Clinical trial NCT02963701
Conditions: Healthy Volunteers
Sponsor: Boehringer Ingelheim
Start date: 2016-12-20; Completion date: 2017-02-08
Enrollment: 56 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Primary objective To demonstrate the bioequivalence of a fixed dose combination tablet containing 400 mg Ibuprofen and 60 mg Pseudoephedrine-HCl vs. RhinAdvil® (2 tablets containing 200 mg Ibuprofen and 30 mg Pseudoephedrine-HCl) as a fixed dose combination tablet with respect to the analytes, ibuprofen and pseudoephedrine.

Secondary objective To assess the bioequivalence of a fixed dose combination tablet containing 400 mg Ibuprofen and 60 mg Pseudoephedrine-HCl vs. RhinAdvil® (2 tablets containing 200 mg Ibuprofen and 30 mg Pseudoephedrine-HCl) as a fixed dose combination tablet with respect to R- and S-ibuprofen (enantiomers of ibuprofen).

Detailed description:

Arms: arm 1: Fixed dose combination arm 2: Fixed Dose Combination
Interventions: intervention 1: Ibuprofen intervention 2: Pseudoephedrine-HCl
Intervention descriptions: intervention 1: Fixed dose combination intervention 2: Fixed dose combination

Protocol documents:
Prot_000.pdf: 
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TITLE PAGE
Clinical Trial Protocol
Document Number:
c11001605-04
EudraCT No.: 
EU Trial No:
Not applicable
BI Trial No.:
1024.9
BI Investigational
Product(s):
Ibuprofen and Pseudoephedrine
Title:
Bioequivalence of a fixed dose combination tablet containing 400 mg
Ibuprofen and 60 mg Pseudoephedrine-HCl compared to two film coated 
fixed dose combination tablets RhinAdvil® (200 mg Ibuprofen and 30 mg 
Pseudoephedrine-HCl) administered in at least 48 healthy male and female 
subjects (Open-label, randomized, laboratory blind, single dose, two-way 
crossover, Phase I trial).
Lay Title:
Bioequivalence of a fixed dose combination tablet containing 400 mg
Ibuprofen and 60 mg Pseudoephedrine-HCl compared to two film coated 
fixed dose combination tablets RhinAdvil®(200 mg Ibuprofen and 30 mg 
Pseudoephedrine-HCl) administered in healthy subjects.
Clinical Phase:
I
Trial Clinical Monitor:
on behalf of:
Phone: 
 Fax: 
Principal Investigator:
 
Tel: 
 (Reception)
Fax: 
Status:
Final Protocol (Revised Protocol based on Global Amendment 01)
Version and Date:
Version:
Date:
3.0
20 February 2017
Proprietary confidential information.
2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies. All rights reserved.
This document may not - in full or in part - be passed on, reproduced, published or otherwise used without prior written permission.


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BI Trial No.: 1024.9                                                                                 
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Trial Protocol
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CLINICAL TRIAL PROTOCOL SYNOPSIS
Name of company:
Boehringer Ingelheim
Name of finished product:
N/A
Name of active ingredient:
Ibuprofen and Pseudoephedrine
Amended Protocol date:
30 January 2017
Trial number:
1024.9
Revision date:
20 February 2017
Title of trial:
Bioequivalence of a fixed dose combination tablet containing 400 mg Ibuprofen 
and 60 mg Pseudoephedrine-HCl compared to two film coated fixed dose 
combination tablets RhinAdvil® (200 mg Ibuprofen and 30 mg Pseudoephedrine-
HCl) administered in at least 48 healthy male and female subjects (Open-label, 
randomised, laboratory blind, single dose, two-way crossover, Phase I trial).
Principal Investigator:
 (
Tel: 
 (Reception)
Fax: 
Trial site(s):
Bloemfontein Early Phase Clinical Unit, PAREXEL International (South Africa)
Clinical phase:
I
Objectives:
Primary objective:
To demonstrate the bioequivalence of a fixed dose combination tablet containing
400 mg Ibuprofen and 60 mg Pseudoephedrine-HCl vs. RhinAdvil® (2 tablets 
containing 200 mg Ibuprofen and 30 mg Pseudoephedrine-HCl) as a fixed dose 
combination tablet with respect to the analytes, ibuprofen and pseudoephedrine.
Secondary objective:
To assess the bioequivalence of a fixed dose combination tablet containing
400 mg Ibuprofen and 60 mg Pseudoephedrine-HCl vs. RhinAdvil® (2 tablets 
containing 200 mg Ibuprofen and 30 mg Pseudoephedrine-HCl) as a fixed dose 
combination tablet with respect to R- and S-ibuprofen (enantiomers of ibuprofen).


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BI Trial No.: 1024.9                                                                                 
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Trial Protocol
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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished product:
N/A
Name of active ingredient:
Ibuprofen and Pseudoephedrine
Amended Protocol date:
30 January 2017
Trial number:
1024.9
Revision date:
20 February 2017
Methodology:
Open-label, randomised, single dose, two-way crossover design
No. of patients:
Fifty-six eligible subjects will be entered into the study, to complete with no less
than 48 evaluable subjects (no less than 16 of each gender).
Total entered:
56
Diagnosis:
Not applicable
Main criteria for 
inclusion:
Healthy male and female subjects, age ≥21 and ≤50 years, BMI range: ≥18.5 and
≤29.9 kg/m2. Minimum of 1/3 of each gender should complete the study. Signed
informed consent of the subject according to the present law.
Test product(s):
Fixed dose combination 400 mg Ibuprofen and 60 mg Pseudoephedrine-HCl film-
coated tablet
Dose:
400 mg Ibuprofen and 60 mg Pseudoephedrine-HCl
Mode of administration:
Oral administration with 240 mL water in standing position after an overnight fast 
of at least 10 hours
Comparator products:
2 tablets containing Fixed Dose combination RhinAdvil® (200 mg Ibuprofen and 
30 mg Pseudoephedrine-HCl)
Dose:
200 mg Ibuprofen and 30 mg Pseudoephedrine-HCl


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BI Trial No.: 1024.9                                                                                 
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Trial Protocol
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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Name of company:
Boehringer Ingelheim
Name of finished product:
N/A
Name of active ingredient:
Ibuprofen and Pseudoephedrine
Amended Protocol date:
30 January 2017
Trial number:
1024.9
Revision date:
20 February 2017
Mode of administration:
Oral administration with 240 mL water in standing position after an overnight fast 
of at least 10 hours
Duration of treatment:
Single dose in each treatment period separated by a wash-out phase of at least 
5 days
Endpoints
Primary endpoints: AUC0-tz and Cmax of ibuprophen and pseudoephedrine-HCl in 
plasma
Secondary endpoints: AUC0-∞of ibuprofen and pseudoephedrine-HCl in plasma; 
AUC0-tz, AUC0-∞and Cmax of R-ibuprofen and S-ibuprofen in plasma; and 
S/R-ibuprofen ratio for AUC0-tz (i.e., AUC0-tz S-ibuprofen / AUC0-tz R-ibuprofen)
of R- ibuprofen and S-ibuprofen in plasma
 
Safety criteria:
Physical examination, vital signs (BP, PR), 12-lead ECG, laboratory tests, adverse
events, tolerability assessment
Statistical methods:
The assessment of bioequivalence will be based upon two-sided 90% confidence
intervals (CIs) for the ratios of the geometric means (test/reference) for the 
primary and secondary endpoints using an acceptance range of 80.00-125.00%. 
This method is equivalent to the two one-sided t-tests procedure, each at the 5% 
significance level. The statistical model will be an ANOVA on the logarithmic 
scale including effects for ‘sequence’, ‘subjects nested within sequences’, ‘period’ 
and ‘treatment’. CIs will be calculated based on the residual error from ANOVA.
Descriptive statistics will be calculated for all endpoints.


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BI Trial No.: 1024.9                                                                                 
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FLOW CHART
-
Visit
Day
Planned time
[h:min]
Clock time of actual day
[h:min]1
Event and comment
Blood sampling for PK8
Laboratory tests
ECG
Vital Signs9
Recording AEs /
concomitant therapy
Screening
1
-21 to -1
Screening examination2, 5
x5 & 7
x
x
X
Treatment
period 4
1 or 2
2 or
34
-11:50 
until
0:00
20:30 
until
0:00
Admission to trial
center, Pregnancy 
test
x
x6
x
X
1
0:00
8:00
Study drug administration
X
0:10
8:10
x
X
0:20
8:20
x
X
0:30
8:30
x
x
X
0:45
8:45
x
X
1:00
9:00
x
X
1:15
9:15
x
X
1:30
9:30
x
X
1:45
9:45
x
X
2:00
10:00
x
x
X
2:30
10:30
x
X
3:00
11:00
x
x
X
4:00
12:00
Lunch
x
X
6:00
14:00
x
X
8:00
16:00
Snack
x
X
10:00
18:00
Dinner
x
X
12:00
20:00
x
X
2
24:00
8:00
x
X
30:00
14:00
Discharge from trial centre
x
X
End of
study
4
End-of-study examination3
x5
x
x
X
1
Actual clock time depends on the time of dosing.
2
Screening will occur within 21 days before first drug administration and will include subject information,
informed consent, demographics, vital signs, physical examination, ECG, determination of the body height and weight,
smoking and alcohol history, medical history, concomitant medication, laboratory and review of inclusion and exclusion
criteria.
3
End-of-study examination to be performed within 7 days of last study drug administration or if the subject was 
withdrawn or withdrew from the study but not earlier than last PK sampling, including physical examination, 
vital signs, ECG, laboratory, pregnancy test, concomitant medication, and review of adverse events.
4
Two identical treatment periods with an interval of at least 5 days between drug administrations.
5
Clinical chemistry, haematology, urinalysis, pregnancy test.
In addition at visit 1: drug screening, serology (HBV, HCV, HIV), and alcohol breath test.
6
Baseline: Only substrates, haematology and enzymes. Baseline assessments are done for safety reasons.
7
On admission for treatment period 1 and 2: alcohol breath test, and urine pregnancy test.
8
Time interval allowance for the PK sampling: 0-1 hours: ± 2 min; 1-8 hours: ± 5 min; 8-30 hours: ± 15 min.
9
Vital signs: Body temperature only at screening and pre dose.


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BI Trial No.: 1024.9                                                                                 
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TABLE OF CONTENTS
TITLE PAGE......................................................................................................1
CLINICAL TRIAL PROTOCOL SYNOPSIS................................................2
FLOW CHART ..................................................................................................5
TABLE OF CONTENTS...................................................................................6
ABBREVIATIONS.............................................................................................9
1.
INTRODUCTION ....................................................................................11
1.1
MEDICAL BACKGROUND ............................................................................11
1.2
DRUG PROFILE ...............................................................................................12
2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT..........................................................................................15
2.1
RATIONALE FOR PERFORMING THE TRIAL........................................15
2.2
TRIAL OBJECTIVES.......................................................................................15
2.2.1
Primary objective..................................................................................15
2.2.2
Secondary objective ..............................................................................15
2.3
BENEFIT – RISK ASSESSMENT...................................................................15
3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION ..............17
3.1
OVERALL TRIAL DESIGN AND PLAN ......................................................17
3.1.1
Administrative structure of the trial....................................................17
3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S).....................................................................................18
3.3
SELECTION OF TRIAL POPULATION ......................................................18
3.3.1
Main diagnosis for trial entry ..............................................................18
3.3.2
Inclusion criteria ...................................................................................18
3.3.3
Exclusion criteria ..................................................................................19
3.3.4
Removal of subjects from therapy or assessments.............................20
4.
TREATMENTS ........................................................................................23
4.1
INVESTIGATIONAL TREATMENTS ..........................................................23
4.1.1
Identity of the Investigational Medicinal Products ............................23
4.1.2
Selection of doses in the trial................................................................23
4.1.3
Method of assigning subjects to treatment groups.............................23
4.1.4
Drug assignment and administration of doses for each patient ........24
4.1.5
Blinding and procedures for unblinding.............................................24
4.1.6
Packaging, labelling, and re-supply.....................................................24
4.1.7
Storage conditions.................................................................................25
4.1.8
Drug accountability ..............................................................................25
4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, 
RESTRICTIONS ...............................................................................................26
4.2.1
Other treatment and emergency procedures .....................................26
4.2.2
Restrictions ............................................................................................26


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4.3
TREATMENT COMPLIANCE.......................................................................26
5.
VARIABLES AND THEIR ASSESSMENT..........................................27
5.1
TRIAL ENDPOINTS.........................................................................................27
5.1.1
Primary Endpoint(s).............................................................................27
5.1.2
Secondary Endpoints ............................................................................27
................................................................................27
5.2
ASSESSMENT OF EFFICACY.......................................................................28
5.3
ASSESSMENT OF SAFETY............................................................................28
5.3.1
Physical examination ............................................................................28
5.3.2
Vital Signs..............................................................................................28
5.3.3
Safety laboratory parameters ..............................................................28
5.3.4
Electrocardiogram................................................................................30
5.3.5
Medical Examination / Global assessment..........................................31
5.3.6
Assessment of adverse events ...............................................................31
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS..................................................................................35
5.4.1
Assessment of Pharmacokinetics.........................................................35
5.4.2
Methods of sample collection ...............................................................35
5.4.3
Analytical determinations ....................................................................36
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship .........................36
5.5
ASSESSMENT OF BIOMARKERS(S)...........................................................36
5.6
OTHER ASSESSMENTS .................................................................................37
5.7
BLOOD VOLUME ............................................................................................37
5.8
APPROPRIATENESS OF MEASUREMENTS.............................................37
6.
INVESTIGATIONAL PLAN..................................................................38
6.1
VISIT SCHEDULE............................................................................................38
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS ................38
6.2.1
Screening and run-in period(s)............................................................38
6.2.2
Treatment period(s) ..............................................................................38
6.2.3
Follow Up Period and Trial Completion ............................................39
7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE..........................................................................................40
7.1
STATISTICAL DESIGN - MODEL................................................................40
7.2
NULL AND ALTERNATIVE HYPOTHESES ..............................................41
7.3
PLANNED ANALYSES....................................................................................42
7.3.1
Primary analyses...................................................................................42
7.3.2
Secondary analyses ...............................................................................42
7.3.3
Safety analyses.......................................................................................43
7.4
INTERIM ANALYSES .....................................................................................43
7.5
HANDLING OF MISSING DATA ..................................................................43
7.5.1
Safety......................................................................................................43
7.5.2
Plasma concentration – time profiles...................................................44
7.5.3
Pharmacokinetic parameters ...............................................................44


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7.6
RANDOMISATION ..........................................................................................44
7.7
DETERMINATION OF SAMPLE SIZE ........................................................44
8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY ..........................................46
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
..............................................................................................................................46
8.2
DATA QUALITY ASSURANCE AND DATA MANAGEMENT................46
8.2.1
Data Quality Assurance........................................................................46
8.2.2
Data Management.................................................................................46
8.3
RECORDS..........................................................................................................47
8.3.1
Source documents .................................................................................47
8.3.2
Direct access to source data and documents.......................................47
8.3.3
Storage period of records .....................................................................47
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS .................................48
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY.......48
8.5.1
Storage of biological samples ...............................................................48
8.6
TRIAL MILESTONES .....................................................................................48
9.
REFERENCES .........................................................................................50
9.1
PUBLISHED REFERENCES...........................................................................50
9.2
UNPUBLISHED REFERENCES.....................................................................51
10. APPENDICES...........................................................................................52
11. DESCRIPTION OF GLOBAL AMENDMENT(S)...............................53


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ABBREVIATIONS
AE
Adverse Event
ALT
Alanine transaminase (SGPT) 
ANOVA
Analysis of variance
AP
Alkaline Phosphatase
AST
Aspartate transaminase (SGOT)
AUC0-∞
Area under the concentration-time curve of the analyte in plasma from
0 hours extrapolated to infinity
AUC0-tz
Area under the concentration-time curve of the analyte in plasma over the 
time interval from 0 to the last quantifiable data point
BIRDS
Boehringer Ingelheim Regulatory Documents for Submission
BLQ
Below the limit of quantification
BMI
Body Mass Index (weight divided by height squared) 
BP
Blood Pressure
Cmax
Maximum measured concentration of the analyte in plasma
CML
Local Clinical Monitor
CPMP
Committee for Proprietary Medicinal Products
CRA
Clinical Research Associate
CRF
Case Report Form
CTP
Clinical Trial Protocol 
CTR
Clinical Trial Report 
CYP
Cytochrome P450
DILI
Drug Induced Liver Injury
eCRF
eCRF Electronic Case report form: PAREXEL data capture system 
ClinBase™ 
ECG
Electrocardiogram
EDTA
Ethylendiaminetetraacetic acid
FAS
Full Analysis Set
FC
Flow Chart
FDC
Fixed dose combination
G-6-PD
Glukose-6-phosphat-dehydrogenase
GCP
Good Clinical Practice
γ-GT
Gamma-glutamyl-transferase (GGT) 
gCV
Geometric coefficient of variation 
gMean
Geometric Mean
HBV
Hepatitis B virus 
HCl
Hydrochloric acid 
HCV
Hepatitis C virus
HIV
Human immunodeficiency virus
IB
Investigator’s Brochure
ICH
International committee on harmonisation
IEC
Independent Ethics Committee
IRB
Institutional Review Board
ISF
Investigator Site File
IUD
Intrauterine device
λz
Terminal rate constant of the analyte in plasma
LDH
Lactic-dehydrogenase 


