A Randomized, Double-blind, Multi-site, Comparator-controlled, Phase III Trial to Evaluate the Efficacy and Safety of a Fixed-dose Combination of Tramadol Hydrochloride and Diclofenac Sodium in Acute Moderate to Severe Pain After Third Molar Extraction
Phase: PHASE3
Conditions: Acute Pain
Sponsor: Grünenthal GmbH

Confidential
Protocol KF8001-01
including Amendment 02
Page 1 of 72
SDR-PRO-TEMPLATE-02
CONFIDENTIAL
The contents of this document may not be disclosed to any other person without written permission from the sponsor, 
unless required by good clinical practice or applicable regulatory requirements. Any supplemental documentation for 
the clinical trial is also covered by this provision.
Trial code:
KF8001-01
Title of trial:
A randomized, double-blind, multi-site, comparator-controlled, Phase III trial to 
evaluate the efficacy and safety of a fixed-dose combination of tramadol 
hydrochloride and diclofenac sodium in acute moderate to severe pain after 
third molar extraction
Brief title:
Tramadol/diclofenac fixed-dose combination Phase III trial in acute pain after 
third molar extraction
Indication:
Moderate to severe acute pain after third molar extraction
Coordinating
investigator a:
DMD, PhD
USA
Phone 
Trial sites:
Multi-site trial (up to 10 sites in Mexico)
Documentation of the involved trial sites will be maintained.
Trial sponsor a:
Grünenthal S.A.
Edificio Torres de las Américas
C-3100 Panama City
Panama
Sponsor’s signatory a:
 MD
Head of Clinical Product Development Latin America
grunenthal.com
Public contact point a:
Clinical Operations Project Manager
grunenthal.com
a) Contact detail changes during the course of the trial will be documented and do not require a protocol amendment.
Version
Date
DMS version number
Valid for
Original
08 Apr 2016
1.0
Mexico
Amendment 01
07 Sep 2016
2.0
Mexico
Amendment 02
19 Oct 2017
3.0
Mexico
Universal Trial Number:
U1111-1179-2333
DMS version: 
 
ID: 
 
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GRUNENTHAL
NCT03714672 Date:19Oct2017 

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1
PROTOCOL SYNOPSIS
1.1
Trial design
This is a prospective, randomized, double-blind, diclofenac- and tramadol-controlled, parallel-
group, multi-site, interventional Phase III trial to evaluate the analgesic efficacy and safety of 
administration of fixed-dose combinations (FDCs) of tramadol hydrochloride (HCl)/diclofenac 
sodium (25 mg/25 mg and 50 mg/50 mg) in subjects with acute moderate to severe pain after third 
molar extraction. All subjects will receive a 24-hour treatment course.
1.1.1
Flow diagram summary of the trial
The investigational medicinal products (IMPs) will be administered as soon as the subject’s baseline pain intensity has 
been evaluated and meets the criteria of moderate to severe pain (i.e., ≥5 on an 11-point numerical rating scale [NRS]) 
within 4 hours after the end of the surgery. The IMP administration will be repeated after 8 hours (±10 minutes) at the 
clinic and after 16 hours (1 hour) at home.
HCl = Hydrochloride, n = number of subjects treated.
1.1.2
Brief description of the sequence and duration of all trial periods
The trial is divided into 3 periods. The Enrollment Period comprises the Enrollment Visit [Visit 1] 
on Day -10 to Day -1 and an at least 24-hour washout of previously used analgesic medication. The 
Treatment Period includes dental surgery and treatment allocation on Day 1 (Allocation Visit, 
Visit 2), administration of 2 investigational medicinal product (IMP) doses at the site and of a third 
dose in an out-patient setting, and an End-of-treatment Visit (Visit 3) at the site. A Follow-up 
Period concludes with a phone call or an on-site visit (Final Visit) on Day 14 to assess subject’s 
safety.
See Section 1.1.1 for a summary of the trial as a flow diagram and Section 1.8 for a tabular schedule 
of events.
Each subject is expected to be in the trial for approximately 14 days to 24 days.
Tramadol HCl/diclofenac sodium 25 mg/25 mg (n = 200)
Diclofenac sodium 50 mg (n = 200)
A
L
L
O
C
A
T 
I
O
N
Tramadol HCl 50 mg (n = 200)
Tramadol HCl/diclofenac sodium 50 mg/50 mg (n = 200)
Enrollment
Visit 1 
(Day -10 to Day -1)
Third 
molar 
extractions
Washout
Period
(24 hours)
Visit 2 
(Day 1)
Visit 3 
(Day 2)
Follow-up
safety
assess-
ment
Visit 4 
(phone call or
on-site visit)
(Day 14)
End of trial
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1.2
Trial objectives and endpoints/outcomes
Objective
Endpoint/outcome
Primary
Primary
The primary objective is to demonstrate the 
analgesic efficacy of the tramadol 
HCl/diclofenac sodium FDC at 2 dose levels 
(50 mg/50 mg, 25 mg/25 mg) in comparison 
to the monotherapy of diclofenac sodium 
50 mg and tramadol HCl 50 mg.
The specific primary objective is to 
demonstrate that:
•
Either tramadol HCl/diclofenac sodium 
50 mg/50 mg has superior analgesic 
efficacy than monotherapy with 
diclofenac sodium 50 mg, 
•
Or tramadol HCl/diclofenac sodium 
50 mg/50 mg has superior analgesic 
efficacy than monotherapy with tramadol 
HCl 50 mg,
•
Or tramadol HCl/diclofenac sodium 
25 mg/25 mg is not inferior to 
monotherapy with tramadol HCl 50 mg,
•
Or tramadol HCl/diclofenac sodium 
25 mg/25 mg is not inferior to 
monotherapy with diclofenac sodium 
50 mg.
•
Pain relief expressed as Total Pain Relief 
over the 4 hours post-dose period 
(TOTPAR4).
Secondary
Secondary
To further explore the efficacy of the 
tramadol HCl/diclofenac sodium FDC at 
2 dose levels (50 mg/50 mg, 25 mg/25 mg) in 
comparison to the monotherapy of diclofenac 
sodium 50 mg and tramadol HCl 50 mg.
•
Total Pain Relief at 6 hours (TOTPAR6), 
8 hours post-dose (TOTPAR8). 
•
Summed Pain Intensity Difference (SPID) 
at 4, 6, 8, and 24 hours post-dose.
•
Time to achieve a 50% reduction in baseline 
pain (pain at least half gone).
•
Time to onset of first perceptible pain relief.
•
Time to onset of meaningful pain relief.
•
Time to intake of first rescue medication 
dose.
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Objective
Endpoint/outcome
To compare the overall impression of the 
subject on the treatment they received.
•
Subject’s global evaluation of the treatment 
(5-point Likert Scale) 8 hours or before first 
intake of rescue medication (whatever the 
first) and 24 hours after the first dose of 
IMPs.
To evaluate the safety profile of the FDC
product in comparison to the safety profiles of 
the monotherapies.
•
Incidence and type of adverse events.
Data collected not directly supporting an objective
Data collected
Rationale for collecting data not directly 
supporting an objective
•
Date of signature on the informed consent 
form, sex, age, smoking status, race, 
ethnicity, height and weight, body mass 
index (calculated). 
•
Prior/concomitant medication. 
•
Clinically relevant medical history 
(prior/concomitant diseases and surgical 
interventions). 
•
Physical examination outcome.
•
Radiological examination result. 
•
Details on local anesthesia and surgery.
•
Surgical outcomes (number of teeth, 
degree of impaction of each tooth, 
duration of surgery, amount and timing of 
all anesthetic drugs).
•
Vital signs results. 
•
Pregnancy test results.
•
Clinical laboratory parameters (clinical 
chemistry, hematology, and coagulation)
and urinalysis results.
Demographic data and other subject 
characteristics; data required to judge on 
inclusion or exclusion of subjects; data required 
for safety evaluation.
1.3
Trial subjects - the population to be studied
Subjects are eligible for the trial if they are in good general health (except for the third molars
requiring extraction) as it will be determined by medical history evaluation and a physical 
examination. They must comply with the inclusion/exclusion criteria given.
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1.3.1
Inclusion criteria
1.
The subject has read the informed consent form, has understood the relevant aspects of the 
clinical trial, and grants his/her authorization to participate by signing the informed consent 
form prior to the inclusion in the clinical trial and the performance of any procedure.
2.
Male and female subjects >18 years to 60 years.
3.
Female subjects of childbearing potential must be practicing an acceptable method of birth 
control and must have a negative urine pregnancy test at enrollment with confirmation at 
Visit 2.
4.
Subjects are in good health, i.e., the medical record, vital signs, physical examination, and 
laboratory parameter assessments do not show any abnormal deviations impeding the 
participation in the clinical trial.
5.
Subjects requiring extraction of 3 or more third molars with 2 mandibular impacted third 
molars.
6.
Clinical and radiological diagnosis of impacted lower third molars.
7.
Class I and Class II molars according to Pell and Gregory’s classification (Gay Escoda et al. 
2004).
8.
Subjects must be able to swallow the IMPs.
1.3.2
Exclusion criteria
1.3.2.1
Exclusion criteria at Visit 1
1.
Findings in the medical record, vital signs, and/or physical examination demonstrating 
abnormal conditions of subject’s general state of health preventing his/her participation in the 
clinical trial according to the investigator’s opinion.
2.
Subject unable to speak, read, or write in Spanish language.
3.
Clinical laboratory parameters exceed the pre-defined alert ranges (i.e., 1 standard deviation 
above or below the upper/lower limit of the normal ranges).
4.
Known hypersensitivity to the IMPs, the anesthetic to be used during surgery, or to the rescue 
medication (ibuprofen, ketorolac).
5.
Known alcohol or drug abuse in the last 6 months or any history of seizures. Alcohol abuse is 
defined as the consumption of more than 3 ounces (about 90 mL) of liquor or spirits or 
18 ounces (about 530 mL) of beer per day, for 5 consecutive days during the 6-month period. 
Drug abuse is defined as the use of any recreational drug for 5 consecutive days during the 
6-month period.
6.
Subjects who take analgesic medication for chronic pain, monoamine oxidase inhibitors, 
tricyclic antidepressants, neuroleptics, or other drugs that reduce the seizure threshold within 
4 weeks of enrollment.
7.
Pregnant or lactating women.
8.
Subjects who received systemic corticosteroids or opioid analgesics less than 2 weeks before
surgery.
9.
Subjects with molars linked to the mandibular canal.
10. Subjects requiring immediate dental procedures other than third and fourth molars extraction.
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1.3.2.2
Exclusion criteria at Visit 2
11. Subject received a long-acting non-steroidal anti-inflammatory drug (NSAID) within 24 hours 
or 5 times the elimination half-life of that drug prior to surgery, whatever the longer.
12. Subject received any analgesic medication other than short-acting pre-operative or intra-
operative anesthetic agents within 24 hours before taking IMPs.
13. Subject received more than 300 mg of lidocaine in total.
14. Subject received any analgesic medication other than the IMPs immediately after the oral 
surgical procedure was completed.
15. Baseline pain intensity of the subject after oral surgical procedure remains below 5 points on 
the 11-point numerical rating scale (NRS).
1.4
Trial treatments
1.4.1
Investigational medicinal products
Subjects will be randomly allocated to 1 of 4 groups of treatments in a 1:1:1:1 ratio. 
Group A: Diclofenac sodium 50 mg, enteric-coated tablets, oral.
Group B: Tramadol HCl 50 mg, immediate-release capsules, oral.
Group C: Tramadol HCl/diclofenac sodium 50 mg/50 mg FDC, immediate-release tablets, oral.
Group D: Tramadol HCl/diclofenac sodium 25 mg/25 mg FDC, immediate-release tablets, oral.
In all treatment groups, each dose comprises 1 active treatment and 3 placebo tablets or capsules 
matching the other active treatment groups. All subjects will receive IMPs on Day 1 covering 
24 hours of treatment (1 dose each at 0 hours, 8 hours, and 16 hours).
1.4.2
Rescue medication
Subjects will be encouraged to wait for at least 120 minutes after each dose of IMP before taking 
any rescue medication to allow for sufficient time for the IMP to take effect.
Rescue medication (ibuprofen 400 mg, oral, as often as every 6 hours) will be allowed in case of 
pain due to the dental extraction and will be available to the subject throughout the trial. Ketorolac 
tromethamine (30 mg, intramuscular, as often as every 4 hours to 6 hours) may be applied as 
second-line rescue medication at the site if ibuprofen 400 mg fails to relieve pain within 2 hours.
The number of units used, frequency of use, and the observation of any possible adverse event must 
be reported in the case report form (CRF) and in the source document(s).
1.4.3
Anesthetics for standardized surgery
Commercially available cartridges containing 36 mg of lidocaine hydrochloride plus 0.018 mg of 
epinephrine in a total volume of 1.8 mL will be provided by the sponsor.
1.5
Prior/concomitant medications
The use of antibiotics and other concomitant medications except for analgesics and systemic 
corticosteroids is allowed at the discretion of the investigator. They have to be in line with common 
practice of the investigator and with the information provided in the reference safety information 
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(investigator’s brochure). All concomitant medications must be reported in the CRF and the source 
document(s).
1.6
Statistical analyses
The primary endpoint TOTPAR4 will be calculated as a weighted sum of the observed pain relief 
scores during the first 4 hours after first dose with weights proportional to the time since the last 
pain relief assessment and time since previous pain relief assessment for all subsequent 
assessments. TOTPAR scores can be interpreted as estimates of the area under the longitudinal pain 
relief curve (AUC). 
