investigational product administration (i.e. for at least 10 h, overnight).

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL 
 
Study report CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 22APR15 
16. 
APPENDICES 
 
16.1 
Study information 
 
16.1.1 
Protocol and protocol amendments 
 
The following documents are enclosed: 
 
 Clinical study protocol, Final version 1.0, 28JUL14 
 Protocol amendment No. 1, Final version 2.0, 25NOV14 
 
 
 


CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
 
Study protocol CRO-PK-14-288 - Sponsor code KSL0114 
 
 
Two-way crossover, randomised, single dose and two-stage 
bioequivalence phase I study of ketoprofen lysine salt as 
immediate release tablets formulation (40 mg) versus ketoprofen 
lysine salt as granules for oral solution (80 mg bipartite sachet, 
half sachet) after oral administration to healthy volunteers of both 
sexes 
 
Single centre, single-dose, open, randomised, two-way cross-over, two-stage bioequivalence 
study 
 
Test formulation: 
Ketoprofen lysine salt (KLS), immediate release tablets 40 mg, 
corresponding to 25 mg as ketoprofen, Dompé s.p.a., Italy 
 
 
Reference formulation: 
OKi® 80 mg granules for oral solution (bipartite sachet), half 
sachet containing 40 mg of KLS corresponding to 25 mg as 
ketoprofen, Dompé s.p.a., Italy 
 
 
Sponsor: 
Dompé s.p.a. 
Via Campo di Pile, 67100 L’Aquila  
Milan offices:  
Via Santa Lucia 6, 20122 Milano - Italy 
Phone:  +39.02.58383.1 
Fax:  
+39.02.58383.324 
Email: mauro.ferrari@dompe.it 
 
 
Investigators: 
Milko Radicioni, MD - Principal investigator 
Antonio Rusca, MD, FMH - Co-investigator 
CROSS Research S.A., Phase I Unit, Via F.A. Giorgioli 14 
CH-6864 Arzo, Switzerland 
Phone: +41.91.63.00.510 
Fax: 
+41.91.63.00.511 
Email: clinic@croalliance.com 
 
 
Development phase: 
I 
 
 
Version and date: 
Final version 1.0, 28JUL14 
 
 
This study will be conducted in accordance with Good Clinical Practice (GCP), ICH topic E6 
 
Property of the sponsor 
May not be used, divulged, published or otherwise disclosed without the consent of the sponsor 
 
This document comprises 59 pages  
CROSS Research S.A. 
Page 1 








CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
STUDY SYNOPSIS 
 
Title: Two-way crossover, randomised, single-dose and two-stage bioequivalence phase I study of ketoprofen 
lysine salt as immediate release tablets formulation (40 mg) versus ketoprofen lysine salt as granules for oral 
solution (80 mg bipartite sachet, half sachet) after oral administration to healthy volunteers of both sexes 
 
Protocol number: CRO-PK-14-288 - Sponsor study code KSL0114 
 
Clinical phase: Phase I 
 
Study design: Single centre, single-dose, open, randomised, two-way cross-over, two-stage bioequivalence 
study 
 
Planned nr. of centres / countries: 1/Switzerland 
 
Sponsor: Dompé s.p.a. Via Campo di Pile, 67100 L’Aquila  Milan offices:  Via Santa Lucia 6, 20122 Milano - 
Italy 
 
Investigator and centre: Principal Investigator: Milko Radicioni, MD; Co-Investigator: Antonio Rusca, MD, 
FMH; Cross Research Phase I Unit, Via F. A. Giorgioli 14 CH-6864 Arzo, Switzerland 
 
Investigational product(s):  
TEST (T):  
Ketoprofen lysine salt (KLS), immediate release tablets 40 mg, corresponding to 25 mg 
as ketoprofen, Dompé s.p.a., Italy 
REFERENCE (R): 
OKi®, 80 mg granules for oral solution (bipartite sachets), each half sachet containing 
40 mg of KLS corresponding to 25 mg as ketoprofen, Dompé s.p.a., Italy 
 
Dose regimen:  A single oral dose (40 mg) of each formulation (test and reference) will be administered to 
healthy volunteers under fasting conditions in two consecutive study periods with a wash-out interval of at least 
4 days between the two administrations. 
 
Objective: To investigate the bioequivalence between two formulations containing ketoprofen lysine salt (KLS) 
when administered as single oral dose in two consecutive study periods to healthy male and female volunteers 
under fasting conditions. 
 
End-points:  
Primary end-point: to evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of absorption of ketoprofen 
after single dose administration of test and reference.  
Secondary end-points:  
 to describe the pharmacokinetic (PK) profile of ketoprofen after single dose administration of test and 
reference; 
 to collect safety and tolerability data after single dose administration of test and reference. 
 
Study variables: 
Primary variables: Cmax and AUC0-t of ketoprofen calculated from plasma concentrations after single oral dose 
of test and reference. 
Secondary variables:  
 AUC0-, tmax, t1/2, λz and Frel of ketoprofen calculated from plasma concentrations after single oral dose of 
test and reference; 
 Treatment-emergent AEs (TEAEs), vital signs (BP, PR, BT), body weight, ECG, laboratory parameters 
 
Analytics: Ketoprofen free acid will be determined in plasma by a HPLC-UV validated assay at Dompé 
Bioanalytical Laboratories, L’Aquila, Italy. Analytical facilities and procedures are in compliance with GLP 
regulations. 
 
Safety and tolerability assessments: Treatment-emergent adverse events (TEAEs); vital signs (blood pressure 
[BP], pulse rate [PR], body temperature [BT]), body weight, physical examinations; laboratory tests performed 
at screening and final visit/early termination visit (ETV); electrocardiogram (ECG) at screening and final 
visit/ETV 
 
 
CROSS Research S.A. 
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CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
STUDY SYNOPSIS (cont.) 
 
Sample size: in a first study stage 30 healthy volunteers (at least 12 subjects per sex) will be included and 
treated receiving test and reference treatment according to the cross-over design. Drop-out subjects will not be 
replaced. After the end of study stage 1, PK parameters will be calculated and an ad interim bioequivalence test 
will be performed on the calculated PK parameters Cmax, AUC0-t and AUC0-∞. To safeguard the overall type I 
error, the Pocock spending function will be used to determine the α level of the bioequivalence test. Should 
bioequivalence be proven with the results of the subjects of the first stage and with an a posteriori calculated 
power of at least 80%, the primary objective of the study would then be satisfied and the second study stage will 
not take place. Should bioequivalence not be proven with the results of the subjects of the first stage or should it 
be proven with an a posteriori calculated power lower than 80%, the overall sample size for the study (stage 1 
plus 2) will be calculated on the basis of the ad interim bioequivalence results. The Sponsor will decide whether 
the study has to continue or not. In the first case, the additional subjects will be enrolled into the second study 
stage. After completion of stage 2, the PK analysis and the bioequivalence test will be performed on the pooled 
subjects of the two study stages. The second stage will be performed after notification of the sample size to the 
local Ethics Committee and to the central Swiss authority (Swissmedic). 
 
Main selection criteria:  
Inclusion criteria: 
1. Informed consent: signed written informed consent before inclusion in the study  
2. Sex and Age: males/females, 18-55 years old inclusive 
3. Body Mass Index (BMI): 18.5-30 kg/m2 inclusive 
4. Vital signs: systolic blood pressure (SBP) 100-139 mmHg, diastolic blood pressure (DBP) 50-89 mmHg, 
pulse rate (PR) 50-90 bpm and body temperature (BT) ≤ 37.5° C, measured after 5 min of rest in the sitting 
position; 
5. Full comprehension: ability to comprehend the full nature and purpose of the study, including possible risks 
and side effects; ability to co-operate with the investigator and to comply with the requirements of the entire 
study 
6. Contraception and fertility (females only): females of child-bearing potential and with an active sexual life 
must be using at least one of the following reliable methods of contraception: 
a. 
Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 months before the 
screening visit 
b. A non-hormonal intrauterine device [IUD] or female condom with spermicide or contraceptive sponge 
with spermicide or diaphragm with spermicide or cervical cap with spermicide for at least 2 months 
before the screening visit 
c. 
A male sexual partner who agrees to use a male condom with spermicide 
d. A sterile sexual partner 
Female participants of non-child-bearing potential or in post-menopausal status for at least 1 year will be 
admitted. For all female subjects, pregnancy test result must be negative at screening. 
 
Exclusion criteria: 
1. Electrocardiogram (ECG 12-leads, supine position): clinically significant abnormalities 
2. Physical findings: clinically significant abnormal physical findings which could interfere with the objectives 
of the study 
3. Laboratory analyses: clinically significant abnormal laboratory values indicative of physical illness 
4. Allergy: ascertained or presumptive hypersensitivity to the active principles (ketoprofen) and/or 
formulations' ingredients; history of hypersensitivity to drugs (in particular to NSAIDs) or allergic reactions 
in general, which the Investigator considers may affect the outcome of the study 
5. Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory (including 
asthma), skin, haematological, endocrine or neurological and autoimmune diseases that may interfere with 
the aim of the study 
6. Medications: medications, including over the counter (OTC) drugs [in particular ketoprofen and 
acetylsalicylic acid (ASA), and NSAIDs in general], herbal remedies and food supplements taken 2 weeks 
before the start of the study. Hormonal contraceptives for females will be allowed  
7. Investigative drug studies: participation in the evaluation of any investigational product for 3 months before 
this study. The 3-month interval is calculated as the time between the first calendar day of the month that 
follows the last visit of the previous study and the first day of the present study (date of the informed 
consent signature) 
 
CROSS Research S.A. 
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CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
STUDY SYNOPSIS (cont.) 
 
Exclusion criteria (cont.): 
8. Blood donation: blood donations for 3 months before this study 
9. Drug, alcohol, caffeine, tobacco: history of drug, alcohol [> 1 drink/day for females and > 2 drinks/day for 
males, defined according to the USDA Dietary Guidelines 2010 (6)], caffeine (> 5 cups coffee/tea/day) or 
tobacco abuse ( 6 cigarettes/day)  
10. Drug test: positive result at the drug test at screening  
11. Alcohol test: positive alcohol breath test at day -1 
12. Diet: abnormal diets (< 1600 or > 3500 kcal/day) or substantial changes in eating habits in the 4 weeks 
before this study; vegetarians 
13. Pregnancy (females only): positive or missing pregnancy test at screening or day -1, pregnant or lactating 
women 
 
Schedule: 
 
Visit 
Day 
Procedures/Assessments 
Notes 
Screening – visit 1 
From day -14    
to day -2 
 Explanation to the subject of study aims, procedures 
and possible risks 
 Informed consent signature 
 Screening number (as S001, S002, etc.) 
 Demographic data and life style recording 
 Medical/surgical history 
 Previous/concomitant medications 
 Full physical examination (body weight, height, 
vital signs, physical abnormalities) 
 ECG recording 
 Laboratory analyses: haematology, blood chemistry, 
urine analysis, serum virology and serum pregnancy 
test (females only) 
 Urine multi-drug kit test 
 AE monitoring 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
Note: The first two 
letters of the surname 
followed by the first 
two letters of the first 
name will be used in 
the 
clinical 
centre 
source document only 
and 
will 
not 
be 
transferred 
to 
the 
sponsor 
Visit 2 
Day -1 
 Alcohol breath test 
 Vital signs measurement 
 Urine pregnancy test (females only) 
 AE and concomitant medications 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation  
 Enrolment and Randomisation  
Arrival at the clinical 
centre in the evening 
Confinement until the 
evening of day 1 
Standardised 
low-fat 
dinner 
Fasting for at least 10 h 
(overnight) 
Visit 3 
Day 1 
 IMP administration: 8:00 ± 1h 
 Vital signs measurement: 8h post-dose 
 Blood sample collection for PK analysis: pre-dose 
(0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h 
post-dose  
 AE and concomitant medications 
Day 1 
Standardised lunch at 
13:00 (5 h post-dose) 
Discharge 
from 
the 
clinical centre in the 
evening after the 8 h 
blood sample collection 
and vital signs check 
 
 
CROSS Research S.A. 
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CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
STUDY SYNOPSIS (cont.) 
 
Schedule (cont.): 
 
Wash- 
out 
At least 4 days 
A wash-out interval of at least 4 days between the 
two administrations of the two study periods 
 
Visit 4 
Day -1 
As visit 2, with the exclusion of Inclusion/exclusion 
criteria evaluation, Eligibility evaluation, Enrolment 
and Randomisation 
Arrival at the clinical 
centre in the evening 
Confinement until the 
evening of day 1 
Standardised 
low-fat 
dinner 
Fasting for at least 10 h 
(overnight) 
 
Visit 5 
Day 1 
As visit 3. Test or reference IMP administered 
according to the randomisation list and cross-over 
design 
Day 1 
Standardised lunch at 
13:00 (5 h post-dose) 
Final discharge from 
the clinical centre after 
the 8 h blood sample 
collection 
and 
final 
visit 
 
Final Visit/ETV 
Day 1 of period 
2 / 
at ETV in case 
of 
discontinuation 
 Full physical examination (body weight, physical 
abnormalities and, in case of ETV, vital signs) 
 ECG recording 
 Laboratory analyses as at screening, with the 
exception of serum virology, urine drug test and 
pregnancy test 
 AE and concomitant medications 
 
In case of clinically significant results at the final 
visit, the subjects will be followed-up by the 
investigator until the normalisation of the concerned 
clinical parameter(s) 
 
Upon 
leaving, 
the 
subjects 
will 
be 
instructed to contact 
immediately 
the 
investigator in case of 
occurrence 
of 
any 
adverse reactions 
 
 
During confinement, the subjects will not take any food or drinks (except water) for at least 10 h (i.e. overnight) 
before IMP administration. Water will be allowed as desired, except for one h before and two h after IMP 
administration. In order to maintain an adequate hydration, the subjects will be encouraged to drink at least 180 
mL of mineral water every 2 h for 6 h post-dose, starting at 2 h post-dose. In the evening of day -1, the subjects 
will receive a standardised light and low-fat dinner. On day 1 of each study period, the subjects will remain 
fasted until 5 h post-dose. Standardised lunch will be served at approximately 5 h post-dose. 
Coffee, tea and any other food containing xanthines (i.e. coke, chocolate, etc.) will be forbidden during 
confinement. Alcohol and grapefruit will be forbidden from 48 h before the first administration until the end of 
the study. During confinement, routine ambulant daily activities will be strongly recommended. 
The subjects will be allowed to smoke not more than 1 cigarette after lunch. 
 
CROSS Research S.A. 
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CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
STUDY SYNOPSIS (cont.) 
 
Data analysis:  
The PK analysis and the statistical analysis of PK parameters will be performed using Phoenix WinNonlin® 
version 6.3 or higher, Pharsight Corporation and SAS® version 9.3 (TS1M1) or higher. The statistical analysis of 
safety data will be performed using SAS® version 9.3 (TS1M1) for Windows or higher. Cmax and AUC will be 
compared between T and R using analysis of variance (ANOVA) for a cross-over design on log-transformed 
data. ANOVA will be performed on the data from stage 1 and, if applicable, the combined data from stage 1 and 
stage 2. The statistical analysis will take into account treatment, period, sequence and subject (sequence) as 
source of variation in the first stage. If the analysis of combined data from the two stages is required, stage, 
treatment, period (stage), sequence, sequence*stage and subject (sequence*stage), will be taken into account as 
source of variation. Acceptance criterion for bioequivalence is a 94.12% confidence interval for the T/R ratio of 
the geometric means of the parameters under consideration within the 80.00-125.00% range, according to the 
current guidelines for bioequivalence studies and to the Pocock α spending function. tmax will be analysed using 
the non-parametric Friedman test. The data documented in this trial and the measured clinical parameters will be 
described using classic descriptive statistics for quantitative variables and frequencies for qualitative variables 
 
Timing:  
EC meeting: 26AUG14; planned clinical phase: NOV14; planned reporting: 25 working days after availability of 
analytical results 
 
 
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CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
 
STUDY SCHEDULE 
 
ACTIVITIES 
Screening 
PERIOD 1, 2  
(wash-out at least 4 days) 
Visit 
V1 
V2, V4 
V3, V5 
Final/Early 
Termination 
Visit (ETV)8 
Days -14/-2 
Day -1 
Day 1 
 
Informed consent 
x 
 
 
 
Demography 
x 
 
 
 
Lifestyle 
x 
 
 
 
Medical history and underlying 
disease 
x 
 
 
 
Physical abnormalities 
x 
 
 
x 
Previous and concomitant treatments 
x 
x 
x 
x 
Height 
x 
 
 
 
Body weight 
x 
 
 
x 
Alcohol breath test 
 
x 
 
 
Laboratory analysis1 
x 
 
 
x 
Virology 
x 
 
 
 
Drug screening 
x 
 
 
 
BP, PR, BT 
x 
x 
x2 
x2 
Pregnancy test3 
x 
x 
 
 
ECG 
x 
 
 
x 
Inclusion/exclusion criteria evaluation
x 
x9 
 
 
Eligibility evaluation 
x 
x9 
 
 
Enrolment and Randomisation 
 
x9 
 
 
Confinement 
 
x 
 
 
Discharge 
 
 
x 
 
Drug administration4 
 
 
x 
 
Blood samplings5 
 
 
x 
 
Standardised meals6  
 
x 
x 
 
AEs monitoring7 
x 
x 
x 
x 
 
1. Full laboratory analysis will be performed at screening visit. The same analysis will be performed at final 
visit with the exclusion of virology, drug screening and serum pregnancy test 
2. at 8 h post-dose, corresponding to the final visit assessment at the end of period 2; at early termination visit 
(if applicable)  
3. Females only. Serum -HCG test at screening visit; urine test at the clinical centre on day -1 of each study 
period 
4. at 8:00 ± 1 h 
5. Pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose 
6. Standardised meal will be served at approximately 5 h after the 1st drug administration. A standardised light 
and low-fat dinner will be served on day -1 of each period 
7. AEs will be monitored from the screening visit, immediately after informed consent, up to the final visit. 
8. on day 1 of period 2, after the 8 h blood sampling and vital signs check, subjects will undergo a final visit. 
In case of discontinuation, subjects will undergo an ETV 
9. On visit 2 only 
 
 
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CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
TABLE OF CONTENTS 
 