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ln
Natural logarithm
LoEE
List of Essential Element
MedDRA
Medical Dictionary for Drug Regulatory Activities
N
Number
NC
Not calculated
NOA
Not analysed
NOR
No valid result
NOS
No sample available
NSAID
Nonsteroidal anti-inflammatory drug
OPU
Operative Unit
pH
Pondus hydrogenii; negative logarithm of the hydrogen ion concentration
PK
Pharmacokinetics 
p.o.
per os (oral)
PR
Pulse rate
R
Reference treatment SAE
Serious Adverse Event 
SGAE
Significant adverse event
T
Test treatment
in plasma
TCM
Trial Clinical Monitor 
TMF
Trial Master File 
TMW
Trial Medical Writer
TSAP
Trial Statistical Analysis Plan


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1.
INTRODUCTION
1.1
MEDICAL BACKGROUND
The common cold remains the most prevalent cause of acute morbidity. The cause is a viral 
infection, mostly by rhinovirus (up to 80%), corona virus (10-15%), parainfluenza (5%) or 
respiratory syncytial virus (5%) (R13-2920).
Looking at the typical course of a common cold it mostly starts with sore throat, followed 
by the simultaneous occurrence of rhino sinusitis and headache and/or muscle ache. While 
these symptoms gradually resolve, a dry cough may occur. In a later stage, the dry cough 
will develop into cough accompanied by thick tenacious secretion.
As the common cold is a disease of viral origin and usually benign in nature, symptomatic 
treatment is currently the mainstay in the therapy (P88-35100).
Different products are available on the market to treat the single symptoms such as:

Nasal decongestants against nasal congestion

Analgesics against headache, pain and fever

Antihistamines with a drying effect on the nasal passages and a decrease in sneezing

Cough suppressants against dry cough

Mucolytics and secretolytics against productive cough.
Symptomatic treatment with several individual non-prescription products may be 
inconvenient and present a significant additional cost to the patient. Indeed, in a survey in
250 community pharmacists in five European countries, 60% of the questioned pharmacists 
said that they preferred to treat themselves with a combination-product when suffering from 
a common cold (P97-6591).
Most symptoms of common cold are present sometime during the course of the cold, they 
appear, peak and resolve at different times. Nasal congestion and headache or muscle ache 
are often concurrent and both are considered as being bothersome by the patient.
Therefore the development of a fixed dose combination product of an analgesic and a nasal 
decongestant for the treatment of both concurrent and most bothersome symptoms was 
considered.
The combination of an analgesic and a decongestant for treatment of the symptoms 
associated with the common cold is based on the rational of relief from inflammation-based 
symptoms and nasal congestion.
Ibuprofen has been in therapeutic use for decades as nonsteroidal anti-inflammatory drug 
(NSAID). Pseudoephedrine has been in therapeutic use for decades as decongestant, 
respectively.
Their combination provides the cold and influenza sufferer with a convenient and effective 
treatment for the relief of their symptoms (P10-06083).


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Based on positive experience with free combination of both compounds also fixed dose 
combination products with 200 mg ibuprofen and 30 mg pseudoephedrine-HCl have been 
developed and introduced into the European market.
In 2005 a mutual recognition process was granted with France as reference member state 
and Germany, Austria and Luxembourg as concerned member states. Local registrations 
were granted in UK in the 1990ies and Poland in 2004.
A fixed dose combination (FDC) product containing 400 mg ibuprofen free acid and 60 mg 
pseudoephedrine-HCl per film-coated tablet is going to be developed. This product should 
be registered via a decentralised procedure and marketed throughout Europe.
1.2
DRUG PROFILE
Ibuprofen
Ibuprofen is a NSAID of the arylpropionic acids class. This non-selective cyclooxygenase 
inhibitor exhibits marked stereo selectivity in pharmacokinetics (inversion, elimination) and 
pharmacodynamics, as the S-(+) enantiomer is considerably more potent and formed by 
unidirectional inversion of the R-(-)-enantiomer.
Main indications are the treatment of mild to moderate pain from various origins, in 
particular in the therapy of osteo-arthritis, rheumatoid arthritis and soft-tissue disorders. In 
addition, antipyretic activity and short time inhibition of platelet aggregation were observed.
Absorption occurs rapidly and completely after oral administration. Absolute bioavailability 
is almost 100%. Individual peak plasma concentrations are observed within three hours after 
administration of the free acid, with mean values reported as one to two hours. Rate of 
absorption, and thus maximum plasma concentrations (Cmax), may be significantly 
influenced by formulation properties while total exposure (AUC) remains unaffected. The 
apparent volume of distribution is 0.1 to 0.2 L/kg. As this value approximates plasma 
volume, it is suggested that plasma protein binding (> 98%) is preferred to tissue binding.
Following oral administration, about 80% of an ibuprofen dose is recovered as hydroxyl-
and carboxy-metabolites, either conjugated or unconjugated, in the urine within 24 hours. 
Only about 10% is found in the faeces. The major metabolic pathway involves CYP 2C9 and 
probably CYP 2C8. Most important metabolites are 2-hydroxy- and carboxy-ibuprofen 
while 1- and 3- hydroxy-ibuprofen were found in only very small concentrations. No 
pharmacologically active metabolite is known.
Pharmacokinetics of ibuprofen is dose dependent. At doses greater than 600 mg, the 
unbound fraction of the drug increases, probably due to saturation of the protein binding, 
resulting in an increased clearance and less than proportional area under the curve. Mean 
terminal elimination half-life is reported as 2 hours. For additional information please refer
to RhinAdvil® Summary of Product Characteristics. Evidence for accumulation or time
dependency of pharmacokinetics after multiple dosing was not found.


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There are some concerns about the use of NSAIDs. Much of these concerns are related to 
long-term therapy with higher doses in special indications such as e.g. rheumatoid arthritis. 
Ample safety data is available for indications other than upper respiratory tract infections. 
However, this data will not be addressed here in detail. One of the few studies providing 
safety information on the use of ibuprofen in the treatment of cold and flu symptoms was 
reported recently.
In a double-blind randomised study, the tolerability of ibuprofen (up to 1.2 g daily), 
acetylsalicylic acid and acetaminophen (both up to 3 g daily) was investigated in 2815 
patients with mild to moderate pain resulting from cold/flu symptoms or sore throat for 
seven days. The main outcome was the rate of significant adverse events (SGAE). Rates of 
SGAE for ibuprofen, acetylsalicylic acid and paracetamol were respectively 12.0%, 15.7% 
and 12.3%. Ibuprofen was significantly better tolerated than acetylsalicylic acid (p=0.02) 
and showed comparable tolerability compared to paracetamol. The latter was also true for 
total digestive system events and for abdominal pain and dyspepsia. For all other adverse 
events the results were consistent with SGAEs, i.e. comparable proportions of patients in the 
ibuprofen and paracetamol groups and higher percentages of patients in the acetylsalicylic 
acid group than in the ibuprofen group. In conclusion patients with mild to moderate pain 
resulting from cold/flu symptoms or sore throat, ibuprofen used in over-the- counter is well 
tolerated (P04-01312).
Ibuprofen has an excellent safety profile in multiple-dose use with a frequency of 
gastrointestinal adverse events comparable to placebo.
Pseudoephedrine
Pseudoephedrine is a natural alkaloid, commonly manufactured by yeast fermentation. This 
sympathomimetic drug exhibits weak agonist activity at α- and β-adrenergic receptors and 
initiates release of endogenous norepinephrine from storage vesicles in presynaptic neurons. 
Thus, it is used as decongestant of mucous membranes.
The compound is rapidly and completely absorbed after oral administration with peak 
plasma concentrations occurring within 20 to 120 minutes. No information is available on 
plasma protein binding of pseudoephedrine, the apparent volume of distribution is reported 
as 2 −3.3 L/kg.
Pseudoephedrine is metabolised in the liver, but only to a small extent. Main metabolite is 
the pharmacologically active nor-pseudoephedrine. Between 70 and 90% of a given dose is 
excreted unchanged in the urine, only 1% as nor-pseudoephedrine.
Mean terminal elimination half-life is reported between five and six hours, individual values 
of up to 8 hours have been observed (R09-2316). Obviously, pH of the urine exhibits certain 
impact on urinary excretion with normal values at pH of 5 to 6. Higher and lower pH-values 
may increase or decrease half-life significantly due to changes in solubility and tubular 
reabsorption.
In a meta-analysis of 2 repeated dose studies using pseudoephedrine for the symptomatic 
treatment of the common cold, no overall differences in the risk of adverse events compared 


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to placebo have been shown (R07-2230).
For further detailed information, please refer to the (RhinAdvil® Summary of Product
Characteristics)


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2.
RATIONALE, OBJECTIVES, AND BENEFIT - RISK 
ASSESSMENT
2.1
RATIONALE FOR PERFORMING THE TRIAL
Ibuprofen and pseudoephedrine are being used therapeutically for decades as NSAID and
decongestant, respectively.
Also combinations of pseudoephedrine with NSAID or antihistamines are common.
Based on positive experience with free combination of both compounds, also fixed dose
combination products with 200 mg ibuprofen and 30 mg pseudoephedrine-HCl have been 
developed and introduced into the market in some European countries.
Marketing Authorisation Application in the EU is planned for a fixed dose combination 
product as film coated tablets containing 400 mg of ibuprofen and 60 mg of 
pseudoephedrine as the test product.
Bioequivalence to RhinAdvil® as reference product, an approved and marketed product in 
France, Germany, (in the past also in Austria, Belgium and Luxumburg) will be assessed 
by means of a clinical phase I study.
Rationale of the study is to establish bioequivalence of the test product to the reference 
product.
2.2
TRIAL OBJECTIVES
2.2.1
Primary objective
To demonstrate the bioequivalence of a fixed dose combination tablet containing
400 mg Ibuprofen and 60 mg Pseudoephedrine-HCl vs. RhinAdvil® (2 tablets containing 
200 mg Ibuprofen and 30 mg Pseudoephedrine-HCl) as a fixed dose combination tablet with 
respect to the analytes, ibuprofen and pseudoephedrine.
2.2.2
Secondary objective
To assess the bioequivalence of a fixed dose combination tablet containing
400 mg Ibuprofen and 60 mg Pseudoephedrine-HCl vs. RhinAdvil® (2 tablets containing 
200 mg Ibuprofen and 30 mg Pseudoephedrine-HCl) as a fixed dose combination tablet with 
respect to R- and S-ibuprofen (enantiomers of ibuprofen).
2.3
BENEFIT – RISK ASSESSMENT
Participation in this bioequivalence study is without any therapeutic benefit for the healthy 
subjects. Their participation in the study, however, is of importance for the development of a 
new oral fixed dose combination of nonsteroidal anti-inflammatory drug (NSAID) and 
decongestant containing Ibuprofen 400 mg and Pseudoephedrine 60 mg.


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The subjects are exposed to:

the risks of the study procedures

the known risks related to the exposure with the study medication
The use of an indwelling cannula for the purpose of blood sampling may be accompanied 
by mild bruising and also, in rare cases, by transient inflammation of the wall of the vein. 
After initial irritation, the presence of an indwelling cannula is usually painless and hardly 
noticeable. The same applies to vein puncturing for further blood sampling. In rare cases a 
nerve might be injured while inserting the cannula. This could be followed by paresthesia, 
reduced sensibility or pain for a long-term period.
The total volume of blood withdrawn during the entire study will be about ~ 362.5 ml. No 
safety related risk is expected from this blood withdrawal.
Drug related risks
Ibuprofen:
Reported main side effects of Ibuprofen are:
Agranulocytosis, haemolytic anaemia, dysopia, dyspepsia, epigastralgia,
gastrointestinal bleeding, impaired gastrointestinal motility, nausea, vomiting,
oedema, hypersensitivity, aseptic meningitis, increased levels of transaminase,
dizziness, headache, renal dysfunction, oliguria, asthma, progression of chronic
urticaria, pruritus, skin eruption, rash, erythema multiforme, angioedema.
Pseudoephedrine:
Reported main side effects of pseudoephedrine-HCl are:
Palpitations, tachycardia, narrow-angle glaucoma, dry mouth, nausea, vomiting, rare
cases of haemorrhagic stroke, headache, convulsion*, anxiety, restlessness*,
abnormality in behaviour*, hallucinations*, dysuria, retention of urine, sweating,
exanthema, pruritus, urticaria, hypertony
*have been reported rarely, particularly in children
For further detailed information, please refer to the (RhinAdvil® Summary of Product
Characteristics)
Overall Risk – Benefit assessment
Overall the risk for subjects participating in this trial is considered to be low and 
acceptable. Because of the anticipated benefit that a successful clinical development of the 
film coated fixed dose combination tablet containing ibuprofen 400 mg and 
pseudoephedrine-HCl 60 mg (Test Product) could provide patients a respectable amount of 
release of the symptoms associated with common cold. The sponsor feels the benefit of a 
successful clinical development of one film coated fixed dose combination tablet to 
outweigh the risk.


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3.
DESCRIPTION OF DESIGN AND TRIAL POPULATION
3.1
OVERALL TRIAL DESIGN AND PLAN
The study will be performed as an open-label, single dose, randomised, laboratory blind, 
two-way crossover trial.
The following treatments will be administered in the fasting state:
Test (T):
Film coated fixed dose combination tablet containing
Ibuprofen 400 mg and Pseudoephedrine 60 mg
Reference (R):
RhinAdvil® two fixed dose combination tablets containing
Ibuprofen 200 mg and Pseudoephedrine 30 mg
The two treatment sequences T-R and R-T will be randomly allocated to the subjects.
3.1.1
Administrative structure of the trial
The trial is sponsored by Boehringer Ingelheim (BI).
The conduct of the study will be monitored by a representative of the Sponsor to ensure 
compliance with applicable regulatory requirements and GCP. The summary of the 
documentation of the monitoring visits will form part of the study documentation and will be 
archived as such.
Safety Reporting will be done according to BI SOPs and will be described further in
Section 5.3.6.2.
Tasks and functions assigned in order to organise, manage, and evaluate the trial are defined 
in accordance with PAREXEL standard procedures.
A local laboratory service will be used in this trial. Procedures will be in accordance with 
PAREXEL standard procedures. Tests not performed by the local laboratory will be 
outsourced to PAREXEL’s preferred vendor laboratory for analysis. The results from the 
preferred vendor laboratory will be transmitted to ClinBase™and electronically transferred 
to Data Management.
Data Management and Statistical Evaluation will be done according to PAREXEL standard 
procedures. PK Analysis will be done according to non-compartmental analyses guidance and 
the TSAP.
A list of SOPs will be contained in the ISF.
A list of responsible persons and relevant local information will be contained in the ISF.


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3.2
DISCUSSION OF TRIAL DESIGN, INCLUDING THE CHOICE OF 
CONTROL GROUP(S)
For bioequivalence studies, the crossover design is viewed favourably due to its efficiency: 
since each subject serves as his own control, the comparison between treatments is based 
on a comparison within subjects rather than between subjects. This means that the inter-
subject variability is removed from the comparison between treatments [R94-1529].
The open-label treatment is not expected to bias results, since the study endpoints are derived 
from measurement of plasma concentrations of the analytes, which are provided by a 
bioanalytical laboratory that is blinded to treatment allocation.
3.3
SELECTION OF TRIAL POPULATION
It is planned that 56 healthy male and female subjects will be randomised in the study, to 
complete with at least 48 evaluable subjects. At least 16 of each gender should be included in 
the evaluable population. Subjects will be recruited from the subjects’ pool of Bloemfontein 
Early Phase Clinical Unit, PAREXEL International (South Africa).
A log of all patients enrolled into the trial (i.e. who have signed informed consent) will be 
maintained in the ISF at the investigational site irrespective of whether they have been treated 
with investigational drug or not.
3.3.1
Main diagnosis for trial entry
The trial will be performed in healthy subjects.
Please refer to Section 8.3.1 (Source Documents) for the documentation requirements 
pertaining to the in- and exclusion criteria.
3.3.2
Inclusion criteria
1
Healthy males and females according to the following criteria:
2
Based upon a complete medical history, including physical examination, vital signs (BP, 
PR), 12-lead ECG, clinical laboratory tests
3
Age ≥21 to ≤50 years
4
Minimum weight 50kg – both males and females
5
BMI ≥18.5 to ≤29.9 kg/m2
6
Signed and dated written informed consent in accordance with GCP and local legislation
prior to admission to the trial
7
Male or female patients. Women of childbearing potential1 must be ready and able to use 
highly effective methods of birth control per ICH M3 (R2) that result in a low failure rate of
less than 1% per year when used consistently and correctly e.g. implants, injectables, 
                                                          
1 Women of childbearing potential are defined as:
-
having experienced menarche and
-
not postmenopausal (12 months with no menses without an alternative medical cause) and
not permanently sterilised (e.g., tubal occlusion, hysterectomy, bilateral oophorectomy or bilateral salpingectomy).