1.6.1
Sample size rationale
A total number of 720 subjects or 180 subjects per treatment group are required to achieve an 
overall power of at least 85% to reject the null hypothesis of at least 1 of the 4 formal statistical 
tests in the primary analysis of the trial (1-sided t-test, type I error of α/4 with α = 2.5%) assuming a 
common standard deviation of change from baseline values of 4 points (TOTPAR4) and an 
expected treatment difference of at least 2 points (TOTPAR4) on the primary efficacy endpoint in 
the comparisons between tramadol HCl/diclofenac sodium 50 mg/50 mg and the monotherapies of 
diclofenac sodium 50 mg and tramadol HCl 50 mg, and using a non-inferiority margin of 
= 1.5 points (TOTPAR4). To achieve 180 evaluable subjects per arm and accounting that up to 
10% of subjects will not be evaluable for the analysis set for the primary analysis, 200 subjects per 
arm or 800 subjects in total will be allocated to IMP.
Assuming an enrollment failure rate of about 25% which is usually observed in clinical trials in 
Mexico, about 1065 subjects are planned to be enrolled (i.e., sign the informed consent) in order to 
allocate 800 subjects to IMP, i.e., about 130 subjects per trial site in approximately 8 to 12 sites.
1.6.2
Subject populations
The Safety Set will comprise all subjects allocated and treated with IMPs. The Full Analysis Set 
(FAS) will comprise all subjects allocated and treated, and with at least 1 non-missing pain relief 
assessment during the first 4 hours post-baseline. The Per Protocol Set (PPS) will comprise a subset 
of the subjects in the FAS without any major protocol deviations affecting the primary endpoint
analysis.
1.6.3
Statistical methods and analysis
Treatment allocation will be stratified to ensure an equal distribution of subjects with severe
baseline pain among the 4 treatment groups.
The primary analysis will be performed on the FAS. The primary analysis model will be an analysis 
of covariance (ANCOVA) with treatment, baseline pain, and site as covariates. 
Each of the 4 treatment comparisons of the specific primary objective of the trial will be conducted 
based on results of the primary analysis and will be investigated by a formal statistical test. The trial 
will be positive if the null hypothesis of at least 1 of the 4 formal statistical tests gets rejected. A 
Bonferroni-Holm procedure will be used to control the trial family-wise error rate (FWER) in the 
strong sense at the pre-defined significance level of α = 2.5% (1-sided).
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For the non-inferiority comparisons, a non-inferiority margin of = 1.5 points (TOTPAR4) will be 
used.
Missing pain relief assessments in the first 4 hours after first dose as well as pain relief assessments 
after start of intake of rescue medication use will be imputed as follows:
•
by Last Observation Carried Forward (LOCF) for intermittent missing data, 
•
by substitution by δ of missing data after premature discontinuation from the trial or 
disregarded pain relief assessments after start of rescue medication intake.
The parameter δ depends on the reason for discontinuation and treatment group. The primary 
analysis will be repeated as sensitivity analysis on the PPS. Additional sensitivity analyses will use 
classical single imputation techniques (LOCF, substitution by Zero) to investigate the impact of 
missing data approach on the constancy assumption.
1.7
References (synopsis)
Gay Escoda C, Piñera Penalva M, Velasco Vivancos V, Berini Aytés L. Cordales incluidos. 
Patología, clínica y tratamiento del tercer molar incluído. In: Gay Escoda C, Berini Aytés L. (eds.). 
Tratado de Cirugía Bucal. Tomo I. Madrid: Ergón; 2004. p. 355-85.
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1.8
Schedule of events
Procedure
Visit 1
(Enrollment
Visit)
Visit 2 
(Allocation 
Visit)
Visit 3 
(End-of-
treatment 
Visit)
Visit 4
(Final Visit
[phone call or 
on-site visit])
Day
-10 to -1
1
2
14
Obtain informed consent
X
Distribute subject trial card
X
Evaluate inclusion/exclusion criteria
X
X
Obtain radiological confirmation of impacted 
third molars (if not available from previous 
visit)
X
(X)
Record demographic data (date of informed 
consent, sex, age, race, ethnicity, weight, 
height) and smoking status
X
Record medical and dental history
X
Perform physical examination a
X
Take blood samples for clinical laboratory 
parameter assessments and
urine for urinalysis a, b
X
Record vital signs (pulse rate, systolic and 
diastolic blood pressure, respiratory rate)
X
X
Perform urine pregnancy test (female subjects 
with childbearing potential only)
X
X
Record prior medication
X
Record concomitant medication
X
X
X
Schedule appointment for dental surgery
X
Record details of local anesthesia and dental 
surgery (3rd molar extractions)
X
Allocate subject to treatment group
X
Dispense IMPs
X
Handout 2 stopwatches and a pain assessment 
booklet to each subject
X
Record administration of IMPs
X
Record pain intensity (NRS) c
X
X
Record pain relief (5-point VRS) d
X
Record pain at least half gone (YES/NO) e
X
X
Transfer stopwatch times f to CRF
X
Document IMP intake and rescue medication 
use (request/intake)
X
X
Dispense IMPs to be taken at home and rescue 
medication
X
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Procedure
Visit 1
(Enrollment
Visit)
Visit 2 
(Allocation 
Visit)
Visit 3 
(End-of-
treatment 
Visit)
Visit 4
(Final Visit
[phone call or 
on-site visit])
Day
-10 to -1
1
2
14
Collect IMPs and rescue medication and 
perform drug accountability
X
Record subject’s global evaluation of the 
treatment (5-point Likert scale) g
X
X
Record all adverse events
X
X
X
a) Physical examination results and clinical laboratory parameter and urinalysis data must be available at the latest at 
Visit 2.
b) Clinical laboratory parameter assessments will be performed by contracted local certified clinical laboratories.
c) NRS pain scores will be assessed before the first dose of IMPs, and 15, 30, 45, 60, and 90 minutes (±2 minutes), and 
2, 3, 4, 5, 6, 7, 8, 16, and 24 hours (±6 minutes) after the first dose of IMPs.
d) Pain relief will be assessed 15, 30, 45, 60, and 90 minutes (±2 minutes), and 2, 3, 4, 5, 6, 7, 8, and 16 hours 
(±6 minutes) after administration of the first dose of IMPs.
e) Pain at least half gone (YES/NO) will be answered 15, 30, 45, 60, and 90 minutes (±2 minutes), and 2, 3, 4, 5, 6, 7, 8, 
and 24 hours (±6 minutes) after the first dose of IMPs.
f) Time to onset of first perceptible pain relief (Stopwatch 1) and time to onset of meaningful pain relief (Stopwatch 2).
g) Subject’s global evaluation of the treatment will be assessed 8 hours after the first dose of IMPs or before first intake 
of rescue medication (whatever the first), and 24 hours after the first dose of IMPs.
CRF = case report form; IMP = investigational medicinal product; NRS = numerical rating scale; VRS = verbal rating 
scale.
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2
TABLE OF CONTENTS
1
PROTOCOL SYNOPSIS
2
1.1
Trial design
2
1.1.1
Flow diagram summary of the trial
2
1.1.2
Brief description of the sequence and duration of all trial periods
2
1.2
Trial objectives and endpoints/outcomes
3
1.3
Trial subjects - the population to be studied
4
1.3.1
Inclusion criteria
5
1.3.2
Exclusion criteria
5
1.4
Trial treatments
6
1.4.1
Investigational medicinal products
6
1.4.2
Rescue medication
6
1.4.3
Anesthetics for standardized surgery
6
1.5
Prior/concomitant medications
6
1.6
Statistical analyses
7
1.6.1
Sample size rationale
7
1.6.2
Subject populations
7
1.6.3
Statistical methods and analysis
7
1.7
References (synopsis)
8
1.8
Schedule of events
9
2
TABLE OF CONTENTS
11
LIST OF IN-TEXT TABLES
15
3
ABBREVIATIONS AND DEFINITIONS OF TERMS
16
3.1
Abbreviations
16
3.2
Definition of terms
17
4
ETHICS
18
4.1
Independent ethics committees
18
4.2
Subject information and informed consent
18
4.3
Informing the subject’s healthcare provider
18
5
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE
19
5.1
Investigators and trial site personnel
19
5.1.1
Investigators
19
5.1.2
Trial site personnel assigned trial-related duties
19
5.2
Contract research organizations
20
5.3
The sponsor and sponsor’s personnel
20
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6
INTRODUCTION AND TRIAL BACKGROUND
20
6.1
Introduction
20
6.2
Relevant non-clinical and clinical data
20
6.3
Trial rationale
21
7
TRIAL OBJECTIVES AND ENDPOINTS
21
7.1
Definition of primary endpoint
21
8
TRIAL DESIGN
22
8.1
Discussion of the trial design
22
8.1.1
Rationale for the IMPs and the selected doses
22
8.1.2
Rationale for the number and the frequency of visits/assessments
23
8.2
Benefit/risk analysis
23
9
SUBJECT ENROLLMENT AND TRIAL DISCONTINUATION
23
9.1
Subject enrollment procedure
23
9.1.1
Handling of low enrollment
23
9.2
Inclusion/exclusion criteria
23
9.3
Subject discontinuation from the trial or IMP
24
9.3.1
Subject discontinuation from the trial
24
9.3.2
Subject discontinuation from the IMPs
24
9.3.3
Procedure for the handling of discontinued subjects
24
9.3.4
Premature termination or suspension of the trial
25
10
TRIAL TREATMENTS
25
10.1
Investigational medicinal products
25
10.1.1
Identity and composition – tramadol hydrochloride/diclofenac sodium 
fixed-dose combination tablets
25
10.1.2
Identity and composition – diclofenac sodium tablets
26
10.1.3
Identity and composition – tramadol capsules
26
10.1.4
Identity and composition – placebo capsules and tablets
26
10.1.5
Packaging and labeling
26
10.1.6
Delivery, storage, and disposal
26
10.2
Administration of investigational medicinal products
27
10.3
Method of assigning subjects to treatment groups (allocation)
27
10.4
Blinding and unblinding
28
10.4.1
Methods of blinding
28
10.4.2
Methods of unblinding
28
10.4.3
Identification of IMPs in emergency situations
28
10.5
Rescue medication
29
10.6
Lidocaine/epinephrine for anesthesia
29
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10.7
Allowed and forbidden concomitant medications
29
10.8
Documentation of drug accountability
29
11
COURSE OF THE TRIAL AND CONDITIONS
30
11.1
Course of the trial
30
11.1.1
Enrollment Period (Visit 1)
30
11.1.2
Treatment Period (Visit 2 and Visit 3)
31
11.1.3
Final Visit (follow-up phone call or on-site visit on Day 14)
34
11.2
Conditions during the trial
34
11.2.1
Medical care
34
11.2.2
General restrictions
34
11.2.3
Meals and fluid intake restrictions
34
11.2.4
Counseling of women of reproductive age
35
11.2.5
Counseling of male subjects
35
11.3
Subject trial cards
35
11.4
Provisions of any additional care of subject after trial termination
35
12
TRIAL ASSESSMENTS
35
12.1
Collection of demographic data and other baseline characteristics
35
12.1.1
Demographic data, height and weight
35
12.1.2
Prior and concomitant medication
36
12.1.3
Relevant prior/concomitant diseases and surgical interventions
36
12.1.4
Dental history
36
12.1.5
Other baseline characteristics
36
12.2
Collection of efficacy data
37
12.2.2
Time to achieve a 50% reduction of baseline pain
38
12.2.3
Subject’s global evaluation of the treatment (Likert scale)
38
12.2.4
Rescue medication request and intake
39
12.3
Collection of safety data
39
12.3.1
Adverse events
39
12.3.2
Vital signs
44
12.3.3
Safety laboratory
44
12.4
Appropriateness of measurements
45
12.5
Compliance
46
13
DOCUMENTATION OF TRIAL DATA
46
13.1
Case report forms
46
13.2
Subject reported outcomes
46
13.3
Data management
47
13.4
Source data
48
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13.5
Investigator’s site file and the trial master file
48
14
QUANTITATIVE ANALYSES
49
14.1
Statistical methods and sample size determination
49
14.1.1
Sample size rationale
49
14.2
General description of statistical analyses
49
14.3
Analysis populations (analysis sets)
50
14.4
Analysis of demographic data and other baseline characteristics
50
14.5
Analysis of efficacy data
50
14.5.1
Analysis population for primary efficacy analysis
50
14.5.2
Overall testing strategy
51
14.5.3
Analysis of primary endpoint
52
14.5.4
Analysis of additional efficacy outcomes
52
14.5.5
Missing data
53
14.5.6
Subgroup analyses
54
14.6
Analysis of safety data
54
14.6.1
Adverse events
54
14.6.2
Clinical laboratory parameters and urinalysis
54
14.6.3
Vital signs
54
15
QUALITY SYSTEM, AUDIT AND INSPECTION
54
15.1
Quality system
54
15.2
Data quality assurance
55
15.3
Inspections
55
16
GENERAL CONDITIONS AND AGREEMENTS
55
16.1
Insurance
55
16.2
Legal regulations
55
16.3
Contracts
56
16.4
Subject data and data protection
56
16.5
Public disclosure
56
16.6
Trial results reporting
56
16.7
Approval
57
16.7.1
Sponsor
57
16.7.2
Coordinating investigator
57
17
REFERENCES
57
18
APPENDIX
60
18.1
List of potentially important medical concepts – classified by System 
Organ Class
60
18.2
Justification of non-inferiority margin
62
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18.3
Previous clinical trials with a combined treatment of tramadol and 
diclofenac
63
18.4
Rescue medication and comparator prescribing information
65
19
PROTOCOL AMENDMENTS
65
19.1
Protocol Amendment 01
65
19.2
Protocol Amendment 02
71
LIST OF IN-TEXT TABLES
Table 1:
Statistical tests and null hypotheses (all 1-sided) of the primary objective 
of the trial
51
Table 2:
Previous clinical trials with combination of tramadol and diclofenac
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3
ABBREVIATIONS AND DEFINITIONS OF TERMS
3.1
Abbreviations
Abbreviation
Explanation
ANCOVA
Analysis of covariance
AUC
Area under the longitudinal pain relief curve
COXIB
Selective cyclooxygenase-2 inhibitor
CRF
Case report form
CRO
Contract research organization
FAS
Full Analysis Set
FDC
Fixed-dose combination
FWER
Family-wise error rate
GCP
Good clinical practice
HCl
Hydrochloride
ICF
Informed consent form
IEC
Independent ethics committee
IMP
Investigational medicinal product
IRT
Interactive Response Technology
IVRS
Interactive voice response system
IWRS
Interactive web response system
LOCF
Last Observation Carried Forward
LoE
Lack of efficacy
MedDRA
Medical Dictionary for Regulatory Activities
NRS
Numerical rating scale
NSAID
Non-steroidal anti-inflammatory drug
PID
Pain Intensity Difference
PPS
Per Protocol Set
SAE
Serious adverse event
SMO
Site Management Organization
SOP
Standard operating procedure (used as synonym for all procedural documents)
SPID
Summed Pain Intensity Difference
TOTPAR
Total Pain Relief
VRS
Verbal rating scale
WHO-DD
World Health Organization-Drug Dictionary
Système International d’Unités units and standard hematological and biochemical abbreviations are not listed.