PROTOCOL APPROVAL 
2 
STUDY SYNOPSIS 
5 
STUDY SCHEDULE 
10 
TABLE OF CONTENTS 
11 
LIST OF ABBREVIATIONS 
15 
1 
INTRODUCTION 
17 
1.1 
Background 
17 
1.2 
Investigational Product 
17 
1.3 
Preclinical Data 
17 
1.4 
Clinical Safety Data 
17 
1.5 
Rationale 
18 
1.6 
Risks and benefits 
18 
2 
STUDY OBJECTIVES 
19 
2.1 
Primary end-point 
19 
2.2 
Secondary end-points 
19 
3 
CLINICAL SUPPLIES 
20 
3.1 
Treatment 
20 
3.1.1 
Description of products 
20 
3.1.2 
Dose regimen 
20 
3.1.3 
Route and method of administration 
20 
3.1.4 
Investigational product distribution 
21 
3.2 
Packaging and labelling 
21 
3.3 
Storage conditions 
22 
3.4 
Drug accountability 
22 
4 
INVESTIGATIONAL PLAN 
23 
4.1 
Overall study design 
23 
4.2 
Discussion of design 
23 
5 
STUDY POPULATION 
24 
5.1 
Target population 
24 
5.2 
Inclusion criteria 
24 
5.3 
Exclusion criteria 
24 
5.3.1 
Not allowed treatments 
25 
5.3.2 
Allowed treatments 
25 
6 
STUDY SCHEDULE 
26 
6.1 
Study visits and procedures 
26 
6.2 
Diet and lifestyle 
28 
6.2.1 
Restrictions 
28 
7 
DESCRIPTION OF SPECIFIC PROCEDURES 
29 
7.1 
Physical examination 
29 
7.1.1 
Body weight and height 
29 
7.1.2 
Vital signs 
29 
7.1.3 
ECGs 
29 
7.2 
Clinical laboratory assays 
29 
7.3 
Sampling for pharmacokinetic analysis 
30 
7.3.1 
Venous blood sampling 
30 
7.3.2 
Analytics 
31 
7.3.3 
Labelling, storage and transport of samples 
32 
7.4 
Total number of samples and blood withdrawn 
33 
8 
ASSIGNMENT OF STUDY TREATMENT 
34 
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CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
8.1 
Randomisation 
34 
8.2 
Treatment allocation 
34 
8.3 
Blinding 
34 
9 
EVALUATION PARAMETERS 
35 
9.1 
Study variables 
35 
9.1.1 
Primary variables 
35 
9.1.2 
Secondary variables 
35 
9.2 
Pharmacokinetic assessments 
35 
9.2.1 
Pharmacokinetic parameters 
35 
9.3 
Safety assessments 
36 
10 
STATISTICAL METHODS 
37 
10.1 
Analysis Sets 
37 
10.1.1 
Definitions 
37 
10.1.2 
Reasons for exclusion from the PK set 
38 
10.2 
Sample size and power considerations 
38 
10.3 
Interim analysis at the end of study stage 1 
39 
10.4 
Demographic, baseline and background characteristics 
39 
10.5 
Analysis of pharmacokinetic parameters 
39 
10.5.1 
Descriptive pharmacokinetics 
39 
10.5.2 
Statistical comparison of pharmacokinetic parameters 
39 
10.6 
Safety and tolerability evaluation 
40 
11 
DEFINITION AND HANDLING OF ADVERSE EVENTS (AES) 
41 
11.1 
Applicable SOPs 
41 
11.2 
Definitions 
41 
11.2.1 
Adverse Events 
41 
11.2.2 
Non-Serious Adverse Event (SAE) Definition 
41 
11.2.3 
Serious Adverse Event (SAE) Definition 
41 
11.2.4 
Reference Safety Information (RSI) 
42 
11.3 
Unexpected Adverse Reaction 
42 
11.4 
Documentation 
42 
11.5 
Assessment of Adverse Event Severity and Relationship 
42 
11.6 
Type and Duration of the Follow-up of Subjects after Adverse Events 
43 
11.7 
Reporting 
44 
11.8 
Reporting Procedure to IEC and to Regulatory Authorities 
45 
11.9 
Follow-up of Subjects with Adverse events 
46 
11.10 
Pregnancy in the Clinical Trial 
46 
12 
DATA MANAGEMENT PROCEDURES 
47 
12.1 
Data collection – CRFs 
47 
12.2 
Unique subject identifier 
47 
12.3 
Database management 
47 
12.3.1 
Coding dictionaries 
48 
13 
STUDY MONITORING, QUALITY CONTROL AND QUALITY ASSURANCE 
49 
13.1 
Monitoring 
49 
13.2 
Quality Control and Quality Assurance 
49 
13.3 
Applicable SOPs 
50 
13.4 
Data access 
50 
13.5 
Audits and inspections 
50 
14 
ETHICAL CONSIDERATIONS 
51 
14.1 
Ethics and Good Clinical Practice (GCP) 
51 
14.2 
Informed consent 
51 
14.3 
Insurance policy 
52 
14.4 
Withdrawal of subjects 
52 
14.4.1 
Primary reason for discontinuation 
52 
14.4.2 
Discontinuation procedures 
52 
14.5 
Study termination 
53 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
15 
ADMINISTRATIVE PROCEDURES 
54 
15.1 
Material supplied to the clinical centre 
54 
15.2 
Protocol amendments 
54 
15.3 
Study documentation and record keeping 
54 
15.4 
Study subjects’ recruitment 
55 
15.5 
Confidentiality and data protection 
55 
15.6 
Publication policy 
56 
16 
STUDY RESPONSIBLE PERSONS 
57 
16.1 
Sponsor 
57 
16.2 
Institutes performing the study 
57 
16.2.1 
Clinical centre 
57 
16.3 
Drug assay 
57 
16.4 
Centralised clinical laboratory 
58 
16.5 
Co-ordination, data analysis & reporting 
58 
16.6 
Monitoring 
58 
17 
REFERENCES 
59 
 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
TABLES 
Page 
 
Table 7.3.1.1 
Recommended maximal deviations from the scheduled sampling times 
31 
Table 11.5.1 
Intensity (Severity) of the Adverse Event 
43 
Table 11.5.2 
Relationship of the Adverse Event to the Investigational Product 
43 
 
 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
  
LIST OF ABBREVIATIONS 
 
-HCG 
human chorionic gonadotropin  
-GT 
-Glutamyl transpeptidase 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALCOA 
Attributable-Legible-Contemporaneous-Original-Accurate 
ALT 
Alanine aminotransferase 
ANOVA 
Analysis of Variance 
ASA 
Acetylsalicylic acid 
AST 
Aspartate aminotransferase 
AUC0-t 
Area under the concentration-time curve from time zero to time t 
AUC0- 
Area under the concentration vs. time curve up to infinity 
BE 
Bioequivalence 
BLQL 
Below Lower Quantification Limit 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BT 
Body temperature 
CA 
Competent Authority 
CDISC 
Clinical Data Interchange Standards Consortium 
CI 
Confidence Interval 
Cmax 
Peak drug concentration 
CMS 
Clinical Medical Service 
CPL 
Clinical Project Leader 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CSP 
Clinical Study Protocol 
CRS 
Clinical Study Report 
CS 
Clinically Significant 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
ETV 
Early Termination Visit 
Frel 
Relative Bioavailability 
FSFV 
First Subject First Visit 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
KLS 
Ketoprofen lysine salt 
HBs Ag 
Hepatitis B virus surface antigen 
HCV Ab 
Hepatitis C virus antibodies 
HIV 
Human Immunodeficiency Virus 
IB 
Investigator’s Brochure 
ICH 
International Conference on Harmonisation 
IRB/IEC 
Institutional Review Board/Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IUD 
Intra-Uterine Device 
LQL 
Lower Quantification Limit 
LSLV 
Last Subject Last Visit 
MCH 
Mean Cell Haemoglobin 
MCHC 
Mean Cell Haemoglobin Concentration 
MCV 
Mean Cell Volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRT 
Mean Residence Time 
MW 
Molecular Weight 
N 
Normal 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
NA 
Not Applicable 
NC 
Not calculated 
NCS 
Not clinically significant 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
OTC 
Over The Counter 
PE 
Point Estimate 
PK 
Pharmacokinetics 
PR 
Pulse Rate 
PT 
Preferred Term 
PTAE 
Pre-Treatment Adverse Event 
R 
Reference 
RBC 
Red Blood Cells 
SAE 
Serious Adverse Event 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SDTM 
Study Data Tabulation Model 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
T 
Test 
TEAE 
Treatment-Emergent Adverse Event 
THC 
delta-9-tetrahydrocannabinol 
t1/2 
Half-life 
Tmax 
Time to achieve Cmax 
USDA 
United States Department of Agriculture 
WBC 
White Blood Cells 
WHODDE 
World Health Organisation Drug Dictionary Enhanced 
 
 
 
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CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
1 
INTRODUCTION 
 
1.1 
Background 
 
NSAIDs are a chemically heterogeneous group of compounds, often chemically unrelated, 
which share some therapeutic actions and adverse events. The principal therapeutic effects of 
NSAIDs derive from their ability to inhibit prostaglandin production through the inhibition of 
an important enzyme in the prostaglandin synthetic pathway, cyclo-oxygenase or COX. All 
NSAIDs have antipyretic, antalgic and anti-inflammatory properties, and are commonly used 
for the treatment of inflammatory diseases, especially musculoskeletal disorders, 
characterised by pain and inflammation. The most common adverse events of NSAIDs are 
gastrointestinal and cardiovascular effects (1). 
 
1.2 
Investigational Product 
 
Ketoprofen lysine salt (KLS) is a propionic acid derivative and exerts an antipyretic action 
without interfering with the normal thermoregulatory processes. Painful inflammatory 
conditions are eliminated or attenuated facilitating articular mobility. The oral administration 
of the active ingredient in an aqueous solution leads to a rapid increase of plasma levels, an 
early attainment of peak values, a quicker onset and a higher intensity of the antalgic and anti-
inflammatory effect. Ketoprofen binds to plasma proteins for 95-99%. The compound is 
extensively metabolised by the liver (about 60-80%) and elimination is essentially renal (1, 2).  
 
1.3 
Preclinical Data 
 
Prolonged treatment in the rat, dog and monkey, with oral KLS at doses equivalent to or 
higher than the recommended therapeutic dose, did not cause any toxic events. KLS was 
found not to have mutagenic or carcinogenic effects in animals. The administration of 
inhibitors of prostaglandin synthesis has been shown to induce in animals an increase of pre 
and post-implantation losses, embryo-foetal lethality and various malformations, including 
cardiovascular (2). 
 
1.4 
Clinical Safety Data 
 
In comparative studies, ketoprofen appears to be at least as effective as other anti-
inflammatory and antalgic agents (3). The side effects of ketoprofen are similar to those of all 
NSAIDs, gastrointestinal disturbances being the most frequent: nausea, vomiting, diarrhoea, 
flatulence, constipation, dyspepsia, abdominal pain, more rarely peptic ulcerations, 
perforation, gastritis or gastrointestinal bleeding (3). Approximately 30% of patients 
experience mild gastrointestinal side effects with ketoprofen, which are decreased if the drug 
is taken with food or antacids (1). Other less frequent undesirable effects of ketoprofen are 
cutaneous events (urticaria, erythema, cutaneous rash), general events (allergic and 
anaphylactoid reactions), nervous events (dizziness and vertigo), cardiovascular events 
(palpitations, tachycardia, hypotension and hypertension) respiratory events (bronchospasm, 
dyspnoea), renal events (retention of water) and disorders of haematic crasis and of the 
urinary tract (2). In most of the cases, symptoms are temporary and resolve with the 
suspension of the therapy and with a specific pharmacological treatment (2). 
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CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
 
OKiTASK® 40 mg as orodispersible granules was first approved for use in Italy on 17 
September 2012 (International Birth Date).  
The majority of the ADRs related to treatment with OKiTASK concerns events included in 
the SOC “Gastrointestinal Disorders”, with upper abdominal pain as the most frequent 
reported term and the SOC “Nervous system disorders”. The overall frequency of ADRs is 
very rare. 
In the previous phase I clinical trials performed (KSL0109 - EudraCT 2009-015924-27 and 
KSL0112- CRO-PK-11-262, Swissmedic ref n° 2012DR1020) both OKi®, 80 mg soluble 
granules (half sachet – 40 mg) and OKiTASK® 40 mg orodispersible granules were well 
tolerated by healthy volunteers (4, 5). 
 
 
1.5 
Rationale 
 
As a part of the Dompé extension line program, Dompé develops a new immediate release 
tablets formulation of ketoprofen lysine salt 40 mg.  
 
The present bioequivalence phase I study is needed to compare the bioavailability and the 
concentration-time profile of the new immediate release formulation of KLS 40 mg with the 
reference compound OKi®, ketoprofen lysine salt 80 mg granules for oral solution (bipartite 
sachets).  
 
The new immediate release tablets formulation of KLS 40 mg (corresponding to 25 mg of 
ketoprofen free acid) is expected to be essentially similar to the formulations of ketoprofen 25 
mg for oral administration, that are already available in the European Community (e.g.: 
Toprec®, Rhone-Poulenc Rorer, France; Toprek®, Rhone-Poulenc Rorer, Italy, Fastum® 25 
mg tablets, Menarini, Italy) with the same indications: pain such as episodic tension-type 
headache, dental pain, neuralgia, dysmenorrhoea, postpartum pain, muscular and 
osteoarticular pain. 
 
1.6 
Risks and benefits 
 
Study subjects will not receive any direct therapeutic benefit from taking part in this study. 
No particular safety risks are foreseen with respect to the safety profile of the marketed OKi® 
80 mg granules for oral solution. Considering that for test and reference the planned KLS 
dose is 40 mg and the IMP will be administered as a single dose with a wash-out period of 4 
days, no concern for the safety of study participants is expected.  
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CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
2 
STUDY OBJECTIVES 
 
The objective of the study is to investigate the bioequivalence between two formulations 
containing ketoprofen lysine salt (KLS) when administered as single oral dose in two 
consecutive study periods to healthy male and female volunteers under fasting conditions. 
 
2.1 
Primary end-point 
 
 To evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of absorption of ketoprofen 
after single dose administration of test and reference. 
 
2.2 
Secondary end-points 
 
 
To describe the pharmacokinetic (PK) profile of ketoprofen after single dose 
administration of test and reference; 
 to collect safety and tolerability data after single dose administration of test and 
reference. 
 
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CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
3 
CLINICAL SUPPLIES 
 
3.1 
Treatment 
 
3.1.1 
Description of products 
 
The analytical certificates will be enclosed with the investigational medicinal products 
(IMPs).  
 
3.1.1.1 
Test product 
 
TEST (T) 
 
IMP 
Ketoprofen lysine salt (KLS) immediate release tablets 40 mg, 
corresponding to 25 mg of ketoprofen free acid 
Manufacturer 
(finished product) 
Dompé s.p.a. – Via Campo di Pile snc – 67100 L’Aquila, Italy 
Pharmaceutical form 
Immediate release tablets   
Dose 
40 mg 
Administration route 
Oral 
 
 
3.1.1.2 
Reference product 
 
REFERENCE (R) 
 
IMP 
OKi®: 80 mg granules for oral solution (bipartite sachets: each 
half sachet containing 40 mg of KLS corresponding to 25 mg 
of ketoprofen free acid) 
Distributor 
Dompé s.p.a. – Via Campo di Pile snc – 67100 L’Aquila, Italy 
Manufacturer 
(finished product) 
Dompé s.p.a. – Via Campo di Pile snc – 67100 L’Aquila, Italy 
Pharmaceutical form 
Granules for oral solution 
Dose 
40 mg (half of a bipartite sachet) 
Administration route 
Oral 
 
3.1.2 
Dose regimen 
 
A single oral dose (40 mg) of each formulation (test and reference) will be administered to 
healthy volunteers under fasting conditions in two consecutive study periods with a wash-out 
interval of at least 4 days between the two administrations.  
 
3.1.3 
Route and method of administration 
 
Test: One (1) tablet of test formulation will be administered to the subjects in the morning 
with 240 mL of still mineral water. Afterwards, no fluid intake will be permitted for 2 h. 
 
Reference: the content of half sachet of the reference formulation will be dissolved in 190 mL 
of still mineral water. The entire solution will be drunk immediately by the subject. Then 50 
CROSS Research S.A. 
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CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
mL of still mineral water will be used to rinse the glass and the rinse will also be drunk 
immediately. Afterwards, no fluid intake will be permitted for 2 h.  
 
All subjects will be in fasting conditions from the evening before (at least 10 h, overnight). 
 
The investigator will check that all subjects take the medication appropriately (mouth check). 
 
3.1.4 
Investigational product distribution 
 
The test and reference IMP will be administered by the investigator or by his/her deputy. The 
IMP will be exclusively used for the present clinical study and will only be administered to 
the subjects enrolled in the study.  
 
3.2 
Packaging and labelling 
 
The clinical centre will be provided with 30 subject individual boxes (subject kits). The 
number of kits is deemed sufficient for study stage 1 and 2. Each individual kit will contain 1 
tablet of test and one bipartite sachet of reference formulation for the dosing of both periods. 
 
The formulation labelling will report all the information requested according to the Annex 13 
to the Good Manufacturing Practice (published by the Commission in The rules governing 
medicinal products in the European Community, Volume 4) as follows: 
a. 
Name, address and telephone number of the sponsor, contract research organisation or 
investigator (the main contact for information on the product, clinical study and 
emergency unblinding) 
b. Pharmaceutical dosage form, route of administration, quantity of dosage units, and in the 
case of open studies, the name/identifier and strength/potency 
c. 
The batch and/or code number to identify the contents and packaging operation 
d. A study reference code allowing identification of the study, site, investigator and sponsor 
if not given elsewhere 
e. 
The study subject identification number/treatment number and where relevant, the visit 
number 
f. 
The name of the investigator (if not included in (a) or (d)) 
g. Directions for use (reference may be made to a leaflet or other explanatory document 
intended for the study subject or person administering the product) 
h. “For clinical study use only” or similar wording 
i. 
The storage conditions 
j. 
Period of use (use-by date, expiry date or re-test date as applicable), in month/year format 
and in a manner that avoids any ambiguity 
k. “Keep out of reach of children” 
 
Labels will be in English. 
 
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CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
The sponsor will provide a reserve kit for each subject to be used if needed. 
 
3.3 
Storage conditions 
 
The IMP will be stored at ≤ 25° C in a dry locked place, sheltered from light.  
 
3.4 
Drug accountability 
 
The test and reference IMPs will be provided directly to the investigator by the sponsor, in 
excess of the amount necessary for the study. 
 
After receipt of the IMPs supply, the pharmacist will confirm in writing by signing and dating 
standard drug accountability forms. 
 
At the end of the study, used, unused and partially used supplies of test and reference IMPs 
provided by the sponsor will either be destroyed on site (upon written authorisation) or 
returned to the sponsor, after assessment of drug accountability. 
In the event that the IMPs will be destroyed on site, a destruction certificate will be provided 
to the sponsor  
 
 
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CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
4 
INVESTIGATIONAL PLAN 
 
4.1 
Overall study design 
 
Single centre, single-dose, open, randomised, two-way cross-over, two-stage bioequivalence 
study. 
 
4.2 
Discussion of design 
 
The trial has been designed in agreement with the “Guideline on the investigation of 
bioequivalence” (CPMP/QWP/EWP/1401/98 Rev. 1, 20 January 2010) (9, 10). 
 
Due to the lack of information about the PK profile of the new formulation it was not possible 
to calculate the sample size properly. 
For this reason it was decided to use a “two stage” bioequivalence study design. The sample 
size of 30 subjects is regarded as sufficient to satisfy the primary objective for the first stage 
of the study. 
After the end of study stage 1, PK parameters will be calculated and an ad interim 
bioequivalence test will be performed on the calculated PK parameters Cmax, AUC0-t and 
AUC0-∞. To safeguard the overall type I error, the Pocock spending function will be used to 
determine the α level of the bioequivalence test. Should bioequivalence be proven with the 
results of the subjects of the first stage and with an a posteriori calculated power of at least 
80%, the primary objective of the study would then be satisfied and the second study stage 
will not take place. Should bioequivalence not be proven with the results of the subjects of the 
first stage or should it be proven with an a posteriori calculated power lower than 80%, the 
overall sample size for the study (stage 1 plus 2) will be calculated on the basis of the ad 
interim bioequivalence results. The Sponsor will decide whether the study has to continue or 
not. In the first case, the additional subjects will be enrolled into the second study stage. After 
completion of stage 2, the PK analysis and the bioequivalence test will be performed on the 
pooled subjects of the two study stages. The second stage will be performed after notification 
of the sample size to the local Ethics Committee and to the central Swiss authority 
(Swissmedic). 
 
An open design was chosen as it was considered adequate to evaluate objective measures such 
as pharmacokinetic parameters. All the personnel involved in the analytical determinations of 
the ketoprofen in the plasma samples withdrawn from the volunteers will be maintained in 
blinding.  
 
The sequence of treatments in the two study periods will be assigned to each randomised 
subject according to a computer generated randomisation list (see § 8.1).  
 