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combined hormonal contraceptives, intrauterine device, or surgical sterilisation (including 
hysterectomy). In addition to this, also a barrier method (e.g. male condom) will be required, 
if the female is not surgically sterilised. A list of contraception methods meeting these 
criteria is provided in the patient information. Abstaining from sexual activity (if this is the 
usual lifestyle of the subject) is considered an acceptable method of birth control.
3.3.3
Exclusion criteria
1
Any finding of the medical examination (including BP, PR and ECG) deviating from normal 
and of clinical relevance at the discretion of the investigator
2
Any evidence of a clinically relevant concomitant disease
3
Any relevant Gastrointestinal (e.g. ulcera, hernia, bleedings and spasm), hepatic, renal, 
respiratory, cardiovascular, metabolic, immunological or hormonal disorders
4
Any relevant surgery of the gastrointestinal tract (except appendectomy)
5
Diseases of the central nervous system (such as epilepsy) or psychiatric disorders or relevant 
neurological disorders at the discretion of the investigator
6
History of relevant orthostatic hypotension, fainting spells or blackouts
7
Chronic or relevant acute infections
8
History of relevant allergy or hypersensitivity (including allergy to drug or its excipients) as 
judged clinically relevant by the investigator
9
Intake of drugs with a long half-life (>24 hours) within at least 1 month or less than 10 half-
lives of the respective drug prior to first drug administration
10 Use of drugs which might reasonably influence the results of the trial based on the 
knowledge at the time of protocol preparation within 14 days prior to randomisation
11 Participation in another trial with an investigational drug within 2 months prior to
administration or during the trial
12 Smoker (>10 cigarettes or >3 cigars or >3 pipes/day)
13 Inability to refrain from smoking on trial days as judged by the investigator
14 Alcohol abuse (average consumption of more than 2 units per day for females and more than 
3 units per day for males)
15 Drug abuse
16 Blood donation (more than 100 mL within four weeks prior to administration of the trial 
drug in this study)
17 Excessive physical activities within 1 week prior to randomisation or during the trial
18 Any laboratory value outside the reference range that is of clinical relevance at the 
discretion of the investigator
19 Inability to comply with dietary regimen of the study centre
20 Unwilling to avoid excessive sunlight exposure
21 Use of drugs which might reasonably influence the results of the trial or that prolong the 
QT/QTc interval within 14 days prior to administration or during the trial, and CYP2C8 
substrates such as amiodarone, amodiaquine, paclitaxel, rosiglitazone, pioglitazone and 
repaglinide or CYP2C9 such as warfarin, tolbutamide, phenytoin, losartan,
22 A marked baseline prolongation of the QTc B interval (e.g., repeated demonstration of a 
QTc B interval >450 ms)


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23 A history of additional risk factors for torsade de pointes (e.g., heart failure, hypokalaemia, 
family history of Long QT Syndrome)
Special exclusion criteria:
24 Subjects with history of bronchospasm, rhinitis or urticaria associated with NSAID -
Asthma
25 Risk of or manifested narrow-angle glaucoma
26 Risk of urinary retention due to urethro-prostatic diseases / prostatic enlargement
27 Subjects with the rare hereditary problems of fructose intolerance, glucose-galactose 
malabsorption or sucrase isomaltase deficiency
28 Regular treatment with any systemically available medication (except hormonal 
contraceptives and hormonal replacement therapy e.g. estrogens, L-thyroxine)
29 Subjects, who report a frequent occurrence of migraine attacks
For female subjects of childbearing potential only:
30. Positive pregnancy test, pregnancy or planning to become pregnant during the study or 
within 2 months after study completion
31 No adequate contraception during the study including three months before first dosing until 
2 month after study completion.
32 Lactation
Administrative reasons:
33 Subjects suspected or known not to follow instructions
34 Subjects who are unable to understand the written and verbal instructions, in particular 
regarding the risks and inconveniences they will be exposed to during their participation in 
the study
The exclusion criteria are chosen to assure that subjects with specific risks for administration of
the investigational medicinal products and subjects with conditions, which may have an impact
on pharmacokinetic parameters, cannot be included
3.3.4
Removal of subjects from therapy or assessments
3.3.4.1
Removal of individual subjects
Trial criteria:
The trial as a whole will be terminated prematurely if:
New toxicological findings or serious adverse events invalidate the earlier positive benefit-
risk-assessment
Subject criteria:
An individual subject is to be withdrawn from the trial if:
The subject withdraws consent for trial treatment or trial participation, without the need to 
justify the decision


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The subject has to take any concomitant drugs interfering with the study medication
The subject is no longer able to participate for other medical reasons (e.g. pregnancy, surgery, 
adverse events or other diseases)
In addition to these criteria, the investigator may discontinue subjects at any time based on 
his or her clinical judgment.
A subject can also be removed from the trial, if eligibility criteria are being violated or if the 
subject fails to comply with the protocol (for instance, by non-adherence to dietary rules, or 
non-attendance at study assessments.
If a subject is removed from or withdraws from the trial prior to the first administration of trial 
medication, the data of this subject will not be entered in the electronic case report form 
(eCRF) or trial database and will not be reported in the clinical trial report (CTR). If a subject 
is removed from or withdraws from the trial after the first administration of trial medication, 
this will be documented and the reason for discontinuation must be recorded in the eCRF; in 
addition, the data will be included in the eCRF/trial database and will be reported in the CTR. 
At the time of discontinuation, a complete end-of-trial examination will be performed, if 
possible, and the information will be recorded in the eCRF. If the discontinuation occurs 
shortly after administration, the discontinued subject should be evaluated for AEs and 
concomitant therapies if possible as long as measureable drug levels are still likely to be 
present, assuming the subject agrees to such an evaluation.
If it is known that a subject becomes pregnant during the trial, administration of the trial 
medication is to be stopped immediately, and the subject is to be removed from the trial. The 
subject is to be followed until she has given birth or until the end of the pregnancy. The 
subject’s data are to be collected until the end of the trial (last visit of last subject) and 
reported in the CTR.
3.3.4.2
Replacement of subjects
Subjects who withdraw or are withdrawn from the study will not be replaced, unless fewer 
complete the study than the estimated number of evaluable subjects.
If a subject is replaced, the replacement will be allocated the subject number of 500 plus the 
subject number being replaced (e.g., Subject
will be replaced by
). The subject numbers
being replaced will be selected such that the replacement subjects receive the same treatment
sequence as the withdrawn subjects and the sequence balance is maintained.
Replacement subject must preferably be of the same gender as the withdrawn subjects, if this is
needed to secure the requirement that at least 1/3 of each gender should complete the study.
3.3.4.3
Discontinuation of the trial by the sponsor
Boehringer Ingelheim reserves the right to discontinue the trial overall or at a particular trial site
at any time for the following reasons:


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1
Failure to meet expected enrolment goals overall or at a particular trial site
2
Emergence of any efficacy/safety information invalidating the earlier positive benefit-risk-
assessment that could significantly affect the continuation of the trial
3
Violation of GCP, the CTP, or the contract disturbing the appropriate conduct of the trial
The Investigator / the trial site will be reimbursed for reasonable expenses incurred in case of 
trial termination (except in case of the third reason).


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4.
TREATMENTS
4.1
INVESTIGATIONAL TREATMENTS
4.1.1
Identity of the Investigational Medicinal Products
The characteristics of the test product are described below. 
Substance:
Ibuprofen+Pseudoephedrine-HCl
Pharmaceutical form:
Fixed dose combination film-coated tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
400 mg Ibuprofen, 60 mg Pseudoephedrine-HCl
Posology:
1-0 (1 tablet in each treatment period) 
Route of administration:
oral
Manufacturer:
Przedsiebiorstwo Prodkcji Farmaceutycznej Hasco – Lek
Country of Origin:
Poland
The characteristics of the reference products are described below. Substance:
Ibuprofen+Pseudoephedrine-HCl (RhinAdvil®)
Pharmaceutical form: Fixed dose combination tablet
Source:
Boehringer Ingelheim Pharma GmbH & Co. KG, Germany
Unit strength:
200 mg Ibuprofen, 30 mg Pseudoephedrine-HCl 
Posology:
2-0 (2 tablets, single dose, in each treatment period) 
Route of administration:
oral
Manufacturer:
Pfizer Consumer Manufactoring Italy, Via Nettunese 90, 04011
Aprilia, Italy
Country of Origin:
Italy
4.1.2
Selection of doses in the trial
The doses selected for this trial are fully in line with already registered products.
4.1.3
Method of assigning subjects to treatment groups
This trial is a two-way crossover study. Subjects will receive either the test or reference 
products, according to the randomisation schedule.
The randomisation schedule will be provided by PAREXEL Biostatistics. The randomisation 
schedule will be generated utilizing the PROC PLAN procedure of SAS® software.
The allocation of subjects to study subject numbers will be performed prior to the first 
administration of trial medication, without any exposure of the subjects to the randomisation 
list (i.e. subjects will not select study subject numbers on basis of treatment sequence). 
Subjects will be assigned randomisation numbers
sequentially. Possible 
replacements will be handled according to Section 3.3.4.2.
Subjects then will be randomised to one of two treatment sequences (RT or TR) using the 


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randomisation schedule.
Blinding is described in Section 4.1.5.1.
4.1.4
Drug assignment and administration of doses for each patient
The study drugs will be administered in the morning of day 1 between usually 07:30 and
10:00 hours clock time. After an overnight fast of at least 10 hours, the medication will be 
administered as a single oral dose together with 240 mL water in the standing position under
supervision of the investigating physician or an authorised designee. Subjects will be kept
under close medical surveillance for the duration of the in-house period and are not allowed to lie
down during the 2 hours following drug administration. Subjects will remain fasted until at 
least 4 hours after drug intake. Water will be allowed except 1 hour before to 2 hours after
drug administration. Standardised meals will be served in each period of the study.
4.1.5
Blinding and procedures for unblinding
4.1.5.1
Blinding
This is an open-label, laboratory-blind study. Access to the randomisation schedule will be
restricted to assigned study staff members of PAREXEL Biostatistics and PAREXEL 
Pharmaceutical Services, as well as the PI and designee. Study staff members of the 
laboratories of BASD are not allowed access to the randomisation schedule until after 
statistical analysis of the study results. The final statistical analysis will be done according
to the Statistical Analysis Plan (SAP) and will be based on data following database lock.
4.1.5.2
Unblinding and breaking the code
Not applicable.
4.1.6
Packaging, labelling, and re-supply
Drug supplies will be provided by the Department of Pharmaceutical Development of 
Boehringer Ingelheim Pharma GmbH & Co. KG, Biberach, Germany. The clinical trial 
supply consists of containers with trial- and site identification that hold the trial 
medication.
The containers will be labelled with the required information according to the German
Drug Law (16. AMG Novelle) as well as Annex 13/EU-GMP.
Smaller boxes in the clinical trial supply containers are labelled with:

Trial number

Name of product and strengths or identification code

Pharmaceutical dosage form, quantity of dosage units

Route and mode of administration: According to the protocol

Term "for clinical trial use" (domestic language)

Sponsor name and address

Storage conditions


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
Use-by date

Number of batch
Two complete sets of study medication will be sent to the study site. The 
investigator/designee will use the medication set labelled with “study” to be used in the 
trial. The “reserve” labelled medication set will be used if needed.
No re-supply is planned.
4.1.7
Storage conditions
Drug supplies will be kept in their original packaging and stored according to the labelled 
storage conditions.
The trial medication must be stored securely, e.g. in a locked cupboard or at a pharmacy. It 
may only be dispensed to trial subjects according to the protocol by authorised personnel as 
documented in the form "Investigator's Trial Staff".
All unused or partially used medication must be returned to the sponsor or destroyed after the 
end of the study. Receipt, usage and return must be documented on the respective forms. 
Account must be given for any discrepancies.
If the storage conditions are found to be outside the specified range, the local clinical monitor
(as provided in the list of contacts) must be contacted immediately.
4.1.8
Drug accountability
The Investigator and/or Pharmacist will receive the investigational drugs delivered by the 
sponsor when the following requirements are fulfilled:

Approval of the trial protocol by the IRB / ethics committee

Availability of a signed and dated clinical trial contract between the sponsor and the head 
of the investigational site,

Approval/notification of the regulatory authority, e.g. competent authority,

Availability of the curriculum vitae of the principal Investigator,

Availability of a signed and dated clinical trial protocol
The Investigator and/or Pharmacist must maintain records of the product’s delivery to the 
trial site, the inventory at the site, the use by each patient, and disposal of unused products at 
the end of the study.
These records will include dates, quantities, batch / serial numbers, expiry (‘use- by’) dates, 
and the unique code numbers assigned to the investigational product and trial patients. The
Investigator / Pharmacist / investigational drug storage manager will maintain records that 
document adequately that the patients were provided the doses specified by the CTP and 
reconcile all investigational products received from the sponsor. At the time of return to the 
sponsor or at time of destruction, the Investigator/Pharmacist must verify that all unused or 
partially used drug supplies have been returned/destructed and that no remaining supplies are 
in the investigator’s possession.


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4.2
OTHER TREATMENTS, EMERGENCY PROCEDURES, RESTRICTIONS
4.2.1
Other treatment and emergency procedures
There are no special emergency procedures to be followed.
4.2.2
Restrictions
4.2.2.1
Restrictions regarding concomitant treatment
Primarily, no concomitant therapy will be allowed except for hormonal contraceptives as well 
as ovary and thyroid hormone replacement. However, in case of adverse events in need of 
treatment, symptomatic therapy according to the judgment of the investigator will be 
permitted. All concomitant and/or rescue therapies will be recorded on the appropriate pages 
of the electronic case report forms (eCRFs).
In the case of adverse events the subjects will be treated as necessary and if necessary kept 
under constant supervision at the study site or transferred to hospital until such time that all 
the results of the evaluations have returned to a medically acceptable level.
4.2.2.2
Restrictions on diet and life style
Subjects should abstain from alcoholic beverages and methyl xanthine containing products for
24 hours, as well as from the intake of any citrus products or apples, for 72 hours prior to 
each study period and until after the last sample from each period is collected.
While admitted to the trial site the subjects are restricted from consuming any foods or 
drinks other than those provided by the site staff.
Excessive physical activity (competitive sport etc.) and direct exposure to the sun
(including solarium) should be avoided during the whole study.
In each treatment period, the total fluid intake on day 1 should not exceed 2.5 liters.
4.2.2.3
Restrictions regarding women of childbearing potential
Women of childbearing potential must use the contraception methods described in the patient 
information.
4.3
TREATMENT COMPLIANCE
Subjects who are non-compliant, e.g., they do not appear for treatment or violate the 
restrictions, may be withdrawn from the trial and the eCRF will be completed accordingly 
(for further procedures).
Compliance will be assured by administration of all study medication under supervision of 
the investigating physician or a designee at the study site. The measured plasma 
concentrations will provide additional information about compliance.