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3.2
Definition of terms
Term
Definition
Allocated subjects
Enrolled subjects who are allocated to IMPs.
Applicable regulatory 
requirement(s)
Any law(s) and regulation(s) addressing the conduct of clinical trials of IMPs of the 
jurisdiction where the trial is conducted.
Discontinuation
The act of concluding the participation of an enrolled subject in a trial prior to 
completion of all activities required by the protocol.
End of the trial
The trial-related end of the trial is defined as the date of last subject out. 
The subject-related end of trial is defined as date of last contact with the subject 
according to the protocol.
Enrolled subjects
Subjects who signed an informed consent form.
Enrollment failures
Enrolled subjects who were not allocated to IMP.
First subject allocated
First subject that was allocated to IMP.
First subject in
Date of first enrolled subject.
Investigational medicinal 
product
A generic term describing the preparations under investigation in this trial, i.e., the 
FDC product under development or comparator.
Last subject out
Date of last contact with the last subject according to the protocol. 
Screened subjects
Screened subjects are subjects undergoing screening. Screening is any activity 
concerning subjects who could potentially be enrolled into the trial before the informed 
consent form is signed.
Subject
Individual who participates in a clinical trial, either as recipient of an IMP or as 
control.
Treated subjects
Subjects with at least 1 administration of IMP.
Treatment completers
Treatment completers are treated subjects who completed IMP administration 
according to the protocol.
Use of the terms “must” and “should”
When “must” is used, the action/item is always mandatory. Non-compliance with this instruction 
constitutes a protocol deviation. 
When “should” is used, the action/item is recommended but not mandatory. Non-compliance with 
this instruction does not constitute a protocol deviation. 
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4
ETHICS
This trial will be conducted according to this protocol, the ethical principles that have their origin in 
the Declaration of Helsinki, good clinical practice (GCP), and applicable regulatory requirements.
This trial will be registered in public registries according to the local laws and requirements.
4.1
Independent ethics committees
The relevant independent ethics committees (IECs) for this trial will be provided with all documents 
required to fulfill their responsibilities. Any updates thereof will be provided according to GCP and 
applicable regulatory requirements. All correspondence between the IECs and the investigators at 
the trial sites will be retained in the investigator’s site file and copies provided to the CRO/sponsor 
for the trial master file.
Trial activities will only start when approval from the relevant IECs is available.
Documentation of all involved IECs will be maintained according to GCP and applicable regulatory 
requirements.
4.2
Subject information and informed consent
Before any trial-related procedure will be performed, freely given informed consent must be 
obtained.
The informed consent discussion, the information sheet (if used) and the informed consent form 
provided to subjects must adhere to GCP and applicable regulatory requirements. The informed 
consent discussion with the subject must be performed by the principal investigator or an 
appropriately trained delegate. The information sheet and informed consent form agreed with the 
sponsor must be used. Prior to use, these documents must be approved by the relevant IECs. Each 
subject must be provided with a duplicate of the signed informed consent form for their records.
Subjects must be informed as soon as possible if new information becomes available that may be 
relevant to their willingness to continue participation in the trial. The communication of this 
information must be documented.
4.3
Informing the subject’s healthcare provider
Only if the subject agrees in writing in the informed consent form and is being treated by a 
healthcare provider, e.g., general practitioner, the subject’s healthcare provider should be informed 
about the subject’s participation in the trial at trial enrollment. The healthcare provider should be 
informed about the trial code, the principal investigator’s name, and a contact (phone) number at the 
trial site. 
Any communication with the healthcare provider must be documented in the subject’s medical 
records or the investigator’s site file.
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5
INVESTIGATORS AND TRIAL ADMINISTRATIVE STRUCTURE
5.1
Investigators and trial site personnel
5.1.1
Investigators
The trial may be conducted solely at a dental clinic, or management of a subject may be shared 
between a dental clinic and a local research facility of a Site Management Organization (SMO). The 
latter combination is considered a single trial site. 
There must be an investigator at each trial site. 
If the trial is conducted by a team of individuals at the trial site, the investigator leading and 
responsible for the team is called the principal investigator. For each of the local research facilities, 
a principal investigator will be designated and will have primary responsibility for compliance with 
the protocol and GCP at that site (see Section 5.1.2).
All persons assigned responsibility as principal investigator must sign a declaration of their 
responsibilities and their agreement to this protocol before any trial-related procedure is performed.
Curriculum vitae and/or other relevant documents confirming the current qualification of the 
investigators must be provided to the sponsor. This should include any previous training in the 
principles of GCP, experience obtained from work with clinical trials, and experience with subject 
care.
Documentation of all involved investigators must be maintained according to GCP and applicable 
regulatory requirements.
In different countries, there may be country-specific terminology used for the investigator role.
A coordinating investigator will be defined who is responsible for the coordination of principal 
investigators at multiple trial sites in 1 country.
Documentation of all responsibilities assigned to the coordinating investigator must be maintained 
according to GCP and applicable regulatory requirements.
5.1.2
Trial site personnel assigned trial-related duties
The principal investigator may define appropriately qualified personnel at a trial site to perform 
significant trial-related procedures and/or to make trial-related decisions under his/her supervision. 
In this case, the principal investigator must maintain a signed list of the persons to whom they
delegate significant trial-related duties/responsibilities; the delegated trial-related 
duties/responsibilities must be specified in the list.
When personnel or responsibility changes are made, the principal investigator must ensure that the
relevant documentation is updated before any trial-related activities are performed. 
Documentation of all involved trial site personnel performing significant trial-related procedures 
and/or making trial-related decisions must be maintained according to GCP and applicable 
regulatory requirements.
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5.2
Contract research organizations
Contract research organizations (CRO; commercial, academic or other, e.g., local laboratory 
facilities, trial supply management provider, electronic CRF provider) may be contracted by the 
sponsor to perform trial-related duties and functions. The extent of the delegation must be 
documented. All involved CROs will be required to have implemented quality control and quality 
assurance processes, and to support the sponsor’s quality control and quality assurance measures.
Documentation of all involved CROs must be maintained according to GCP and applicable 
regulatory requirements. Documentation of any delegation of responsibilities to CROs must be 
maintained in the trial master file.
5.3
The sponsor and sponsor’s personnel
The trial sponsor listed on the title page accepts the responsibilities of the sponsor according to GCP 
and applicable regulatory requirements.
The sponsor must designate appropriately qualified personnel to advise on trial-related topics. The 
trial site will be provided with contact details for these personnel before any trial-related procedure 
is performed. 
A list of key sponsor personnel involved in the preparation of this protocol and the conduct of the 
trial, including their full names, titles, roles, and responsibilities, must be maintained.
If non-sponsor monitors are involved in the monitoring of this trial, a list of all non-sponsor 
monitors including their full names, addresses, and responsibilities, must be maintained.
6
INTRODUCTION AND TRIAL BACKGROUND
6.1
Introduction
The American Society of Anesthesiologists Task Force on Acute Pain Management (2004) states in 
its update report of the practice guidelines for acute pain management in the perioperative setting
that literature supports the administration of 2 analgesics that act by different mechanisms via a 
single route to provide superior analgesic efficacy with equivalent or reduced adverse effects. The 
Task Force believes that NSAID, selective cyclooxygenase-2 inhibitor (COXIB), or acetaminophen 
administration has a dose-sparing effect for systemically administered opioids. Whenever possible, 
doctors should use the strategy of multimodal or balanced analgesia aiming to individualize therapy 
of acute pain. This consensus group has suggested that the development of new drug combinations 
or routes of administration are opportunities to improve pain management meeting the individual 
needs of every patient. 
6.2
Relevant non-clinical and clinical data
Grünenthal is Marketing Authorization Holder for tramadol/diclofenac FDC tablets (25 mg/25 mg 
or 50 mg/50 mg of tramadol HCl/diclofenac sodium), which are indicated for the relief of acute 
inflammatory pain of moderate to severe intensity. In adults and young people over 16 years old, 
the total daily dose of diclofenac sodium must not exceed 200 mg, resulting in a maximum tramadol 
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HCl daily dose of 200 mg for the FDC as well. The maximum single dose is 1 tablet every 6 hours 
as needed for pain relief and up to a maximum of 4 tablets per day. 
The 25 mg/25 mg tablets are marketed under the tradename Adorlan Comprimidos® or Adorlan 
Tabletas® in 7 countries in Latin America: Colombia, Dominican Republic, Ecuador, El Salvador, 
Guatemala, Honduras, and Panama. Based on the sales of more than 34 million single-dose units 
since the International Birth Date (05 Oct 2009) of the product, the estimated total cumulative post 
authorization patient exposure to diclofenac/tramadol was between 8.6 million (with 4 tablets per 
day) and 11.5 million patient treatment days (with 3 tablets per day) for the time period from 
Jan 2011 (first launch) to Oct 2015 (data lock point 04 Oct 2015 for most recent Periodic Safety 
Update Report).
For details about the clinical particulars, contraindications, and special warnings and precautions for 
use, interactions with other medicinal products and other forms of interaction, and adverse drug 
reactions, please see the investigator’s brochure.
Previous clinical trials in various indications have demonstrated a benefit of the combined treatment 
with tramadol and diclofenac (see Appendix 18.3).
6.3
Trial rationale 
The combination of analgesics is a common therapeutic practice (e.g., in ZALDIAR which 
combines tramadol HCl and acetaminophen/paracetamol). Combining tramadol with diclofenac is 
expected to provide the beneficial analgesic effects of the 2 products. The components are 
anticipated to be complementary. Pre-clinical studies and clinical trials in inflammatory pain 
models showed that the combination of tramadol and diclofenac has a synergistic and additive 
effect that allows its administration at tramadol HCl 25 mg and diclofenac sodium 25 mg doses, 
with analgesic efficacy and safety in inflammatory pain conditions (Rodríguez-Silverio et al. 2011, 
Auad Saab et al. 2009, Auad et al. 2009).
This trial is conducted in order to complete the dossier on the tramadol HCl/diclofenac sodium FDC 
to obtain the registration in the Latin American countries. It is expected to demonstrate the safety 
and efficacy of the FDC product in comparison to the respective monotherapies.
7
TRIAL OBJECTIVES AND ENDPOINTS
The overall objective of the trial is to evaluate the analgesic efficacy and safety of the tramadol 
HCl/diclofenac sodium FDC at 2 dose levels (50 mg/50 mg, 25 mg/25 mg) in comparison to the 
monotherapy of diclofenac sodium 50 mg and tramadol HCl 50 mg.
The specific primary and secondary trial objectives as well as primary and secondary endpoints are 
listed in Section 1.2.
The primary endpoint is defined in detail in Section 7.1.
7.1
Definition of primary endpoint
Pain relief will be assessed at 15, 30, 45, 60, and 90 minutes, and at 2, 3, 4, 5, 6, 7, 8, and 16 hours 
after first dose using a 5-point verbal rating scale (VRS) with categories 0 (none), 1 (a little), 2 
(some), 3 (a lot), or 4 (complete) (see Section 12.2.1.2).
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The primary endpoint of the trial will be 4-hour Total Pain Relief (TOTPAR4). TOTPAR4 is a 
time-weighted measure of AUC up to 4 hours and is a summary measure that integrates serial 
assessments of a subject’s pain over the duration of 4 hours after first dose. 
TOTPAR4 scores will be calculated as ΣPRt = 4 x [time (hours) elapsed since previous observation] 
where PRt = 4 is the Pain Relief at time point t = 4 in comparison to the assessment before 
administration of IMPs (Max and Laska 1991). For the first pain relief assessment, time (hours) 
elapsed since previous observation is time since first dose of IMP. Pain relief assessments after start 
of rescue medication intake (Section 10.5) will be set to missing and will be imputed as described in 
the statistical section (see Section 14.5.5).
Minimum and maximum potential value for TOTPAR4 are 0 and 16 points, corresponding to a 
value of 0 (none) or 4 (complete) at all pain relief assessments in the first 4 hours after first dose,
respectively. 
8
TRIAL DESIGN
This is a prospective, randomized, double-blind, diclofenac- and tramadol-controlled, parallel-
group, multi-site, interventional Phase III trial to evaluate the analgesic efficacy and safety of 
administrations of tramadol HCl/diclofenac sodium FDCs (25 mg/25 mg and 50 mg/50 mg) in 
subjects with acute moderate to severe pain after third molar extraction.
8.1
Discussion of the trial design
The analgesic control of acute moderate to severe pain after third molar extraction is a 
well-established model to demonstrate safety and efficacy of analgesic anti-inflammatory drugs 
(Barden et al. 2004). The randomized design and the use of matching placebos permit a fair and 
unbiased comparison of the tramadol HCl/diclofenac sodium FDC at 2 levels (25 mg/25 mg and 
50 mg/50 mg) with the monotherapies diclofenac sodium 50 mg and tramadol HCl 50 mg. 