A wash-out period of at least 4 days between the two administrations is justified by the 
elimination half-life of the ketoprofen (1-2 h).  
 
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CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
5 
STUDY POPULATION 
 
5.1 
Target population 
 
The study population will include 30 healthy volunteers (at least 12 subjects per sex) aged 18-
55 years inclusive in the first study stage 
 
5.2 
Inclusion criteria 
 
To be enrolled in this study, subjects must fulfil all these criteria: 
1. Informed consent: signed written informed consent before inclusion in the study  
2. Sex and Age: males/females, 18-55 years old inclusive 
3. Body Mass Index (BMI): 18.5-30 kg/m2 inclusive 
4. Vital signs: systolic blood pressure (SBP) 100-139 mmHg, diastolic blood pressure (DBP) 
50-89 mmHg, pulse rate (PR) 50-90 bpm and body temperature (BT) ≤ 37.5° C, measured 
after 5 min of rest in the sitting position; 
5. Full comprehension: ability to comprehend the full nature and purpose of the study, 
including possible risks and side effects; ability to co-operate with the investigator and to 
comply with the requirements of the entire study 
6. Contraception and fertility (females only): females of child-bearing potential and with an 
active sexual life must be using at least one of the following reliable methods of 
contraception: 
a. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 
months before the screening visit 
b. A non-hormonal intrauterine device [IUD] or female condom with spermicide or 
contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap 
with spermicide for at least 2 months before the screening visit 
c. A male sexual partner who agrees to use a male condom with spermicide 
d. A sterile sexual partner 
Female participants of non-child-bearing potential or in post-menopausal status for at least 
1 year will be admitted. For all female subjects, pregnancy test result must be negative at 
screening. 
 
5.3 
Exclusion criteria 
 
Subjects meeting any of these criteria will not be enrolled in the study: 
1. Electrocardiogram (ECG 12-leads, supine position): clinically significant abnormalities 
2. Physical findings: clinically significant abnormal physical findings which could interfere 
with the objectives of the study 
3. Laboratory analyses: clinically significant abnormal laboratory values indicative of 
physical illness 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
4. Allergy: ascertained or presumptive hypersensitivity to the active principles (ketoprofen) 
and/or formulations' ingredients; history of hypersensitivity to drugs (in particular to 
NSAIDs) or allergic reactions in general, which the Investigator considers may affect the 
outcome of the study 
5. Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory 
(including asthma), skin, haematological, endocrine or neurological and autoimmune 
diseases that may interfere with the aim of the study 
6. Medications: medications, including over the counter (OTC) drugs [in particular 
ketoprofen and acetylsalicylic acid (ASA) and NSAIDs in general], herbal remedies and 
food supplements taken 2 weeks before the start of the study. Hormonal contraceptives for 
females will be allowed  
7. Investigative drug studies: participation in the evaluation of any investigational product 
for 3 months before this study. The 3-month interval is calculated as the time between the 
first calendar day of the month that follows the last visit of the previous study and the first 
day of the present study (date of the informed consent signature) 
8. Blood donation: blood donations for 3 months before this study 
9. Drug, alcohol, caffeine, tobacco: history of drug, alcohol [> 1 drink/day for females and > 
2 drinks/day for males, defined according to the USDA Dietary Guidelines 2010 (6)], 
caffeine (> 5 cups coffee/tea/day) or tobacco abuse ( 6 cigarettes/day)  
10. Drug test: positive result at the drug test at screening  
11. Alcohol test: positive alcohol breath test at day -1 
12. Diet: abnormal diets (< 1600 or > 3500 kcal/day) or substantial changes in eating habits in 
the 4 weeks before this study; vegetarians 
13. Pregnancy (females only): positive or missing pregnancy test at screening or day -1, 
pregnant or lactating women 
 
5.3.1 
Not allowed treatments 
 
No medication, including OTC [NSAIDs in particular ketoprofen and acetylsalicylic acid 
(ASA)] and herbal remedies and food supplements, will be allowed for 2 weeks before the 
start of the study and during the whole study duration.  
 
5.3.2 
Allowed treatments 
 
Paracetamol will be allowed as therapeutic counter-measure for adverse events (AEs) 
according to the investigator’s opinion. Hormonal contraceptives will be allowed too. 
The intake of any other medication will be reported as a protocol deviation. However, it will 
lead to subject's discontinuation from the study only if the investigator, together with the 
sponsor, considers it could affect the study assessments or outcome. 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
 
6 
STUDY SCHEDULE 
 
The schedule of the study is summarised at page 10. 
 
6.1 
Study visits and procedures 
 
Each study subject will undergo 6 visits. 
 
The study protocol foresees 2 periods separated by a wash-out interval of at least 4 days. 
Minimum study duration will be 7 days, screening visit included. Maximum study duration 
will depends to the wash out period followed. A written informed consent will be obtained 
before any study assessment or procedure. 
 
The first subject first visit (FSFV) is defined as the 1st visit performed at the clinical centre by 
the 1st screened subject. The last subject last visit (LSLV) is defined as the last visit performed 
at the clinical centre (or the telephonic follow-up, if applicable) by the last subject, i.e. the last 
visit foreseen by the study protocol, independently of the fact that the subject is a completer or 
a withdrawn subject. 
 
The following phases, visits and procedures will be performed: 
 
 Screening phase 
 Screening – visit 1: between day -14 and day -2 
 Period 1 – visit 2: day -1 
 
 Interventional phase 
 Period 1 – visit 3: day 1 
 Wash-out interval of at least 4 days 
 Period 2 – visit 4: day -1 
 Period 2 – visit 5: day 1 
 
 Final phase 
 Final visit/early termination visit (ETV). In case of early discontinuation, discontinued 
subjects will undergo an early termination visit (ETV) 
 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
 
Visit  
Day 
Procedures/Assessments 
Notes 
Screening – visit 1 
From day -14    
to day -2 
 Explanation to the subject of study aims, procedures 
and possible risks 
 Informed consent signature 
 Screening number (as S001, S002, etc.) 
 Demographic data and life style recording 
 Medical/surgical history 
 Previous/concomitant medications 
 Full physical examination (body weight, height, vital 
signs, physical abnormalities) 
 ECG recording 
 Laboratory analyses: haematology, blood chemistry, 
urine analysis, serum virology and serum pregnancy 
test (females only) 
 Urine multi-drug kit test 
 AE monitoring 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation 
Note: The first two 
letters of the surname 
followed by the first 
two letters of the first 
name will be used in 
the 
clinical 
centre 
source document only 
and 
will 
not 
be 
transferred 
to 
the 
sponsor 
Visit 2 
Day -1 
 Alcohol breath test 
 Vital signs measurement 
 Urine pregnancy test (females only) 
 AE and concomitant medications 
 Inclusion/exclusion criteria evaluation 
 Eligibility evaluation  
 Enrolment and Randomisation  
Arrival at the clinical 
centre in the evening 
Confinement until the 
evening of day 1 
Standardised 
low-fat 
dinner 
Fasting for at least 10 h 
(overnight) 
Visit 3 
Day 1 
 IMP administration: 8:00 ± 1h 
 Vital signs measurement: 8h post-dose 
 Blood sample collection for PK analysis: pre-dose 
(0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h 
post-dose  
 AE and concomitant medications 
Day 1 
Standardised lunch at 
13:00 (5 h post-dose) 
Discharge 
from 
the 
clinical centre in the 
evening after the 8 h 
blood sample collection 
and vital signs check 
Wash- 
out 
At least 4 days 
A wash-out interval of at least 4 days between the two 
administrations of the two study periods 
 
Visit 4 
Day -1 
As visit 2, with the exclusion of Inclusion/exclusion 
criteria evaluation, Eligibility evaluation, Enrolment and 
Randomisation 
Arrival at the clinical 
centre in the evening 
Confinement until the 
evening of day 1 
Standardised 
low-fat 
dinner 
Fasting for at least 10 h 
(overnight) 
 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
Visit  
Day 
Procedures/Assessments 
Notes 
Visit 5 
Day 1 
As visit 3. Test or reference IMP administered 
according to the randomisation list and cross-over 
design 
Day 1 
Standardised lunch at 
13:00 (5 h post-dose) 
Final discharge from the 
clinical centre after the 8 
h 
blood 
sample 
collection and final visit 
 
Final Visit/ETV 
Day 1 of 
period 2 / 
at ETV in case 
of 
discontinuation 
 Full physical examination (body weight , physical 
abnormalities and, in case of ETV, vital signs) 
 ECG recording 
 Laboratory analyses as at screening, with the 
exception of  virology, urine drug test and pregnancy 
test 
 AE and concomitant medications 
 
In case of clinically significant results at the final visit, 
the subjects will be followed-up by the investigator until 
the normalisation of the concerned clinical parameter(s) 
 
 
Upon 
leaving, 
the 
subjects 
will 
be 
instructed 
to 
contact 
immediately 
the 
investigator in case of 
occurrence 
of 
any 
adverse reactions 
 
 
6.2 
Diet and lifestyle 
 
During confinement, the subjects will not take any food or drinks (except water) for at least 
10 h (i.e. overnight) before IMP administration. Water will be allowed as desired, except for 
one h before and two h after IMP administration. In order to maintain an adequate hydration, 
the subjects will be encouraged to drink at least 180 mL of mineral water every 2 h for 6 h 
post-dose, starting at 2 h post-dose. 
In the evening of day -1, the subjects will receive a standardised light and low-fat dinner. 
On day 1 of each study period, the subjects will remain fasted until 5 h post-dose. 
Standardised lunch will be served at approximately 5 h post-dose. 
 
Coffee, tea and any other food containing xanthines (i.e. coke, chocolate, etc.) will be 
forbidden during confinement. Alcohol and grapefruit will be forbidden from 48 h before the 
first administration until the end of the study. 
During confinement, routine ambulant daily activities will be strongly recommended. 
 
The subjects will be allowed to smoke not more than 1 cigarette after lunch.  
 
6.2.1 
Restrictions 
 
During each study period, the subjects will be confined from the evening preceding the IMP 
administration (day -1) until the evening of day 1.  
For the 4 h following the administration, when not involved in study activities, the subjects 
will remain seated. They will not be allowed to lie down.  
 
During confinement, hazardous, strenuous or athletic activities will not be permitted. 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
7 
DESCRIPTION OF SPECIFIC PROCEDURES 
 
7.1 
Physical examination 
 
A full physical examination will be performed at the screening and final visits.  
Information about the physical examination will be recorded by the Investigator. Any 
abnormality will be recorded. Significant findings/illnesses, reported after the start of the 
study and which meet the definition of an AE (see § 11), will be recorded. 
 
7.1.1 
Body weight and height 
 
Body weight will be recorded at: 
 
 Screening and final/ETV visit  
 
Subjects will be weighed (kg) lightly clothed without shoes. Height will be measured at 
screening only and BMI will be recorded. BMI will be calculated as weight [kg]/(height [m] x 
height [m]). 
 
7.1.2 
Vital signs 
 
Blood pressure (BP), pulse rate (PR) and body temperature (BT) will be measured by the 
Investigator or his/her deputy after 5 min of rest (sitting position). 
 
Measurements will be performed at: 
 
 Screening visit; 
 On day -1 of each period; 
 8 h post-dose of each period (on day 1, visit 5, the measure will correspond to the values 
of the final visit); 
 at early termination visit (if applicable). 
 
Body temperature will be measured in the ears. 
 
7.1.3 
ECGs 
 
12-Leads ECGs will be performed (in supine position) at screening and final/ETV visit. 
 
7.2 
Clinical laboratory assays 
 
Samples of blood (12.5 mL) and urine will be collected. The following laboratory analyses 
will be performed at the screening visit: 
 
HAEMATOLOGY 
Leukocytes and leukocyte differential count (percentage values and absolute values), 
erythrocytes, haemoglobin (conv. units), haemoglobin (IS units), haematocrit, MCV, MCH, 
MCHC, thrombocytes. 
 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
 
BLOOD CHEMISTRY 
Electrolytes: sodium, potassium, calcium, chloride, inorganic phosphorus 
Enzymes: alkaline phosphatase, γ-GT, AST, ALT 
Substrates/metabolites: total bilirubin, creatinine, fasting glucose, urea, uric acid, total 
cholesterol, triglycerides 
Proteins: total proteins 
 
Serum pregnancy test (women). 
A serum pregnancy test will be performed by the laboratory at screening. Urine pregnancy 
test will be performed on day -1 of each study period at the clinical centre.  
 
URINE ANALYSIS 
Urine chemical analysis (stick): pH, specific weight, appearance, colour, nitrites, proteins, 
glucose, urobilinogen, bilirubin, ketones, haematic pigments, leukocytes 
Urine sediment (analysis performed only if positive): leukocytes, erythrocytes, flat cells, 
round cells, crystals, cylinders, mucus, bacteria 
 
SERUM VIROLOGY  
Hepatitis B (HBs antigen), Hepatitis C (HCV antibodies), HIV 1/2 (HIV Ag/Ab combo).  
 
DRUG SCREENING 
A urine drug test will be performed at the clinical centre at screening, using a urine multi-drug 
kit. The following drugs will be assessed: cocaine, amphetamine, methamphetamine, 
cannabinoids (delta-9-tetrahydrocannabinol - THC), opiates and ecstasy.  
The same analyses, with the exception of urine drug test, virology and serum pregnancy test, 
will be performed at the final visit/ETV. 
 
7.3 
Sampling for pharmacokinetic analysis 
 
7.3.1 
Venous blood sampling 
 
Venous blood samples (8 mL) will be collected from a forearm vein at the following times:  
 
 pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose 
 
Actual sampling times for each subject will be recorded in the individual case report forms 
(CRFs). Deviations in actual sampling times should not exceed the recommended ranges 
reported in the following table. Any deviations outside the recommended ranges will be 
verified through Data Clarification Forms and will not automatically lead to the exclusion of 
the concerned subjects from the PK Sets. 
 
 
 
 
 
 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
Table 7.3.1.1 
Recommended maximal deviations from the scheduled sampling times 
Sampling time 
Deviation 
Pre-dose (0) 
Within 30 minutes before IMP administration 
0.0833 h (5 min), 0.25 h (15 min) 
0 min 
0.5 h (30 min) 
± 1 min 
0.75 h (45 min) 
± 2 min 
1, 1.5 h 
± 3 min 
2, 3, 4 h 
± 5 min 
5, 6, 8 h 
± 10 min 
 
Blood samples for PK analysis will be collected using an indwelling catheter with switch 
valve. The cannula will be rinsed, after each sampling, with about 1 mL of sterile saline 
solution containing 20 I.U./mL Na-heparin. The first 2 mL of blood will be discarded at each 
collection time to avoid contamination of the sample with heparin. 
 
The remaining 6 mL will be collected from the catheter and transferred with a syringe into 
heparinised tubes (Li-heparin). 
 
The samples will be stored on ice for a maximum of 15 min. Then the samples will be 
centrifuged at 4° C for 10 min at 2500 g to obtain plasma. Each plasma sample will be 
immediately divided into two aliquots, P1 and P2, in pre-labelled polypropylene tubes, and 
stored frozen at -20° C until analyses.  
 
If any clinical assessment, such as vital signs measurement or ECG recording, is foreseen at 
the same time-point of blood sampling for PK analysis, blood collection will be performed at 
the scheduled time. However, vital signs and ECG parameters can be influenced by the blood 
sampling. Therefore, these assessments can be performed up to 30 min before the collection 
of the pre-dose PK sample and up to 10 min before the collection of the other scheduled PK 
samples. Any deviations outside the recommended time will be verified through Data 
Clarification Forms. However, since vital signs measurements and ECG recordings will be 
performed for safety reasons only, deviations from the planned time schedule will be 
considered not relevant. 
 
7.3.2 
Analytics  
 
The concentration of ketoprofen will be determined in plasma at Dompé Bioanalytical 
Laboratories in L’Aquila, Italy using a fully validated HPLC-UV (High Performance Liquid 
Chromatography) assay. 
 
Analyses will be performed according to the general Principles of “OECD Good Laboratory 
Practices for testing of chemicals" C(81) 30 (final). 
 
The method validation report and the analytical report will be attached to the final report. 
 
 
 
 
 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
7.3.3 
Labelling, storage and transport of samples 
 
7.3.3.1 
Samples labelling 
 
Each sample tube will be clearly and unequivocally identified with a label resistant to the 
storage temperature and reporting: 
Study code 
Study code CRO-PK-14-288 - Sponsor code KLS0114 
Subject number 
001-030 (first stage) 
Tube identification 
P1/P2 
Period  
1, 2 
Scheduled sampling time as h; see § 7.3.1 
 
7.3.3.2 
Samples storage and transport 
 
During the study the samples will be stored at ≤- 20° C. At the end of each collection day, 
aliquots 1 and 2 will be stored in separate freezers. 
 
All aliquots 1, packed in sufficient solid CO2, will be shipped by an authorised courier from 
Cross Research Phase I Unit to Dompé Bioanalytical Laboratories in L’Aquila, Italy. Aliquots 
1 will remain stored at Dompé Bioanalytical Laboratories until the finalisation of the 
bioanalytical report. Afterwards, the samples will be destroyed and a certificate of destruction 
will be provided to the sponsor. 
 
The counter-samples (aliquot 2) will remain stored at CROSS Research S.A., Switzerland. 
These samples could either be: 
 sent to the laboratory for reanalysis should this become necessary for analytical reasons 
or if any problems occur during the delivery of aliquots 1, or 
 destroyed at an authorised site, or 
 transferred to the sponsor upon written request, or 
 stored at CROSS Research S.A., for a maximum time of 5 years 
 
No analyses different from those stated in this protocol and agreed by the subjects when 
signing the informed consent form will be performed unless a new informed consent and a 
new approval from the Ethical Committee is obtained. The subjects may ask to destroy their 
own samples at any time. 
 
 
 
 
 
 
 
 
 
 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
7.4 
Total number of samples and blood withdrawn 
 
During the study the following volume of blood will be collected:  
 
For routine laboratories analysis: 
Screening visit: 
12.5 mL 
Final visit/ETV: 12.5 mL 
 
For PK analysis: 
Treatment T:  
8x13=104 mL 
Treatment R: 
8x13=104 mL 
 
In total 233 mL of blood (not exceeding a normal blood donation) will be withdrawn from 
each subject. 
 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
8 
ASSIGNMENT OF STUDY TREATMENT 
 
8.1 
Randomisation 
 
The randomisation list will be computer-generated by the Biometry Unit of the Clinical 
Contract Research Organization (CRO), using the PLAN procedure of the SAS® version 9.3 
(TS1M1) (8) or higher (the actual version will be stated in the final report). The 
randomisation list will be supplied to the study site before study start. The randomisation list 
will be attached to the final clinical study report. 
 
8.2 
Treatment allocation 
 
Subjects will be assigned to the sequence of treatments (TR or RT) in the two study periods 
according to the randomisation list. Subjects will be randomised to receive one of the two 
treatments (i.e. either test or reference) during period 1 and the other treatment during period 
2. 
Randomisation number will be given to the subjects on study day -1, period 1, and will be 
used to assign the treatment sequence according to the randomisation list, as detailed above. 
 
8.3 
Blinding 
 
This is an open study. No masking procedure will be applied.  
 
 
 
 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
9 
EVALUATION PARAMETERS 
 
9.1 
Study variables 
 
9.1.1 
Primary variables 
 
 Cmax and AUC0-t of ketoprofen calculated from plasma concentrations after single oral 
dose of test and reference. 
 
9.1.2 
Secondary variables 
 
 AUC0-∞, tmax, t1/2, λz and Frel of ketoprofen calculated from plasma concentration after 
single oral dose of test and reference;  
 Treatment-emergent AEs (TEAEs), vital signs (BP, PR, BT), body weight, ECG, 
laboratory parameters.  
 