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5.
VARIABLES AND THEIR ASSESSMENT
5.1
TRIAL ENDPOINTS
The following endpoints will be analysed during the course of the trial.
5.1.1
Primary Endpoint(s)
The following primary endpoints will be determined for the analytes ibuprophen and 
pseudoephedrine-HCl:

AUC0-tz (area under the concentration-time curve of the analytes in plasma over the 
time interval from 0 to the time of last quantifiable time point)

Cmax (maximum measured concentration of the analytes in plasma)
5.1.2
Secondary Endpoints
The following secondary endpoints will be determined for the analytes ibuprofen and
pseudoephedrine-HCl:

AUC0-∞(area under the concentration-time curve of the analytes in plasma over the 
time interval from 0 extrapolated to infinity)
The following secondary endpoints will be determined for the analytes R-ibuprofen and 
S-ibuprofen:

AUC0-tz (area under the concentration-time curve of the analytes in plasma over the 
time interval from 0 to the time of last quantifiable time point)

AUC0-∞(area under the concentration-time curve of the analytes in plasma over the 
time interval from 0 extrapolated to infinity)

Cmax (maximum measured concentration of the analytes in plasma)

S/R-ibuprofen ratio for AUC0-tz (i.e., AUC0-tz S-ibuprofen / AUC0-tz R-ibuprofen)


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5.2
ASSESSMENT OF EFFICACY
Efficacy measurements will not be performed.
5.3
ASSESSMENT OF SAFETY
Safety and tolerability of the investigational drug(s) will be assessed based on:

Vital signs (BP, PR)

12-lead ECG (electrocardiogram)

Clinical laboratory tests (haematology, clinical chemistry and urinalysis)

Adverse events (including clinically relevant findings from the physical examination)

Assessment of tolerability by the investigator
5.3.1
Physical examination
Physical examination includes assessment of heart, lung, abdomen and measurement of 
weight and height. Abnormal findings at the time of screening will be recorded as baseline 
conditions on the appropriate CRF page. New abnormal findings or worsening of baseline 
conditions detected at the subsequent physical examinations will be recorded as adverse 
events on the appropriate CRF page.
5.3.2
Vital Signs
Vital signs will be measured after 10 minutes of rest in the supine/sitting position. All 
recordings shall be made using the same blood pressure recording instrument on the same 
arm (cf. Flow_Chart for time points). Body temperature will be taken during screening and 
pre dose.
5.3.3
Safety laboratory parameters
A total amount of ~ 36 mL blood will be taken per subject during the whole course of the 
study for laboratory parameters. This amount may be exceeded if unscheduled (additional) 
monitoring of laboratory results is warranted.
The parameters that will be determined are listed in Table 5.3.3: 1 and Table 5.3.3: 2.
The respective reference ranges will be provided in the Investigator Site File (ISF), Section
10 (cf. Flow Chart for time points of laboratory blood sampling).
The laboratory tests listed inTable 5.3.3: 1 and Table 5.3.3: 2 will be performed at:
PAREXEL Bioanalytical Services Division
Kampuslaan Suid
Campus of the University of the Free State
9301 Bloemfontein
South Africa
The tests listed in Table 5.3.3: 2 constitute exclusionary lab safety tests. These tests may be 


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repeated as required. Laboratory data will be transmitted to ClinBase™from where it will be
transferred to Data Management electronically.
Pregnancy tests (HCG in urine) will be performed at the trial site (e.g. Expect pregnancy 
test) on trial days. At screening and at the end of study pregnancy test will be performed in 
serum.
Table 5.3.3: 1 Routine laboratory tests
Category
Test name
Haematology
Haematocrit (Hct) 
Haemoglobin (Hb)
Red Blood Cell Count / Erythrocytes
Mean corpuscular volume (MCV) 
Mean corpuscular hemoglobin (MCH)
Mean corpuscular hemoglobin concentration (MCHC) 
White Blood Cells / Leucocytes
Platelet Count / Thrombocytes
ESR (only at SCR) 
Diff Automatic (relative count)
Neutrophiles
Eosinophils
Basophils 
Monocytes 
Lymphocytes
Diff Manual (if diff automatic is abnormal)
Neutrophiles, bands (Stabs) Neutrophiles
Polymorphonuclear (PMN) Eosinophils
Basophils
Monocytes
Lymphocytes
Enzymes
AST/GOT, SGOT 
ALT/GPT,SGPT
Alkaline Phosphatase (AP/ALP) 
Gamma-Glutamyl Transferase GGT/γ-GT)
Lactic Dehydrogenase (LDH)
Lipase
Amylase
Substrates
Glucose 
Creatinine
Bilirubin Total
Bilirubin Direct
Bilirubin Indirect
Protein,Total
Protein Electrophoresis (only at SCR) 
Albumin
Alpha-1-Globulin 
Alpha-2-Globulin
Beta-Globulin
Gamma-Globulin
C-Reactive Protein
Uric Acid
Urea 
Cholesterol, total Triglycerides
Electrolytes
Calcium Sodium Potassium


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Table 5.3.3: 1 Routine laboratory tests cont.
Category
Test name
Hormones
β-HCG (only at SCR and EOS.) 
Urine analysis (Stix)
Urin Nitrite
Urine Protein
Urine Glucose 
Urine Ketone 
Urobilinogen 
Urine Bilirubin 
Urine Blood 
Urine
WBC/Leukocytes
Urine pH
Urine
hCG
(trial days)
The following tests will be performed only at screening examination; the results will not 
be part of the CTR.
Table 5.3.3: 2 Drug Screening and infectious serology
Category
Test name
Drug screening (Urine)
Cannabis 
Benzodiazepine 
Barbiturates 
Opiates 
Cocaine 
Amphetamines 
Methadone
Phencyclidine (phenylcyclohexalpiperidine) 
Methamphetamine
Tricyclic antidepressants
Oxycodone
Propoxyphene
Infectious serology
Hepatitis B Surface Antigen Hepatitis C 
Antibodies
HIV combi (HIV-1 antigen and total antibodies to HIV-1 
and HIV-2)
To encourage compliance, an alcohol breath test may be performed at any time during the 
study by the discretion of an investigator or designee. The results will not form part of the 
report.
Baseline laboratory test for substrates, haematology and enzymes will only be performed for 
safety reasons.
5.3.4
Electrocardiogram
12-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded using the GE 
Healthcare CAM14 acquisition module.
The ECGs will be recorded for 10 second duration after the subjects have rested for at least


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5 minutes in a supine position. Electrode placement will be performed according to the 
method of Wilson, Goldberger and Einthoven. The ECGs will be evaluated by the study 
investigator or a designate but not imported into the data base, ECGs may be repeated for 
quality reasons and the repeat used for analysis. Additional ECGs may be collected by the 
investigator for safety reasons. Clinically relevant abnormal findings will be reported as 
adverse events.
ECG-recordings will be made at the time points described in the Flow Chart.
5.3.5
Medical Examination / Global assessment
At the screening visit, the medical examination will include documentation of subject 
information, informed consent, demographics including height and weight, smoking and 
alcohol history, relevant medical history and concomitant medication, review of inclusion 
and exclusion criteria, review of vital signs (blood pressure, pulse rate and body 
temperature), 12-lead ECG, laboratory tests (including a pregnancy test in females), and a 
physical examination.
The end- of-study examination will include review of vital signs, 12-lead ECG, laboratory 
tests (including pregnancy test), and a physical examination. Adverse events and 
concomitant therapies will be assessed throughout the study.
The investigator will assess tolerability based on adverse events and the laboratory 
evaluation. Tolerability will be assessed by the investigator according to the categories 
“good”, “satisfactory”, “not satisfactory”, and “bad”.
5.3.6
Assessment of adverse events
The subjects will be required to report spontaneously any AEs as well as the time of 
onset, duration and intensity of these events. The clinical judgment of the intensity will 
be made by the physician.
In addition, each subject will be assessed regularly by the medical staff throughout the 
clinical trial and whenever necessary as deemed by the investigator. Assessment will be 
made using non-specific questions such as “How do you feel?” Specific questions will be 
asked wherever required or useful to more precisely describe an AE.
A written record of all AEs shall be kept by the investigator in charge of the study. Records 
of adverse events shall include data on the time of onset, end time and intensity of the event
as well as any treatment or action required for the event and its outcome.
5.3.6.1
Definitions of AEs
Adverse event
An adverse event (AE) is defined as any untoward medical occurrence in a patient or clinical
investigation subject administered a medicinal product and which does not necessarily have to
have a causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally


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associated with the use of a medicinal product, whether or not considered related to the 
medicinal product.
Adverse reaction
An adverse reaction is defined as a response to a medicinal product which is noxious and
unintended. Response in this context means that a causal relationship between a medicinal 
product and an adverse event is at least a reasonable possibility. Adverse reactions may arise 
from use of the product within or outside the terms of the marketing authorisation or from 
occupational exposure. Conditions of use outside the marketing authorization include off-label 
use, overdose, misuse, abuse and medication errors.
Serious adverse event
A serious adverse event (SAE) is defined as any AE which:

results in death,

is life-threatening, this refers to an event in which the patient was at risk of death at the 
time of the event; it does not refer to an event that hypothetically might have caused 
death if more severe.

requires inpatient hospitalisation or

prolongation of existing hospitalisation,

results in persistent or significant disability or incapacity, or

is a congenital anomaly / birth defect, 
or

is to be deemed serious for any other reason if it is an important medical event when 
based upon appropriate medical judgment which may jeopardise the patient and may 
require medical or surgical intervention to prevent one of the other outcomes listed in 
the above definitions.
Medical and scientific judgement should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalisation but might jeopardise the patient 
or might require intervention to prevent one of the other outcomes listed above. Examples of 
such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalisation or 
development of dependency or abuse. Any suspected transmission via a medicinal product of an 
infectious agent is also considered a serious adverse reaction.
AEsconsidered“AlwaysSerious”
Cancers of new histology and exacerbations of existing cancer must be reported as a serious
event regardless of the duration between discontinuation of the drug and the occurrence of the 
cancer.
In accordance with the European Medicines Agency initiative on Important Medical Events, 
Boehringer Ingelheim has set up a list of further AEs, which by their nature, can always be 
considered to be “serious” even though they may not have met the criteria of an SAE as given 
above.
A copy of the latest list of “Always Serious AEs” will be provided to you upon request. These 
events should always be reported as SAEs as described above.


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Adverse events of special interest (AESIs)
No AESIs have been defined for this trial.
Intensity of AEs
The intensity of the AE should be judged based on the following:
Mild:
Awareness of sign(s) or symptom(s) that is/are easily tolerated
Moderate:
Enough discomfort to cause interference with usual activity
Severe:
Incapacitating or causing inability to work or to perform usual activities
Causal relationship of AEs
The definition of an adverse reaction implies at least a reasonable possibility of a causal
relationship between a suspected medicinal product and an adverse event. An adverse reaction, 
in contrast to an adverse event, is characterised by the fact that a causal relationship between a 
medicinal product and an occurrence is suspected.
Medical judgment should be used to determine the relationship, considering all relevant factors, 
including pattern of reaction, temporal relationship, de-challenge or re-challenge, confounding 
factors such as concomitant medication, concomitant diseases and relevant history.
Arguments that may suggest that there is a reasonable possibility of a causal relationship could 
be:

The event is consistent with the known pharmacology of the drug

The event is known to be caused by or attributed to the drug class.

A plausible time to onset of the event relative to the time of drug exposure.

Evidence that the event is reproducible when the drug is re-introduced

No medically sound alternative aetiologies that could explain the event (e.g. pre-
existing or concomitant diseases, or co-medications).

The event is typically drug-related and infrequent in the general population not exposed 
to drugs (e.g. Stevens-Johnson syndrome).

An indication of dose-response (i.e. greater effect size if the dose is increased, smaller 
effect size if dose is diminished).
Arguments that may suggest that there is no reasonable possibility of a causal relationship could 
be:

No plausible time to onset of the event relative to the time of drug exposure is evident 
(e.g. pre-treatment cases, diagnosis of cancer or chronic disease within days / weeks of 
drug administration; an allergic reaction weeks after discontinuation of the drug 
concerned)

Continuation of the event despite the withdrawal of the medication, taking into account 
the pharmacological properties of the compound (e.g. after 5 half-lives).

Of note, this criterion may not be applicable to events whose time course is prolonged 
despite removing the original trigger.

Additional arguments amongst those stated before, like alternative explanation (e.g. 
situations where other drugs or underlying diseases appear to provide a more likely 
explanation for the observed event than the drug concerned).

Disappearance of the event even though the study drug treatment continues or remains 


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unchanged.
5.3.6.2
Adverse event collection and reporting
AE Collection
The Investigator shall maintain and keep detailed records of all AEs.
The following must be collected and documented on the appropriate CRF(s) by the
Investigator:

From signing the informed consent onwards, until individual patient’s end of trial:
-all AEs (serious and non-serious).

After the individual patient’s end of trial:
the Investigator does not need to actively monitor the patient for AEs but should only 
report relevant SAEs of which the Investigator may become aware of.
The residual effect period (REP) for ibuprofen and pseudoephedrine when measurable drug 
levels or PD effects are still likely to be present, was defined as 48 hours after administration 
(based on half-lives of 3 and 8 hours of ibuprofen and pseudoephedrine, respectively). However,
for assigning AEs to treatments a conservative approach will be used, i.e. post- treatment periods
based on REP will not be defined (see Section 7.3.3).
AE reporting to sponsor and timelines
The Investigator must report SAEs, and non-serious AEs which are relevant for the reported
SAE, on the BI SAE form via fax immediately (within 24 hours) to the sponsor’s unique entry
point (country specific contact details will be provided in the ISF). The same timeline applies if
follow-up information becomes available. In specific occasions the Investigator could inform the
sponsor upfront via telephone. This does not replace the requirement to complete and fax the BI
SAE form.
With receipt of any further information to these events, a follow-up SAE form has to be 
provided. For follow-up information the same rules and timeline apply as for initial information.
Information required
For each AE, the Investigator should provide the information requested on the appropriate eCRF
pages and the BI SAE form. The Investigator should determine the causal relationship to the 
trial medication.
The following should also be recorded as an (S)AE in the eCRF and SAE form (if applicable):

Worsening of pre-existing conditions

Changes in vital signs, ECG, physical examination and laboratory test results, if they 
are judged clinically relevant by the Investigator.

If such abnormalities already pre-exist prior trial inclusion they will be considered as 
baseline conditions.
All (S)AEs, including those persisting after individual patient’s end of trial must be followed up 
until they have resolved, have been sufficiently characterised, or no further information can be 
obtained.
Pregnancy


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In rare cases pregnancy may occur in a clinical trial. Once a patient has been enrolled into this 
clinical trial and has taken trial medication, the Investigator must report immediately (within 
24 hours) a potential drug exposure during pregnancy (DEDP) to the sponsor’s unique entry 
point (country-specific contact details will be provided in the ISF). The Pregnancy Monitoring 
Form for Clinical Trials (Part A) should be used.
The outcome of the pregnancy associated with the drug exposure during pregnancy must be 
followed up and reported to the sponsor’s unique entry point on the Pregnancy Monitoring Form 
for Clinical Trials (Part B).
The ISF will contain the Pregnancy Monitoring Form for Clinical Trials (Part A and B).
As pregnancy itself is not to be reported as an AE, in the absence of an accompanying SAE, 
only the Pregnancy Monitoring Form for Clinical Trials and not the SAE form is to be 
completed. If there is an SAE associated with the pregnancy an SAE form must be completed in 
addition.
5.4
DRUG CONCENTRATION MEASUREMENTS AND 
PHARMACOKINETICS
5.4.1
Assessment of Pharmacokinetics
Date and exact clock time of administration as well as of pharmacokinetic sampling times have 
to be recorded.
Actual sampling times relative to dosing, rather than nominal times will be used in the 
calculation of all derived PK parameters.
5.4.2
Methods of sample collection
5.4.2.1
Plasma sampling for pharmacokinetic analysis
PK blood samples will be collected at the following time points:
Table 5.4.2.1: 1 Plasma sampling schedule
Day
Time points of each treatment phase
1
Pre dose , 0:10, 0:20, 0:30, 0:45, 1:00, 1:15, 1:30, 1:45, 2:00, 2:30, 3:00, 4:00, 6:00,
8:00, 10:00, 12:00
2
24:00, 30:00 (total: 19 samples per treatment period)
The actual blood sampling times will be recorded on ClinBase™.
Venous blood samples, 8.5 mL each, for the determination of ibuprofen (including R- and 
S-ibuprofen) and pseudoephedrine concentrations will be collected into labelled tubes containing
dipotassium ethylene-diamine- tetra-acetic acid as anti-coagulant.