The TOTPAR was selected as primary variable as it is most sensitive to detect pain differences
(Singla et al. 2015). The analysis after 4 hours (TOTPAR4) minimizes the impact an additional 
intake of rescue medication might have. Furthermore, an analysis after 4 hours allows a comparison 
of the efficacy of the FDC with the efficacy of the monotherapies (diclofenac or tramadol) before 
plasma levels drop below published minimum effective concentrations (data on file, Phase I trial for 
Adorlan).
The tramadol HCl/diclofenac sodium FDC 25 mg/25 mg is currently registered and marketed under 
the tradename Adorlan Comprimidos® or Adorlan Tabletas® in 7 countries in Latin America for 
the relief of mild to moderate inflammatory pain: Colombia, Dominican Republic, Ecuador, El 
Salvador, Guatemala, Honduras, and Panama.
The selection of the endpoints for the trial matches the requirements laid down in the drafted
Guidance for Industry on Analgesic Indications: Developing Drug and Biological Products 
(Feb 2014).
8.1.1
Rationale for the IMPs and the selected doses
The selected treatments and the doses for the FDC of tramadol and diclofenac were chosen based on 
the experience gathered in previous clinical trials (Auad Saab et al. 2009 and Auad et al. 2009). 
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Diclofenac sodium 50 mg and tramadol HCl 50 mg were chosen as comparators since the Mexican 
and Brazilian Legislation on Fixed-dose Combinations recommends comparing the FDC with the 
individual components of the combination.
Ibuprofen 400 mg was selected as rescue medication because it has shown efficacy in a randomized
double-blind trial in the post-surgical model of extracted third molars (Bakshi et al. 1994).
Ketorolac tromethamine 30 mg (intramuscularly) was selected as second-line rescue medication for 
subjects who do not experience sufficient pain relief with ibuprofen.
8.1.2
Rationale for the number and the frequency of visits/assessments
The frequency of the assessments was based on the literature available for previous trials with other 
kinds of drugs using the dental pain model (third molar extraction).
8.2
Benefit/risk analysis
Subjects participating in this trial will benefit as the medical need of required third molar extraction 
is covered as well as the proper management of the pain associated with this procedure. The risks 
are implied in the surgical procedure of dental extraction as pain and bleeding. Adverse events of 
the drug combination are described in the investigator’s brochure. It is expected that their 
frequencies will be similar to or lower than those with the individual drugs.
The investigators must become familiar with all sections of the investigator’s brochure, the 
ibuprofen product information, and the ketorolac product information prior to initiation of the trial.
9
SUBJECT ENROLLMENT AND TRIAL DISCONTINUATION
9.1
Subject enrollment procedure
Subjects will be screened to identify those who could potentially be enrolled into the trial. 
Potentially eligible subjects will be asked to enroll into the trial by giving written informed consent. 
If required by applicable regulatory requirements, the principal investigator must keep suitable logs 
of the subject enrollment procedure.
9.1.1
Handling of low enrollment
Trial sites with a low recruitment rate and/or which persistently deviate from the protocol may be 
required by the sponsor/coordinating investigator/sponsor’s authorized delegate to stop further 
recruitment at once or to cease participation in the trial.
An activated site can be considered to have a low recruitment rate if it has not allocated a subject to 
treatment within 6 weeks, i.e., less than 6 subjects in 6 weeks, after trial treatment was available at 
the trial site.
9.2
Inclusion/exclusion criteria
The trial population must comply with the inclusion/exclusion criteria given in Section 1.3.
Subjects will only receive IMP if documentation is available showing that they comply with all of 
these criteria.
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9.3
Subject discontinuation from the trial or IMP
Once a subject enrolls in this trial, whilst protecting subject safety, the trial site should make every 
effort to retain the subject for the planned duration of the trial.
A subject may withdraw consent at any time.
9.3.1
Subject discontinuation from the trial
If subjects are not eligible to be allocated to the IMPs, they must be classified as enrollment failures 
and be discontinued from the trial. It is at the discretion of the investigator to discontinue subjects 
from the trial if they cannot comply with the requirements of the protocol.
A subject must be discontinued from the trial if any of the following criteria are met after 
enrollment. 
•
Subject meets exclusion criteria at Visit 2.
•
Subject withdraws consent.
9.3.2
Subject discontinuation from the IMPs
The principal investigator may decide to discontinue a subject from the IMPs if she/he considers
continued treatment of the subject to pose an undue risk to the subject, e.g., due to particular 
adverse events. All subjects treated with IMPs must be followed up within the trial until the end of 
the trial, the subject’s death, their withdrawal of consent, or loss to follow-up.
9.3.3
Procedure for the handling of discontinued subjects
9.3.3.1
Handling of subjects who discontinued from the trial
The principal investigator must document any discontinuation of a subject and inform the sponsor. 
Where applicable, the relevant IECs must be informed with a detailed written explanation. 
The following must be done for all discontinued subjects, including those who withdrew informed 
consent:
•
Document the main reason for discontinuation from the trial.
•
Ensure that all data collected until the day of discontinuation is transferred to the CRF.
•
Ensure that any dispensed pain assessment booklet is returned.
•
Ensure that any unused IMPs and rescue medication (including all packaging) is returned.
•
If possible, perform all tests as defined for the End-of-treatment Visit (Visit 3).
•
Complete any other trial-related formalities, e.g., those related to discharge from the trial 
site.
•
For subjects withdrawing consent, document in the source data the date and time of 
withdrawal.
•
Document in writing, if a subject withdraws consent but agrees to attend the End-of-
treatment Visit (Visit 3) and the Final Visit (Visit 4).
9.3.3.2
Handling of subjects discontinued from the IMP but not from the trial
If a subject is discontinued from IMP, the overall timeline for subsequent visits will be maintained 
as close as possible to the originally planned timeline.
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Subjects must continue with the subsequent planned Visit 3 and the follow-up phone call/on-site 
visit (for details, see Section 11.1.2.2 and Section 11.1.3); however, the following does not have to 
be performed:
•
Administer IMPs.
•
Check discontinuation criteria.
9.3.3.3
Replacement of subjects
Subjects will not be replaced.
9.3.4
Premature termination or suspension of the trial
The following criteria for premature termination or suspension of the trial apply.
•
The trial will be prematurely terminated, if the perception of the benefit/risk ratio becomes 
unfavorable for the continuation of the trial.
•
The trial may be suspended or terminated by the sponsor should the Adorlan® FDC 
(tramadol HCl/diclofenac sodium 25 mg/25 mg) be withdrawn from the Latin America 
market for any reasons by the sponsor.
•
The sponsor of the trial may suspend it for commercial reasons.
The relevant IECs, the regulatory authorities, or the sponsor or the sponsor’s authorized delegate 
alone or in conjunction have the power to make a binding decision to prematurely terminate or 
suspend the trial at any or all trial sites. In addition, for an individual trial site, this decision can be 
made by the principal investigator. 
The party prematurely terminating or suspending the trial must promptly inform all other parties 
(i.e., the principal investigators, the relevant IECs, the relevant regulatory authorities, or the 
sponsor/the sponsor’s authorized delegate, as applicable). 
In addition, if the principal investigator decides to terminate or suspend the trial at the trial site, they
must promptly inform the subjects, ensure appropriate follow-up for any enrolled subjects, and 
provide the relevant IECs and the sponsor or the sponsor’s authorized delegate, as applicable, with a 
written explanation of the termination or suspension.
The coordinating investigator must be informed immediately if the trial is prematurely terminated 
or suspended.
10
TRIAL TREATMENTS
10.1
Investigational medicinal products
10.1.1
Identity and composition – tramadol hydrochloride/diclofenac sodium 
fixed-dose combination tablets
Name:
Tramadol HCl/diclofenac sodium immediate-release tablets
Active components:
Tramadol HCl and diclofenac sodium
Dose (strength):
25 mg/25 mg, 50 mg/50 mg
Supplier:
Tecnandina S.A., Quito, Ecuador
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Diclofenac sodium 25 mg is equivalent to 23.279 mg diclofenac base.
Tramadol HCl 25 mg is equivalent to 21.957 mg tramadol base.
For further information about the identity and composition of the IMPs, see the clinical supply 
specification (available on request).
10.1.2
Identity and composition – diclofenac sodium tablets
Name:
Voltaren enteric-coated tablets 
Active component:
Diclofenac sodium
Dose (strength):
50 mg
Supplier:
Novartis
For further information about the identity and composition of the IMP, see the prescribing 
information for Voltaren enteric-coated tablets.
10.1.3
Identity and composition – tramadol capsules
Name:
Tramadol immediate-release capsules
Active component:
Tramadol HCl
Dose (strength):
50 mg
Supplier:
Tecnandina S.A., Quito, Ecuador
For further information about the identity and composition of the IMP, see the prescribing 
information for Tramadol capsules.
10.1.4
Identity and composition – placebo capsules and tablets
Placebos matching tramadol capsules, placebos matching diclofenac tablets, and placebos matching 
the FDC tablets are supplied by Tecnandina S.A., Quito, Ecuador. For further information about the 
identity and composition of the IMPs, see the clinical supply specification (available on request).
10.1.5
Packaging and labeling
For detailed information about the packaging and labeling, see the clinical supply specification 
(available on request).
Primary and secondary package of the trial medication will be identical for all treatment groups.
Active treatments and their placebo will be identical in the primary and secondary packaging.
For each subject in every treatment group, there will be 1 treatment box. The treatment box will 
contain 3 kits, 1 for each dose. Each kit will contain 4 blisters with 1 active treatment and 
3 placebos (capsule or tablets). Active treatments and their placebo will be identical in the primary 
and secondary packaging.
10.1.6
Delivery, storage, and disposal
For detailed information about the distribution of the IMPs, see the clinical distribution 
specification (available on request).
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At the investigator’s site, the IMPs will be stored in a secure and temperature-controlled room with 
restricted access and temperature monitoring. All IMPs must not be stored above 25°C. They must 
not be frozen or refrigerated in order to maintain the quality of the packaging and labeling. Further 
special storage conditions are not required.
Subjects should store the IMPs (for the third dose) at home in a place where children have no access 
to it and return any unused IMP and all packaging material to the site for drug accountability and 
drug compliance assessments. 
Latest at the end of the trial, after the final drug accountability, partially used and unused trial 
medication will be returned to the appropriate warehouse and destroyed.
Controls will be implemented at the trial sites to ensure documented compliance with these 
requirements.
10.2
Administration of investigational medicinal products
Please refer to Section 1.4.1 for a description of the IMPs/treatment groups. 
Subjects must be healthy except for the impacted lower third molars requiring extraction as it will 
be determined by medical history, and by physical and radiological examination. 
The analgesic therapy will be started as soon as the subject’s baseline pain intensity has been 
evaluated and meets the criteria of moderate to severe pain (i.e., 5 on the 11-point NRS) within 
4 hours after the end of the surgery. The first dose of IMPs (1 active treatment and 3 placebos) in 
the post-surgical period will be administered at the site with some purified water (approximately 
250 mL). A second dose will be administered 8 hours (10 minutes) later at the site as well. The 
times of the IMP intake must be documented in the CRF. 
Subjects will stay at the dental clinic or other research facility for at least for 8 hours after the first 
IMP dose before they can leave the trial site facilities. They should take their last dose of IMPs as 
an outpatient 16 hours (1 hour) after the first IMP dose. The time of IMP intake must be 
documented by the subject in the booklet and be transferred to the CRF at Visit 3 by the 
investigator. No further IMP intake is planned.
10.3
Method of assigning subjects to treatment groups (allocation)
An electronic data capture system will be used to assign a subject number at the Enrollment Visit 
(Visit 1). An Interactive Response Technology system (IRT, voice and web based [IVRS or IWRS]) 
will be used to support the drug supply chain management processes of distribution. Details of the 
vendor and the system will be filed in the trial master file.
The investigator or person assigned by the investigator must log into the system using their own 
user identification number and a password. The investigator or person assigned by the investigator 
will enter the subject’s number and other information required by the system to obtain a medication 
number. The medication number is then used to select the correct package of IMPs and rescue 
medication to give to the subject.
Treatment allocation (randomization) will be done at the Allocation Visit (Visit 2). Subjects who 
comply with all inclusion criteria and do not meet any of the exclusion criteria will be randomly 
allocated to 1 of the 4 treatment groups in a 1:1:1:1 ratio. Treatment assignment will be performed 
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centrally using an IRT system prior to the first administration of IMP. Allocation will be performed 
using a stratified block randomization with site and, following the IMMPACT recommendations 
(Cooper et al. 2016), pain intensity at baseline (categories “moderate” and “severe” as defined in 
Section 12.2.1.1) as stratification factors.
10.4
Blinding and unblinding
10.4.1
Methods of blinding
This trial will use double-blind and double-dummy methods to guarantee the blinding of all 
personnel involved in the trial. Active treatments and their placebo will be identical in the primary 
and secondary packaging. Subjects, sponsor, and investigators will be blinded to the subjects’ 
treatments.
Randomization and blinding will be done in accordance with the sponsor’s standard operating 
procedures (SOPs).
Briefly, each subject will have a treatment box: it will be an identified box with 3 smaller boxes 
inside. Besides the identification code, each small box will be marked as first, second and third
dosage. There will be 4 blisters inside each box. Each blister will contain 1 unit; 3 blisters will have 
a tablet, and 1 blister a capsule. Only 1 of the units will have an active treatment and the other 
3 units will have placebos matching the active treatments.
10.4.2
Methods of unblinding
The investigator, the responsible department at the sponsor, and the responsible Drug Safety 
department and contract research organization will receive appropriate methods for unblinding of 
single cases, i.e., IRT (IVRS/IWRS) system access. 
Unblinding of the trial will only be carried out after entry of all clinical data and database lock. 
Unblinding will be initiated by the sponsor’s department of Biostatistics according to the sponsor’s 
SOPs for unblinding. Personnel in the sponsor’s department of Clinical Trial Supply are unblinded 
according to the SOP for the blinding assurance within packaging and labeling of clinical trial 
supplies. The qualified person for pharmacovigilance may be unblinded at any time during the trial.