9.2 
Pharmacokinetic assessments 
 
9.2.1 
Pharmacokinetic parameters 
 
The following PK parameters will be measured and/or calculated for ketoprofen, using the 
validated software Phoenix WinNonlin® version 6.3 (7) or higher (actual version will be 
stated in the final report): 
 
Cmax: 
Maximum plasma concentration 
 
tmax: 
Time to achieve Cmax 
 
λz: 
Terminal elimination rate constant, calculated, if feasible, by log-linear 
regression using at least 3 points 
 
t1/2: 
Half-life, calculated, if feasible, as ln2/λz 
 
AUC0-t: 
Area under the concentration-time curve from administration to the last 
observed concentration time t, calculated with the linear trapezoidal method 
 
AUC0-: 
Area under the concentration-time curve extrapolated to infinity, calculated, if 
feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration
 
%AUCextra: 
Percentage of the residual area (Ct/z) extrapolated to infinity in relation to 
the total AUC0-, calculated, if feasible, as 100×[(Ct/z)/AUC0-] 
 
Frel: 
Relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference) 
 
AUC0-t is considered a reliable estimate of the extent of absorption if the ratio AUC0-t/AUC0- 
equals or exceeds a factor of 0.8, i.e. if %AUCextra is <20%.  
 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
The quality of log-linear regression (and, consequently, the reliability of the extrapolated PK 
parameters) should be demonstrated by a correlation coefficient R2 > 0.8. 
 
9.3 
Safety assessments 
 
Safety and general tolerability of the IMP will be based on TEAEs, physical examinations 
including body weight, vital signs, ECG and routine haematology, blood chemistry and 
urinalysis laboratory tests. 
 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
10 
STATISTICAL METHODS 
 
The data documented in this study and the parameters measured will be evaluated and 
compared using classic descriptive statistics, i.e. geometric mean (PK data only), arithmetic 
mean, SD, CV (%), minimum, median and maximum values for quantitative variables, and 
frequencies for qualitative variables. 
 
Not available data will be evaluated as “missing values”. The statistical analysis of 
demographic and safety data will be performed using SAS® version 9.3 (TS1M1) (8) or 
higher (the actual versions will be stated in the final report). 
The statistical analysis of PK parameters will be performed using Phoenix WinNonlin® 
version 6.3 (7) or higher and SAS® version 9.3 (TS1M1) or higher. 
 
10.1 
Analysis Sets 
 
10.1.1 
Definitions 
 
A subject will be defined as screened after the signature of the informed consent, regardless of 
the completion of all the screening procedures. 
 
A subject will be defined as eligible if he/she meets all the inclusion/exclusion criteria. 
Otherwise he/she will be defined as a screen failure.  
 
A subject will be defined as enrolled in the study if he/she is included into the interventional 
phase of the study. The enrolment can be performed through randomised or non-randomised 
allocation to a treatment arm/treatments sequence. 
 
An eligible but not enrolled subject will be defined as a reserve. 
 
A subject will be defined as randomised in the study when he/she is assigned to a randomised 
treatment arm/treatments sequence. 
 
 Enrolled set: all enrolled subjects. This analysis set will be used for demographic, 
baseline and background characteristics 
 Safety set: all subjects who receive at least one dose of the investigational medicinal 
product(s). This analysis set will be used for the safety analyses 
 PK set: all randomised subjects who fulfil the study protocol requirements in terms of 
investigational medicinal product(s) intake and have evaluable PK data readouts for the 
planned treatment comparisons, with no major deviations that may affect the PK results. 
This analysis set will be used for the statistical analysis of the PK results 
 
Each subject will be coded by the CRO Biometry Unit as valid or not valid for the Safety set 
and the PK set. Subjects will be evaluated according to the treatment they actually receive. 
 
 
 
 
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Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
10.1.2 
Reasons for exclusion from the PK set  
 
Reasons for the exclusion of subjects from the PK set are the following: 
 
Before bioanalysis 
 vomiting and diarrhoea after drug intake which could render the plasma concentration-
time profile unreliable 
 intake of concomitant medications which could render the plasma concentration-time 
profile unreliable 
 AEs which could render the plasma concentration-time profile unreliable 
 administration errors which could render the plasma concentration-time profile unreliable 
 other events which could render the plasma concentration-time profile unreliable 
If one of these events occurs, it will be noted in the CRF as the study is being conducted. 
 
After bioanalysis 
 
Exclusion of subjects on the basis of pharmacokinetic reasons is possible only for: 
 subjects with lack of any measurable concentrations or only very low plasma 
concentrations for the reference medicinal product. A subject is considered to have very 
low plasma concentrations if his/her AUC is less than 5% of the reference medicinal 
product geometric mean AUC (which should be calculated without inclusion of data from 
the outlying subject) 
 subjects with implausible concentrations (i.e. different from the known, expected 
concentration profiles) for the reference medicinal product. The exclusion of these 
subjects must be justified on the basis of sound scientific reasons and mutually agreed 
between the CRO and the Sponsor 
 subjects with non-zero baseline concentrations > 5% of Cmax 
The samples from the subjects excluded from the PK set should still be assayed and the 
results listed. Subjects should not be excluded from the PK set if the AUC0-t covers less than 
80% of the AUC0-∞. 
 
10.2 
Sample size and power considerations 
 
In a first study stage 30 healthy volunteers (at least 12 subjects per sex) will be included and 
treated to receive both test and reference investigational product according to the cross-over 
design. Drop-out subjects will not be replaced. After the end of study stage 1, PK parameters 
will be calculated and an ad interim bioequivalence test will be performed on the calculated 
PK parameters Cmax, AUC0-t and AUC0-∞. To safeguard the overall type I error, the Pocock 
spending function will be used to determine the α level of the bioequivalence test. Should 
bioequivalence be proven with the results of the subjects of the first stage and with an a 
posteriori calculated power of at least 80%, the primary objective of the study would then be 
satisfied and the second study stage will not take place. Should bioequivalence not be proven 
with the results of the subjects of the first stage or should it be proven with an a posteriori 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
calculated power lower than 80%, the overall sample size for the study (stage 1 plus 2) will be 
calculated on the basis of the ad interim bioequivalence results. The Sponsor will decide 
whether the study has to continue or not. In the first case, the additional subjects will be 
enrolled into the second study stage. After completion of stage 2, the PK analysis and the 
bioequivalence test will be performed on the pooled subjects of the two study stages. 
 
10.3 
Interim analysis at the end of study stage 1 
 
An interim bioequivalence test on the available PK data will be performed at the end of stage 
1, as described in § 4.2 above. Should bioequivalence not be proven at this stage, the sample 
size for the study (study stage 1 and 2) will be calculated on the basis of the interim 
bioequivalence test results. 
 
The second stage will be performed after notification of the sample size to the local Ethics 
Committee and to the central Swiss authority (Swissmedic). 
 
10.4 
Demographic, baseline and background characteristics 
 
Critical demographic characteristics will be examined according to qualitative or quantitative 
data. Qualitative data will be summarised in contingency tables. Quantitative data will be 
summarised using classic descriptive statistics. 
 
10.5 
Analysis of pharmacokinetic parameters 
 
10.5.1 
Descriptive pharmacokinetics 
 
A descriptive PK will be presented. The results will be displayed and summarised in tables 
and figures. Individual and mean curves (+SD at sampling times), indicating inter-subject 
variability, will be plotted. Data below the lower quantification limit (BLQL) will be 
considered as 0 in the calculations and presented as BLQL in listings and tables. As a 
consequence of BLQL (i.e. 0) values, calculated geometric means (if requested) could be null. 
For this reason, in the presence of any null value, the geometric mean will be reported as not 
calculated (NC). The date and time of PK sample collection will be listed by treatment. 
 
10.5.2 
Statistical comparison of pharmacokinetic parameters 
 
According to the current European Guideline on the Investigation of Bioequivalence (9) and 
the European Questions & Answers document (10), the PK parameters AUC0-t, AUC0- (if 
feasible) and Cmax will be analysed using ANOVA. Before analysis, the data will be 
transformed using a neperian logarithmic transformation. ANOVA will be performed on the 
data from study stage 1 taking into account treatment, period, sequence and subject 
(sequence) as sources of variation. For the analysis of the combined data of stage 1 and stage 
2 (if any), stage, treatment, period (stage), sequence, sequence*stage and subject 
(sequence*stage) will be taken into account as sources of variation. 
 
For both the interim analysis (stage 1 data) and the final combined analysis (stage 1 and 2 
data, if any), acceptance criterion for bioequivalence will be a 94.12% confidence interval for 
the T/R ratio of the geometric means of the PK parameters under consideration within the 
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Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
80.00-125.00% range, according to the current guidelines for bioequivalence studies and to 
the Pocock α spending function. 
 
tmax will be compared between treatments using the non-parametric Friedman test.  
 
10.6 
Safety and tolerability evaluation 
 
 AEs 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT), 
using the Medical Dictionary for Regulatory Activities (MedDRA). 
AEs will be classified as pre-treatment AEs (PTAEs) and treatment-emergent AEs (TEAEs), 
according to the period of occurrence, as follows:  
 PTAEs: all AEs occurring before the first dose of IMP and not worsening after the 
first dose of IMP 
 TEAEs: all AEs occurring or worsening after the first dose of IMP 
Individual PTAEs and TEAEs will be listed in subject data listings. No summary table will be 
provided for PTAEs. TEAEs will be summarised by treatment and overall. The number and 
percentage of subjects with any TEAE and the number of TEAEs will be tabulated by SOC 
and PT, seriousness, relationship to treatment and severity.  
 
 Physical examination 
Significant findings/illnesses, reported after the start of the study and that meet the definition 
of an AE (see § 11), will be recorded in the subject source documents. Date of the physical 
examination and overall investigator’s interpretation (as normal [N], abnormal not clinically 
significant [NCS] or abnormal clinically significant [CS]) will be reported in the CRF. 
 
 Laboratory data  
Date/time of samples collection and overall investigator’s interpretation (N, NCS or CS) will 
be recorded in the CRF and listed in the final clinical study report. Hard copies of the 
laboratory print-outs will be attached to the CRFs. All clinically significant abnormalities 
after the screening visit will be recorded as AEs. All laboratory results will be listed and a 
table of all the abnormal values will be presented.  
 
 Vital signs 
Values of vital signs will be listed and summarised by descriptive statistics.  
 
 Body weight  
Values of body weight will be listed and summarised by descriptive statistics. 
 
 ECG 
Date/time of ECG recording and overall investigator’s interpretation (N, NCS or CS) will be 
reported in the CRF and listed in the final clinical study report. Hard copies of the ECGs will 
be attached to the CRF. All clinically significant abnormalities after the screening visit will be 
recorded as AEs.  
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Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
11 
DEFINITION AND HANDLING OF ADVERSE 
EVENTS (AEs) 
 
11.1 
Applicable SOPs 
 
AE definition, classification and management will follow the Sponsor SOPs, based upon 
applicable local and international regulations. An operative summary of relevant SOPs will be 
made available to the clinical centre, as appropriate. The monitoring of AE will start from the 
Informed Consent signature. 
 
A brief summary of AE definition, classification and management is reported below. 
 
11.2 
Definitions 
 
11.2.1 
Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical 
trial subject administered a medicinal product, which does not necessarily have a causal 
relationship with the study treatment (Directive 2001/20/EC). 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 (investigational) product, whether or 
not related to the medicinal (investigational) product. 
 
11.2.2 
Non-Serious Adverse Event (SAE) Definition 
A non-serious AE is defined as any untoward change in a subject's medical conditions that 
does not meet serious criteria noted below (e.g., is not fatal, is not life-threatening, does not 
require hospitalization, does not prolong a current hospitalization, is not disabling, etc.). 
 
11.2.3 
Serious Adverse Event (SAE) Definition 
 
A serious adverse event (SAE) is defined in line with Directive 2001/20/EC as any adverse 
experience that meets any of the following criteria: 
 
 results in death 
 is life-threatening  
(NOTE: Life-threatening means that the subject was at immediate risk of death from 
the reaction as it occurred, i.e., it does not include a reaction which hypothetically 
might have caused death had it occurred in a more severe) 
 
 requires inpatient hospitalization or prolongation of existing hospitalization 
(NOTE: In general, hospitalization means that the individual remained at the hospital 
or emergency ward for observation and/or treatment (usually involving an overnight 
stay) that would not have been appropriate in the physician's office or an out-subject 
setting. Complications that occur during hospitalization are AEs. If a complication 
prolongs hospitalization or fulfils any other serious criteria, the event is serious. When 
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Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
in doubt as to whether “hospitalization” occurred, the event should be considered 
serious 
 
 results in persistent or significant disability/incapacity 
(NOTE: The term disability means a substantial disruption of a person’s ability to 
conduct normal life functions. This definition is not intended to include experiences of 
relatively minor medical significance such as uncomplicated headache, nausea, 
vomiting, diarrhoea, influenza, or accidental trauma (e.g., sprained ankle) which may 
interfere or prevent everyday life functions but do not constitute a substantial 
disruption) 
 
 results in a congenital anomaly/birth defect 
  is an important medical event 
(NOTE: An important medical event is an event that may not result in death, be life-
threatening, or require hospitalization but may be considered a SAE when, based upon 
appropriate medical judgment, it may jeopardize the subject’s well being and may 
require medical or surgical intervention to prevent one of the outcomes listed in the 
definitions for SAEs. Examples of such medical events include allergic bronchospasm 
requiring intensive treatment in an emergency room or at home, blood dyscrasias or 
convulsions that do not result in subject hospitalization or the development of drug 
dependency or drug abuse) 
 
11.2.4 
Reference Safety Information (RSI) 
 
In order to assess whether an adverse reaction is expected, the Investigator’s Brochure (IB) 
for test formulations and the leaflet for the reference formulations will be used. 
 
11.3 
Unexpected Adverse Reaction 
 
An unexpected adverse reaction is an adverse reaction, the nature and severity of which is not 
consistent with the information in the Investigator’s Brochure relating to the study or in the 
case of a product with a marketing authorisation, the summary of product characteristics. The 
Sponsor will be responsible for ensuring that the Investigator is provided with an up to date 
Investigator’s Brochure for the test investigational product and the SmPC for the reference 
compound (see attachment 1 of the Investigator’s Brochure).  
 
11.4 
Documentation 
 
All data related to an AE, type of event, onset date, intensity (mild, moderate or severe), 
relationship with study drug or other relevant information, must be reported in the specific 
section of CRF, including abnormal laboratory values. 
 
11.5 
Assessment of Adverse Event Severity and Relationship 
 
For every AE, the Investigator must assess the intensity (severity) and causality (relationship 
to study treatment). Specifically, the intensity of events should be classified as mild, 
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moderate, or severe. The assessment of causality will be based upon the categories of related 
and not related. These classifications should be based on the following definitions: 
 
Table 11.5.1 Intensity (Severity) of the Adverse Event  
Mild 
Grade 1 - Does not interfere with subject’s usual function (awareness of symptoms or 
signs, but easily tolerated [acceptable]). 
Moderate 
Grade 2 - Interferes to some extent with subject’s usual function (enough discomfort 
to interfere with usual activity [disturbing]). 
Severe 
Grade 3 - Interferes significantly with subject’s usual function (incapacity to work or 
to do usual activities [unacceptable]) 
 
Table 11.5.2 Relationship of the Adverse Event to the Investigational Product  
None (Intercurrent Event) 
An event that is not and cannot be related to the investigational product, e.g. 
subject is a passenger in a road traffic accident 
Unlikely (remote) 
Relationship is not likely e.g. a clinical event including laboratory test abnormality 
with temporal relationship to drug administration which makes a causal 
relationship improbable and in which other drugs, chemicals or underlying disease 
provide plausible explanations 
Possible 
Relationship may exist, but could have been produced by the subject’s condition or 
treatment or other cause 
Probable 
Relationship is likely, the AE abates upon discontinuation of investigational 
product and cannot be due to the subject’s condition 
Highly Probable 
Strong relationship, the event abates upon discontinuation of investigational 
product and, if applicable, re-appears upon repeat exposure 
 
 
11.6 
Type and Duration of the Follow-up of Subjects after Adverse Events 
 
AE will be followed by the Investigator (by phone or visit) until resolved or considered stable.  
Outcome of AEs will be defined as: 
 
 Resolved. Subject recovered from AE/SAE without any after‐effect of disease or injury. 
 Resolving. Subject is not completely recovered from AE/SAE at the time of reporting, but 
conditions improved. 
 Not Recovered. Subject has not recovered or AE/SAE is currently ongoing at the time 
AE/SAE Form is completed. 
 Recovered with Sequelae. Subject recovered from AE/SAE but after‐effect of disease or 
injury resulted. Please specify what sequelae resulted in Section “Narrative”. 
 Fatal. SAE directly resulted in death of the Subject. If death is checked, complete the 
appropriate section “Details of Death”. 
 Unknown. Outcome is unknown. Check box when no information is available at the time 
the SAE Form is completed. Follow up information on the outcome should be provided. 
 
 
 
 
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Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
11.7 
Reporting 
 
Adverse Events:  
All AEs (non-serious and serious) which occur during the course of the study will be recorded 
in the CRF. Any pre-existing medical conditions or signs/symptoms present in a subject prior 
to the start of the study (i.e., before informed consent is signed) should be specified in the 
CRF. Subsequent to signing an informed consent form, all untoward medical occurrences that 
occur during the course of the study must be documented on the CRF. When possible, signs 
and symptoms indicating a common underlying pathology should be documented as one 
comprehensive event. For each recorded event, the AE documentation must include the onset 
date, outcome, resolution date (if event is resolved), intensity (i.e., severity), any action with 
study treatment taken as a result of the event, and an assessment of the adverse event 
relationship to the study treatment.  
Serious Adverse Events:  
The Investigator must record all SAEs, occurring at any time during the study regardless of 
presumed causal relationship, on the Serious Adverse Event form. Within 24 hours from first 
knowledge of the SAE, the Investigator shall send the filled in and signed SAE form to the 
CRO and to the Sponsor at the following addresses: 
 
Sponsor  
Dompé Drug Safety  
Laura Boga, Senior Safety Manager  
Email to:  farmacovigilanza@dompe.it  
or Fax:  +39.02.36026913 
 
Dompé Medical Expert 
Elisabetta Grillo,  
Email to: elisabetta.grillo@dompe.it  
or Fax:  +39.02.58383297 
 
Dompé Clinical Development Manager 
Mauro Ferrari 
Email to: mauro.ferrari@dompe.it 
or Fax:  +39.02.58383324 
 
CRO:  
Email to: angelo.vaccani@croalliance.com 
or Fax to:  +41.91.630.05.11 
 
If assistance is needed with the reporting of a SAE, contact details for the CRO/Sponsor are 
provided in the section “Study Responsible Person”(§ 16).  
Serious adverse events will be managed directly by the Dompé Drug Safety department, with 
CRO support for Follow Up requests. 
 
The clinical site can be contacted using the phone and fax numbers stated in this protocol or 
calling the mobile phone number +41.79.822.35.07 (operative 24-h/day, 365 days/year). This 
mobile phone can be called by the study participants to communicate to the clinical staff any 
SAE occurring outside the clinical facility. 
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Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
 
Depending on the nature and seriousness of the AE, the Sponsor may request further 
information, including copies of appropriate medical records of the subject, as well as results 
of laboratory tests performed. If the subject was hospitalized, a copy of the discharge 
summary should be provided to the Sponsor as soon as it is available, if possible.  
In any case, the Investigator shall further follow up each SAE to complete case information 
till resolution of the event, as appropriate, and provide the follow up information to the 
Sponsor .Follow-up SAE information should be communicated through a new SAE form duly 
filled in and signed, within 24 hours from awareness, to: 
Dompé Drug Safety (e-mail: farmacovigilanza@dompe.it or Fax: +39 02 36026913), Dompé 
Medical Expert (elisabetta.grillo@dompe.it), Dompé Clinical Development Manager 
(mauro.ferrari@dompe.it) and CRO (angelo.vaccani@croalliance.com) whenever becoming 
aware of new available information regarding the SAE, once the condition is resolved or 
stabilized and when no more information about the event is expected.  
 