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Blood samples are routinely placed on ice between sample collection and centrifuging. Within
30 minutes of collection, centrifuging of blood samples will commence at approximately2700 g
within a range of 0C to 8C for 10 minutes. Thereafter, the supernatant of each sample will be
divided into 4 aliquots (2 aliquots of at least 0.4 mL plasma each for ibuprofen (including R- and 
S-ibuprofen) analysis, and 2 aliquots of at least 1.3 ml each for the determination of
pseudoephedrine) and transferred to labelled, plastic tubes. The plasma samples will be flash-
frozen on dry ice immediately after preparation. One of the two aliquots for each analyte will be
considered as a duplicate set in case of re-assay.
All sample tube labels will contain at least the following information: study number, analyte, 
time (protocol time and/or relative sampling time), subject number, blood sample number and 
treatment period. Plasma samples will be stored at approximately -20C until transfer to 
PAREXEL Bioanalytical Services Division (BASD). Pooled samples for concentration range 
estimation will be prepared according to PAREXEL SOPs. These range estimation samples 
originate from some of the blood samples collected for drug assays and may be used by the 
analytical laboratory to determine suitable quantification ranges.
5.4.2.2
Urine sampling for pharmacokinetic analysis
Not applicable
5.4.3
Analytical determinations
Quantitative analysis of ibuprofen (including R- and S-ibuprofen) and pseudoephedrine in the
collected plasma samples will be performed by the Bioanalytical Services Division of
PAREXEL (BASD) using liquid chromatography with tandem mass spectrometry
(LC-MS/MS).
BASD will purchase pure substances of ibuprofen (including R- and S-ibuprofen) and
pseudoephedrine from a reputable certified source on behalf of the sponsor. These pure
substances will be used as analytical standards for the preparation of calibration standards
and quality control samples that will be required for the quantitative analysis of ibuprofen
(including R- and S-ibuprofen and pseudoephedrine.
All the samples received at BASD, including samples of subjects who withdrew/were 
withdrawn, will be analysed. Bioanalytical data will be processed according to the relevant
SOPs of BASD.
Complete method validation and bioanalytical reports will be provided.
5.4.4
Pharmacokinetic – Pharmacodynamic Relationship
Not applicable.
5.5
ASSESSMENT OF BIOMARKERS(S)
Not applicable


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5.6
OTHER ASSESSMENTS
Not applicable
5.7
BLOOD VOLUME
The total blood volume to be collected from each subject during the study is indicated in Table
5.7: 1.
Table 5.7: 1 Total Blood Volume to be collected during the Study
Assay
Volume per
sample (mL)
Total number of
samples
Total blood volume
(mL)
Ibuprofen
(including R- and 
S-ibuprofen) & 
Pseudoephidrine1
8.5
19 x2 treatment periods
323
Haematology
4
4
16
Clinical chemistry2
5
4
20
Protein
Electrophoresis
3.5
1
3.5
Total blood volume
(entire study)3
362.5mL
1
Total number of samples and total blood volume are given for both treatment periods.
2
Serum pregnancy tests (females only) at screening and end of study and serology tests at screening
will be performed on the sample collected for clinical chemistry. Urine pregnancy tests on admission 
for period 1 and 2.
3
Excluding repeat laboratory investigations.
5.8
APPROPRIATENESS OF MEASUREMENTS
All measurements performed during this trial are appropriate standard measurements and will be 
performed in order to monitor safety aspects and to determine analyte concentrations for the 
calculation of pharmacokinetic parameters.
The laboratories of BASD have been certified as Good Laboratory Practice (GLP)
compliant, based on the Organization for Economic Cooperation and Development (OECD)
guidelines ENV/MC/CHEM (98) 17 revised in 1997. Additionally, the clinical laboratory is
accredited according to the International Organization for Standardization / the International
Electrotechnical Commission (ISO/IEC) 17025 Standard. Analytical methods are validated
according to internationally accepted standards. The quality and integrity of the analytical
work generated in this study will be evaluated according to the acceptance criteria, as
described in the SOPs of BASD.
Therefore, the appropriateness of all measurements applied in this trial is given.


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6.
INVESTIGATIONAL PLAN
6.1
VISIT SCHEDULE
Exact times of measurements outside the permitted time windows will be documented. Time 
windows are permitted as follows:
General medical examination: at screening (1 to 21 days prior to the first study day) and at the 
end-of-study evaluation (within 7 days following the last trial procedure).
The tolerance for vital signs, ECG and laboratory tests will be provided in a Window Allowance 
Document.
For planned individual plasma concentration sampling times refer to the Flow_Chart. While 
these nominal times should be adhered to as closely as possible, the actual sampling times will 
be recorded and used for determination of pharmacokinetic parameters.
Study measurements and assessments scheduled to occur on study day 1 prior to drug 
administration have to be performed and completed at least 15 minutes prior to drug 
administration. This will be addressed in the Window Allowance Document. If a subject misses 
an appointment, it will be rescheduled if possible.
6.2
DETAILS OF TRIAL PROCEDURES AT SELECTED VISITS
6.2.1
Screening and run-in period(s)
ScreeningPeriod
After having been informed about the trial, all subjects will give their written informed 
consent in accordance with GCP and the local legislation prior to inclusion to the study.
For the physical and laboratory examinations during the screening visit, cf. Section 5.3.5
and Section 5.3.3.
Drug and virus screening will be performed only at the screening visit.
6.2.2
Treatment period(s)
Each subject will undergo two treatment periods which are separated by a wash-out period 
between drug administrations. The wash-out period is specified in the Flow Chart. The 
subjects will be kept under close medical surveillance until discharge from the trial site.
For details on time points for collection of plasma samples for PK analysis, cf. Flow Chart.
For details on time points for all other trial procedures, cf. Flow Chart.
Adverse events and concomitant medication will be evaluated continuously from screening 
until the end-of-study examination


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6.2.3
Follow Up Period and Trial Completion
At the end of the study, the end-of-study evaluation will be performed including a physical 
examination, measurement of blood pressure and pulse rate, a 12-lead ECG, standard 
laboratory tests, and pregnancy testing.
All clinically significant abnormal values (including laboratory parameters) will be 
followed up using the appropriate tests until a return to a medically acceptable level is 
achieved.
Adverse events persisting after trial completion must be followed up, until they have
resolved, have been sufficiently characterised, or no further information can be obtained.


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7.
STATISTICAL METHODS AND DETERMINATION OF 
SAMPLE SIZE
7.1
STATISTICAL DESIGN - MODEL
The statistical methodology below describes the statistical analysis as it is foreseen when the
study is being planned. A SAP will be prepared with more details on the planned statistical
methodology and will be finalized prior to database lock.
If applicable, deviations from the original SAP and reasons for the deviations, as well as any
alternative or additional statistical analysis that may be performed, will be documented in
the CTR.
The objective of the trial is to establish the bioequivalence of Test treatment (T), one fixed 
dose combination tablet compared to reference treatment (R) RhinAdvil® two fixed dose 
combination tablets given to healthy male and female subjects.
The study will be conducted according to an open-label, randomised, single-dose, two-way 
crossover design. For bioequivalence studies, the crossover design is viewed favourably due
to its efficiency: since each subject serves as his/her own control, the comparison between
formulations is based on a comparison within subjects rather than between subjects. This 
means that the inter-subject variability is removed from the comparison between formulations 
(R94-1529).
Bioequivalence is primarily to be determined on the basis of the endpoints AUC0-tz and Cmax.
of the analytes, ibuprofen and pseudoephedrine-HCL.  Additionally, AUC0-∞and other
secondary endpoints that are described in Section 5.1.2 will be calculated undergoing the same 
analyses as described for the primary endpoints (estimation of relative bioavailability). The
derivation of the PK parameters will be specified in the TSAP.
Safety and tolerability will be determined on the basis of the following parameters: adverse 
events, laboratory tests, physical examination, vital signs (BP, PR), 12-lead ECG, and 
assessment of tolerability by the investigator.
The statistical model used for the analysis of the AUC0-tz, Cmax and AUC0-∞will be an 
ANOVA (analysis of variance) model on the logarithmic scale. This model will include 
effects accounting for the following sources of variation: ‘sequence’, ‘subjects within 
sequences’, ‘period’ and ‘treatment’. All effects will be considered as fixed. The model is 
described by the following equation
yijkm = + i + sim + j + k + eijkm, where
yijkm = logarithm of response (AUC or Cmax) measured on subject m in sequence i
receiving treatment k in period j,
= the overall mean, i = the ith sequence effect, i = 1, 2,


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sim = the effect associated with the mth subject in the ith 
sequence, m = 1, 2, ..., 24
j = the jth period effect, j = 1, 2,
k = the kth treatment effect, k = 1, 2,
eijkm = the random error associated with the mth subject in sequence i who received 
treatment k in period j.
7.2
NULL AND ALTERNATIVE HYPOTHESES
Bioequivalence is established by using the average bioequivalence method to ensure that the
ratio of the primary endpoints of the two treatments (T/R) is contained within a pre-specified
acceptance range (see below). This goal is accomplished by testing the below hypothesis on the
log scale.
Null hypothesis H0 (Inequivalence): T R or
T R 

(i.e. the difference of the population average responses is either less than or equal to 
the lower bound or greater than or equal to the upper bound of the acceptance 
range),
Alternative hypothesis Ha (Equivalence):
T R 

(i.e. the difference of the population average responses is both greater than the lower bound and
less than the upper bound of the acceptance range), where T and R are the population average 
responses of the log-transformed measures for the formulations Test and Reference, and is the
bioequivalence limit that defines the acceptance range for AUC and Cmax on the logarithmic scale
In this trial, is taken to be ln(1.25). This translates to an acceptance range of 80 to 125% for the
geometric mean of the ratio of the parameters on the original scale.
This hypothesis and its alternative can be decomposed into two one-sided null hypotheses, H01
and H02, with their accompanying alternatives:
H01:
T R vs.
Ha1:
µT  µR   δ
H02:
µ T µ R δ
vs.
Ha2:
µ T µ R δ
Due to the nature of normal-theory confidence intervals, the test of the null hypothesis at the =
0.05 level is equivalent to carrying out two one-sided tests of the above null hypotheses each at
the = 0.05 level of significance. The rejection of both null hypotheses H01 and H02 at the =
0.05 level is equivalent to the inclusion of the 90% confidence interval for T R in the
acceptance range.


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7.3
PLANNED ANALYSES
7.3.1
Primary analyses
The PK analysis population (PKS, PK set) will include all treated subjects that provide 
observations for both periods for at least one primary endpoint evaluable (see below) and 
without any major protocol deviation thought to interfere with the absorption, distribution,
metabolism, and excretion of the compound to be measured. PK parameters for subjects who
discontinue after a single treatment may be presented in the listings but will not be used for
summary statistics or any statistical analysis.
The total ibuprofen and pseudoephedrine pharmacokinetic parameters AUC0-tz and Cmax of test
(T) and reference will be log transformed (natural logarithm) prior to fitting the ANOVA
model. The difference between the expected means for log(T)-log(R) will be estimated by the 
difference in the corresponding Least Square Means (point estimate) and two-sided 90% 
confidence intervals based on the t-distribution will be computed. These quantities will then be
back-transformed to the original scale to provide the point estimate and 90% CIs for each
endpoint.
A claim of bioequivalence will be made if the 90% confidence intervals of the geometric 
means of both ratios AUC0-tz and Cmax of ibuprofen and pseudoephedrine-HCL are contained
in the pre-defined acceptance range.
7.3.2
Secondary analyses
The parameter AUC0-∞of total ibuprofen and pseudoephedrine will statistically be assessed
using the same methods as described for the primary endpoints.
Additionally, R- and S-ibuprofen pharmacokinetic parameters AUC0-tz, AUC0-∞and Cmax will
statistically be assessed using the same methods as described for the primary endpoints
(analysis of relative bioavailability).  The same methods will be applied for the 
S/R-ibuprofen ratio for AUC0-tz.
Concentrations will be used for graphs and calculations in the format that is reported in the 
bioanalytical report.
Plasma concentrations will be plotted graphically versus time for all subjects as listed in the 
drug plasma concentration-time tables. For the presentation of the mean profiles, the geometric
mean and the planned blood sampling times will be used.
The following descriptive statistics will be calculated for plasma concentrations as well as for 
all primary and secondary pharmacokinetic parameters: N, arithmetic mean, standard 
deviation, minimum, median, maximum, arithmetic coefficient of variation, geometric mean,
geometric coefficient of variation. The data format for descriptive statistics of concentrations
will be defined in the TSAP.


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7.3.3
Safety analyses
All subjects who received at least one dose of study drug will be included in the safety evaluation
(safety population). Safety analyses will be descriptive in nature and will be based on BI
standards
Measurements (such as ECG, vital signs, or laboratory parameters) or AEs will be assigned to 
treatments (see Section 4.1) based on the actual treatment at the planned time of the 
measurement or on the recorded time of AE onset (concept of treatment emergent AEs). In 
general, all adverse events occurring between start of treatment and end of the residual effect 
period are considered ‘treatment-emergent’. The residual effect period (REP) was defined as
2 days which is shorter than the wash-out period. In the special setting of single doses in the 
cross-over design AEs will be assigned to treatments as detailed below without taking into 
account the residual effect period separately.
AEs will be assigned to treatments based on start date/time of the AE in relation to dosing in 
each period.

All AEs with start date/time prior to dosing in period 1 are pre-treatment AEs and will 
be assigned to screening.

All AEs with start date/time after the date/time of dosing in period 1, but before dosing 
in period 2, will be assigned to the treatment received in period 1.

AEs with start date/time after the date/time of dosing in period 2 will be assigned to the 
treatment received in period 2.
With this definition AEs occurring in wash-out will be assigned to the treatment received in 
period 1. AEs up to the follow-up visit will be assigned to the treatment received in period 2 if
the start date/time of the AE was after dosing in period 2.
Independent of this rule, the relationship of an adverse event to the treatments will be assessed by
the investigator.
Adverse events will be coded using the Medical Dictionary for Regulatory Activities 
(MedDRA). Frequency, severity, and causal relationship of AEs will be tabulated by 
treatment, system organ class, and preferred term. SAEs, and other significant AEs 
(according to ICH E3) will be listed separately.
Global tolerability will be assessed by the Investigator.
7.4
INTERIM ANALYSES
No interim analysis is planned.
7.5
HANDLING OF MISSING DATA
7.5.1
Safety
With respect to safety evaluations, it is not planned to impute missing values.


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7.5.2
Plasma concentration – time profiles
Concentration data identified with NS (no sample), NR (not reportable) and BLQ (below the
limit of quantification) will be ignored and not replaced by zero at any time point (applies also
to the lag phase including the pre-dose value). Descriptive statistics of concentrations at
specific time points will be calculated only when at least 2/3 of the individuals have
concentrations within the validated concentration range. The overall sample size to decide
whether the “2/3 rule” is fulfilled will be based on the total number of samples intended to be
drawn for that time point (i.e. BLQ, NR and NS are included).
7.5.3
Pharmacokinetic parameters
In the non-compartmental analysis, concentration data identified with NS and NR will not be
considered. BLQ in the lag phase will be set to zero. The lag phase is defined as the period
between time zero and the first time point with a concentration above the quantification limit.
All other BLQ values of the profile will be ignored.
Data may/will be excluded from PK analysis (concentrations listed only) if any of the following
criteria are fulfilled:

The pre-dose concentration is greater than 5% of the corresponding Cmax in any given 
treatment period.

Subject experienced emesis within 2 x the reported median tmax for the analyte (Median 
tmax is to be determined excluding the subjects experiencing emesis).
Descriptive statistics of parameters are calculated only when at least 2/3 of the individual 
parameter estimates of a certain parameter are available. If the actual sampling time will not be
recorded or will be missing for a certain time point, the planned time will generally be used 
for this time point instead. Pharmacokinetic parameters which cannot be determined will be 
identified by "not calculated" (NC).
7.6
RANDOMISATION
Subjects will be randomised to one of the two treatment sequences (T-R, R-T) in a 1:1 ratio.
Stratification by gender will not be done.
The randomisation schedule will be provided by PAREXEL Biostatistics. The 
randomisation schedule will be generated utilizing the PROC PLAN procedure of SAS® 
software.
7.7
DETERMINATION OF SAMPLE SIZE
The intra-individual variability of the primary endpoints of both analytes was determined 
based on a similar internal study (1024.7) with the same test and reference products but lower
doses. For Cmax the coefficient of variation (gCV) was estimated below 19 % for both analytes,
while for AUC, the gCV for both analytes was lower than 12%. For Cmax the T/R ratio
estimate (gMean) was not lower than 91%, for AUC not greater than 105%.


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Hence the sample size for this trial was determined based on the Cmax, accounting for multiple
testing of the two analytes, i.e. the overall power of the study is the product of the power of
the test of each analyte, as their endpoints are assumed to be uncorrelated. Using gCVs of 19
and 20% and a power of 95% for the single test (in order to achieve an overall power greater than 
90%) to reject the null hypothesis of bio-inequivalence for Cmax in favour of equivalence at the
5% level of significance is displayed in Table 7.7: 1 under various assumptions for the T/R-
subject ratio. The total sample size is double the size per sequence group.
Table 7.7: 1
Required sample sizes per sequence to achieve an overall power greater than
90% for concluding equivalence (with respect to an acceptance range of 80-125%) assuming
a coefficient of variation of 19% or 20% and various intra-subject ratios, for a two-way 
crossover based on Cmax data of 1024.7 (ibuprofen)
gCV
20
20
19
20
20
20
T/R Ratio1
Power of Single
Test
Overall power
N per sequence 
group
90%
95%
91%
32
91%
95%
91%
27
91%
95%
91%
24
92%
95%
91%
23
100%
95%
91%
11
105%
95%
91%
15
1
This ratio reflects the median intra-subject ratio defined by exp(µT)/exp(µR) and is estimated by the
geometric mean of the intra-subject ratios
From the above table, a sample size of 48 will have a more than 90% power to conclude 
bioequivalence if the T/R ratio is not lower than 91%, the lowest ratio in study 1014.7 (Cmax of
ibuprofen). Accounting for up to 8 dropouts, a total of N = 48 + 8 = 56 subjects will be entered
into the study
The calculation was performed as described by Diletti et al (cf. R94-1445) using nQuery.
The calculation was performed using the MTE2co routine from commercial software nQuery
Advisor
[R07-0364].