10.4.3
Identification of IMPs in emergency situations
The code may be broken when it is necessary and in that subject’s interest in order to identify the
IMPs given, e.g., if knowing the identification of the treatment group would lead to the investigator
treating the subject differently. In addition, within the sponsor’s Drug Safety department, the code
may be broken for regulatory reporting, medico-scientific assessment of adverse events, or on 
request of the qualified person for pharmacovigilance.
For every subject whose blind was broken, the following information must be documented
according to the sponsor’s SOPs:
•
The reason for, the date, and time of unblinding.
•
The person(s) informed of the treatment allocation must be identified.
In order to maintain the double-blind nature of the trial, the IMP allocation for the subject must not 
be communicated further unless required for the surveillance of the subject or if necessary for
urgent risk to benefit re-evaluation and/or measures for urgent risk minimization.
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If required by local regulations, it may be that the IEC or the coordinating investigator needs to be 
informed.
10.5
Rescue medication
Details on rescue medication are provided in Section 1.4.2.
Subjects can request and take rescue medication at any time after the first administration of the 
IMPs if their trial medication does not provide sufficient pain relief. However, they will be 
encouraged (but not required) to refrain from rescue medication intake until at least 120 minutes 
after the intake of the first dose of IMPs (i.e., until diclofenac and tramadol have reached their 
maximum plasma concentration) to be able to reliably assess the efficacy of the IMPs first. 
The time will be registered when subjects first request rescue medication and the time they take 
their first dose. Subjects taking rescue medication will be asked to complete the trial procedures as 
planned. 
10.6
Lidocaine/epinephrine for anesthesia
Details on the local anesthetic are provided in Section 1.4.3. The administration details are provided
in Section 11.1.2.1.
10.7
Allowed and forbidden concomitant medications
Subjects will be instructed to only use allowed concomitant medications during the trial. 
Use of antibiotics and other concomitant medications except for analgesics and systemic 
corticosteroids is allowed by the protocol, according to the common practice of the investigator and 
the investigator’s brochure. All concomitant medication must be registered in the CRF and the 
source document(s) (see also Section 1.5).
The allowed and forbidden concomitant medications will be explained to the subject by the 
investigator.
In emergency situations, subjects should be treated according to standard medical practice (see 
Section 11.2.1). 
For information about potential drug-drug interactions, see the investigator’s brochure.
10.8
Documentation of drug accountability
The principal investigator must ensure that documentation is maintained for the receipt, inventory, 
use, and destruction or return of unused, used, or partially used packages of IMPs and rescue 
medication. The documentation must include trial treatment name, dates, quantities, subject 
numbers, batch/serial numbers or other identification numbers, expiration dates, and the means to 
identify the subject to whom it was given.
Documentation must be maintained for the checking of drug accountability.
Before the unused IMPs and rescue medication supplied to the trial site are returned or destroyed, 
the principal investigator must allow sponsor representatives to perform drug reconciliation. The 
entries in the documentation will be compared with the returned and residual IMPs and rescue 
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medication, and the administration/intake as documented in the CRF, with clarification of any 
discrepancies or inconsistencies. 
11
COURSE OF THE TRIAL AND CONDITIONS
See Section 1.1.1 for a flow diagram summary of the trial and Section 1.8 for a tabular schedule of 
events.
11.1
Course of the trial
The trial course will comprise 4 visits: 3 visits for which subjects have to be at the trial site, and 
1 visit which can be a phone call or an on-site visit. At any time during the trial, the investigator 
may ask the subject to come for an unscheduled additional visit outside the trial schedule if deemed 
necessary according to his/her normal practice.
11.1.1
Enrollment Period (Visit 1)
A planned number of 1065 male and female subjects will be enrolled in this trial. During the first 
visit, the investigator and sub-investigators will explain the objectives of the trial to the potential 
participant as well as possible benefits and risks. If the subject decides to participate, the informed 
consent will be obtained and the subject will be assigned a subject number.
Thereafter, the following procedures will be performed and data will be documented in the CRF:
•
Evaluate the subject’s suitability for the trial and verify selection criteria including 
inclusion and exclusion criteria defined in Section 1.3.1 and Section 1.3.2.
•
Record subject’s demographic data (date of signing the informed consent, sex, age, race, 
ethnic group, body weight and height), and smoking status (see Section 12.1.1 and 
Section 12.1.5.2). The body mass index will be calculated in the CRF.
•
Collect a urine sample and perform a pregnancy test in female subjects with childbearing 
potential (see Section 12.1.5.3).
•
Take blood samples for clinical laboratory parameter assessments and urine for urinalysis.
Clinical laboratory parameter assessments will be performed by contracted local certified 
clinical laboratories. If results of laboratory parameters deviate from normal range values, 
assessments may be repeated at the discretion of the investigator at an unscheduled visit 
during the Enrollment Period (see Section 12.3.3).
•
Record relevant prior/concomitant diseases and surgical interventions (to be done by a 
certified physician) (see Section 12.1.3).
•
Record dental history (see Section 12.1.4).
•
Perform a physical examination (to be done by a certified surgeon) (for details see 
Section 12.1.5.1).
•
Record prior (administered within 14 days before enrollment and up to the time of surgery) 
and concomitant medications (see Section 12.1.2).
•
Perform a radiological examination of the affected third molars and document the impacted 
ones if this information is not available from a previous X-ray taken up to 1 month before 
the Enrollment Visit (see Section 12.1.5.4).
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•
Measure and record the subject’s vital signs (pulse rate, systolic and diastolic blood 
pressure, and respiratory rate) (see Section 12.3.2).
•
Schedule an appointment for the dental surgery.
•
Inform the subject that tramadol-containing products, like other centrally acting analgesics, 
may impair the mental and/or physical abilities required for the performance of potential 
hazardous tasks such as driving a car or operating machinery. Subjects should be aware that 
they are not supposed to drive a car when they can leave the clinic on the day of surgery.
11.1.2
Treatment Period (Visit 2 and Visit 3)
11.1.2.1
Allocation Visit (Visit 2)
For restrictions concerning meals and fluid intake before and after surgery, please see 
Section 11.2.3.
Standardized local anesthesia
Extraoral antisepsis will be performed with e.g., 2.0% chlorhexidine. Intraoral antisepsis will be 
performed with e.g., a 0.12% chlorhexidine rinse. To numb the mouth, blocking of the inferior 
alveolar, lingual, and buccal nerves will be carried out by using 1-3 cartridges of lidocaine plus 
epinephrine per third molar not exceeding a maximum total amount of 300 mg of lidocaine per 
subject (8.3 cartridges). The anesthetics will be provided as cartridges of 1.8 mL with 36 mg of 
lidocaine hydrochloride plus 0.018 mg of epinephrine. No other kind of anesthetic is allowed. The 
exact amount of lidocaine administered and times of administration must be documented in the CRF
and the source document(s). Maxillary anesthesia will be obtained using local infiltration, posterior 
superior nerve blocks, and palatal blocks.
When the anesthetic takes effect, the tissue will be opened and the upper and lower molars will be 
extracted.
Standardized surgery
The dental surgery will be the extraction of 3 or more third molars. Incision from the anterior border 
of the mandibular ramus continued as a marginal incision to the mesiobuccal part of the mandibular 
third molar will be made. Thereafter, the buccal mucoperiostal flap is elevated; bone is removed 
and irrigated with sterile physiologic saline solution. If necessary, splitting of the tooth will be 
performed. The ipsilateral maxillary third molar will be surgically removed, if indicated. The 
wounds will be cleaned, irrigated with sterile saline, and closed with sutures, if indicated.
Basic data of the surgical procedure performed, i.e., the number and position of the molars
concerned (i.e., 01, 16, 17, or 32), duration (start/end time) of surgery, the degree of impaction of 
each tooth, and the extent of tissue damage must be recorded in the CRF and the source 
document(s).
Any deviations from surgical protocol must be thoroughly documented in the CRF. Deviations that 
may significantly influence postoperative pain assessments or safety and tolerability of the IMP will 
disqualify the subject for treatment allocation.
Subjects requiring fourth molar extraction are allowed in the trial. Subjects with molars linked to 
the mandibular canal and those requiring immediate dental procedures other than third and fourth 
molar extraction must not be included in the trial.
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Postoperative baseline examination and treatment allocation
After surgery, subjects will assess their pain on an 11-point NRS. Subjects who report at least 
moderate baseline pain intensity (5 on the NRS) within 4 hours after surgery will be allocated to 
treatment. If 4 hours elapse without the development of moderate to severe dental pain following
the completion of surgery, subjects must not be allocated and must be discontinued from the trial.
The first dose of the IMPs (1 capsule or tablet with active treatment plus 3 placebos) will be 
administered as soon as subjects report a pain intensity 5 on the NRS. The time of dosing will be 
recorded. The use of cold compresses or ice bags on the cheeks of subjects is allowed 4 hours after 
the administration of IMP; their use must be avoided in the 30-minute period before each pain 
assessment.
Subjects who undergo surgery and receive IMPs will stay in the dental clinic or other research 
facility for at least 8 hours after the initial dose and will receive the second dose of IMPs at 8 hours
(10 minutes). If pain assessments will take place in other research facilities, subjects must be 
transported to the facility between 15 minutes after the end of surgery and the first IMP 
administration; the commuting time may be up to 30 minutes. During transfer, subjects must be 
accompanied by a member of the SMO staff. Both must have written directions in the case of 
emergency.
Thereafter, they can leave the site and take their third dose of IMPs at home 16 hours (1 hour)
after the first dose of IMPs. They will be asked to document the intake time and to return for Visit 3
the next day at a time which allows a pain assessment 24 hours after the initial IMP dose was given.
At the site, subjects will be provided with 2 stopwatches and a pain assessment booklet. They will 
be asked to record their pain assessments during the following 8 hours as follows.
•
The baseline pain intensity score (11-point NRS) before the first dose of IMPs
(Section 12.2.1.1).
•
Pain intensity scores at 15, 30, 45, 60, and 90 minutes (±2 minutes), and at 2, 3, 4, 5, 6, 7, 
8 hours (±6 minutes) after the first dose of IMPs (Section 12.2.1.1). 
•
Pain relief on a 5-point VRS at 15, 30, 45, 60, 90 minutes (±2 minutes), and at 2, 3, 4, 5, 6, 
7, and 8 hours (±6 minutes) after administration of the first dose of IMPs (Section 12.2.1.2).
•
Stopwatch 1: subject documents the moment she/he feels the onset of first perceptible pain 
relief (Section 12.2.1.5).
•
Stopwatch 2: subject documents the moment she/he feels the time to onset of a meaningful
pain relief (Section 12.2.1.5).
•
Response to the question if pain is at least half gone (see Section 12.2.2).
A summary of scheduled procedures for the Allocation Visit (Visit 2) is as follows:
•
Check if any of the exclusion criteria for Visit 2 apply (see Section 1.3.2.2).
•
Check availability of results of clinical laboratory parameters (to assess Inclusion 
Criterion 4 if not done before).
•
Perform a radiological examination of the affected third molars and document the impacted 
ones if not done previously (see Section 12.1.5.4).
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•
Collect a urine sample and perform a pregnancy test in female subjects with childbearing 
potential (see Section 12.1.5.3).
•
Measure and record the subject’s vital signs (pulse rate, systolic and diastolic blood 
pressure, and respiratory rate) (see Section 12.3.2).
•
Record the subject’s prior medication stopped before surgery and any concomitant 
medication (see Section 12.1.2).
•
Monitor the subject for and record any adverse event that occurred during or after the 
surgery (see Section 12.3.1).
•
Instruct the subject on how to complete the pain assessments following surgery. 
•
Hand out stopwatches and a pain assessment booklet (NRS).
•
Reinforce instructions regarding procedures for completion of the pain assessments.
•
Administer IMPs immediately after the baseline pain assessment and record time.
•
Commence time monitoring using the stopwatches provided for first perceptible and 
meaningful pain relief immediately upon IMP administration.
•
Collect the pain assessment booklet and stopwatches before the subject leaves the clinic and 
transcribe the subject-reported data to the CRF.
•
Ask the subject to perform a global evaluation of the treatment they received (5-point 
Likert scale) before the subject leaves the clinic, i.e., 8 hours after first IMP intake or before 
the first intake of rescue medication (whatever the first). 
•
Handout IMPs to be taken 16 hours (±1 hour) after first IMP dose to cover 24 hours of
treatment.
•
Hand out sufficient rescue medication (ibuprofen 400 mg) to cover 24 hours of treatment of 
dental pain if insufficiently resolved by the intake of IMPs.
•
Hand out an information sheet to the subject with the protocol directions and contact 
details.
•
Hand out a booklet and ask the subject to document at home:
−
Pain intensity and pain relief at 16 hours.
−
The intake of the third dose of IMPs.
−
Any use of rescue medication.
−
Any use of other medication.
−
Adverse events they might experience.
•
Check that the subjects are in a condition to leave the site.
•
Before subjects leave the site they should be reminded that tramadol-containing products, 
may impair the mental and/or physical abilities required for the performance of potential 
hazardous tasks such as driving a car or operating machinery. 
•
Ask the subject to come to the site on the next day at a pre-set time (24 hours after first IMP 
intake) for Visit 3.
Dental clinics must have an emergency kit according to local regulations (Norma Oficial Mexicana 
NOM-005-SSA3-2010). An emergency crash cart will be mandatory at each research facility any
time an IMP is being administered.
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11.1.2.2
End-of treatment Visit (Visit 3)
At the End-of treatment Visit (Visit 3), i.e., 24 hours after the first intake of the IMP, the following 
procedures will be performed:
•
Collect all unused IMP and rescue medication and all packaging material.
•
Perform drug accountability for the IMPs and for any rescue medication taken at home.