Any additional data from these follow-up procedures must be documented and made available 
to the Sponsor who will determine when the data need to be documented in the CRFs. 
 
11.8 
Reporting Procedure to IEC and to Regulatory Authorities 
 
The Sponsor, within 2 working days from the receipt of a serious adverse event including 
fatal or life threatening events, shall perform an assessment of the expectedness and the 
causality of each serious adverse event.  
Expectedness will be assessed with respect to the current Investigator’s Brochure for the test  
formulation and leaflet for the reference formulation.  
For a serious adverse event reported by the Investigator as not related that is subsequently 
revised to be related by the Sponsor, the Investigator will receive a notification. 
Events considered “Possible”, “Probable” and “Highly Probable” related to the IMP treatment 
will be reported to appropriate regulatory authorities. 
 
During the course of the clinical trial, Dompé shall report any suspected unexpected serious 
adverse reaction (SUSAR) case to the Competent Authority (according to specific law 
requirements) while the CRO shall submit SUSAR case to the concerned IEC which approved 
the protocol as soon as possible and in no event later than: 
 
(a)  seven calendar days after becoming aware of the information if the event is fatal or 
life threatening;  
(b)  fifteen calendar days after becoming aware of the information if the event is neither 
fatal nor life threatening. 
 
Dompé shall, within eight days after having informed the IEC/Competent Authority under 
paragraph (a), submit a complete report in respect of that information that includes an 
assessment of the importance and implication of any findings, made on the basis of follow up 
information provided by the Investigator. 
 
The Sponsor shall be responsible to prepare and submit periodical update reports as 
appropriate. 
 
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11.9 
Follow-up of Subjects with Adverse events 
 
The Investigator is responsible for adequate and safe medical care of subjects during the trial 
and for ensuring that appropriate medical care and relevant follow-up procedures are 
maintained after the trial. All AEs should be followed-up to determine outcome of the 
reaction or until 10 days after the final visit. The Investigator should follow-up the event until 
resolution or stabilization of the condition. It is the Investigator's responsibility to assure that 
the subjects experiencing AEs receive definite treatment for any AE, if required. 
 
11.10 
Pregnancy in the Clinical Trial 
 
Women of childbearing potential are not excluded from the study as long as adequate birth 
control methods are being utilized. Women of childbearing potential are defined as all women 
physiologically capable of becoming pregnant. Adequate birth control methods are 
summarized in the protocol’s exclusion criteria. 
 
Prior to enrolment in the clinical trial, female subjects of childbearing potential and their 
partners must be advised of the importance of avoiding pregnancy during the entire course of 
the study treatment and for the 30 days after the study treatment period ends and of the 
potential risks associated with an unintentional pregnancy. During the trial, female subjects 
are to be instructed to contact the Investigator immediately if they suspect they might be 
pregnant; in the same way, male subjects who become aware that the partner might be 
pregnant, are to be instructed to contact the Investigator immediately.  The study Sponsor 
must be contacted immediately and a decision will be made regarding continuation of the 
pregnant woman in the study based upon the circumstances surrounding the pregnancy. 
Pregnancy is not reportable as an adverse event; however, complications may be reportable 
and will be assessed for reportability on a case by case basis. A form prepared by the Sponsor 
will be utilized to capture all pregnancy-related information until the birth of the child for 
both the subject and the partner during the study treatment period (4 weeks) and follow-up 
period (total 8 weeks). 
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12 
DATA MANAGEMENT PROCEDURES 
 
12.1 
Data collection – CRFs 
 
The investigator must ensure that the clinical data required by the study protocol are carefully 
reported in a single copy CRFs. He must also check that the data reported in the CRFs 
correspond to those in the subject’s source documents. All the data reported in the CRF will 
have the correspondent source document.   
To ensure legibility, the CRFs should be filled out in English, in block capitals with a ball-
point pen (not pencil, felt tip or fountain pen). Any correction to the CRFs' entries must be 
carried out by the investigator or a designated member of staff. Incorrect entries must not be 
covered with correcting fluid, or obliterated, or made illegible in any way. A single stroke 
must be drawn through the original entry. Corrections have to be dated and initialled. In the 
interest of completeness of data acquisition, the questions which are repeated in each section 
of the CRFs should be answered in full, even if there are no changes from a previous 
examination. The investigator must provide a reasonable explanation for all missing data. 
The CRFs will be completed, signed by the investigator, sent to the CRO Biometry Unit for 
data management procedures and finally sent to the sponsor.  
 
12.2 
Unique subject identifier 
 
All the subjects who sign the informed consent form for the present study will be coded with 
“unique subject identifiers” when data are extracted from the study database into the domains 
of the CDISC SDTM model. The unique subject identifier consists of the sponsor study code 
(i.e. KSL0114), the 3-digit site number (i.e. 001), the 4-digit screening number (e.g. S001, 
S002, etc.) and, if applicable, the 3-digit subject randomisation number (e.g. 001, 002, etc.). 
Study code, site number, screening number and subject randomisation number are separated 
by slashes (“/”) [example: KSL0114/001/S001/001]. The last 8 digits of the unique subject 
identifier (enrolled subjects), corresponding to the subject screening and subject 
randomisation numbers separated by a slash, or the last 4 digits of the unique subject 
identifier (not enrolled subjects), corresponding to the subject screening number, will appear 
as subject identifier in the individual listings and figures of the clinical study report and will 
be used to identify the subjects in in-text tables or wording (if applicable) [example: 
S001/001]. 
 
12.3 
Database management 
 
The CRO will provide double data entry with 100% sight verification of data by a second data 
entrist and discrepancy resolution by a third individual and will update and verify the database 
and create the final SAS data sets. The final data file will be transferred to the sponsor in the 
agreed format with all the other study documentation. 
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Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
 
12.3.1 
Coding dictionaries 
 
Medical/surgical history and underlying diseases, physical examination abnormalities and 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA™). 
Previous and concomitant medications will be coded using the WHO Drug Dictionary 
Enhanced (WHODDE). The version of the coding dictionaries will be stated in the study 
report. 
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13 
STUDY MONITORING, QUALITY CONTROL AND 
QUALITY ASSURANCE 
 
13.1 
Monitoring 
 
The monitoring visits will be conducted by appropriate staff of Clinical Medical Service Sagl, 
Switzerland.  
 
Monitoring activities, including monitoring purpose, selection and qualifications of monitors, 
extent and nature of monitoring, monitoring procedures, monitoring reports will comply with 
ICH-GCP chapter 5.18 requirements. . 
 
Adequate time and availability for monitoring activities should be ensured by the investigator 
and key study personnel. 
 
Data verification is required and will be done by direct comparison with source documents, 
always giving due consideration to data protection and medical confidentiality. In this respect 
the investigator will assure support to the monitor at all times. 
 
The investigator agrees, by written consent to this protocol, to fully co-operate with 
compliance checks by allowing authorised individuals to have access to all the study 
documentation. In addition to the monitoring activities performed by the study monitor, the 
sponsor could perform some quality control activities to verify the compliance with the study 
procedures and the ICH-GCP guidelines.  
 
13.2 
Quality Control and Quality Assurance  
 
The CRO has implemented and maintain(s) a Quality System that includes quality controls 
and audits at different study steps with written SOPs to ensure that the study is conducted in 
compliance with the protocol and all effective amendments, ICH-GCP, and the applicable 
regulatory requirement(s) and that data have been reliably and correctly generated, recorded, 
processed and reported, in agreement with the ALCOA principles (Attributable-Legible-
Contemporaneous-Original-Accurate). 
 
The clinical site(s) is responsible for implementing and maintaining quality assurance and a 
quality control system to ensure that the study is conducted and data are generated, 
documented (recorded), and reported in compliance with the protocol, ICH-GCP, and the 
applicable regulatory requirement(s). 
 
The CROs and the sponsor will be responsible each one for their respective activities. 
 
The sponsor may transfer any or all of the sponsor’s trial-related duties and functions to a 
CRO, but the ultimate responsibility for the quality and integrity of the trial data always 
resides with the sponsor. 
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13.3 
Applicable SOPs 
 
The sponsor, the clinical centre and the CRO will follow their respective SOPs in the conduct 
of the respective activities, unless otherwise stated in written agreements. SOPs will be made 
available for review, if required. 
 
13.4 
Data access 
 
The investigator and the CRO will ensure that all raw data records, medical records, CRFs 
and all other documentation that is relevant to this study will be made accessible for 
monitoring activities, audits, IEC review and regulatory inspections. 
 
13.5 
Audits and inspections 
 
The sponsors, independent bodies acting on behalf of the sponsor and the CRO have the right 
to perform audits according to ICH-GCP responsibilities. 
 
The study may also be inspected by regulatory authorities.  
 
The investigator and the CRO agree, by written consent to this protocol, to fully co-operate 
and support audits and inspections compliance checks by allowing authorised individuals to 
have access to all the study documentation. 
 
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Final version 1.0, 28JUL14 
 
14 
ETHICAL CONSIDERATIONS 
 
14.1 
Ethics and Good Clinical Practice (GCP) 
 
The study will be performed in accordance with the relevant guidelines of the Declaration of 
Helsinki. 
The approval of the study protocol by the local (Canton Ticino) IEC and by the Federal 
Health Authorities (Swissmedic) will be obtained before the start of the study.  
 
The present clinical study will be carried out according to the general principles of “ICH 
Topic E6, CPMP/ICH/135/95”, July 1996 including post Step 4 errata, status September 1997 
and post Step errata (linguistic corrections), July 2002. 
 
14.2 
Informed consent 
 
Before being screened into the clinical study, the subjects must have expressed their consent 
to participate, after the investigator has explained to them, clearly and in details, the scope, the 
procedures and the possible consequences of the clinical study. Information will be given in 
both oral and written form. The information sheet and informed consent form will be prepared 
in the local language by the CRO and must be approved by the Sponsor, EC and regulatory 
authorities. It will include all the elements required by law according to the ICH-GCP 
recommendations.  
In addition to the standard requirements that physicians are currently obliged to observe when 
providing information, the following points must also be covered: 
 a description of the aims of the study and how it will be organised 
 the type of treatment (information on the IMP(s) and treatment procedures, as applicable) 
 any potential negative effects attributable to the study product or treatment 
 the freedom to ask for further information at any time 
 the subjects’ right to withdraw from the clinical study at any time without giving reasons 
and without jeopardising their further course of medical treatment  
 the existence of a subject insurance cover and obligations following from this cover 
Adequate time and opportunity to satisfy questions will be given to the subjects and the time 
will be recorded. 
 
The investigator will be supplied with an adequate number of blank informed consent forms 
to be used. The forms will be signed and dated by both the investigator and the subject.  
A copy of the signed form will be given to the subject. 
 
To ensure medical confidentiality and data protection, the signed informed consent forms will 
be stored in the investigator's study file according to the regulatory requirements (see § 15.3). 
The investigator will allow inspection of the forms by authorised representatives of the 
sponsor, EC members and regulatory authorities. He will confirm, by signing and dating the 
form, that informed consent has been obtained. 
 
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14.3 
Insurance policy 
 
The insurance is in compliance with the local regulation and with the requirements of the 
Health Authorities. 
 
14.4 
Withdrawal of subjects 
 
It will be documented whether or not each subject completed the clinical study. If, for a 
subject, study treatment or observations are discontinued, the primary reason for 
discontinuation will be recorded. 
 
14.4.1 
Primary reason for discontinuation 
 
 Adverse event: any (significant) adverse event that in the opinion of the investigator or 
concerned subject is not compatible with study continuation. For the definition of AE, 
please refer to § 11.2. 
 death: the absence of life or state of being dead 
 lost to follow-up: the loss or lack of continuation of a subject to follow-up 
 non-compliance with study drug: an indication that a subject has not agreed with or 
followed the instructions related to the study medication 
 physician decision: a position, opinion or judgment reached after consideration by a 
physician with reference to the subject 
 pregnancy: pregnancy is the state or condition of having a developing embryo or fetus in 
the body (uterus), after union of an ovum and spermatozoon, during the period from 
conception to birth 
 protocol deviation: an event or decision that stands in contrast to the guidelines set out by 
the protocol 
 study terminated by sponsor: an indication that a clinical study was stopped by its 
sponsor 
 technical problems: a problem with some technical aspect of a clinical study, usually 
related to an instrument 
 withdrawal by subject: study discontinuation requested by a subject for whatever reason 
 other: different than the ones previously specified 
 
14.4.2 
Discontinuation procedures 
 
For any subject discontinuing the study, the investigator will:  
 ask the subject to undergo, as far as possible, a final medical visit (ETV) to examine the 
subject's health conditions and perform the required blood sampling for the laboratory 
assays. This examination will verify that all values tested at screening have remained 
within a clinically acceptable range (i.e. not clinically significant changes compared to 
screening) 
 arrange for alternative medical care of the withdrawn subject, if necessary 
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 record the subject decision about the use of collected biological samples 
 report in the CRF date and time of the last dose administration, and date and primary 
reason of study discontinuation 
 record in the CRF any follow-up, if the subject is withdrawn for an AE 
Discontinued subjects will not be replaced.  
 
14.5 
Study termination 
 
The study will be considered terminated at the date of the last visit of the last subject or upon 
completion of any follow-up procedure described in protocol. The investigator and the 
sponsor have the right to discontinue the study at any time for reasonable medical and/or 
administrative reasons. As far as possible, this should occur after mutual consultation. 
Reasons for discontinuation have to be documented appropriately. 
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15 
ADMINISTRATIVE PROCEDURES 
 
15.1 
Material supplied to the clinical centre 
 
Beside IMP(s), the following study material will be supplied to the clinical centre: 
 final version of the study protocol 
 CRF for each subject plus some spare copies 
 copy of the investigator’s brochure (IB) relative to the IMP 
 informed consent forms 
Moreover, before the start of the study, the investigator(s) will be provided with the following 
documents: ICH guidelines, confidentiality agreement (if applicable), protocol amendments 
(if any), declaration of Helsinki, insurance statement, SAE forms, pregnancy form, financial 
agreement, confidential subject identification code list form, drug accountability forms, 
investigator and study staff list form. 
 
15.2 
Protocol amendments 
 
In order to obtain interpretable results, neither the investigator nor the sponsor will alter the 
study conditions agreed upon and set out in this protocol. Amendments should be made by 
mutual agreement between the investigator and the sponsor. Any amendment must be set out 
in writing, giving the reasons, and being signed by all concerned parties. The amendment 
becomes then part of the protocol. 
 
All substantial amendments will be sent to EC and Swissmedic, as appropriate. The 
amendment will be applicable only when it is approved, unless the changes consist of urgent 
safety measures to protect study subjects. 
 
Non substantial amendments will be notified according to the current regulations. 
 
15.3 
Study documentation and record keeping 
 
The investigator should ensure the accuracy, completeness, legibility, and timeliness of the 
data reported to the sponsor in the CRFs and in all required reports. 
 
The investigator must keep source documents for each subject in the study. All information 
on the CRFs must be traceable to these source documents, which are generally stored in the 
subject's medical file. The source documents should contain all demographic and medical 
information, including laboratory data, ECGs, etc., and the original signed informed consent 
forms. 
 
Data reported on the CRF that are derived from source documents should be consistent with 
the source documents or the discrepancies should be explained. 
 
The investigator and the sponsor should maintain the study documents as specified in the 
“Essential Documents for the Conduct of a Clinical Trial” chapter 8 of ICH-GCP and as 
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required by the applicable regulatory requirement(s). The period of documents retention by 
CRO and Sponsor will be according to ICH-GCP chapter 5.5.11.  
According to the national regulations the clinical site will retain the study documentation for 
at least 10 years from the end of the study. The study documents destruction will be 
performed after sponsor authorisation. 
 
These are documents which individually and collectively permit evaluation of a study and the 
quality of the data produced and include groups of documents, generated before the study 
commences, during the clinical study, and after termination of the study and include but are 
not limited to, study protocol, amendments, submission and approval of EC, raw data of 
subjects including lab tests and ECG tracing, insurance contracts, certificate of analysis of the 
IMP(s), drug accountability records, signed informed consent forms, confidential subjects 
identification code, CRFs, curricula vitae of the investigator and other participants in the 
study, study staff lists and responsibilities, monitoring reports and final study report. 
 
The investigator and the sponsor should take measures to prevent accidental or premature 
destruction of these documents. 
 
Study documents must be retained by the investigator and the sponsor as long as needed to 
comply with ICH-GCP, national and international regulations. By signing the protocol, the 
investigator and the sponsor agree to adhere to these requirements. 
 
15.4 
Study subjects’ recruitment 
 
Study participants will be recruited from the volunteers’ database maintained by the CRO. 
This database contains a pool of volunteers that are contacted whenever necessary to enrol 
subjects in a new study. Before the start of the new study, the principal investigator and other 
relevant staff discuss with the volunteers’ recruiter the study recruitment needs and specific 
requirements. On the basis of this information, the volunteers’ recruiter queries the database, 
contacts potential participants to propose the study and evaluate their interest and availability. 
In addition to the volunteers’ database, new subjects often call or email the CRO asking to 
become a research volunteer, after hearing of the clinical site activities from other volunteers 
or friends or after checking the company web site. 
 
The CRO and its clinical site have detailed SOPs on the recruitment process. 
 
15.5 
Confidentiality and data protection 
 
By signing this protocol, the investigator and the CRO agree to keep all the information 
provided by the sponsor in strict confidentiality and to request the same confidentiality from 
his/her staff. Study documents provided by the sponsor (protocols, IB, CRFs and other 
materials) will be stored appropriately to ensure confidentiality. The information provided by 
the sponsor to the investigator and to the CRO cannot be disclosed to others without direct 
written authorisation from the sponsor, except for the extent necessary to obtain the informed 
consent from the subjects wishing to participate in the study. 
 
Data on subjects collected in the CRFs during the study will be documented in an anonymous 
way (see § 12.2). If, as an exception, for safety or regulatory reasons identification of a 
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subject becomes necessary, the monitor, the sponsor and the investigator will be bound to 
keep this information confidential. 
 
 
15.6 
Publication policy 
 
The sponsor agrees that the study results (including negative and inconclusive as well as 
positive results) can be made publicly available by the investigator publishing in peer 
reviewed journals, presenting results at scientific congresses and posting information and 
results on internet-based public registers and databases. 
Study results will be communicated in full to the competent Health Authorities by the 
submission of a complete clinical study report. 
 
As the sponsor agrees that the study results can be published by the investigator(s), the 
investigator agrees to submit any manuscript (abstract, publication, paper, etc.) to the sponsor 
before any public disclosure. 
This will be done in order to ensure that clinical study results are reported in an objective, 
accurate and balanced manner. The sponsor reviews the proposed manuscripts, before 
submission, within a reasonable period of time (30-90 days in relation with the complexity of 
the work). 
 