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8.
INFORMED CONSENT, TRIAL RECORDS, DATA 
PROTECTION, PUBLICATION POLICY
The trial will be carried out in compliance with the protocol, the ethical principles laid down in
the Declaration of Helsinki, in accordance with the ICH Harmonized Tripartite Guideline for
Good Clinical Practice (GCP), relevant PXL and BI Standard Operating Procedures (SOPs), and
other relevant regulations.
The Investigator will inform the sponsor immediately of any urgent safety measures taken to 
protect the trial subjects against any immediate hazard, and also of any serious breaches of the
protocol or of ICH GCP*.
The Boehringer Ingelheim transparency and publication policy can be found on the following 
web page: trials.boehringer-ingelheim.com. The rights of the Investigator and of the sponsor 
with regard to publication of the results of this trial are described in the Investigator contract. As 
a rule, no trial results should be published prior to finalization of the Clinical Trial Report. The 
certificate of insurance cover is made available to the Investigator and the subjects, and is stored 
in the ISF (Investigator Site File).
8.1
TRIAL APPROVAL, PATIENT INFORMATION, INFORMED CONSENT
This trial will be initiated only after all required legal documentation has been reviewed and 
approved by the respective Institutional Review Board (IRB) / Independent Ethics Committee 
(IEC) and competent authority (CA) according to national and international regulations. The 
same applies for the implementation of changes introduced by amendments.
Prior to subject participation in the trial, written informed consent must be obtained from each
subject according to ICH / GCP and to the regulatory and legal requirements of the 
participating country. Each signature must be personally dated by each signatory and the 
informed consent and any additional subject-information form retained by the Investigator as
part of the trial records. A signed copy of the informed consent and any additional patient 
information must be given to each patient or the patient’s legally accepted representative.”
8.2
DATA QUALITY ASSURANCE AND DATA MANAGEMENT
8.2.1
Data Quality Assurance
A quality assurance audit/inspection of this trial may be conducted by the sponsor, sponsor’s 
designees, or by IRB / IEC or by regulatory authorities. The quality assurance auditor will 
have access to all medical records, the Investigator’s trial-related files and correspondence, 
and the informed consent documentation of this clinical trial.
8.2.2
Data Management
PAREXEL will utilize standardized and validated procedures and systems to collect, process and
file the clinical data of this study. Any system used will be compliant with FDA 21 CFR Part 11


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requirements. A data management plan (DMP) will be prepared to describe the work- and data-
flow within the clinical study. If applicable, sponsor-specific requests, timelines, versions for the
computer systems and the coding will be defined in the DMP. The DMP must be finalized before
data entry. Different levels of data validation checks may be developed based on the different
data sources. A data validation specification (DVS) may be created if not covered by standard
processes. In such case study-specific checks will be added to the standard checks that are
already available. If applicable the DVS must be finalized before data validation. The raw data
intended for further processing will be checked by standard routines or according to the DVS and
queries will be generated and sent to the investigator for answers. Corrections resulting from
these queries will be confirmed on the data clarification forms (DCFs). This process will be
repeated until no further discrepancies are found. The study monitor will confirm that all queries
have been closed out appropriately. The data will be then be declared as clean. Applicable
documentation will be stored in the study files. Only trained study staff will have access to the
clinical database and every change in data will have a full audit trail.
8.3
RECORDS
For drug accountability, refer to Section 4.1.8.
8.3.1
Source documents
Source documents provide evidence for the existence of the subject and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site.
Data reported in the eCRFs that are transcribed from source documents must be consistent 
with the source documents or the discrepancies must be explained.
The investigator may need to request previous medical records or transfer records, depending 
on the trial; also current medical records must be available.
8.3.2
Direct access to source data and documents
The sponsor will monitor the conduct of the trial by regular on-site monitoring visits and in-
house data quality review. The frequency of on-site monitoring will be determined by assessing
all characteristics of the trial, including its nature, objective, methodology and the degree of any
deviations of the intervention from normal clinical practice.
The Investigator /institution will allow on-site trial-related monitoring, audits, IRB / IEC review
and regulatory inspections. Direct access must be provided to the eCRF and all source 
documents/data, including progress notes, copies of laboratory and medical test results, which 
must be available at all times for review by the CRA, auditor and regulatory inspector (e.g.
FDA). The CRA and auditor may review all eCRFs and informed consents. The accuracy of the
data will be verified by direct comparison with the source documents described in Section 8.3.1. 
The sponsor will also monitor compliance with the protocol and ICH GCP.
8.3.3
Storage period of records
Trial site(s):


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The trial site(s) must retain the source and essential documents (including ISF) according to the
national or local requirements (whatever is longer) valid at the time of the end of the trial. 
Sponsor:
The sponsor must retain the essential documents according to the sponsor’s SOPs.
8.4
EXPEDITED REPORTING OF ADVERSE EVENTS
BI is responsible to fulfil their legal and regulatory reporting obligation in accordance with 
regulatory requirements.
8.5
STATEMENT OF CONFIDENTIALITY AND SUBJECT PRIVACY
Individual subject data obtained as a result of this trial is considered confidential and disclosure
to third parties is prohibited with the exceptions noted below. Subject privacy will be ensured by
using study subject number.
Data protection and data security measures are implemented for the collection, storage and 
processing of subject data in accordance with the principles 6 and 12 of the WHO GCP 
handbook.
Treatment data may be given to the subject’s personal physician or to other appropriate medical
personnel responsible for the subject’s welfare. Data generated as a result of the trial need to be
available for inspection on request by the participating physicians, the sponsor’s representatives,
by the IRB / IEC and the regulatory authorities.
8.5.1
Storage of biological samples
The principal investigator or designee will ensure that all biological fluids collected during the
study will not be used for purposes other than as directed by the clinical study protocol. All
collected biological fluids used for safety investigations will be destroyed within 3 months after
the clinical execution of the study has been completed.
Unused duplicate plasma PK samples will be stored at BASD for up to 6 months after 
completion of the bioanalysis phase of the study. The Sponsor will be required to indicate 
whether additional storage is needed or whether the samples may be discarded.
8.6
TRIAL MILESTONES
The start of the trial is defined as the date of the enrolment of the first subject in the trial. The
end of the trial is defined as the date of the last visit of the last subject in the trial (“Last Patient
Out”) Early termination of the trial is defined as the premature termination of the trial due to
any reason before the end of the trial as specified in this protocol.
Temporary halt of the trial is defined as any unplanned interruption of the trial by the sponsor
with the intention to resume it.


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Suspension of the trial is defined as an interruption of the trial based on a Health Authority 
request.
The IEC / competent authority in each participating EU member state will be notified about the
trial milestones according to the respective laws.
A final report of the clinical trial data will be written only after all subjects have completed the
trial.
The sponsor will submit to the EU database a summary of the final trial results within one year
from the end of a clinical trial as a whole, regardless of the country of the last subject (EU or
non-EU).


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9.
REFERENCES
9.1
PUBLISHED REFERENCES
P88-35100
Sperber SJ, Hayden FG. Chemotherapy of Rhinovirus Colds.
Antimicrob Agents Chemother 1988;32:409-419.
P97-6591
Michel FB. Multisymptom management in the common cold. Int
Pharm J 1996;10(5)(Suppl):4-9.
P04-01312
Moore N, Parc JM le, Ganse E van, Wall R, Schneid H, Cairns R.
Tolerability of ibuprofen, aspirin and paracetamol for the treatment of cold 
and flu symptoms and sore throat pain. Int J Clin Pract 2002; 56(10):732-
734.
R94-1445       Diletti E, Hauschke D, Steinijans VW. Sample size determination 
for bioequivalence assessment by means of confidence intervals. 
Int J Clin Pharmacol Ther Toxicol 1992;30(Suppl 1):S51-S58.
R94-1529
Chow SC, Liu JP, editors. Design and Analysis of Bioavailability 
and Bioequivalence Studies. New York: Marcel Dekker Inc; 1992.
R07-2230
Taverner D, Latte J. Nasal decongestants for the common cold (review).
Cochrane Database Syst Rev 2007(1).
R07-0364
Elashoff  JD. nQuery Advisor version 6.0 user's guide. Cork: Statistical
Solutions 2005
R09-2316
Luecker PW, Birkel M, Hey B, Loose I, Schaefer A. Relative 
bioavailability and bioequivalence of a newly developed fixed 
combination sachet of acetylsalicylic acid and pseudoephedrine 
compared with a preliminary combination. Methods Find Exp Clin 
Pharmacol 2003;25(8):631-637.
P10-06083
Sperber SJ, Sorrentino JV, Riker DK, Hayden FG. Evaluation of an alpha 
agonist alone and in combination with a nonsteroidal antiinflammatory 
agent in the treatment of experimental rhinovirus colds. Symp on 
Combination Therapies: New and Emerging Uses for Cyclooxygenase 
Inhibitors, Calcium Blockers, and Biological Response Modifiers on 
Immunity, New York, 2 - 3 Jun 1988. Bull NY Acad Med
1989;65(1):145-160.
R13-2920
ArrudaE, Pitkaranta A, Witek TJ, Doyle CA, Hayden FG Frequency and 
natural history of rhinovirus infections in adults during autumn. J Clin 
Microbiol 35 (11), 2864 - 2868 (1997)


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9.2
UNPUBLISHED REFERENCES
Not applicable


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10.
APPENDICES
Not applicable


001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Boehringer Ingelheim
20 February 2017
BI Trial No.: 1024.9                                                                                 
c11001605-04
Trial Protocol
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11.
DESCRIPTION OF GLOBAL AMENDMENT(S)
This is the revised protocol according to Amendment 01
Number of global amendment
01
Date of CTP revision
20 February 2017
EudraCT number
Not applicable
BI Trial number
1024.9
BI Investigational Product(s)
Fixed dose combination 400 mg Ibuprofen and 
60 mg Pseudoephedrine-HCl film-coated tablet
Title of protocol
Bioequivalence of a fixed dose combination tablet 
containing 400 mg Ibuprofen and 60 mg 
Pseudoephedrine-HCl compared to two film-coated 
fixed dose combination tablets RhinAdvil® 
(200 mg Ibuprofen and 30 mg Pseudoephedrine-
HCl) administered in at least 48 healthy male and 
female subjects (Open-label, randomised, laboratory 
blind, single dose, two-way crossover, Phase I trial).
To be implemented only after
approval of the IRB / IEC / 
Competent Authorities
Yes
To be implemented
immediately in order to 
eliminate hazard –
IRB / IEC / Competent 
Authority to be notified of 
change with request for approval
No
Can be implemented without
IRB / IEC / Competent 
Authority approval as changes 
involve logistical or 
administrative aspects only
No
Section to be changed
See tracked version of the amended protocol for the 
sections where changes were made.


001-MCS-40-106-RD-03 (13.0) / Saved on: 05 Aug 2015
Boehringer Ingelheim
20 February 2017
BI Trial No.: 1024.9                                                                                 
c11001605-04
Trial Protocol
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Proprietary confidential information © 2017 Boehringer Ingelheim International GmbH or one or more of its affiliated companies
Description of change
Addition of a secondary trial objective to assess the 
bioequivalence of a fixed dose combination tablet 
containing 400 mg Ibuprofen and 60 mg 
Pseudoephedrine-HCl vs. RhinAdvil® (2 tablets 
containing 200 mg Ibuprofen and 30 mg 
Pseudoephedrine-HCl) as a fixed dose combination 
tablet with respect to R- and S-ibuprofen 
(enantiomers of ibuprofen).
Updating applicable sections of the trial protocol to 
provide for the added PK analyses of R- and 
S-ibuprofen.
Due to technical problems, document number 
extension needs to be -03 and due to second-step 
signature workflow needed, document number 
extension -04 is current.
Rationale for change
To add an additional secondary trial objective.


 
 
 
 
APPROVAL / SIGNATURE PAGE 
 
Document Number: 
 
Technical Version Number:
 
Document Name: 
 
 
 
                                                                                                                 
 
Title: 
 
 
 
 
                                                                                                                   
 
Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c11001605
4.0
clinical-trial-protocol-version-03
Bioequivalence of a fixed dose combination tablet containing 400 mg Ibuprofen and
60 mg Pseudoephedrine-HCl compared to two film coated fixed dose combination
tablets RhinAdvil® (200 mg Ibuprofen and 30 mg Pseudoephedrine-HCl)
administered in at least 48 healthy male and female subjects (Open-label,
randomized, laboratory blind, single dose, two-way crossover, Phase I trial).
Approval–Clinical Monitor
24 Feb 2017 10:57 CET
Author-Trial Statistician
24 Feb 2017 10:57 CET
Approval-Therapeutic Area 
24 Feb 2017 12:45 CET
Approval-Team Member Medicine
24 Feb 2017 15:29 CET
Verification-Paper Signature
Completion
24 Feb 2017 15:32 CET


Boehringer Ingelheim 
Page 2 of 2
Document Number: 
 Technical Version Number:
 
 
 
(Continued) Signatures (obtained electronically) 
 
Meaning of Signature  
Signed by 
Date Signed 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
c11001605
4.0

SAP_001.pdf: 
PAREXEL International 
Statistical Analysis Plan 
 
Boehringer Ingelheim 
 
Final 4.0 
1024.9 
 
09/Mar/2017 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 1 of 37 
 
STATISTICAL ANALYSIS PLAN 
 
 
 
 
1024.9 
 
Bioequivalence of a fixed dose combination tablet containing 400 mg Ibuprofen and 60 mg 
Pseudoephedrine-HCl compared to two film coated fixed dose combination tablets RhinAdvil®  (200 
mg Ibuprofen and 30 mg Pseudoephedrine- HCl) administered in at least 48 healthy male and female 
subjects  (Open-label, randomised, laboratory blind, single dose, two-way crossover, Phase I trial). 
 
 
 
 
Version:  Final 4.0 
 
Date: 09/Mar/2017 
 
 


PAREXEL International 
Statistical Analysis Plan 
 
Boehringer Ingelheim 
 
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1024.9 
 
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Related to:  SOP-EP.BS-WW-002 
 
Page 2 of 37 
 
REVISION HISTORY 
Version 
Version Date 
Author 
Summary of Changes Made 
Draft 1.0 
01/Feb/2017 
 
New Document 
Draft 2.0 
20/Feb/2017 
 
Comments from sponsor from 10 Feb. 2017 
processed 
Draft 3.0 
03/Mar/2017 
 
Added rounding for percentages in safety tables. 
All percentages now at 2 decimal places. Added 
abbreviations. Cleaned up text. Added codes to 
protocol deviation categories. Added flag for 
topline results. Corrected title listing 16.2.6.5. 
Removed change from baseline from safety 
laboratory.   
Draft 4.0 
09/Mar/2017 
 
Comments sponsor received 8 March processed 
 
 


P AREXEL International 
Statistical Analysis Plan 
SIGNATURE PAGE- BOEHRINGER INGELHEIM 
Declaration 
The undersigned has/have reviewed and agree to the statistical analyses and procedures of this clinical study, as 
presented in this document. 
 (Trial Statistician) 
Phone:
Fax: 
 
 (Trial Clinical Monitor) 
on behalf of:Boehringer lngelheim Pharrna GmbH & Co. KG 
Binger Str. 173 
D-55216 lngelheim am Rhein 
Phone: 
 
Fax: 
 
Boehringer lngelheim 
1024.9 
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Effective date: 29 Jull5 
Related to: SOP-EP.BS-WW-002 
Date (DD Mmm YY) 
Date (DD Mmm YY) 
Fina14.0 
09/Mar/20 17 
Page 3 of37 


P AREXEL International 
Statistical Analysis Plan 
SIGNATURE PAGE- BOEHRINGER INGELHEIM 
Declaration 
The undersigned has/have reviewed and agree to the statistical analyses and procedures of this clinical study, as 
presented in this document. 
 (Trial Statistician) 
Phone:
Fax: 
 
 (Trial Clinical Monitor) 
on behalf of: Boehringer lngelheim Pharma GmbH & Co. KG 
Binger Str. 173 
D-55216 Ingelheim am Rhein 
Phone:
Fax: 
 
Boehringer lngelheim 
1024.9 
TP-EP.BS-WW-001-05 
Effective date: 29 Jul 15 
Related to: SOP-EP.BS-WW-002 
Date (DD Mmm YY) 
Date (DD Mmm YY) 
Final4.0 
09/Mar/20 17 
Page 3 of37 