•
Transfer all information collected in the subject’s booklet at home to the CRF.
•
Ask the subject to assess the 24-hour pain intensity (NRS), to state if their pain is at least 
half gone, and to evaluate the treatment they received (5-point Likert scale) in a booklet. 
Document the data in the CRF. 
•
Document any newly prescribed concomitant medication or changes in dose or route if 
applicable.
•
Record all adverse events reported since Visit 2.
11.1.3
Final Visit (follow-up phone call or on-site visit on Day 14)
Thirteen days after the surgery day, the subjects will be contacted by phone or will be asked to visit 
the site to learn about their health status and the possible occurrence of adverse events.
All adverse events that occurred between Visit 3 and Visit 4 will be documented in the CRF and the 
medical records.
11.2
Conditions during the trial
11.2.1
Medical care
For any adverse events, a causal or symptomatic treatment according to standard medical practice 
should be provided if deemed necessary by the investigator. The medical care given to, and medical 
decisions made on behalf of the subjects must be the responsibility of a qualified physician.
See the guidance in the investigator’s brochure for precautions and the handling of emergencies.
11.2.2
General restrictions
During hospitalization at the trial site, subjects are not allowed to smoke.
Strenuous or unusual physical activities will not be allowed from the Enrollment Visit until the 
Final Examination.
If subjects absent themselves from the trial site, they will be warned not to drive cars or operate 
dangerous machinery for 8 hours after last IMP intake.
11.2.3
Meals and fluid intake restrictions
Subjects may have a low-fat dinner the night before the surgery. They may have soft beverages like 
Ensure® up to 1 hour before surgery. Drinking water or juices (apple juice, orange juice) and low-
fat milk are allowed after surgery. From 3 hours after IMP administration, subjects can have soft 
food (Jell-O™, mashed potatoes, milk shake, Ensure®). Water and soft food must be provided at 
room temperature. High-fat meals, ice creams, and sorbets must be avoided.
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11.2.4
Counseling of women of reproductive age
All women, including those with tubal ligation, will be considered to be of childbearing potential 
unless they have been postmenopausal for at least 2 years or have undergone a hysterectomy.
All women of childbearing potential must be counseled on the need to practice medically acceptable 
methods of birth control during the trial and on the importance of avoiding pregnancy. Medically 
acceptable methods of birth control are methods with a failure rate (percentage of women 
experiencing an unintended pregnancy within 1 year of use of the method) of less than 1%, e.g., 
hormonal contraceptives or intra-uterine devices used according to the product’s instruction for use, 
or double barrier method (male or female condom; diaphragm). The combination of 2 independent 
methods will result in multiplied failure rates per year, e.g., 0.63% for the concomitant use of a 
condom (with a 9% failure rate) and a diaphragm (with a 7% failure rate).
Note: A female condom and a male condom must not be used together as friction between the 2 can 
result in either product failing.
Women will be counseled to contact the investigator or trial site staff immediately if pregnancy is 
suspected once an informed consent form is signed and up to the Final Visit.
11.2.5
Counseling of male subjects
Male subjects will be counseled to contact the investigator or trial site staff immediately if a 
pregnancy of their partner is suspected.
11.3
Subject trial cards
Subjects who are allocated in the trial will receive a subject trial card (the time of card distribution 
will be given in Section 1.8). The subject trial card will list the following information:
•
Name of the subject and a statement that she/he is currently participating in a clinical trial.
•
Trial code.
•
Name of the principal investigator for that trial site.
•
Contact (phone) number at the trial site.
The card will be collected at the last visit if the subject visits the site.
11.4
Provisions of any additional care of subject after trial termination
After trial termination, subjects will be treated by their physicians according to the standard medical 
practice in the country concerned.
12
TRIAL ASSESSMENTS
12.1
Collection of demographic data and other baseline characteristics
12.1.1
Demographic data, height and weight
Demographic data are: date of signing the informed consent, sex, age (in years), race, ethnic group, 
body weight, height, and body mass index. 
Body weight will be measured in light clothes. The body mass index will be calculated.
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12.1.2
Prior and concomitant medication
All medication requiring prescriptions (including oral contraceptives), over-the-counter medication, 
traditional medicine, phytotherapy, and any other treatment ingested or applied to the skin or 
mucosal surface within 14 days prior to enrollment and up to the end of the trial must be recorded in 
the CRF. Toothpastes and mouthwashes need not be documented.
For the purposes of data reporting by the site, all medication used 14 days prior to enrollment and 
up to the time of surgery is considered prior medication. Concomitant medication is all medication 
not stopped before surgery or newly added thereafter.
Any addition to or change in dosage, regimen, or route for concomitant medications during the trial 
must be recorded in the CRF as a new entry.
12.1.3
Relevant prior/concomitant diseases and surgical interventions
Subjects’ medical and surgical history, including any relevant diseases and surgical interventions,
will be recorded in the CRF at Visit 1 by a certified physician. 
All medical conditions controlled by medication must be recorded.
Childhood illnesses do not need to be documented, unless they could potentially give rise to an 
adverse event based on the pharmacology of the trial treatments or related to trial procedures.
12.1.4
Dental history
Subject’s dental history will be recorded at Visit 1 and should include tooth extractions (within the 
last 6 months), any other dental surgeries (e.g., root canal), dental or periodontal disease, use of 
dentures, and other significant dental history. 
12.1.5
Other baseline characteristics
12.1.5.1
Physical examination
A directed physical examination must be carried out by a certified surgeon and should include 
assessments of the general condition, ears, nose and throat, mouth (including teeth and gums), head, 
neck, heart, and lung. The outcome of the physical examination will be documented.
Prior to allocation to treatment, any clinically relevant findings from the physical examination will 
be documented as part of the medical history.
12.1.5.2
Smoking status
Subjects will be asked if they are current smokers (every day or on some days per week), recent 
former smokers (smoked within the last 12 months), long-term former smokers (smoked 1 to more 
than 15 years ago), of never smoked regularly. The number of cigarettes/cigars/pipes smoked per 
week will be recorded for current smokers.
12.1.5.3
Beta-human chorionic gonadotropin pregnancy test
Urine samples will be collected from women with a childbearing potential at Visit 1 and Visit 2. A 
urine ß-human chorionic gonadotropin pregnancy dipstick test will be performed at the site (see 
Section 1.8). The results of the dipstick test will be directly entered into the CRF and the medical 
records.
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12.1.5.4
Radiological examination
If not done before Visit 1, an X-ray has to be collected during the Enrollment Period or – at the 
latest – at the Allocation Visit (see Section 1.8) to obtain a radiological confirmation of impacted 
third molars. The position of the impacted molars (i.e., 01, 16, 17, or 32) must be recorded on the 
appropriate CRF page and in the subject’s medical records.
12.2
Collection of efficacy data
For the timings of assessments, see the schedule of events (Section 1.8).
12.2.1.1
Pain intensity (numerical rating scale)
Pain intensity will be evaluated using an 11-point NRS. 
Subjects will be asked to assess their current pain by selecting a number corresponding to their pain, 
with anchors at 0 for “no pain” and 10 for “pain as bad as you can imagine”.
The subjects will be asked to answer the following question:
“Please rate your pain by selecting the one number that best describes how much pain you have 
right now”.
The pain intensity score assessed before IMP intake will be considered the baseline pain intensity 
and will be used for stratification.
Pain intensity will be categorized as:
•
None 
NRS score of 0
•
Mild 
NRS score of 1 and <5
•
Moderate 
NRS score of 5 and 6
•
Severe 
NRS score of 7.
12.2.1.2
Pain relief
The subject’s pain relief will be assessed using a 5-point VRS by completion of the following 
statement.
“My relief from starting pain is”
•
None 
(0)
•
A little 
(1)
•
Some 
(2)
•
A lot 
(3)
•
Complete 
(4)
12.2.1.3
Total Pain Relief
Total Pain Relief (TOTPAR) will be defined as ΣPRt x [time (hours) elapsed since previous
observation] where PRt is the Pain Relief at time point t in comparison to the assessment before 
administration of IMPs (Max and Laska 1991).
The TOTPAR will be calculated at 4, 6, and 8 hours.
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12.2.1.4
(Summed) Pain Intensity Difference
Pain Intensity Difference (PIDt) will be defined as the difference between baseline pain intensity 
and pain intensity at time point t, and Summed Pain Intensity Difference (SPID) defined as ΣPIDt x 
[time (hours) elapsed since previous observation] (Max and Laska 1991).
The PID (NRS) compared to baseline at 15, 30, 45, 60, and 90 minutes, and at 2, 3, 4, 5, 6, 7, 8, and 
24 hours will be calculated.
The Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 hours post-dose will be calculated.
12.2.1.5
Time to onset of first perceptible and meaningful pain relief
At the time of dosing with the IMPs, the investigator will start 2 stopwatches for each subject. The 
subject will be instructed to stop the first stopwatch at the time of first perceptible pain relief and 
the second stopwatch at the time when they first experience meaningful pain relief. The definitions 
of the perceptible and meaningful pain relief are as follows:
Time to onset of first perceptible pain relief
When the subject begins to feel any pain-relieving effect from the IMPs.
Subject instruction: 
“I would like you to stop the stopwatch when you first feel any pain relief whatsoever. This does not 
mean you feel completely better, although you might, but when you first feel any difference in the 
pain that you have had.”
Time to onset of meaningful pain relief
When the subject feels their pain relief is meaningful to them.
Subject instruction: 
“I would like you to stop the stopwatch when you have meaningful pain relief. That is, when the 
relief is meaningful to you.”
12.2.2
Time to achieve a 50% reduction of baseline pain
The subject’s 50% reduction of starting pain will be assessed by answering the following statement 
with YES or NO:
“My starting pain is at least half gone”
The subject should be reminded that each assessment should be performed independently of 
previous assessments.
12.2.3
Subject’s global evaluation of the treatment (Likert scale)
The subject’s overall impression (overall assessment) of the analgesic efficacy of the IMPs will be 
obtained 8 hours after the first dose of IMPs or before first intake of rescue medication (whatever 
the first) and 24 hours after the first dose of IMPs. Subjects will be asked the following question 
and will be requested to also record the time at which it was answered:
“How would you rate the study medication you received for pain?”
•
Excellent 
(4)
•
Very good 
(3)
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•
Good 
(2)
•
Fair 
(1)
•
Poor 
(0)
12.2.4
Rescue medication request and intake
The day/actual time of ibuprofen (and of ketorolac if needed) request and the day/actual time and 
amount of ibuprofen intake (or ketorolac administration) must be documented in the CRF and the 
source document(s).
The time from baseline to the first dose of rescue medication will be calculated. 
The amount of rescue medication used within 24 hours after surgery will be calculated based on 
drug accountability information available.
12.3
Collection of safety data
The following safety data will be collected: Adverse events, clinical laboratory parameters, and 
vital signs.
For the timings of assessments, see the schedule of events (Section 1.8).
Clinically relevant abnormal values (investigator’s judgment) must be recorded as adverse events.
12.3.1
Adverse events
Adverse events will be documented from the time of enrollment (i.e., Visit 1, the time the informed 
consent form is signed) up to the time of the last protocol scheduled contact, i.e., date of last 
visit/contact (can be a phone call, e.g., in case of withdrawal). 
Definition of adverse events
An adverse event is any untoward medical occurrence in a subject enrolled in a clinical trial. An 
adverse event can therefore be any unfavorable and unintended sign (e.g., an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product.
Pre-existing diseases or conditions occurring before enrollment are not considered to be adverse 
events unless there is an untoward change in intensity, frequency, or quality after enrollment. 
Lack of efficacy (LoE), as such, is not considered to be an adverse event while its consequences 
(e.g., deterioration of the treated disease) are considered to be an adverse event.
A newly diagnosed pregnancy of an enrolled female subject will not be considered an adverse event
itself unless it is suspected that the trial treatment interacted with a contraceptive method. In this 
case, the pregnancy will be considered an adverse event. A congenital anomaly as an outcome of
this pregnancy will be considered a serious adverse event (SAE).
All newly diagnosed pregnancies of enrolled female subjects must be reported to the 
CRO/sponsor’s Drug Safety department within 24 hours after first knowledge. These pregnancies 
will be documented using a Pregnancy Reporting Form with all available information provided and 
followed up to determine the outcome post parturition.
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For newly diagnosed pregnancies of partners of enrolled subjects, a reasonable attempt (i.e., due 
diligence) must be made to report the pregnancy to the CRO/sponsor’s Drug Safety department 
within 24 hours after first knowledge.
Definition of serious adverse events
An SAE is any untoward medical occurrence that at any dose:
•
Results in death.
•
Is life-threatening.
•
Requires inpatient hospitalization or prolongation of existing hospitalization.
•
Results in persistent or significant disability/incapacity.
•
Is a congenital anomaly/birth defect.
•
Is considered a clinically important medical event. The medical concepts included in 
Section 18.1 should be taken into account when applying this seriousness criterion.
An elective hospital admission, e.g., for pre-planned surgery, will not be considered an SAE if 
documented at enrollment. Short-lasting (<24 hours) hospital admissions, e.g., for clinical check-
ups, not meeting any of the other above mentioned criteria will also not be considered SAEs.
Special procedures for serious adverse events
If SAEs occur that are not tolerable, the investigator will decide for that subject whether to stop the 
trial and/or treatment of the subject. For further details, see Section 9.3.
Expectedness of adverse events
Expectedness will be assessed by the sponsor.
An unexpected adverse event is one where the nature or intensity is not consistent with the 
information in the investigator’s brochure. 
Furthermore, reports that add significant information about the specificity or severity of a known, 
already documented adverse reaction constitute unexpected adverse events. For example, an
adverse event more specific or more severe than expected would be considered “unexpected”.
Definition of adverse drug reactions
An adverse drug reaction is any untoward and unintended response to an IMP or a medicinal 
product related to any dose administered. 
A list of adverse drug reactions seen for the IMPs is given in the reference safety information, i.e., 
in the investigator’s brochure.