The investigator(s) will also be provided by the sponsor with the clinical study report and the 
results of any additional analysis, tables, figures, etc. undertaken for the purposes of the 
article, in order to take responsibility for the content of the publication(s). 
On an exceptional basis, the sponsor may temporarily delay registration of certain data 
elements (e.g. compound, name, outcome, measures, etc.) to seek necessary intellectual 
property protection. This is because early disclosure of such data could, in some 
circumstances, prevent or negatively impact patentability. 
CROSS Research S.A. 
Page 56 


CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
16 
STUDY RESPONSIBLE PERSONS 
 
16.1 
Sponsor 
 
Dompé s.p.a. - Via Campo di Pile; I-67100 L'Aquila, Italy 
Milan Offices: Via S. Santa Lucia 6,  I-20122 Milan, Italy 
Phone:   +39.02.583831 
Fax:   
+39.02.58383324 
 
Sponsor representative 
 
Clinical Development Manager  
Mauro P. Ferrari, PharmD  
Email: mauro.ferrari@dompe.it 
 
Research & Development Director  
Marcello Allegretti, ChemD 
Email: marcello.allegretti@dompe.it 
 
Medical Expert 
Elisabetta Grillo, MD  
Email: elisabetta.grillo@dompe.it 
 
Dompé Drug Safety  
Laura Boga, BscD 
Email: farmacovigilanza@dompe.it 
 
16.2 
Institutes performing the study 
 
16.2.1 
Clinical centre 
 
CROSS Research S.A. – Phase I Unit, Via F.A. Giorgioli 14, CH-6864 Arzo, Switzerland 
Phone: 
+41.91.63.00.510 
Fax: 
+41.91.63.00.511 
Email: 
clinic@croalliance.com 
 
Principal investigator 
Milko Radicioni, MD 
 
Co-investigator 
Antonio Rusca, MD, FMH 
 
16.3 
Drug assay 
 
Dompé Analytical Laboratories S.p.A. - Via Campo di Pile; I-67100 L'Aquila, Italy 
Phone: 
+39.0862.338367 
Fax: 
+39.0862.338219 
Mobile:  +39 347 4838904 
CROSS Research S.A. 
Page 57 


CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
Email: 
danniballe@dompe.it  
 
Analytics representative 
Gaetano D’Anniballe, BSc 
 
16.4 
Centralised clinical laboratory 
 
Unilabs Ticino, via Rovere 8, CH-6932 Breganzona, Switzerland 
Phone: 
+41.91.960.73.73 
Fax: 
+41.91.960.73.74 
Email: 
bmathis@unilabs.ch 
 
16.5 
Co-ordination, data analysis & reporting 
 
CROSS S.A., Switzerland, and its affiliated companies CROSS Research S.A. and CROSS 
Metrics S.A., sharing the same quality assurance system. 
 
CROSS Research S.A. 
Via F.A. Giorgioli 14, CH-6864 Arzo, Switzerland 
 
Coordination 
Angelo Vaccani, PhD, Clinical Project Leader 
Email: 
angelo.vaccani@croalliance.com 
 
Pharmacokinetic Analysis 
Luca Loprete, MSc, Senior Pharmacokineticist 
Email: 
luca.loprete@croalliance.com 
 
Biometry Unit Representative 
Matteo Rossini, Biometry Manager, MSc, Unit Head 
Email: 
statistics@croalliance.com 
 
Quality Assurance Unit Representative 
Maurizio Cuocolo, PharmD, Quality Assurance  
Email: qau@croalliance.com 
 
16.6 
Monitoring 
 
Clinical Medical Service Sagl 
Via Collina Azzurra 8, CH-6900 Paradiso, Switzerland 
Legal address: Via Motta 24, CH-6830 Chiasso, Switzerland 
Mobile: +41.79.827.27.67 
Fax: 
+41.91.649.57.14 
Email: 
cmed@cmed.ch 
CROSS Research S.A. 
Page 58 


CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 28JUL14 
CROSS Research S.A. 
Page 59 
17 
REFERENCES 
 
1. Goodman & Gilman’s. The Pharmacological Basis of Therapeutics. 11th Edition, 2006. 
2. OKi®. Summary of Product Characteristics. 
3. Veys EM. 20 years' experience with ketoprofen. Scand J Rheumatol Suppl. 1991;90:Suppl 1-44. 
4. Three way crossover, randomised, single dose comparative bioavailability phase I study of ketoprofen lysine 
salt as orodispersible granules (40 mg administered with or without water) versus ketoprofen lysine salt as 
granules for oral solution (80 mg bipartite sachet, half sachet) after oral administration to healthy volunteers 
of both sexes.  Dompé S.p.A., 2009, report on file. 
5. Two-way crossover, randomised, single dose bioequivalence phase I study of ketoprofen lysine salt as 
orodispersible granules (40 mg administered without water) versus ketoprofen lysine salt as granules for oral 
solution (80 mg bipartite sachet, half sachet) after oral administration to healthy volunteers of both sexes. .  
Dompé S.p.A., 2012, report on file. 
 
6. U.S. Department of Health and Human Services and U.S. Department of Agriculture, Nutrition and your 
health: Dietary Guidelines for Americans, 2010 
7. Phoenix 1.3 User’s Guide, Pharsight Corporation 
8. SAS/STAT® User’s Guide 
9. Guidance on the investigation of bioequivalence. CPMP/EWP/QWP/1401/98 Rev. 1/Corr **, 20 January 
2010 
10. Questions & Answers: Positions on specific questions addressed to the pharmacokinetics working party. 
EMA/618604/2008 Rev. 8, 10 October 2013 
 


CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Amendment Nr.1, Final version 2.0, 25NOV2014 
 
 
AMENDMENT Nr. 1 
 
 
EC ref. n°: CE 2840; Swissmedic ref. n°: 2014DR1181 
 
Study CRO-PK-14-288 - Sponsor code KSL0114 
 
TITLE:  
 
Two-way crossover, randomised, single dose and two-stage bioequivalence phase I study 
of ketoprofen lysine salt as immediate release tablets formulation (40 mg) versus 
ketoprofen lysine salt as granules for oral solution (80 mg bipartite sachet, half sachet) 
after oral administration to healthy volunteers of both sexes 
 
Single centre, single-dose, open, randomised, two-way cross-over, two-stage bioequivalence 
study 
 
REASON: 
 
The present amendment introduces the following changes in the study protocol: 
 
- 
The assumptions regarding the expected point estimate for the T/R ratio of the 
geometric means, the expected variability, the type I error level and the power used 
for the estimation of the number of subjects included into the stage 1 are clearly stated 
in the relevant sections of the study protocol 
- 
On the basis of the a priori power analysis for the calculation of the stage 1, the a 
posteriori power analysis in case the bioequivalence will be proved with the results of 
the subjects of the first stage, is no more necessary and has been removed 
- 
The stopping criteria of the study have been amended in order to avoid uncontrolled 
inflation of type I error due to the enrolment of a too high number of subjects in the 
stage 2 (overpowered bioequivalence)  
 
The following scientific publications justify the changes decided for the statistical section. 
 
1. Fuglsang A. Futility rules in bioequivalence trials with sequential designs. AAPS Journal 
2013, 16: 79-82 
2. Montague TH, Potvin D., DiLiberti CE., et al. Additional results for sequential design 
approaches for bioequivalence studies with crossover design. Pharmaceut. Statist. 2012, 
11:8-13 
3. Potvin D., DiLiberti CE., Hauck WW., et al. sequential approaches for bioequivalence 
studies with crossover designs. Pharm Stat. 2008 Oct-Dec;7(4):245-62 
 
The present amendment also introduces the following minor changes in the study protocol: 
 
- 
Federico Saibene, MD, replace Elisabetta Grillo, MD, as medical expert of the study 
CRO-PK-14-288 
Page 1 of 11 


CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Amendment Nr.1, Final version 2.0, 25NOV2014 
- 
The name of the company in charge of the study monitoring changed. Clinical 
Medical Service Sagl  is now Clinical Medical Services di Maria Pia Savorelli 
- 
Chiara Leuratti has been added as Medical Writing Department representative for 
reporting activities 
- 
Dompè s.p.a will be replaced by Dompè farmaceutici s.p.a. with effective date from 
01 December 2014. The change resulted from a merge of the two companies. No 
impact on the study is foreseen. A simplified procedure was followed since Dompè 
s.p.a was 100 % owned by Dompè farmaceutici s.p.a.. As result of this change the 
insurance has been updated. 
 
This amendment is considered substantial because the changes in the statistical section will 
affect the stopping criteria of the study and the evaluation of the primary objective, whereas 
the subject safety and the number of the subjects foreseen in the stage 1 are not affected. 
 
Changes from study protocol Final version 1.0, 28JUL2014 are outlined below. 
The amended text is in bold characters; the deleted text is in bold characters and crossed-out 
with a deleting line (deleted text still visible). 
 
AMENDED DOCUMENTS: 
 
Study protocol, Final version 1.0, 28JUL2014, § 4.2 “Discussion of design” and any other 
affected section of the synopsis and protocol. 
 
ORIGINAL TEXT: 
 
… 
 
Due to the lack of information about the PK profile of the new formulation it was not possible 
to calculate the sample size properly. 
For this reason it was decided to use a “two stage” bioequivalence study design. The sample 
size of 30 subjects is regarded as sufficient to satisfy the primary objective for the first stage 
of the study. 
After the end of study stage 1, PK parameters will be calculated and an ad interim 
bioequivalence test will be performed on the calculated PK parameters Cmax, AUC0-t and 
AUC0-∞. To safeguard the overall type I error, the Pocock spending function will be used to 
determine the α level of the bioequivalence test. Should bioequivalence be proven with the 
results of the subjects of the first stage and with an a posteriori calculated power of at least 
80%, the primary objective of the study would then be satisfied and the second study stage 
will not take place. Should bioequivalence not be proven with the results of the subjects of the 
first stage or should it be proven with an a posteriori calculated power lower than 80%, the 
overall sample size for the study (stage 1 plus 2) will be calculated on the basis of the ad 
interim bioequivalence results. The Sponsor will decide whether the study has to continue or 
not. In the first case, the additional subjects will be enrolled into the second study stage. After 
completion of stage 2, the PK analysis and the bioequivalence test will be performed on the 
pooled subjects of the two study stages. The second stage will be performed after notification 
of the sample size to the local Ethics Committee and to the central Swiss authority 
(Swissmedic). 
 
CRO-PK-14-288 
Page 2 of 11 


CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Amendment Nr.1, Final version 2.0, 25NOV2014 
… 
 
AMENDED TEXT: 
 
… 
 
Due to the lack of information about the PK profile of the new formulation it was not possible 
to calculate the sample size properly. 
For this reason it was decided to use a “two stage” bioequivalence study design. The 
sample size of 30 subjects is regarded as sufficient to satisfy the primary objective for 
the first stage of the study. 
 
For this reason it was decided to use a “two stage” bioequivalence study design, that 
allows a re-calculation of the sample size in case the number of subjects initially enrolled 
in the study is not large enough to provide a reliable answer to the questions addressed 
due to underestimation of the variability or misleading estimation of the point estimate 
for the T/R ratio of the geometric means. 
 
The sample size of stage 1 was calculated assuming a point estimate for the T/R ratio of 
the geometric means of 1.053 (i.e. µR=0.95·µT) and a multiplicative coefficient of 
variation (CVm) of 20% for both AUC0-t and Cmax. A power of 90% was considered and, 
according to the Pocock spending function and to the current European bioequivalence 
guideline, the α level was set to 0.0294. Fifteen (15) subjects per sequence (i.e. 30 subjects 
overall) will be enrolled in the first stage of the study. 
 
After the end of study stage 1, PK parameters will be calculated and an ad interim 
bioequivalence test will be performed on the calculated PK parameters Cmax, AUC0-t and 
AUC0-∞. To safeguard the overall type I error, the Pocock spending function will be used to 
determine the α level of the bioequivalence test. Should bioequivalence be proven with the 
results of the subjects of the first stage and with an a posteriori calculated power of at least 
80%, the primary objective of the study would then be satisfied and the second study stage 
will not take place. Should bioequivalence not be proven with the results of the subjects of the 
first stage and with an a posteriori calculated power > 90% for both AUC0-t and Cmax, the 
study will be stopped and the bioequivalence will not be proven. or should it be proven 
with an a posteriori calculated power lower than 80% Should bioequivalence not be 
proven with the results of the subjects of the first stage and with an a posteriori 
calculated power ≤ 90% for AUC0-t or Cmax, the overall sample size for the study (stage 1 
plus 2) will be calculated on the basis of the ad interim bioequivalence results. The Sponsor 
will decide whether the study has to continue or not. In the first case, tThe additional 
subjects will be enrolled into the second study stage. After completion of stage 2, the PK 
analysis and the bioequivalence test will be performed on the pooled subjects of the two study 
stages. The second stage will be performed after notification of the sample size to the local 
Ethics Committee and to the central Swiss authority (Swissmedic). 
 
… 
 
 
CRO-PK-14-288 
Page 3 of 11 


CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Amendment Nr.1, Final version 2.0, 25NOV2014 
 
 
AMENDED DOCUMENTS: 
 
Study protocol, Final version 1.0, 28JUL2014, § 10.2 “Sample size and power 
considerations” and any other affected section of the synopsis and protocol. 
 
ORIGINAL TEXT: 
 
In a first study stage 30 healthy volunteers (at least 12 subjects per sex) will be included and 
treated to receive both test and reference investigational product according to the cross-over 
design. Drop-out subjects will not be replaced. After the end of study stage 1, PK parameters 
will be calculated and an ad interim bioequivalence test will be performed on the calculated 
PK parameters Cmax, AUC0-t and AUC0-∞. To safeguard the overall type I error, the Pocock 
spending function will be used to determine the α level of the bioequivalence test. Should 
bioequivalence be proven with the results of the subjects of the first stage and with an a 
posteriori calculated power of at least 80%, the primary objective of the study would then be 
satisfied and the second study stage will not take place. Should bioequivalence not be proven 
with the results of the subjects of the first stage or should it be proven with an a posteriori 
calculated power lower than 80%, the overall sample size for the study (stage 1 plus 2) will be 
calculated on the basis of the ad interim bioequivalence results. The Sponsor will decide 
whether the study has to continue or not. In the first case, the additional subjects will be 
enrolled into the second study stage. After completion of stage 2, the PK analysis and the 
bioequivalence test will be performed on the pooled subjects of the two study stages. 
 
AMENDED TEXT: 
 
The sample size of stage 1 was calculated assuming a point estimate for the T/R ratio of 
the geometric means of 1.053 (i.e. µR=0.95·µT) and a multiplicative coefficient of 
variation (CVm) of 20% for both AUC0-t and Cmax. A power of 90% was considered and, 
according to the Pocock spending function and to the current European bioequivalence 
guideline, the α level was set to 0.0294. Fifteen (15) subjects per sequence (i.e. 30 subjects 
overall) will be enrolled in the first stage of the study. 
 
Table 10.2.1 Stage 1 - Sample size calculation data 
PK 
Parameter 
Alpha 
(one-sided) 
µT/µR 
CVm 
sqrt(MSE) 
Power 
N per 
sequence 
Sample 
size 
AUC0-t 
0.0294 
1.053 
20% 
0.198 
90% 
15 
30 
Cmax 
0.0294 
1.053 
20% 
0.198 
90% 
15 
30 
 
In a first study stage 30 healthy volunteers (at least 12 subjects per sex) will be included and 
treated to receive both test and reference investigational product according to the cross-over 
design. Drop-out subjects will not be replaced. After the end of study stage 1, PK parameters 
will be calculated and an ad interim bioequivalence test will be performed on the calculated 
PK parameters Cmax, AUC0-t and AUC0-∞. To safeguard the overall type I error, the Pocock 
spending function will be used to determine the α level of the bioequivalence test. Should 
CRO-PK-14-288 
Page 4 of 11 


CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Amendment Nr.1, Final version 2.0, 25NOV2014 
bioequivalence be proven with the results of the subjects of the first stage and with an a 
posteriori calculated power of at least 80%, the primary objective of the study would then 
be satisfied and the second study stage will not take place. Should bioequivalence not be 
proven with the results of the subjects of the first stage and with an a posteriori calculated 
power > 90% for both AUC0-t and Cmax, the study will be stopped and the bioequivalence 
will not be proven. or should it be proven with an a posteriori calculated power lower 
than 80% Should bioequivalence not be proven with the results of the subjects of the 
first stage and with an a posteriori calculated power ≤ 90% for AUC0-t or Cmax, the 
overall sample size for the study (stage 1 plus 2) will be calculated on the basis of the ad 
interim bioequivalence results. The Sponsor will decide whether the study has to continue 
or not. In the first case, tThe additional subjects will be enrolled into the second study stage. 
After completion of stage 2, the PK analysis and the bioequivalence test will be performed on 
the pooled subjects of the two study stages. 
 
 
AMENDED DOCUMENTS: 
 
Study protocol, Final version 1.0, 28JUL2014, page 1 and any other affected section of the 
synopsis and protocol. 
 
ORIGINAL TEXT: 
 
Dompé s.p.a. 
Via Campo di Pile, 67100 L’Aquila  
Milan offices:  
Via Santa Lucia 6, 20122 Milano - Italy 
Phone:  +39.02.58383.1 
Fax:  
+39.02.58383.324 
Email: mauro.ferrari@dompe.it 
 
AMENDED TEXT: 
 
Dompé s.p.a. Dompè farmaceutici s.p.a 
Milan offices:  
Via Santa Lucia 6, 20122 Milano - Italy 
Phone:  +39.02.58383.1 
Fax:  
+39.02.58383.324 
Email: mauro.ferrari@dompe.it 
L’Aquila Officies 
Via Campo di Pile, 67100 L’Aquila  
 
 
 
 
 
 
AMENDED DOCUMENTS: 
 
CRO-PK-14-288 
Page 5 of 11 


CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Amendment Nr.1, Final version 2.0, 25NOV2014 
Study protocol, Final version 1.0, 28JUL2014, § 11.7 “Reporting” and any other affected 
section of the synopsis and protocol. 
 
ORIGINAL TEXT: 
 
Dompé Medical Expert 
Elisabetta Grillo,  
Email to: elisabetta.grillo@dompe.it  
or Fax:  +39.02.58383297 
 
AMENDED TEXT: 
 
Dompé Medical Expert 
Elisabetta Grillo, Federico Saibene 
Email to: elisabetta.grillo@dompe.it federico.saibene@dompe.it 
or Fax:  +39.02.58383297 
 
AMENDED DOCUMENTS: 
 
Study protocol, Final version 1.0, 28JUL2014, § 16.1 “Sponsor Representative” and any other 
affected section of the synopsis and protocol. 
 
ORIGINAL TEXT: 
 
Medical Expert 
Elisabetta Grillo, MD  
Email: elisabetta.grillo@dompe.it 
 
AMENDED TEXT: 
 
Medical Expert 
Elisabetta Grillo Federico Saibene, MD  
Email: elisabetta.grillo@dompe.it  federico.saibene@dompe.it 
 
AMENDED DOCUMENTS: 
 
Study protocol, Final version 1.0, 28JUL2014, § 13.1 “Monitoring” and any other affected 
section of the synopsis and protocol. 
 
ORIGINAL TEXT: 
 
The monitoring visits will be conducted by appropriate staff of Clinical Medical Service Sagl, 
Switzerland.  
 
AMENDED TEXT: 
 
The monitoring visits will be conducted by appropriate staff of Clinical Medical Services 
Sagl di Maria Pia Savorelli, Switzerland.  
CRO-PK-14-288 
Page 6 of 11 


CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Amendment Nr.1, Final version 2.0, 25NOV2014 
 
AMENDED DOCUMENTS: 
 
Study protocol, Final version 1.0, 28JUL2014, § 16.5 “Co-ordination, data analysis & 
reporting” and any other affected section of the synopsis and protocol. 
 