P AREXEL International 
Statistical Analysis Plan 
SIGNATURE PAGE- PAREXEL 
Declaration 
The undersigned agree to the statistical analyses and procedures of this clinical study. 
If this document has been signed electronically, signature(s) and date(s) are present at the end of the document: 
Document prepared and approved by: 
 
Senior Biostatistician 
Document prepared and approved by: 
 
QCD Senior Scientist 
Boehringer Ingelheim 
1024.9 
TP-EP.BS-WW-001-05 
Effective date: 29 Jut 15 
Related to: SOP-EP.BS-WW-002 
Date (DD Mmm YY) 
Date (DD Mmm YY) 
Final4.0 
09/Mar/20 17 
Page 4 of37 




PAREXEL International 
Statistical Analysis Plan 
 
Boehringer Ingelheim 
 
Final 4.0 
1024.9 
 
09/Mar/2017 
TP-EP.BS-WW-001-05  
Effective date:  29 Jul 15 
Related to:  SOP-EP.BS-WW-002 
 
Page 5 of 37 
 
TABLE OF CONTENTS 
REVISION HISTORY .................................................................................................................... 2 
SIGNATURE PAGE - BOEHRINGER INGELHEIM .................................................................. 3 
SIGNATURE PAGE - PAREXEL ................................................................................................. 4 
TABLE OF CONTENTS ................................................................................................................ 5 
LIST OF TABLES .......................................................................................................................... 7 
ABBREVIATION AND ACRONYM LIST .................................................................................. 8 
1. 
STATISTICAL ANALYSIS PLAN ................................................................................ 10 
2. 
STUDY OBJECTIVES.................................................................................................... 10 
2.1 
Primary Objective ............................................................................................... 10 
2.2 
Secondary Objective ........................................................................................... 10 
3. 
ENDPOINTS ................................................................................................................... 10 
3.1 
Primary Endpoints .............................................................................................. 10 
3.2 
Secondary Endpoints .......................................................................................... 11 
 
............................................................................................11 
3.3 
Assessment of safety .......................................................................................... 12 
4. 
STUDY DESIGN ............................................................................................................ 12 
5. 
STUDY POPULATION .................................................................................................. 12 
6. 
STATISTICAL BASIS FOR SAMPLE SIZE ................................................................. 12 
7. 
RANDOMIZATION ....................................................................................................... 13 
8. 
STATISTICAL ANALYSIS CONVENTIONS .............................................................. 13 
8.1 
Analysis Variables .............................................................................................. 13 
8.1.1 
Demographic and Background Variables ........................................................13 
8.1.2 
Safety Variables ..............................................................................................14 
8.1.2.1 
Adverse Events ................................................................................14 
8.1.2.2 
Clinical Laboratory Tests .................................................................15 
8.1.2.3 
Vital Signs ........................................................................................15 
8.1.2.4 
Electrocardiograms ..........................................................................15 
8.1.2.5 
Physical Examination .......................................................................15 
8.1.2.6 
Concomitant Medication ..................................................................15 
8.1.3 
Pharmacokinetic Variables ..............................................................................16 
8.1.3.1 
Pharmacokinetic Parameter Calculation Methods ...........................16 
8.2 
Analysis Populations .......................................................................................... 18 
8.2.1 
Safety Population ............................................................................................18 


PAREXEL International 
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8.2.2 
Pharmacokinetic Population ............................................................................18 
8.3 
Statistical Analysis Methods .............................................................................. 18 
8.3.1 
Listings and Descriptive Statistics ..................................................................18 
8.3.2 
Rounding and decimal places ..........................................................................19 
8.3.3 
Statistical Significance Level ..........................................................................20 
8.3.4 
Software ..........................................................................................................20 
8.3.5 
Missing Data ...................................................................................................20 
8.3.6 
Interim Analysis ..............................................................................................20 
8.3.7 
Protocol Deviations .........................................................................................20 
8.3.8 
Demographic Data ...........................................................................................21 
8.3.9 
Concomitant Medication .................................................................................21 
8.3.10 
Exposure to the Investigational Medicinal Product .........................................21 
8.3.11 
Pharmacokinetic Concentrations and Variables ..............................................22 
8.3.11.1 Handling of Values Below the Limit of Quantification (BLQ) in 
Concentration Summaries and Listings ...........................................23 
8.3.11.2 Primary analysis: Assessment of Bioequivalence ............................24 
8.3.11.3 Secondary analysis ...........................................................................26 
8.3.12 
Safety Analysis ................................................................................................26 
8.3.12.1 Adverse Events ................................................................................26 
8.3.12.2 Clinical Safety Laboratory Tests (haematology, biochemistry and 
urinalysis) .........................................................................................26 
8.3.12.3 Vital Signs ........................................................................................27 
8.3.12.4 Twelve-Lead Electrocardiogram ......................................................27 
8.3.12.5 Physical Examination .......................................................................27 
9. 
REFERENCES ................................................................................................................ 28 
 
 


PAREXEL International 
Statistical Analysis Plan 
 
Boehringer Ingelheim 
 
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LIST OF TABLES 
Table 1 
Pharmacokinetic Parameters after Single Dose Administration .............................. 16 
Table 2 
Protocol Deviations Categories ................................................................................ 21 
 
 
 


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ABBREVIATION AND ACRONYM LIST  
Abbreviation / Acronym 
Definition / Expansion 
AE 
Adverse event 
ANOVA 
Analysis of Variance 
AUC 
Area under the concentration-time curve 
AUC0-∞  
AUC of the analyte in plasma from 0 hours extrapolated to infinity 
AUC0-tz  
AUC of the analyte in plasma over the time interval from 0 to the 
last quantifiable data point 
BLQ 
Below the lower limit of quantification 
BMI 
Body Mass Index 
BP 
Blood Pressure 
CI 
Confidence interval 
Clast 
Last quantifiable concentration at tlast 
CL/F 
Apparent clearance following oral administration 
CSP 
Clinical Study Protocol 
Cmax 
Maximum observed concentration 
CS 
Clinically significant 
CV% 
Coefficient of variation 
DRM 
Data Review Meeting 
ECG 
Electrocardiogram 
gCV% 
Geometric CV%  
gMean 
Geometric mean 
ICF 
Informed Consent Form 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
NCS 
Not clinically significant 
NK 
Not known 
NR 
Not Reportable 
NS 
No Sample 


PAREXEL International 
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Abbreviation / Acronym 
Definition / Expansion 
PK 
Pharmacokinetic 
PKS 
Pharmacokinetic analysis population 
PR 
Pulse Rate 
PT 
Preferred Term 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation or single dose 
SOC 
System Organ Class 
TEAE 
Treatment-emergent adverse event 
TLFs 
Tables, Listings and Figures 
tmax 
Time corresponding to occurrence of Cmax 
WHO-DD 
World Health Organisation - Drug Dictionary 
 
 


PAREXEL International 
Statistical Analysis Plan 
 
Boehringer Ingelheim 
 
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1. 
STATISTICAL ANALYSIS PLAN 
The Statistical Analysis Plan (SAP) details the statistical methodology to be used in analyzing study 
data and outlines the statistical programming specifications for the Tables, Listings and Figures (TLFs). 
It describes the variables and populations, anticipated data transformations and manipulations and other 
details of the analyses not provided in the Clinical Study Protocol (CSP). 
The analyses described are based on the final CSP Version 2.0, dated, 30/Jan/2017. The SAP will be 
finalized prior to database lock and describes the statistical analysis as it is foreseen when the study is 
being planned. If circumstances should arise during the study rendering this analysis inappropriate, or if 
improved methods of analysis should arise, updates to the analyses may be made. Any deviations from 
the SAP after database lock, reasons for such deviations and all alternative or additional statistical 
analyses that may be performed, will be described in a SAP Addendum. 
2. 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To demonstrate the bioequivalence of a fixed dose combination tablet containing 400 mg Ibuprofen and 
60 mg Pseudoephedrine-HCl vs. RhinAdvil® (2 tablets containing 200 mg Ibuprofen and 30 mg 
Pseudoephedrine-HCl) as a fixed dose combination tablet with respect to the analytes ibuprofen and 
pseudoephedrine. 
2.2 
Secondary Objective 
To assess the bioequivalence of a fixed dose combination tablet containing 400 mg Ibuprofen and 60 
mg Pseudoephedrine-HCl vs. RhinAdvil® (2 tablets containing 200 mg Ibuprofen and 30 mg 
Pseudoephedrine-HCl) as a fixed dose combination tablet with respect to R- and S-ibuprofen 
(enantiomers of ibuprofen). 
3. 
ENDPOINTS 
3.1 
Primary Endpoints 
The following primary endpoints will be determined for the analytes ibuprofen and pseudoephedrine: 


PAREXEL International 
Statistical Analysis Plan 
 
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 AUC0-tz (area under the concentration-time curve of the analytes in plasma over the time interval 
from 0 to the time of last quantifiable time point) 
 Cmax (maximum measured concentration of the analytes in plasma) 
3.2 
Secondary Endpoints 
The following secondary endpoint will be determined for the analytes ibuprofen and pseudoephedrine-
HCl: 
 AUC0-∞ (area under the concentration-time curve of the analytes in plasma over the time interval 
from 0 extrapolated to infinity) 
The following secondary endpoints will be determined for the analytes R-ibuprofen and S-ibuprofen: 
 AUC0-tz (area under the concentration-time curve of the analytes in plasma over the time interval 
from 0 to the time of last quantifiable time point) 
 Cmax (maximum measured concentration of the analytes in plasma) 
 AUC0-∞ (area under the concentration-time curve of the analytes in plasma over the time interval 
from 0 extrapolated to infinity) 
 S/R-ibuprofen ratio for AUC0-tz (i.e., AUC0-tz S-ibuprofen / AUC0-tz R-ibuprofen) 


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3.3 
Assessment of safety 
Safety and tolerability of the investigational drug(s) will be assessed based on: 
 Vital signs (BP, PR) 
 12-lead ECG (electrocardiogram) 
 Clinical laboratory tests (haematology, clinical chemistry and urinalysis) 
 Adverse events (including clinically relevant findings from the physical examination) 
 Assessment of tolerability by the investigator 
4. 
STUDY DESIGN 
The study will be performed as an open-label, single dose, randomised, laboratory blind, two-way 
crossover trial. The following treatments will be administered in the fasting state: 
Test (T):  
Film coated fixed dose combination tablet containing Ibuprofen 400 mg and 
Pseudoephedrine 60 mg 
Reference (R):  
RhinAdvil® two fixed dose combination tablets containing Ibuprofen 200 mg 
and Pseudoephedrine 30 mg 
The two treatment sequences T-R and R-T will be randomly allocated to the subjects. 
The schedule of assessments is given in the flow chart in section 13. 
5. 
STUDY POPULATION 
The study population will consist of 56 adult healthy subjects. 
Detailed lists of inclusion and exclusion criteria are shown in Sections 3.3.2 and 3.3.3 of the CSP. 
6. 
STATISTICAL BASIS FOR SAMPLE SIZE 
For details on sample size are shown in section 7.7 of the CSP.  


PAREXEL International 
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The sample size for this trial was determined based on the Cmax, accounting for multiple testing of the 
two analytes (ibuprofen and pseudoephedrine), i.e. the overall power of the study is the product of the 
power of the test of each analyte, as their endpoints are assumed to be uncorrelated. 
A sample size of 48 will have a more than 90% power to conclude bioequivalence if the T/R ratio is not 
lower than 91%, the lowest ratio in study 1014.7 (Cmax of ibuprofen). Accounting for up to 8 dropouts, 
a total of N = 48 + 8 = 56 subjects will be entered into the study 
7. 
RANDOMIZATION 
Subjects will be randomized to one of the two treatment sequences (T-R, R-T) in a 1:1 ratio. 
8. 
STATISTICAL ANALYSIS CONVENTIONS 
8.1 
Analysis Variables 
8.1.1 
Demographic and Background Variables 
The following demographic and anthropometric information will be recorded: 
 Date of informed consent 
 Medical history (including previous and current medical conditions and medications) 
 Drug, alcohol and smoking history 
 Age calculated as (date of informed consent – date of birth)/365.25 
 Gender 
 Ethnic origin 
 Race 
 Height, without shoes (cm) 
 Body weight (kg) 
 Body mass index (BMI) calculated as [weight/height2] (kg/m2) 


PAREXEL International 
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All medical history will be coded using Version 19.1 of the Medical Dictionary for Regulatory 
Activities (MedDRA). 
8.1.2 
Safety Variables 
8.1.2.1 Adverse Events 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment. An AE can therefore be any unfavorable and unintended sign 
(including an abnormal laboratory finding, for example), symptom, or disease temporally associated 
with the use of a medicinal product, whether or not considered related to the medicinal product. 
AE intensity should be judged based on the following: 
Mild:  
Awareness of sign(s) or symptom(s) that is/are easily tolerated 
Moderate: 
Enough discomfort to cause interference with usual activity 
Severe: 
Incapacitating or causing inability to work or to perform usual activities. 
All AEs will be coded using version 19.1 of the MedDRA. 
A treatment-emergent adverse event (TEAE) is defined as an AE that begins or that worsens in severity 
after at least one dose of the study drug has been administered. 
 All AEs with start date/time prior to dosing in period 1 are pre-treatment AEs and will be assigned 
to screening. 
 All AEs with start date/time after the date/time of dosing in period 1, but before dosing in period 2, 
will be assigned to the treatment received in period 1. 
 AEs with start date/time after the date/time of dosing in period 2 will be assigned to the treatment 
received in period 2. 
Any AEs with incomplete start and end dates/times will be treated as follows: 
 Adverse events with unknown start and/or end times (but where the date is known) will be imputed 
with a time of 00:00 h for the tabulations but will be shown as NK:NK in the listings (where NK = 


PAREXEL International 
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Not Known). If the date is a treatment date, then the AE will be assigned to the treatment of that 
date. 
 Adverse events with completely unknown start dates will be considered as treatment-emergent 
using the period 1 treatment for the tabulations and will be shown as NK in the listings. 
8.1.2.2 Clinical Laboratory Tests 
The safety laboratory tests (haematology, clinical chemistry and urinalysis) specified in section 5.3.3 of 
the CSP will be measured according to the schedule displayed in section 13.  
8.1.2.3 Vital Signs 
The following vital signs measurements will be obtained according to the schedule of assessments in 
section 13: 
 Blood pressure (BP), systolic and diastolic (mmHg) 
 Pulse rate (PR)  
 Body temperature [°C] 
8.1.2.4 Electrocardiograms  
12-lead ECGs (I, II, III, aVR, aVL, aVF, V1 - V6) will be recorded according to the schedule in section 
13. ECG will be evaluated by the Investigator as ‘Normal’, ‘Abnormal, Not Clinically Significant 
(NCS)’ or ‘Abnormal, Clinically Significant (CS)’. 
8.1.2.5 Physical Examination 
Physical examination will be performed at screening and follow up. 
8.1.2.6 Concomitant Medication 
Concomitant medication will be coded using the World Health Organisation-Drug Dictionary 
(WHO-DD) (Version SEP 2016). 


PAREXEL International 
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8.1.3 
Pharmacokinetic Variables 
Blood for plasma concentrations will be sampled according to the flow chart in section 13. Unless 
otherwise stated, derivation of pharmacokinetic (PK) parameters will be the responsibility of Early 
Phase, Clinical PK/Pharmacodynamic, PAREXEL International.  The following PK parameters will be 
determined for Ibuprofen, Pseudoephedrine-HCl, R- and S-ibuprofen  in plasma following single dose 
administration: 
Table 1 
Pharmacokinetic Parameters after Single Dose Administration 
Parameter 
Definition 
Cmax 
Maximum observed concentration of the analyte in plasma 
tmax 
Time corresponding to occurrence of Cmax 
AUC0-tz 
Area under the concentration-time curve (AUC) of the analyte in plasma 
from 0 hours to the last quantifiable data point 
AUC0-∞ 
AUC from time zero extrapolated to infinity 
AUC0-tz S-ibuprofen / 
AUC0-tz R-ibuprofen 
Ratio of S-ibuprofen/ R-ibuprofen as measured by AUC0-tz 
 
8.1.3.1 Pharmacokinetic Parameter Calculation Methods 
PK parameters will be calculated by non-compartmental analysis methods from the concentration-time 
data using WinNonlin Professional (Version 6.3) following these guidelines: 
 Actual sampling times relative to dosing rather than nominal times will be used in the calculation of 
all derived PK parameters. 
o 
If the actual sampling time will not be recorded or will be missing for a certain time point, 
the planned time will generally be used for this time point instead. 