Documentation of adverse events 
The subjects will be questioned about possible adverse events with non-leading questions before 
administration of the IMP and at regular intervals thereafter as defined in Section 1.8.
All adverse events reported spontaneously by subjects at any time point will also be documented. 
All adverse events will be documented in the CRF with the following information where 
appropriate:
•
Description (adverse event reported term)
•
Start date/time
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•
End date/time or continuation.
•
Whether adverse event was serious.
•
Intensity
•
Outcome
•
Action taken with IMPs.
•
Countermeasures
•
Causal relationship to IMPs. 
Definition of intensity
The clinical intensity of an adverse event will be classified as:
Mild:
Signs and symptoms that can be easily tolerated. Symptoms can be ignored and disappear when the 
subject is distracted.
Moderate:
Symptoms cause discomfort but are tolerable; they cannot be ignored and affect concentration.
Severe:
Symptoms which affect usual daily activity.
For adverse events where the intensity changes over time, the maximum intensity observed during 
the whole duration of the adverse event will be documented. 
Adverse events occurring in the Enrollment Period but before first administration of an IMP and 
worsening on or after IMP administration will be documented as new adverse events.
Definition of outcome at the time of last observation
The outcome at the time of last observation will be classified as:
•
Recovered/Resolved
•
Recovering/Resolving
•
Not recovered/Not resolved
•
Recovered/Resolved with sequelae.
•
Fatal
•
Unknown (unknown should only be used, if at the time of the last visit for a subject in a 
trial, the outcome of the adverse event is unknown to the investigator, e.g., because the 
subject is lost to follow-up).
In the event of irreversible congenital anomalies, the choice “not resolved” should be used. “Fatal” 
should only be used when death is possibly related to the adverse event (note: the causal 
relationship of the IMP to the adverse event is not to be considered for this decision). If there is 
more than 1 adverse event, only the adverse event leading to death (possibly related) will be 
attributed with the outcome “fatal”.
Definition of countermeasures 
“Countermeasures” will be defined as:
None:
No countermeasure given.
Newly started 
medication:
A newly started medication or change in dose or route of application of a medication due 
to the adverse event (to be listed on the prior/concomitant medication page) that is used 
as a countermeasure.
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Trial discontinuation:
It was necessary to discontinue the subject from the trial due to the adverse event.
Other:
All other countermeasures, e.g., physical therapy, surgery.
Except for none, multiple countermeasures for 1 adverse event can be recorded.
Classification of action taken with IMPs when an adverse event occurs:
•
Dose reduced.
•
Drug interrupted.
•
Drug withdrawn.
•
Dose not changed.
•
Not applicable.
•
Unknown.
Classification of causation
The causal relationship of an adverse event to IMPs will be classified using the following 
terminology. The given criteria for each term are for consideration and are neither exhaustive nor 
required to be fulfilled in total for the selection of the respective term:
Terms for classification 
of causation
Criteria for the selection of causality classification terms
Conditional/ 
Unclassified:
Additional data for a proper assessment are under examination.
Unassessable/ 
Unclassifiable:
The available data cannot be judged because information is insufficient or contradictory, 
and cannot be supplemented or verified. 
Not related:
Data with sufficient evidence to accept that there is no causal relationship to IMP 
administration (i.e., there is no temporal relationship to IMP administration or proved 
other cause). 
Unlikely:
Data without sufficient evidence to accept that there is no causal relationship to IMP 
administration, but also with no evidence or argument to suggest a causal relationship 
(e.g., the temporal relationship to IMP administration makes a causal relationship 
improbable, and other drugs, chemicals, or underlying disease[s] provide plausible 
explanations). 
Possible:
Data with limited evidence or argument to suggest a causal relationship (e.g., there is a 
reasonable time sequence to administration of the drug, but the adverse event could also 
be explained by concurrent disease[s] or other drugs or chemicals. Information on drug 
withdrawal may be lacking or unclear). 
Probable/likely:
Data with sufficient evidence or argument to suggest a causal relationship (e.g., there is a 
reasonable time sequence to administration of the drug, the adverse event is unlikely to 
be attributed to concurrent disease[s] or other drugs or chemicals, and a clinically 
reasonable response on withdrawal [dechallenge]).
Certain:
Data with clear evidence for a causal relationship (i.e., a clinical event, including 
laboratory test abnormality, occurs in a plausible time relationship to drug administration, 
and it cannot be explained by concurrent disease or other drugs or chemicals. The 
response to withdrawal of the drug [dechallenge] should be clinically plausible. The 
event must be pharmacologically or phenomenologically definitive, using a satisfactory 
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rechallenge procedure if necessary).
Follow-up of subjects with an adverse event
Any adverse event or clinically relevant abnormal laboratory or vital sign result will be followed 
until it reaches a satisfactory resolution, or becomes stable, or clinical judgment indicates that 
further evaluation is not warranted. 
Notification of serious adverse events
All SAEs (including death, irrespective of cause) during the trial, regardless of their relationship to 
IMPs, must be reported as soon as possible but no later than 24 hours after learning of the event. 
Before any trial-related procedure is performed, the trial site must be provided with contact details
at the CRO/sponsor’s Drug Safety department (drugsafety.mx@grunenthal.com) for this reporting. 
The investigator must submit a report, called a Safety Reporting Form, which includes a description 
of the event, the therapy instituted, and trial procedures. The following information should be 
communicated with the first notification of an SAE:
•
Trial identifier
•
Subject’s identifier.
•
Subject’s date/year of birth (if available, see local data protection requirements) or age (at 
adverse event onset). 
•
Subject’s sex.
•
First administration of IMPs (date and time, if available).
•
Last administration of IMPs (date and time, if available).
•
Adverse event verbatim term (specific diagnosis, if possible).
•
Adverse event onset (date and time, if available).
•
A brief description of the event, the course, and the countermeasures taken.
•
Intensity
•
Seriousness criterion.
•
Outcome
•
Concomitant medication at onset of the event and whether one of the concomitant 
medications is also suspected to have caused the event.
•
Relevant history/pre-existing medical conditions.
•
Investigator’s assessment of the relationship to IMPs.
•
Whether and when blinding was broken (see Section 10.4.3).
All additional information concerning the adverse event until trial termination or definite outcome 
must be communicated per follow-up report without delay.
The immediate and follow-up reports must only identify the subjects using the unique subject 
identifier. 
The investigator must comply with applicable regulatory requirement(s) related to the reporting of 
SAEs to the regulatory authorities and the relevant IECs. Based on the investigator SAE reports, the 
sponsor’s Drug Safety Department will generate Drug Safety Update Reports. They will monitor 
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the Suspected Unexpected Serious Adverse Reaction reports to detect any possible safety signals 
and generate early safety alerts if necessary.
12.3.2
Vital signs
Vital signs will be measured at time points specified in Section 1.8 and comprise pulse rate, systolic 
and diastolic blood pressure, and respiratory rate.
Vital signs will be measured in a sitting position after resting for 10 minutes. While resting, the 
subject should not receive anything to drink or eat. 
12.3.3
Safety laboratory
Sampling for clinical laboratory parameter assessment and for urinalysis will be done at the 
Enrollment Visit (see schedule of events in Section 1.8). The blood samples will be taken by direct 
venipuncture or by means of an indwelling venous cannula.
Clinical laboratory parameter assessment will be performed by contracted local certified clinical 
laboratories. Details on the clinical laboratories will be held in the trial master file and the 
investigator’s site file.
A table of the reference ranges for each of the clinical laboratory parameters measured with a 
description of the methods will be provided by the clinical laboratory before the trial start and will 
be filed in the investigator’s site file and the trial master file. Changes in the reference ranges or in 
the methodology during the course of the trial must be communicated by the local clinical 
laboratory to the investigators and to the sponsor. 
Throughout the clinical part of the trial, the investigator must provide feedback regarding the 
clinical relevance of any laboratory value outside the reference range. 
Additional determination of several parameters from blood may be added at the discretion of the 
investigator.
If clinical laboratory parameters exceed the pre-defined alert ranges (i.e., 1 standard deviation above 
or below the upper/lower limit of the normal range) the subject must not be allocated to treatment.
The original printouts of the clinical laboratory parameter and (if applicable) urinalysis values will 
be considered source documents and will be stored in the subject files. Data will be transferred from 
the printouts to the CRF by the investigator.
For each subject, up to 3 blood samples (total volume 12 mL) will be drawn for clinical laboratory 
parameter assessments.
The following clinical laboratory parameters will be assessed:
Clinical chemistry panel (sample volume approximately 6 mL)
Sodium
Total bilirubin
Potassium
Alkaline phosphatase
Chloride
Creatine kinase
Bicarbonate
Lactate dehydrogenase
Urea
Uric acid
Creatinine (serum)
Calcium
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Clinical chemistry panel (sample volume approximately 6 mL)
Glucose
Phosphorus
Aspartate transaminase
Albumin
Alanine transaminase
Total protein
Gamma-glutamyl transferase
Lipase
Cholesterol
Triglycerides
Hematology panel (sample volume approximately 3 mL)
Hemoglobin
Platelet count
Hematocrit
White blood cell count; manual differential white blood cell count if 
automatic differential white blood cell count is abnormal
Red blood cell count
Mean cell volume
Mean cell hemoglobin
Mean cell hemoglobin concentration
Coagulation panel (sample volume approximately 3 mL)
Activated partial thromboplastin time
International normalized ratio (derived from the prothrombin time)
Prothrombin time
Urinalysis panel
pH
Protein
Glucose
Ketones
Urobilinogen 
Bilirubin
Hemoglobin
Nitrite
Leukocytes
If urinalysis results are positive for leukocyte esterase, nitrite, protein, or blood, a microscopic 
examination of urine must be performed. Results will be reported only for the parameters that are 
present.
12.4
Appropriateness of measurements
The selection of the outcome measures pain intensity and pain relief and the derived parameters 
SPID and TOTPAR to support the secondary endpoints are commonly used in single-dose acute 
pain trials (Cooper et al. 2016). The visual analog scale is amongst the most popular scales to 
measure acute pain. The assessment of the onset of the analgesic effect using the double-stopwatch 
method is standardized and reliable (Desjardins et al. 2002).
The TOTPAR was selected because this summary measure is widely used and acknowledged for 
the scientific evaluation of single-dose trials (Sriwatanakul et al. 1983) and is an accepted endpoint 
for acute pain trials (Singla et al. 2015). The TOTPAR scores can be interpreted as estimates of the 
area under the longitudinal pain relief curve. The time-frame of 4 hours has been chosen as it 
coincides with the time point the comparator concentrations drop below published minimum 
effective concentrations, and as it minimizes the impact of potential rescue medication intake.
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12.5
Compliance
Compliance is the adherence to all requirements of the trial protocol.
Trial site compliance will be assured by the implementation of a quality system and the 
performance of a combination of trial site visits, training, and monitoring visits. Non-compliance 
should lead to prompt action by the sponsor to secure compliance.
Subject compliance will be confirmed by a comparison of IMPs dispensed and returned and by IMP 
administration by the investigator in a controlled environment.
13
DOCUMENTATION OF TRIAL DATA
The trial documentation must be adequate for the reconstruction of the trial.
13.1
Case report forms
The investigator must verify and confirm by signing that the CRFs have been checked and are 
complete, accurate, and compatible with the source documents. All CRF entries, corrections, and 
alterations must be made by the investigator or other authorized personnel under their supervision. 
Case report forms for each subject will be provided to the investigator by the sponsor in electronic
format to document the trial data.
The investigator and personnel delegated the task will use CRFs to record information required by 
the protocol. All personnel entering data will receive instruction on how to complete the CRF.
The investigator will be required to verify that the CRF entries are complete, accurate, and 
compatible with source documents. 
All CRF entries, corrections, and alterations will be made by the investigator or other authorized 
personnel under their supervision. Entries will be checked against appropriate source documents by 
authorized sponsor representatives as deemed appropriate in the monitoring guidelines.
The data will be processed using a validated electronic CRF system. Access to the system will be 
protected with a personal user name and password. Dedicated users (e.g., the investigator, 
designated persons at the trial site, authorized sponsor representatives, and from other parties 
involved, e.g., data management) will be identified and receive access rights according to their role 
in the trial. They will be trained on the use of the system for their intended role before access rights 
are granted and will be able to review data during the trial via a secure internet connection.
All entries and modifications to the CRF will be stored with the personal identification of the 
person who made the entry/changes, a date/time stamp, and the reason for change, if applicable.
The CRF must be signed electronically by the investigator. Any changes made to the CRF pages 
after the investigator has signed will require re-signing by the investigator.
13.2
Subject reported outcomes
Subject’s pain assessments (NRS), pain relief scores, responses to the question if pain is at least half 
gone, and IMP/rescue medication intake at home will be captured by paper. 
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All subject reported outcomes reported on paper will stay as source data at the trial site. The 
investigator is responsible for the accurate transfer of these data into the CRFs (see Section 13.1). 
13.3
Data management
Data management will be performed by sponsor personnel or by authorized sponsor representatives. 
Documentation of the responsibilities and delegation thereof will be maintained in the trial master 
file.
Queries and corrections
During data entry in the CRF, automatic queries will be raised to clarify missing data, 
inconsistencies, and incorrect values. Additional queries will be issued via the CRF system to the 
investigator to clarify inconsistencies (e.g., resulting from additional electronic validation checks or 
medical and manual reviews). Resolutions of queries will be made by the investigator or the trial 
site’s designated persons. The query is to be answered directly in the electronic CRF system and the 
original value will be changed, if necessary.
Corrections to the data without raising a query to the investigator will only be made by the data 
management CRO when the errors and their solutions are self-evident and if they do not change the 
actual meaning of the data as recorded by the investigator. 
A list of all self-evident corrections will be defined in the data management plan and will be sent to 
the investigator for approval at the beginning of the trial. If the investigator does not approve the list 
of self-evident corrections, data clarification forms will be created.