ORIGINAL TEXT: 
 
Coordination 
Angelo Vaccani, PhD, Clinical Project Leader 
Email: 
angelo.vaccani@croalliance.com 
 
Pharmacokinetic Analysis 
Luca Loprete, MSc, Senior Pharmacokineticist 
Email: 
luca.loprete@croalliance.com 
 
Biometry Unit Representative 
Matteo Rossini, Biometry Manager, MSc, Unit Head 
Email: 
statistics@croalliance.com 
 
Quality Assurance Unit Representative 
Maurizio Cuocolo, PharmD, Quality Assurance  
Email: qau@croalliance.com 
 
AMENDED TEXT: 
 
Coordination 
Angelo Vaccani, PhD, Clinical Project Leader 
Email: 
angelo.vaccani@croalliance.com 
 
Medical Writing 
Chiara Leuratti, Medical Writer Manager, Unit Head 
Email: 
medicalwriting@croalliance.com 
 
Pharmacokinetic Analysis 
Luca Loprete, MSc, Senior Pharmacokineticist 
Email: 
luca.loprete@croalliance.com 
 
Biometry Unit Representative 
Matteo Rossini, Biometry Manager, MSc, Unit Head 
Email: 
statistics@croalliance.com 
 
Quality Assurance Unit Representative 
Maurizio Cuocolo, PharmD, Quality Assurance  
Email: qau@croalliance.com 
 
 
AMENDED DOCUMENTS: 
CRO-PK-14-288 
Page 7 of 11 


CONFIDENTIAL 
 
Study protocol CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Amendment Nr.1, Final version 2.0, 25NOV2014 
 
Study protocol, Final version 1.0, 28JUL2014, § 16.6 “Monitoring” and any other affected 
section of the synopsis and protocol. 
 
ORIGINAL TEXT: 
 
Clinical Medical Service Sagl 
Via Collina Azzurra 8, CH-6900 Paradiso, Switzerland 
Legal address: Via Motta 24, CH-6830 Chiasso, Switzerland 
Mobile: +41.79.827.27.67 
Fax: 
+41.91.649.57.14 
Email: 
cmed@cmed.ch 
 
AMENDED TEXT: 
 
Clinical Medical Services Sagl  di Maria Pia Savorelli  
Legal address: Via Motta 24, CH-6830 Chiasso, Switzerland 
Via Indipendenza 29/A, CH-6883 Novazzano, Switzerland 
Mobile:  +41.79.827.27.67 
Email: 
 cmed@cmed.ch 
CRO-PK-14-288 
Page 8 of 11 







SAP_001.pdf: 
CONFIDENTIAL 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
Study CRO-PK-14-288 - Sponsor code KSL0114 
Two-way crossover, randomised, single dose and two-stage 
bioequivalence phase I study of ketoprofen lysine salt as 
immediate release tablets formulation (40 mg) versus ketoprofen 
lysine salt as granules for oral solution (80 mg bipartite sachet, 
half sachet) after oral administration to healthy volunteers of both 
sexes 
Single centre, single-dose, open, randomised, two-way cross-over, two-stage bioequivalence 
study 
STATISTICAL ANALYSIS PLAN 
Test formulation: 
Ketoprofen lysine salt (KLS), immediate release tablets 40 mg, 
corresponding to 25 mg as ketoprofen, Dompé s.p.a., Italy 
Reference formulation: 
OKi® 80 mg granules for oral solution (bipartite sachet), half 
sachet containing 40 mg of KLS corresponding to 25 mg as 
ketoprofen, Dompé s.p.a., Italy 
Sponsor: 
Dompè farmaceutici s.p.a 
Via Campo di Pile, 67100 L’Aquila  
Milan offices:  
Via Santa Lucia 6, 20122 Milano - Italy 
Phone:  +39.02.58383.1 
Fax:  
+39.02.58383.324 
Email: mauro.ferrari@dompe.it 
L’Aquila Officies:  
Via Campo di Pile, 67100 L’Aquila 
Investigator: 
Milko Radicioni, MD - Principal investigator 
Antonio Rusca, MD, FMH - Co-investigator 
CROSS Research S.A., Phase I Unit, Via F.A. Giorgioli 14 
CH-6864 Arzo, Switzerland 
Phone: +41.91.63.00.510 
Fax: 
+41.91.63.00.511 
Email: clinic@croalliance.com 
Development phase: 
Phase I 
Version and date: 
Final version 1.0, 13FEB2015 
This study will be conducted in accordance with Good Clinical Practice (GCP), ICH topic E6 
Property of the sponsor 
May not be used, divulged, published or otherwise disclosed without the consent of the sponsor 
This document comprises 22 pages 
CROSS Research S.A. 
Page 1 




CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN APPROVAL 
2 
TABLE OF CONTENTS 
3 
LIST OF ABBREVIATIONS 
5 
1 
INTRODUCTION 
6 
1.1 
Changes with respect to the study protocol 
6 
2 
STUDY DESCRIPTION 
7 
2.1 
Study objectives 
7 
2.1.1 
Primary end-point 
7 
2.1.2 
Secondary end-points 
7 
2.2 
Overall study design 
7 
2.3 
Discussion of design 
7 
3 
STUDY POPULATION 
10 
3.1 
Target population 
10 
3.2 
Inclusion criteria 
10 
3.3 
Exclusion criteria 
10 
3.3.1 
Not allowed treatments 
11 
3.3.2 
Allowed treatments 
11 
4 
ASSIGNMENT OF STUDY TREATMENT 
12 
4.1 
Randomisation 
12 
4.2 
Treatment allocation 
12 
4.3 
Blinding 
12 
5 
EVALUATION PARAMETERS 
13 
5.1 
Study variables 
13 
5.1.1 
Primary variables 
13 
5.1.2 
Secondary variables 
13 
5.2 
Pharmacokinetic assessments 
13 
5.2.1 
Pharmacokinetic parameters 
13 
5.3 
Safety assessments 
14 
6 
STATISTICAL METHODS 
15 
6.1 
Analysis sets 
15 
6.1.1 
Definitions 
15 
6.1.2 
Reasons for exclusion from the PK set 
16 
6.2 
Sample size and power considerations 
16 
6.2.1 
Stage 1 
16 
6.2.2 
Whole study 
17 
CROSS Research S.A.  
Page 3 
 


CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
6.3 
Demographic and other baseline characteristics 
18 
6.3.1 
Subjects’ disposition 
18 
6.3.2 
Analysis sets 
18 
6.3.3 
Demography 
18 
6.3.4 
Protocol deviations 
18 
6.3.5 
Discontinued subjects 
18 
6.3.6 
Subjects excluded from the PK analysis 
18 
6.3.7 
Medical and surgical history 
18 
6.3.8 
Prior and concomitant medications 
18 
6.3.9 
Subjects study visits 
19 
6.3.10 
Tests 
19 
6.3.11 
Meals 
19 
6.4 
Analysis of pharmacokinetic parameters 
19 
6.4.1 
Descriptive pharmacokinetics 
19 
6.4.2 
Statistical comparison of pharmacokinetic parameters 
19 
6.5 
Interim analysis at the end of the study stage 1 
20 
6.6 
Safety evaluation 
20 
6.6.1 
Adverse events 
20 
6.6.2 
Physical examination 
21 
6.6.3 
Laboratory data 
21 
6.6.4 
Vital signs 
21 
6.6.5 
Body weight 
21 
6.6.6 
ECGs 
21 
6.6.7 
Drug administration 
21 
7 
REFERENCES 
22 
 
 
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CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
LIST OF ABBREVIATIONS 
 
β-HCG 
Human Chorionic Gonadotropin β 
λz 
Terminal elimination rate constant 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
ASA 
Acetylsalicylic Acid 
ATC 
Anatomical Therapeutic Chemical 
AUC0-t 
Area under the concentration-time curve from administration to the last observed 
concentration time t 
AUC0-∞ 
Area under the concentration-time curve extrapolated to infinity 
BE 
Bioequivalence 
BLQL 
Below Lower Quantification Limit 
BMI 
Body Mass Index 
BP 
Blood Pressure 
BT 
Body Temeperature 
CI 
Confidence Interval 
Cmax 
Maximum plasma concentration 
CRF 
Case Report Form 
CRO 
Contract Research Organisation 
CS 
Clinically Significant 
CV 
Coefficient of Variation 
DBP 
Diastolic Blood Pressure 
ECG 
Electrocardiogram 
ETV 
Early Termination Visit 
Frel 
Relative Bioavailability 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IMP 
Investigational Medicinal Product 
IUD 
Intra-Uterine Device 
KLS 
Ketoprofen Lysine Salt 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Normal 
NC 
Not calculated 
NCS 
Not clinically significant 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
OTC 
Over The Counter 
PK 
Pharmacokinetic 
PR 
Pulse Rate 
PT 
Preferred Term 
PTAE 
Pre-Treatment Adverse Event 
R 
Reference 
SAP 
Statistical Analysis Plan 
SBP 
Systolic Blood Pressure 
SD 
Standard Deviation 
SOC 
System Organ Class 
T 
Test 
TEAE 
Treatment-Emergent Adverse Event 
t1/2 
Half-life 
tmax 
Time to achieve Cmax 
USDA 
United States Department of Agriculture 
WHODDE 
World Health Organisation Drug Dictionary Enhanced 
 
 
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CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
1 
INTRODUCTION 
 
The present Statistical Analysis Plan (SAP) has been compiled by the Biometry Unit of the 
Clinical Contract Research Organization (CRO) based on the study protocol version 1.0 
issued on 28JUL2014 and on protocol amendment nr. 1 version 2.0 issued on 25NOV2014. 
The SAP was reviewed by the Sponsor and finalised before database lock. 
 
1.1 
Changes with respect to the study protocol 
 
The amendment nr. 1 version 2.0 issued on 25NOV2014 introduced the following changes 
with respect to the statistical part of the study protocol (1, 2, 3): 
 
- The assumptions regarding the expected point estimate for the T/R ratio of the 
geometric means, the expected variability, the type I error level and the power used for 
the estimation of the number of subjects included into the stage 1 are clearly stated in 
the relevant sections of the study protocol 
- On the basis of the a priori power analysis for the calculation of the sample size for 
study stage 1, the a posteriori power analysis in case the bioequivalence is proved 
with the results of the subjects of the first stage, is not necessary and has been 
removed 
- The stopping criteria of the study have been amended in order to avoid uncontrolled 
inflation of type I error caused by the enrolment of a too high number of subjects in 
study stage 2 (overpowered bioequivalence). 
 
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CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
2 
STUDY DESCRIPTION 
 
2.1 
Study objectives 
 
The objective of the study is to investigate the bioequivalence between two formulations 
containing ketoprofen lysine salt (KLS) when administered as single oral dose in two 
consecutive study periods to healthy male and female volunteers under fasting conditions. 
 
2.1.1 
Primary end-point 
 
• 
To evaluate the bioequivalent rate (Cmax) and extent (AUC0-t) of absorption of ketoprofen 
after single dose administration of test (T) and reference (R). 
 
2.1.2 
Secondary end-points 
 
• 
To describe the pharmacokinetic (PK) profile of ketoprofen after single dose 
administration of T and R; 
• 
to collect safety and tolerability data after single dose administration of T and R. 
 
2.2 
Overall study design 
 
Single centre, single-dose, open, randomised, two-way cross-over, two-stage bioequivalence 
study. 
 
2.3 
Discussion of design  
 
The trial has been designed in agreement with the “Guideline on the investigation of 
bioequivalence” (CPMP/QWP/EWP/1401/98 Rev. 1, 20 January 2010) (4, 5). 
 
Considering the lack of information about the PK profile of the new formulation it was 
decided to use a “two stage” bioequivalence study design, that allows a re-calculation of the 
sample size in case the number of subjects initially enrolled in the study is not large enough to 
provide a reliable answer to the questions addressed due to underestimation of the variability 
or misleading estimation of the point estimate for the T/R ratio of the geometric means. 
 
The sample size for study stage 1 was calculated assuming a point estimate for the T/R ratio 
of the geometric means of 1.053 (i.e. µR=0.95∙µT) and a multiplicative coefficient of 
variation (CVm) of 20% for both AUC0-t and Cmax. A power of 90% was considered and, 
according to the Pocock spending function and to the current European bioequivalence 
guideline, the α level was set to 0.0294. Fifteen (15) subjects per sequence (i.e. 30 subjects 
overall) were enrolled in the first stage of the study. 
 
After the end of study stage 1, PK parameters were calculated and an ad interim 
bioequivalence test was performed on the calculated PK parameters Cmax, AUC0-t and AUC0-
∞. To safeguard the overall type I error, the Pocock spending function was used to determine 
the α level of the bioequivalence test (see § 6.2).  
Should bioequivalence be proven with the results of the subjects of the first stage, the primary 
objective of the study would then be satisfied and the second study stage will not take place. 
CROSS Research S.A.  
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CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
Should bioequivalence NOT have been proven with the results of the subjects of the first 
stage and with an a posteriori calculated power > 90% for both AUC0-t and Cmax, the study 
would have been stopped without any further analysis.  
Should bioequivalence NOT have been proven with the results of the subjects of the first 
stage and with an a posteriori calculated power ≤ 90% for AUC0-t or Cmax, the overall sample 
size for the study (stage 1 plus 2) would have been calculated on the basis of the ad interim 
bioequivalence results. The additional subjects would have been enrolled into the second 
study stage. After completion of stage 2, the PK analysis and the bioequivalence test would 
have been performed on the pooled subjects of the two study stages. The second stage if 
applicable, was to be performed only after notification of the sample size to the local Ethics 
Committee and to the central Swiss authority (Swissmedic). 
 
An open design was chosen as it was considered adequate to evaluate objective measures such 
as pharmacokinetic parameters. All the personnel involved in the analytical determinations of 
ketoprofen in the plasma samples withdrawn from the volunteers will be maintained in 
blinding.  
 
The sequence of treatments in the two study periods will be assigned to each randomised 
subject according to a computer generated randomisation list (see § 4.1).  
 
A wash-out period of at least 4 days between the two administrations is justified by the 
elimination half-life of ketoprofen (1-2 h). 
 
For details on the study schedule see below (TABLE 1). 
 
 
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CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
TABLE 1. 
STUDY SCHEDULE 
 
ACTIVITIES 
Screening 
PERIOD 1, 2  
(wash-out at least 4 days) 
Visit 
V1 
V2, V4 
V3, V5 
Final/Early 
Termination 
Visit (ETV)8 
 
Days -14/-2 
Day -1 
Day 1 
 
Informed consent 
x 
 
 
 
Demography 
x 
 
 
 
Lifestyle 
x 
 
 
 
Medical history and underlying 
disease 
x 
 
 
 
Physical abnormalities 
x 
 
 
x 
Previous and concomitant treatments 
x 
x 
x 
x 
Height 
x 
 
 
 
Body weight 
x 
 
 
x 
Alcohol breath test 
 
x 
 
 
Laboratory analysis1 
x 
 
 
x 
Virology 
x 
 
 
 
Drug screening 
x 
 
 
 
BP, PR, BT 
x 
x 
x2 
x2 
Pregnancy test3 
x 
x 
 
 
ECG 
x 
 
 
x 
Inclusion/exclusion criteria evaluation 
x 
x9 
 
 
Eligibility evaluation 
x 
x9 
 
 
Enrolment and Randomisation 
 
x9 
 
 
Confinement 
 
x 
 
 
Discharge 
 
 
x 
 
Drug administration4 
 
 
x 
 
Blood samplings5 
 
 
x 
 
Standardised meals6  
 
x 
x 
 
AEs monitoring7 
x 
x 
x 
x 
 
1: 
Full laboratory analysis was performed at screening visit. The same analysis was performed at final visit 
with the exclusion of virology, drug screening and serum pregnancy test 
2: 
at 8 h post-dose, corresponding to the final visit assessment at the end of period 2; at early termination visit 
(if applicable)  
3: 
Females only. Serum β-HCG test at screening visit; urine test at the clinical centre on day -1 of each study 
period 
4: 
at 8:00 ± 1 h 
5: 
Pre-dose (0), 5, 15, 30, 45 min, 1, 1.5, 2, 3, 4, 5, 6 and 8 h post-dose 
6: 
Standardised lunch was served at approximately 5 h post-dose. A standardised light and low-fat dinner  
were served on day -1 of each period 
7: 
AEs were monitored from the screening visit, immediately after informed consent, up to the final visit. 
8: 
on day 1 of period 2, after the 8 h blood sampling and vital signs check, subjects underwent a final visit. In 
case of discontinuation, subjects underwent an ETV 
9: 
At visit 2 only 
 
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CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
 
3 
STUDY POPULATION 
 
3.1 
Target population 
 
The first study stage population included 30 healthy volunteers (at least 12 subjects per sex) 
aged 18-55 years inclusive. 
 
3.2 
Inclusion criteria 
 
To be enrolled in this study, subjects must fulfil all of these criteria: 
1. Informed consent: signed written informed consent before inclusion in the study  
2. Sex and Age: males/females, 18-55 years old inclusive 
3. Body Mass Index (BMI): 18.5-30 kg/m2 inclusive 
4. Vital signs: systolic blood pressure (SBP) 100-139 mmHg, diastolic blood pressure (DBP) 
50-89 mmHg, pulse rate (PR) 50-90 bpm and body temperature (BT) ≤ 37.5° C, measured 
after 5 min of rest in the sitting position; 
5. Full comprehension: ability to comprehend the full nature and purpose of the study, 
including possible risks and side effects; ability to co-operate with the investigator and to 
comply with the requirements of the entire study 
6. Contraception and fertility (females only): females of child-bearing potential and with an 
active sexual life must be using at least one of the following reliable methods of 
contraception: 
a. Hormonal oral, implantable, transdermal, or injectable contraceptives for at least 2 
months before the screening visit 
b. A non-hormonal intrauterine device [IUD] or female condom with spermicide or 
contraceptive sponge with spermicide or diaphragm with spermicide or cervical cap 
with spermicide for at least 2 months before the screening visit 
c. A male sexual partner who agrees to use a male condom with spermicide 
d. A sterile sexual partner 
Female participants of non-child-bearing potential or in post-menopausal status for at least 
1 year will be admitted. For all female subjects, pregnancy test result must be negative at 
screening. 
 
3.3 
Exclusion criteria 
 
Subjects meeting any of these criteria were not enrolled in the study: 
1. Electrocardiogram (ECG 12-leads, supine position): clinically significant abnormalities 
2. Physical findings: clinically significant abnormal physical findings which could interfere 
with the objectives of the study 
3. Laboratory analyses: clinically significant abnormal laboratory values indicative of 
physical illness 
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CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
4. Allergy: ascertained or presumptive hypersensitivity to the active principles (ketoprofen) 
and/or formulations' ingredients; history of hypersensitivity to drugs (in particular to 
NSAIDs) or allergic reactions in general, which the Investigator considers may affect the 
outcome of the study 
5. Diseases: significant history of renal, hepatic, gastrointestinal, cardiovascular, respiratory 
(including asthma), skin, haematological, endocrine or neurological and autoimmune 
diseases that may interfere with the aim of the study 
6. Medications: medications, including over the counter (OTC) drugs [in particular 
ketoprofen and acetylsalicylic acid (ASA) and NSAIDs in general], herbal remedies and 
food supplements taken 2 weeks before the start of the study. Hormonal contraceptives for 
females will be allowed  
7. Investigative drug studies: participation in the evaluation of any investigational product 
for 3 months before this study. The 3-month interval is calculated as the time between the 
first calendar day of the month that follows the last visit of the previous study and the first 
day of the present study (date of the informed consent signature) 
8. Blood donation: blood donations for 3 months before this study 
9. Drug, alcohol, caffeine, tobacco: history of drug, alcohol [> 1 drink/day for females and > 
2 drinks/day for males, defined according to the USDA Dietary Guidelines 2010 (6)], 
caffeine (> 5 cups coffee/tea/day) or tobacco abuse (≥ 6 cigarettes/day)  
10. Drug test: positive result at the drug test at screening  
11. Alcohol test: positive alcohol breath test at day -1 
12. Diet: abnormal diets (< 1600 or > 3500 kcal/day) or substantial changes in eating habits in 
the 4 weeks before this study; vegetarians 
13. Pregnancy (females only): positive or missing pregnancy test at screening or day -1, 
pregnant or lactating women 
 
3.3.1 
Not allowed treatments 
 
No medications, including OTC [NSAIDs in particular ketoprofen and acetylsalicylic acid 
(ASA)], herbal remedies and food supplements, were allowed for 2 weeks before the start of 
the study and during the whole study duration. 
 