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 There will be no imputation of missing data.  
 All below the limit of quantification (BLQ) values pre-dose and in the absorption phase prior to the 
first quantifiable concentration will be substituted by zeros. All other BLQ values will be set to 
missing. 
 Data may/will be excluded from PK analysis (concentrations listed only) if any of the exclusion 
criteria from section 8.3.11 are fulfilled. 
PK parameters will be estimated according to the following guidelines: 
 Cmax will be obtained directly from the concentration-time data. 


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8.2 
Analysis Populations 
8.2.1 
Safety Population 
All subjects who received at least one dose of study drug will be included in the safety evaluation 
(safety population). 
8.2.2 
Pharmacokinetic Population 
The PK analysis population (PKS, PK set) will include all treated subjects that provide observations for 
both periods for at least one primary endpoint evaluable (AUC0-tz and Cmax) and without any major 
protocol deviation thought to interfere with the absorption, distribution, metabolism, and excretion of 
the compound to be measured.  PK parameters for subjects who discontinue after a single treatment 
will be presented in the listings but will not be used for summary statistics or any statistical analysis. 
8.3 
Statistical Analysis Methods 
8.3.1 
Listings and Descriptive Statistics 
All original and derived parameters as well as population characteristics will be listed. Data will be 
described using summary statistics as described in the sections below. Frequency counts (number of 
subjects [n] and percentages) will be made for each qualitative variable. Descriptive statistics (n, mean, 
standard deviation [SD], median, minimum and maximum) will be calculated for each quantitative 
variable (unless otherwise stated). All listings will include repeated and unscheduled measurements. 
The following rules will apply to any repeated measurements: 


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 If the repeated measurement occurs prior to the first dose of study drug then the last obtained value 
of any repeated measurement will be used in the descriptive statistics. 
 If the repeated measurement occurs after the first dose of study drug then the original value of any 
repeated measurements will be used in the descriptive statistics. 
All descriptive statistics will be presented by treatment for measurements obtained during each 
treatment period. The baseline for all measurements (where applicable) will be the last pre-dose 
measurement within each period. Descriptive statistics for all data obtained at Screening and follow-up 
will be presented separately. 
8.3.2 
Rounding and decimal places 
 The following rules will be followed with regard to the number of decimal places and presentation 
of data in the tables and listings of safety data: 
1. All data will be listed according to the number of decimal places presented in the source 
data 
2. Mean and median will be tabulated to one more decimal place than the source data 
3. Minimum and maximum values will be tabulated to the same number of decimal places 
as the source data 
4. Standard deviation (SD) will be tabulated to two more decimal places than the source 
data 
5. Coefficient of variation (CV)%, if applicable, will be presented to two decimal place 
6. A maximum of three decimal places will apply to all summary statistics. 
7. Percentages will be displayed to two decimal place. 
 The following rules will be followed with regards to the number of decimal places and presentation 
of data in the tables and listings of PK concentration data: 
1. The individual concentrations will be reported to the same precision as the source data 
(for example, if the source data is presented to five significant digits, the individual 
values will be presented to five significant digits) 
2. The mean, SD, geometric mean (gMean) and median will be tabulated to one more 
significant digit compared to the source data.  
3. Minimum and maximum values will be tabulated to the same precision as the source 
data. 
4. Geometric CV% will be presented to two decimal places. 


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 The following rules will be followed with regards to the number of decimal places and presentation 
of data in the tables and listings of PK parameters: 
1. Individual PK parameters will be presented to three significant digits, 
 
 
 
. In addition, parameters directly 
derived from source data (e.g. Cmax,) shall be reported with the same precision as the 
source data  
2. The mean, gMean, median and SD values will be reported to one more significant digit 
than the source data, except for CV% which will be presented to two decimal place. 
 
 
  
3. Geometric least squares means from the statistical analysis will be presented to three 
significant  digits 
4. Estimates and confidence intervals in the form of percentages will be presented to two 
decimal places 
8.3.3 
Statistical Significance Level 
All statistical tests will be two-sided and will be performed at the 5% level of significance, unless 
otherwise stated.  
8.3.4 
Software 
All statistical analyses will be performed using Statistical Analysis Software (SAS®) Version 9.3 or 
later. The PK analysis will be performed using WinNonlin Professional Software Version 6.3 or later. 
8.3.5 
Missing Data 
There will be no imputation of missing data.  
8.3.6 
Interim Analysis 
Not applicable. 
8.3.7 
Protocol Deviations 
All protocol deviations will be recorded by the Investigator and will be listed by subject and will 
include a description of the deviation, the data/time of the deviation (if available), study day of the 
deviation, time point (if applicable). Protocol deviations will be based on the safety population.  


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All protocol deviations will be discussed between PAREXEL (physician, Data Manager, 
Biostatistician, PK Scientist/Analyst and Medical Writer) and also the Sponsor during the Data Review 
Meeting (DRM) before database lock. Protocol deviations will be classified as major or minor. 
Exclusion/inclusion of subjects based on the deviations will be decided upon at the DRM. The 
classifications and specification will be specified in a separate document, the protocol deviations 
specification. The main categories for protocol deviations that will be considered are described in Table 
2. 
Table 2 
Protocol Deviations Categories 
Code 
Category 
A 
Subject did not meet the inclusion/exclusion criteria   
B 
Subject received prohibited concomitant medications 
C 
Subject did not receive the planned dose 
D 
Deviations from scheduled procedure time outside of the window allowance 
E 
Procedures not performed due to error or subject availability 
F 
Deviations regarding sample processing 
G 
Use of the incorrect ICF, ICF incorrect, etc. 
H 
Any deviation that does not fit into one of the categories listed above 
The window allowance document (WAD, version 2, 24Nov2016) will stipulate the tolerance windows 
for safety and PK assessments. Measurements performed within these tolerance windows will not be 
considered as protocol deviations and will not be reported. 
8.3.8 
Demographic Data 
All demographic data will be presented using the safety population. 
8.3.9 
Concomitant Medication 
All prior and concomitant medication will be listed using the safety population.  
8.3.10 
Exposure to the Investigational Medicinal Product 
Exposure to the investigative product will be shown in a listing. 


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8.3.11 
Pharmacokinetic Concentrations and Variables 
Pharmacokinetic concentration data of all analytes will be shown in a listing including actual sampling 
times relative to dosing using the safety population.  
The analysis of the PK data will be based on the PKS. 
Any data excluded will be discussed in the CSR.  
Plasma concentrations will be summarized by treatment, analyte and timepoint. The following 
descriptive statistics will be presented for plasma concentrations obtained at each nominal time point: 
n, arithmetic mean, SD, coefficient of variation (CV%), gMean, geometric CV% (calculated as: 
gCV%=SQRT(es²-1)*100; where s is the standard deviation of the natural log-transformed values), 
median, minimum and maximum values. Summaries will only be presented when at least 2/3 of the 
subjects have concentrations within the validated concentration range. 
Pharmacokinetic parameters will be listed by subject and summarized by treatment. Descriptive 
statistics for calculated PK parameters will include: n, arithmetic mean, SD, CV%, gMean, gCV%, 
median, minimum and maximum values. 
 
 
 
. No descriptive statistics will be determined when fewer than 2/3 individual PK parameters 
are available. 
Individual plasma concentration versus actual times will be plotted by treatment for each analyte in 
linear and semi-logarithmic scale. Plots of R and S ibuprofen will be combined in one display. 
Combined individual plasma concentrations including gMean will be plotted by product for each 
analyte (spaghetti plot). Mean plasma concentrations versus nominal times will also be presented for all 
analytes in linear and semi-logarithmic scale. R and S-ibuprofen will be overlaid on the same plot. 
 Data may be excluded from PK plasma concentration summaries, PK parameter calculations, PK 
parameter summaries and bioequivalence calculations if any of the following criteria are fulfilled: 
o 
The pre-dose concentration is greater than 5% of the corresponding Cmax in any given 
treatment period. 
o 
Subject experienced emesis within 2 x the reported median tmax for the analyte (median tmax 
is to be determined excluding the subjects experiencing emesis) 


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o 
Concomitant medication, which could render the plasma concentration-time profile 
unreliable  
o 
Subject has moderate or severe diarrhea within 2 x the reported median tmax for the analyte. 
 Data excluded in summaries will also be excluded corresponding plots. 
8.3.11.1 
Handling of Values Below the Limit of Quantification (BLQ) in Concentration 
Summaries and Listings 
Graphical presentation: 
For all graphs missing values will be excluded from the calculations. For graphs of arithmetic means all 
BLQ mean concentrations will be set to missing. Mean values will only be displayed when at least 2/3 
of the individual concentrations are available. Graphs of gMeans include only time points with 
minimum concentration greater than Lower level of quantification (LLOQ). Any arithmetic mean that 
is BLQ will be excluded from log/linear presentation of arithmetic means. Any BLQ values prior to the 
last quantifiable concentration will be excluded from both individual linear/linear graphs and individual 
log/linear graphs. All BLQ values after the last quantifiable concentration will be excluded from 
individual linear/linear and log/linear graphs.  
Handling of values below the limit of quantification (BLQ) in listings and for the calculation of 
descriptive statistics at each time point: 
Concentration below the LLOQ will be indicated by BLQ in the listings, concentration data identified 
as no sample (NS), not reportable (NR) and Below Limit of Quantification (BLQ) will be labelled as 
such in the listing.   
Missing samples will be excluded from descriptive statistics. Values that are BLQ will be substituted 
with zero for the calculation of descriptive statistics of concentration by time point. The summary 
statistics gMean, and gCV% will not be calculated when any BLQ values are used and will be 
displayed as “not calculable” or NC. Descriptive statistics of concentrations will be calculated only 
when at least 2/3 of the individuals have concentrations within the validated concentration range. 


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8.3.11.2 
Primary analysis: Assessment of Bioequivalence 
Bioequivalence will be analyzed using the ratios of the gMeans (test/reference [T/R]) for the Cmax and 
AUC0-tz endpoints of ibuprofen and pseudoephedrine-HCL. Additionally, their two sided 90% 
Confidence Intervals (CI) will be provided.  This method corresponds to the two one sided t-tests 
procedures, each at the 5% significance level.  
The statistical model will be an analysis of variance (ANOVA) on the logarithmic scale including fixed 
effects for sequence, subject nested within sequence, period and product.  Only subjects who complete 
the PK sampling in both periods will be included in the analysis for that specific analyte.  For each 
endpoint, the difference between the expected means for the natural log(T)-log(R) will be estimated by 
the difference in the corresponding adjusted means (LeastSquares Means).  Confidence intervals will 
be calculated based on the residual error from the ANOVA.  The differences between the test and 
reference product and the CIs will be back transformed to the original scale, resulting in point estimates 
of the T/R gMean ratios and 90% CIs.  
The model is described by the following equation 
yijkm = + i + sim + j + k + eijkm,  
where 
yijkm = logarithm of response (AUC or Cmax) measured on subject m in sequence i receiving 
treatment k in period j 
= the overall mean  
i = the ith sequence effect, i = 1, 2 
sim = the effect associated with the mth subject in the ith sequence, m = 1, 2, ..., 24 
j = the jth period effect, j = 1, 2 
k = the kth treatment effect, k = 1, 2 
eijkm = the random error associated with the mth subject in sequence i who received treatment k in 
period j. 
The model will be based on the following SAS code: 
Proc Mixed; 
Class treatment period sequence subject; 
Model var=treatment sequence period subject(sequence); 
/*where "var"=(if doses are different dose  
 
normalized and) log transformed PK parameter*/ 
 
Lsmeans treatment / CL alpha=0.05; 
 
Estimate 'Test - Reference'  treatment   1 -1   / cl alpha=0.1; 
 
ods output estimates=estim 


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  lsmeans=ls_means; 
QUIT; 
Before the data will be analysed the fixed effect treatment will be numerically coded; Test=1 and 
Reference=2.  
Hypothesis for primary analysis 
Bioequivalence is established by using the average bioequivalence method to ensure that the ratio of 
the primary endpoints of the two treatments (T/R) is contained within a pre-specified acceptance 
range (see below). This goal is accomplished by testing the below hypothesis on the log scale. 
Null hypothesis H0 (Inequivalence): T R  or 
T R 
(i.e. the difference of the population average responses is either less than or equal to the lower 
bound or greater than or equal to the upper bound of the acceptance range), 
Alternative hypothesis Ha (Equivalence): 
T R 
(i.e. the difference of the population average responses is both greater than the lower bound 
and less than the upper bound of the acceptance range), where T and R are the population 
average responses of the log-transformed measures for the formulations Test and Reference, 
and  is the bioequivalence limit that defines the acceptance range for AUC and Cmax on the 
logarithmic scale 
In this trial, is taken to be ln(1.25). This translates to an acceptance range of 80 to 125% for the 
gMean of the ratio of the parameters on the original scale. 
This hypothesis and its alternative can be decomposed into two one-sided null hypotheses, H01 and 
H02, with their accompanying alternatives: 
H01: 
 T  R  vs. 
Ha1: 
µ T  µ R   δ 
H02: 
µ T  µ R  δ 
vs. 
Ha2: 
µ T  µ R  δ 
Due to the nature of normal-theory confidence intervals, the test of the null hypothesis at the = 0.05 
level is equivalent to carrying out two one-sided tests of the above null hypotheses each at the = 0.05 
level of significance. The rejection of both null hypotheses H01 and H02 at the = 0.05 level is 
equivalent to the inclusion of the 90% confidence interval for T R in the acceptance range.  


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Rejection of both null hypotheses H01 and H02 for both endpoints Cmax and AUC0-tz of both analytes 
ibuprofen and pseudoephedrine-HCL will lead to the conclusion of bioequivalence. 
8.3.11.3 
Secondary analysis 
The primary analysis of section 8.3.11.2 will be repeated for AUC0-∞ for ibuprofen and 
pseudoephedrine-HCL and for Cmax, AUC0-tz and AUC0-∞ for R-ibuprofen and S-ibuprofen. The same 
methods will be applied for the S/R-ibuprofen ratio for AUC0-tz. 
8.3.12 
Safety Analysis 
The analysis of the safety variables will be based on the safety set. 
8.3.12.1 
Adverse Events 
The following listings will be produced: 
 All pre-treatment AEs and TEAEs. 
 Withdrawals due to AEs (if applicable). 
 Serious AEs (SAEs) (if applicable). 
The following information will be included in the listings: AE number, reported term, System Organ 
Class (SOC), Preferred Term (PT), start and end date/time, intensity, causality, action taken, outcome, 
classified as serious and treatment emergence. 
Numbers of TEAEs will be summarized by treatment, SOC, PT, and also by treatment, SOC, PT and 
severity and also by treatment, SOC, PT and causality to treatment. In addition serious TEAES will be 
summarized by treatment, SOC and PT. 
8.3.12.2 
Clinical Safety Laboratory Tests (haematology, biochemistry and urinalysis) 
Laboratory values (haematology, biochemistry and urinalysis) will be listed by subject and study time 
point. The baseline for the laboratory values will be the last pre dose results. 
All values outside the clinical reference ranges will be flagged in the data listings. The abnormal values 
will be flagged with ‘L’ for values below the lower limit of the clinical reference range and ‘H’ for 
values above the upper limit of the clinical reference range and included in the listings. The 


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Investigator will assess whether the values outside the clinical reference range are clinically significant 
and these will be reported as abnormal not clinically significant (NCS) or abnormal clinically 
significant (CS). Clinically significant laboratory values will be recorded by the Investigator as AEs. 
Abnormal clinical lab values will be listed separately for clinical chemistry, haematology and 
urinalysis. 
Descriptive statistics (for non-categorical data including haematology and biochemistry) will be 
presented by treatment and time point for both individual values (N, mean, SD, median, minimum, 
maximum). 
8.3.12.3 
Vital Signs 
Vital signs data will be listed by subject including changes from baseline. The baseline for the vital 
signs measurements will be the pre-dose measurement. 
Descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values and changes 
from baseline will be presented by treatment and time point. 
8.3.12.4 
Twelve-Lead Electrocardiogram 
All ECG parameters obtained from the ECG measurement will be listed by subject for each treatment 
and time point. There will be no change from baseline for ECG. 
Descriptive statistics (n, mean, SD, median, minimum, maximum) for absolute values will be presented 
by treatment and time point. 
8.3.12.5 
Physical Examination 
The results of the physical examination will be listed by subject and time-point. 
 
 


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9. 
REFERENCES 
1. SAS® Version 9.3 of the SAS System for Personal Computers. Copyright ©2012. SAS Institute 
Inc. SAS and all other SAS Institute Inc. product or service names are registered trademarks or 
trademarks of SAS Institute Inc., Cary, NC, USA. 
2. WinNonlin Professional Software Version 6.3. http://www.pharsight.com 
3. CPMP/EWP/QWP/1401/98 Rev. 1/ Corr, Guideline on the investigation of bioequivalence, 
London, 20 January 2010.  
 
 


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