3.3.2 
Allowed treatments 
 
Paracetamol was allowed as therapeutic counter-measure for adverse events (AEs) according 
to the investigator’s opinion. Hormonal contraceptives were allowed too. 
The intake of any other medication was reported as a protocol deviation. However, it led to 
subject's discontinuation from the study only if the investigator, together with the sponsor, 
considered it could affect the study assessments or outcome. 
 
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CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
4 
ASSIGNMENT OF STUDY TREATMENT 
 
4.1 
Randomisation 
 
The randomisation list was computer-generated by the CRO Biometry Unit, using the PLAN 
procedure of SAS® version 9.3 (TS1M1) (7) or higher (the actual version will be stated in the 
final report). The randomisation list was supplied to the study site before study start. The 
randomisation list will be attached to the final clinical study report. 
 
4.2 
Treatment allocation 
 
Subjects were assigned to the sequence of treatments (TR or RT) in the two study periods 
according to the randomisation list. Subjects were randomised to receive one of the two 
pruducts (i.e. either test or reference) in period 1 and the other product in period 2. 
Randomisation number was given to the subjects on study day -1, period 1, and was used to 
assign the treatment sequence according to the randomisation list, as detailed above. 
 
4.3 
Blinding 
 
This is an open study. No masking procedure was applied. 
 
 
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CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
5 
EVALUATION PARAMETERS 
 
5.1 
Study variables 
 
5.1.1 
Primary variables 
 
• 
Cmax and AUC0-t of ketoprofen calculated from plasma concentrations after single oral 
dose of test and reference. 
 
5.1.2 
Secondary variables 
 
• 
AUC0-∞, tmax, t1/2, λz and Frel of ketoprofen calculated from plasma concentration after 
single oral dose of test and reference; 
• 
Treatment-emergent AEs (TEAEs), vital signs (BP, PR, BT), body weight, ECG, 
laboratory parameters. 
 
5.2 
Pharmacokinetic assessments 
 
5.2.1 
Pharmacokinetic parameters 
 
The following PK parameters were measured and/or calculated for ketoprofen, using the 
validated software Phoenix WinNonlin® version 6.3 (8) or higher (actual version will be 
stated in the final report): 
 
Cmax: 
Maximum plasma concentration 
 
tmax: 
Time to achieve Cmax 
 
λz: 
Terminal elimination rate constant, calculated, if feasible, by log-linear 
regression using at least 3 points 
 
t1/2: 
Half-life, calculated, if feasible, as ln2/λz 
 
AUC0-t: 
Area under the concentration-time curve from administration to the last 
observed concentration time t, calculated with the linear trapezoidal method 
 
AUC0-∞: 
Area under the concentration-time curve extrapolated to infinity, calculated, if 
feasible, as AUC0-t + Ct/λz, where Ct is the last measurable drug concentration 
 
%AUCextra: 
Percentage of the residual area (Ct/λz) extrapolated to infinity in relation to 
the total AUC0-∞, calculated, if feasible, as 100×[(Ct/λz)/AUC0-∞] 
 
Frel: 
Relative bioavailability, calculated as ratio AUC0-t (test)/ AUC0-t (reference) 
 
 
AUC0-t is considered a reliable estimate of the extent of absorption if the ratio AUC0-t/AUC0-∞ 
equals or exceeds a factor of 0.8, i.e. if %AUCextra is < 20%.  
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CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
 
The quality of log-linear regression (and, consequently, the reliability of the extrapolated PK 
parameters) should be demonstrated by a correlation coefficient R2 > 0.8. 
 
5.3 
Safety assessments 
 
Safety and general tolerability of the IMP will be based on TEAEs, physical examinations 
including body weight, vital signs, ECG and routine haematology, blood chemistry and 
urinalysis laboratory tests. 
 
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CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
6 
STATISTICAL METHODS 
 
The data documented in this study and the parameters measured are evaluated and compared 
using classic descriptive statistics, i.e. geometric mean (PK data only), arithmetic mean, SD, 
CV (%), minimum, median and maximum values for quantitative variables, and frequencies 
for qualitative variables. 
 
Not available data are evaluated as “missing values”. The statistical analysis of demographic 
and safety data will be performed using SAS® version 9.3 (TS1M1) (7) or higher (the actual 
versions will be stated in the final report). 
The statistical analysis of PK parameters was performed using Phoenix WinNonlin® version 
6.3 (8) or higher and SAS® version 9.3 (TS1M1) or higher. 
 
6.1 
Analysis sets 
 
6.1.1 
Definitions 
 
A subject will be defined as screened after the signature of the informed consent, regardless of 
the completion of all the screening procedures. 
 
A subject will be defined as eligible if he/she meets all the inclusion/exclusion criteria. 
Otherwise he/she will be defined as a screen failure.  
 
A subject will be defined as enrolled in the study if he/she is included into the interventional 
phase of the study. The enrolment was performed through randomised allocation to a 
treatments sequence. 
 
An eligible but not enrolled subject will be defined as a reserve. 
 
A subject will be defined as randomised in the study when he/she is assigned to a randomised 
treatments sequence. 
 
• 
Enrolled set: all enrolled subjects. This analysis set will be used for demographic, 
baseline and background characteristics 
• 
Safety set: all subjects who receive at least one dose of the investigational medicinal 
product(s). This analysis set will be used for the safety analyses 
• 
PK set: all randomised subjects who fulfil the study protocol requirements in terms of 
investigational medicinal product(s) intake and have evaluable PK data readouts for the 
planned treatment comparisons, with no major deviations that may affect the PK results. 
This analysis set will be used for the statistical analysis of the PK results 
 
Each subject will be coded by the CRO Biometry Unit as valid or not valid for the Safety set 
and the PK set. Subjects will be evaluated according to the treatment they actually receive. 
 
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CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
6.1.2 
Reasons for exclusion from the PK set 
 
Reasons for the exclusion of subjects from the PK set are the following: 
 
Before bioanalysis 
 vomiting and diarrhoea after drug intake which could render the plasma concentration-
time profile unreliable 
 intake of concomitant medications which could render the plasma concentration-time 
profile unreliable 
 AEs which could render the plasma concentration-time profile unreliable 
 administration errors which could render the plasma concentration-time profile unreliable 
 other events which could render the plasma concentration-time profile unreliable 
If one of these events occurs, it will be noted in the CRF as the study is being conducted. 
 
After bioanalysis 
 
Exclusion of subjects on the basis of pharmacokinetic reasons is possible only for: 
 subjects with lack of any measurable concentrations or only very low plasma 
concentrations for the reference medicinal product. A subject is considered to have very 
low plasma concentrations if his/her AUC is less than 5% of the reference medicinal 
product geometric mean AUC (which should be calculated without inclusion of data from 
the outlying subject) 
 subjects with implausible concentrations (i.e. different from the known, expected 
concentration profiles) for the reference medicinal product. The exclusion of these 
subjects must be justified on the basis of sound scientific reasons and mutually agreed 
between the CRO and the Sponsor 
 subjects with non-zero baseline concentrations > 5% of Cmax 
The samples from the subjects excluded from the PK set should still be assayed and the 
results listed. Subjects should not be excluded from the PK set if the AUC0-t covers less than 
80% of the AUC0-∞. 
 
No subject was excluded from the PK set in the interim analysis and no subject will be 
excluded from the PK set in the final analysis. 
 
6.2 
Sample size and power considerations 
 
This is a two-stage study (see also § 2.2 and 2.3). 
 
6.2.1 
Stage 1 
 
The sample size for stage 1 was calculated assuming a point estimate for the T/R ratio of the 
geometric means of 1.053 (i.e. µR=0.95∙µT) and a multiplicative coefficient of variation 
(CVm) of 20% for both AUC0-t and Cmax. A power of 90% was considered and, according to 
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CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
the Pocock spending function and to the current European bioequivalence guideline, the α 
level was set to 0.0294. Fifteen (15) subjects per sequence (i.e. 30 subjects overall) were 
enrolled in the first stage of the study. Sample size calculation data are reported in the 
following table: 
 
Table 6.2.1 
Stage 1 - Sample size calculation data 
PK 
Parameter 
Alpha 
(one-sided) 
µT/µR 
CVm 
sqrt(MSE) 
Power 
N per 
sequence 
Sample 
size 
AUC0-t 
0.0294 
1.053 
20% 
0.198 
90% 
15 
30 
Cmax 
0.0294 
1.053 
20% 
0.198 
90% 
15 
30 
 
In a first study stage 30 healthy volunteers (at least 12 subjects per sex) were included and 
treated to receive test and reference investigational products according to the cross-over 
design. Drop-out subjects were not to be replaced.  
 
6.2.2 
Whole study 
 
After the end of study stage 1, PK parameters were calculated and an ad interim 
bioequivalence test was performed on the calculated PK parameters Cmax, AUC0-t and AUC0-
∞. To safeguard the overall type I error, the Pocock spending function was used to determine 
the α level of the bioequivalence test.  
 
Should bioequivalence be proven with the results of the subjects of the first stage, the primary 
objective of the study would then be satisfied and the second study stage will not take place. 
 
It was planned that, should bioequivalence NOT have been proven with the results of the 
subjects of the first stage and with an a posteriori calculated power > 90% for both AUC0-t 
and Cmax, the study would have been stopped and the bioequivalence not further investigated.  
Should bioequivalence NOT have be proven with the results of the subjects of the first stage 
and with an a posteriori calculated power ≤ 90% for AUC0-t or Cmax, the overall sample size 
for the study (stage 1 plus 2) would have been calculated on the basis of the ad interim 
bioequivalence results. The additional subjects would have been enrolled into the second 
study stage. The second stage, if applicable, would have been performed only after 
notification of the sample size to the local Ethics Committee and to the central Swiss authority 
(Swissmedic). After completion of stage 2, the PK analysis and the bioequivalence test would 
have been performed on the pooled subjects of the two study stages. 
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CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
 
6.3 
Demographic and other baseline characteristics 
 
Critical demographic characteristics will be examined according to qualitative or quantitative 
data. Qualitative data will be summarised in contingency tables. Quantitative data will be 
summarised using classic descriptive statistics. 
 
6.3.1 
Subjects’ disposition 
 
The disposition of all subjects enrolled in the study will be listed and summarised. The 
number and percentage of subjects completing the study, the number and percentage of 
withdrawals and the reasons for withdrawal will be presented. 
 
6.3.2 
Analysis sets 
 
The subjects included in each analysis set will be listed and summarised. 
 
6.3.3 
Demography 
 
Demographic data will be listed and summarised. The number and percentage of subjects in 
each category of categorical variables (e.g. sex) and the descriptive statistics (mean, SD, 
CV%, minimum, median and maximum) of continous variables (e.g. age) will be presented. 
 
6.3.4 
Protocol deviations 
 
All the protocol deviations reported during the clinical trial will be listed and summarised. 
The number and percentage of subjects for each deviation will be reported. 
 
6.3.5 
Discontinued subjects 
 
All subjects who discontinue the clinical trial will be listed. 
 
6.3.6 
Subjects excluded from the PK analysis 
 
All subjects excluded from the primary PK analysis will be listed and the reasons for 
exclusion will be reported. 
 
6.3.7 
Medical and surgical history 
 
All the findings of medical and surgical history of all subjects enrolled in the study will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA) version 17.1 and 
listed. 
 
6.3.8 
Prior and concomitant medications 
 
Prior and concomitant medications/therapies will be listed and summarised as number of 
subjects being treated with any type of medication/therapy classified according to the 
standardised product name of the World Health Organization (WHO) Drug Dictionary 
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CONFIDENTIAL 
 
Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
Enhanced (WHODDE version September 1, 2014) and to the Anatomical Therapeutic 
Chemical (ATC) classification system. 
 
6.3.9 
Subjects study visits 
 
The dates of all subjects study visits will be listed. 
 
6.3.10 
Tests 
 
The test performance dates and the results of the alcohol breath test and pregnancy test will be 
listed. 
 
6.3.11 
Meals 
 
The dates and times of meals will be listed by treatment. 
 
6.4 
Analysis of pharmacokinetic parameters 
 
6.4.1 
Descriptive pharmacokinetics 
 
A descriptive PK will be presented. The results will be displayed and summarised in tables 
and figures. Individual and mean curves (+SD at sampling times), indicating inter-subject 
variability, will be plotted. Data below the lower quantification limit (BLQL) will be 
considered as 0 in the calculations and presented as BLQL in listings and tables. As a 
consequence of BLQL (i.e. 0) values, calculated geometric means (if requested) could be null. 
For this reason, in the presence of any null value, the geometric mean will be reported as not 
calculated (NC). The date and time of PK sample collection will be listed by treatment. 
 
6.4.2 
Statistical comparison of pharmacokinetic parameters 
 
According to the current European Bioequivalence Guideline (1) and European Questions & 
Answers document (5), PK parameters AUC0-t, AUC0-∞ (if feasible) and Cmax were analysed 
using analysis of variance (ANOVA). Before analysis, the data were transformed using a 
neperian logarithmic transformation. For stage 1 data the statistical analysis took into account 
treatment, period, sequence and subject (sequence) as sources of variation.  
 
For the analysis (stage 1 data) acceptance criterion for bioequivalence (BE) is a 94.12% 
confidence interval for the T/R ratio of the geometric means of the parameters within the 80-
125% range, according to the current guidelines for BE studies and to the Pocock α spending 
function. 
 
If the study is terminated after the interim analysis (see § 6.2), the interim analysis will be 
regarded and presented in the CSR as the final data analysis. 
 
tmax will be compared between treatments using the non-parametric Friedman test. 
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Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
 
6.5 
Interim analysis at the end of the study stage 1 
 
An ad interim bioequivalence test on the available PK data was performed at the end of stage 
1, as described in paragraphs § 2.3 and § 6.2. 
 
The pharmacokinetic and statistical analysis on the first study stage data was completed on 
09FEB2015. According to the current European Bioequivalence Guideline (1), 94.12% 
confidence intervals (Pocock correction was applied) were calculated for PK parameters Cmax, 
AUC0-t and AUC0-∞ of the 30 randomised subjects. The CIs corresponded to 97.57-119.81% 
for Cmax, 104.26-117.38% for AUC0-t and 104.35-117.41% for AUC0-∞ and were inside the 
80.00-125.00 limits for all parameters. 
 
Bioequivalence was proven with the results of the subjects of the first stage, the primary 
objective of the study is satisfied and the second study stage will not take place. 
 
6.6 
Safety evaluation 
 
6.6.1 
Adverse events 
 
Adverse events (AEs) will be coded by System Organ Class (SOC) and Preferred Term (PT), 
using the Medical Dictionary for Regulatory Activities (MedDRA) version 17.1. 
AEs will be classified as pre-treatment AEs (PTAEs) and treatment-emergent AEs (TEAEs), 
according to the period of occurrence, as follows:  
• 
PTAEs: all AEs occurring before the first dose of IMP and not worsening after the first 
dose of IMP 
• 
TEAEs: all AEs occurring or worsening after the first dose of IMP 
 
Individual PTAEs and TEAEs will be listed in subject data listings. 
 
No summary table will be provided for PTAEs. 
 
TEAEs will be summarised in tables of frequency. The number and percentage of subjects 
with any TEAE, the number of TEAEs, the number and percentage of subjects with any 
TEAE by severity, the number of TEAEs by severity, the number and percentage of subjects 
with any TEAE related to study drug and the number of TEAEs related to study drug will be 
presented. 
 
Serious TEAEs will be summarized by treatment. Should any serious TEAE occur, the 
number and percentage of subjects with any serious TEAE, the number of serious TEAEs, the 
number and percentage of subjects with any serious TEAE related to study drug and the 
number of serious TEAEs related to study drug will be presented. 
 
All TEAEs leading to death, Serious TEAEs and TEAEs leading to discontinuation will be 
listed, if occurring. 
 
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Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
6.6.2 
Physical examination 
 
Significant findings/illnesses, reported after the start of the study and that meet the definition 
of an AE, will be recorded in the subject source documents. Date of the physical examination, 
overall investigator’s interpretation (as normal [N], abnormal not clinically significant [NCS] 
or abnormal clinically significant [CS]) and clinically significant findings (if any) will be 
listed. 
 
6.6.3 
Laboratory data 
 
Date/time of samples collection and overall investigator’s interpretation (as normal [N], 
abnormal not clinically significant [NCS] or abnormal clinically significant [CS]) will be 
reported in the CRF and listed in the final clinical study report. The Investigator’s 
interpretations will be summarised by tables of frequency. 
 
Hard copies of the laboratory print-outs will be attached to the CRFs. All clinically significant 
abnormalities after the screening visit will be recorded as AEs. All laboratory results will be 
listed and a table of all the abnormal values will be presented. 
 
6.6.4 
Vital signs 
 
Values of vital signs will be listed and summarised by descriptive statistics. Changes from 
baseline (pre-dose assessment) will be summarised by descriptive statistics. 
 
6.6.5 
Body weight  
 
Values of body weight will be listed and summarised by descriptive statistics. Changes from 
baseline (screening assessment) will be summarised by descriptive statistics. 
 
6.6.6 
ECGs 
 
Date of ECG recording and overall investigator’s interpretation (as normal [N], abnormal not 
clinically significant [NCS] or abnormal clinically significant [CS]) will be reported in the 
CRF and listed in the final clinical study report. The Investigator’s interpretations will be 
summarised by tables of frequency. 
 
Hard copies of the ECGs will be attached to the CRF. All clinically significant abnormalities 
after the screening visit will be recorded as AEs. 
 
6.6.7 
Drug administration 
 
The extent of exposure (i.e. dose and dose/body weight) will be listed and summarised by 
descriptive statistics. The actual date/time of each drug administration and the start date/time of 
fasting conditions will be listed. 
 
 
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Statistical analysis plan CRO-PK-14-288 
Sponsor code KSL0114 
Ketoprofen lysine salt 40 mg tablets bioequivalence 
Final version 1.0, 13FEB2015 
7 
REFERENCES 
 
1. 
Fuglsang A. Futility rules in bioequivalence trials with sequential designs. AAPS Journal 2013, 
16: 79-82 
2. 
Montague TH, Potvin D., DiLiberti CE., et al. Additional results for sequential design approaches 
for bioequivalence studies with crossover design. Pharmaceut. Statist. 2012, 11:8-13 
3. 
Potvin D., DiLiberti CE., Hauck WW., et al. sequential approaches for bioequivalence studies with 
crossover designs. Pharm Stat. 2008 Oct-Dec;7(4):245-62 
4. 
Guidance on the investigation of bioequivalence. CPMP/EWP/QWP/1401/98 Rev. 1/Corr **, 20 
January 2010 
5. 
Questions & Answers: Positions on specific questions addressed to the pharmacokinetics working 
party. EMA/618604/2008 Rev. 8, 10 October 2013 
6. 
U.S. Department of Health and Human Services and U.S. Department of Agriculture, Nutrition 
and your health: Dietary Guidelines for Americans, 2010 
7. 
SAS/STAT® User’s Guide 
8. 
Phoenix 1.3 User’s Guide, Pharsight Corporation 
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