External trial data
External trial data (e.g., clinical laboratory parameters) being provided on separate printouts will be 
entered manually directly from the printouts.
The transferred data will be reconciled against other CRF data (details of reconciliation will be 
specified separately in the data validation plan or data management plan but may include trial code, 
trial site number, subject number, age, dates of visits). Procedures will be implemented to resolve 
discrepancies. 
At the end of the trial, the providers/vendors providing these data will provide the data management 
CRO with a complete and clean data transfer.
Coding
Medication names will be coded using the World Health Organization-Drug Dictionary 
(WHO-DD). Medical history terms and adverse events will be coded using the Medical Dictionary 
for Regulatory Activities (MedDRA). Coding will be reviewed by the sponsor’s personnel 
according to standard procedures.
Database lock
When all data have been received and entered into the clinical trial database, all data checks and 
quality control checks have been performed, all queries are resolved, and the final statistical review 
has been held without resulting in new queries, the clinical trial database will be considered clean 
and the data will be locked.
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13.4
Source data
Source data is defined by GCP as “all information in original records and certified copies of original 
records of clinical findings, observations, or other activities in a clinical trial necessary for the 
reconstruction and evaluation of the trial. Source data are contained in source documents (original 
records or certified copies)”.
Source data comprise clinical documentation, data, and records (e.g., clinic/hospital records, clinical 
and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, pharmacy 
dispensing records, recorded data from automated instruments, and data and records arising from 
departments such as the pharmacy, laboratory, and medico-technical departments) that describe or 
record the methods, conduct, or results of the trial, the factors affecting the trial, and the actions 
taken. 
All source data arising from the trial will be kept by the investigator, who must provide direct 
access for trial-related monitoring, audits, ethics committee review, and regulatory inspection.
In certain circumstances, data may only be recorded in the trial-specific CRF and not in other 
documents. When this occurs, the CRF is considered to be the source document. Data expected to 
be only recorded in the CRF are: race/ethnicity and sex.
The nature and location of all source data/clinical documentation will be identified and documented 
by the investigator to ensure that all sources of original data required to complete the CRF are 
known to the sponsor and/or trial site personnel and are accessible for verification during trial-
related monitoring, audits, relevant IEC review, and inspection(s).
During trial conduct, the vendor is responsible for data security related to data captured in the 
electronic CRF or IRT.
All data captured from all subjects will be sent to the sponsor in human readable form on a read-
only compact disc/DVD for filing/archiving according to sponsor SOPs.
The investigator will receive all data captured for his or her subjects, in a human readable form, on 
a read-only compact disc/DVD for his or her files.
13.5
Investigator’s site file and the trial master file 
The principal investigator is responsible for the filing of all essential documents in an investigator’s 
site file. The sponsor is responsible for the timely filing of all essential documents in the trial master 
file. As applicable, these files must be available at monitoring visits and during audits or regulatory
inspections.
After trial completion, the principal investigator must ensure that all source data/documentation 
related to the trial is recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation and verification. The principal investigator must take measures to prevent accidental 
or premature destruction of these documents.
The principal investigator must keep the investigator’s site file, the source data/documentation 
arising from the trial according to the prescribed record retention period in the country and/or 
according to the hospital policy, but at least until informed by the sponsor that the trial-related 
records are no longer required.
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14
QUANTITATIVE ANALYSES
14.1
Statistical methods and sample size determination
14.1.1
Sample size rationale
A total number of 720 subjects or 180 subjects per treatment group are required to achieve an 
overall power of at least 85% to reject the null hypothesis of at least 1 of the 4 formal statistical 
tests in the primary analysis of the trial (1-sided t-test, type I error of α/4 with α = 2.5%) assuming a 
common standard deviation of change from baseline values of 4 points (TOTPAR4) (Bakshi et al. 
1994, Hersh et al. 2004) and an expected treatment difference of at least 2 points (TOTPAR4) 
(Auad et al. 2009, Singla et al. 2014) on the primary efficacy endpoint in the comparisons between 
tramadol HCl/diclofenac sodium 50 mg/50 mg and the monotherapies of diclofenac sodium 50 mg 
and tramadol HCl 50 mg, and using a non-inferiority margin of = 1.5 points (TOTPAR4) (see 
Section 18.2) on the primary efficacy endpoint in the comparisons between tramadol 
HCl/diclofenac sodium 25 mg/25 mg and the monotherapies of diclofenac sodium 50 mg and 
tramadol HCl 50 mg. To achieve 180 evaluable subjects per arm and accounting that up to 10% of 
subjects will not be evaluable for the analysis set for the primary analysis, 200 subjects per arm or 
800 subjects in total will be allocated to IMP.
Assuming an enrollment failure rate of about 25% which is usually observed in clinical trials in 
Mexico, about 1065 subjects are planned to be enrolled (i.e., sign the informed consent) in order to 
allocate 800 subjects to IMP, i.e., about 130 subjects per trial site in approximately 8 to 12 sites.
14.2
General description of statistical analyses
The statistical analysis of this trial will be performed as described and summarized in the protocol. 
Full details of the planned statistical analyses will be described in the trial statistical analysis plan.
The statistical analysis of this trial will be planned, performed, and reported by sponsor personnel or 
by authorized sponsor delegates, in accordance with sponsor SOPs/SOPs of the sponsor’s delegate.
Data collected and derived in the trial will be listed.
Summary statistics and graphical methods will be used to describe endpoints of interest.
The following descriptive statistics will be produced on the basis of the nature of the relevant 
statistical variable:
•
For continuous variables: number of non-missing observations, arithmetic mean, standard 
deviations, minimum, first quartile (Q1), median, third quartile (Q3) and maximum.
•
For categorical variables: frequencies and percentages.
•
For time to event variables: number of non-missing observations, minimum, first quartile 
(Q1), median, third quartile (Q3), and maximum.
All the statistical analyses will be performed in the relevant analysis population of interest (see 
Section 14.3). All the statistical analyses will be performed at least by treatment group.
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14.3
Analysis populations (analysis sets)
Enrolled Set
The Enrolled Set will comprise all subjects who signed the informed consent form.
Safety Set
The Safety Set will comprise all subjects allocated and treated with IMPs.
Analyses on the Safety Set will be conducted according to actual treatment received.
Full Analysis Set
The FAS will comprise all subjects allocated and treated, and with at least 1 non-missing pain relief 
assessment during the first 4 hours post-baseline. Analyses on the FAS will be conducted according 
to allocated treatment. 
Per Protocol Set
The PPS will be defined as a subset of the subjects in the FAS without any major protocol 
deviations affecting the primary endpoint. Only subjects with no rescue medication use in the first 
120 minutes after first dose, who complete at least a follow-up of 4 hours and who comply with the 
protocol procedures will be included in the PPS. Further details of the definition of the PPS will be 
specified in the statistical analysis plan.
14.4
Analysis of demographic data and other baseline characteristics
Subject disposition as well as demographic and baseline data and other subject characteristics (e.g., 
medical history and prior and concomitant medications) will be descriptively summarized for the 
Safety Set, FAS, and PPS.
14.5
Analysis of efficacy data
The primary analysis to investigate the primary objective of the trial (see Section 1.2) is based on 
the primary efficacy endpoint (TOTPAR4) and will be performed on the FAS and repeated as 
sensitivity analysis on the PPS. Additional sensitivity analyses and the analysis of additional 
efficacy parameters will be performed on the FAS only.
14.5.1
Analysis population for primary efficacy analysis 
The primary analysis to investigate the primary objective of the trial (see Section 1.2) is based on 
the primary efficacy endpoint (TOTPAR4) and will be performed on the FAS.
The rationale to choose the FAS as analysis set for the non-inferiority comparisons of the primary 
analysis (for superiority comparisons the FAS population is used as a standard) is the preservation 
of the value of randomization and estimation of real world effectiveness, properties desirable for 
non-inferiority trials as well (Wiens and Zhao 2007). It is important to carefully choose 
conservative imputation methods (see Section 14.5.5) in order to avoid that subjects who 
discontinue the trial before full treatment effects are shown, diminish the difference between 
treatments making them appear more similar than they are and therefore inflate the risk of falsely 
accepting therapeutic non-inferiority when it is not justified. The primary analysis will be repeated 
as sensitivity analysis on the PPS. Additional sensitivity analyses and the analysis of additional 
efficacy parameters will be performed on the FAS only.
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14.5.2
Overall testing strategy
The primary objective of the trial (see Section 1.2) is investigated by 4 formal statistical tests (see 
Table 1). Testing multiple hypotheses, however, may increase the family-wise type I error rate, the 
probability to erroneously reject at least 1 true null hypothesis, beyond the pre-specified 
significance level. In order to control the family-wise type I error rate in the strong sense at the pre-
specified 1-sided significance level of α = 2.5%, a Bonferroni-Holm procedure (Holm 1979) will be 
used. The elementary null hypotheses H01, H02, H03, and H04 and according statistical tests T1, T2, 
T3, and T4 of the primary objective of the trial are listed in Table 1.
Table 1:
Statistical tests and null hypotheses (all 1-sided) of the primary objective of the trial
Test
Description
Null hypothesis
Alternative hypothesis
T1
Superiority of tramadol HCl/diclofenac
sodium 50 mg/50 mg 
vs. tramadol HCl 50 mg
H01: µT50 - µADL50/50 ≥0
HA1: µT50 - µADL50/50 <0
T2
Superiority of tramadol HCl/diclofenac 
sodium 50 mg/50 mg 
vs. diclofenac sodium 50 mg
H02: µD50 - µADL50/50 ≥0
HA2: µD50 - µADL50/50 <0
T3
Non-inferiority of tramadol HCl/diclofenac 
sodium 25 mg/25 mg 
vs. tramadol HCl 50 mg
H03: µT50 - µADL25/25 ≥
HA3: µT50 - µADL25/25 <
T4
Non-inferiority of tramadol HCl/diclofenac 
sodium 25 mg/25 mg 
vs. diclofenac sodium 50 mg
H04: µD50 - µADL25/25 ≥
HA4: µD50 - µADL25/25 <
ADL = Adorlan (tramadol HCl/diclofenac sodium); D = diclofenac sodium; T = tramadol hydrochloride;
HCl = hydrochloride.
= 1.5 is the non-inferiority margin.
The trial will be positive if at least 1 of the according 4 statistical tests rejects the according null 
hypothesis.
According the Bonferroni-Holm procedure, the p-values of the 4 tests T1, T2, T3, and T4 will be 
sorted in ascending order p(1) < p(2) < p(3) < p(4) and the following algorithm will be applied to the 
corresponding null hypotheses H(01), H(02), H(03), H(04): 
•
Step 1. If p(1) <α/4 = 0.625%, reject H(01) and move to the next step. Otherwise retain all 
null hypotheses and stop.
•
Step 2. If p(2) <α/3 = 0.833%, reject H(02) and move to the next step. Otherwise retain H(02), 
H(03) and H(04) and stop.
•
Step 3. If p(3) <α/2 = 1.25%, reject H(03) and move to the next step. Otherwise retain H(03)
and H(04) and stop.
•
Step 4. If p(4) <α = 2.5%, reject H(04) and move to formally testing null hypotheses related to 
secondary endpoints. Otherwise retain H(04).
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14.5.3
Analysis of primary endpoint
14.5.3.1
Primary analysis
The primary endpoint will be TOTPAR4 (see Section 7.1). The TOTPAR4 will be calculated as a 
weighted sum of the observed pain relief scores during the first 4 hours after first dose with weights 
proportional to the time since the last pain relief assessment. TOTPAR scores can be interpreted as 
estimates of the area under the longitudinal pain relief curve. 
The estimand of interest for the primary efficacy analysis is the difference in the primary efficacy 
endpoint in all subjects in the FAS attributable to the initially allocated trial medication 
(Mallinckrodt et al. 2012). The FAS analysis will be the primary analysis for all comparisons. 
Null hypotheses H01  ̶̵  H04 and alternative hypotheses HA1   ̶̵  HA4 of the formal statistical tests of the 
primary efficacy analysis are provided in Table 1. The primary analysis will use an ANCOVA 
model with treatment, site, and baseline pain (measured on an 11-point NRS) as covariates.
A detailed description of missing data imputation methods is provided in Section 14.5.5.
14.5.3.2
Sensitivity analysis
The following sensitivity analyses will be performed to assess the robustness of the primary 
analysis results to the choice of analysis population and missingness assumptions:
Sensitivity analysis 1: Full Analysis Set
To investigate whether results of the trial are sufficiently similar to results of past historical trials 
with respect to all design features that can influence the estimation of treatment effect (constancy 
assumption), single imputation methods used in historical trials of the active comparators diclofenac 
and tramadol will be applied here as well, namely LOCF and substitution by Zero (no relief from 
baseline pain) for missing data after premature discontinuation from the trial or disregarded pain 
relief assessments after start of rescue medication intake.
Sensitivity analysis 2: Per Protocol Set
The primary analysis will be repeated on the PPS.
14.5.4
Analysis of additional efficacy outcomes
The pain intensity scores (NRS) at all the time points (see Section 1.8) after the first dose of IMPs
will be analyzed by an ANCOVA model with treatment, site, and baseline pain as covariates.
Pain relief expressed as Total Pain Relief after 6 hours and after 8 hours (TOTPAR6, TOTPAR8) 
will be analyzed with the same ANCOVA model and missing data handling as the primary analysis.
The specification of the statistical analysis of the following additional efficacy outcomes including 
statistical analysis models, formal statistical tests, and further specifications in detail will be 
provided in the statistical analysis plan:
•
Pain intensity score reductions (Pain Intensity Difference [PID], NRS) for each time point 
after the first dose of IMPs. 
•
Summed Pain Intensity Difference (SPID) at 4, 6, 8, and 24 hours after the first dose of 
IMPs.
•
Pain relief scores for each time point after the first dose of IMPs.
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•
Time to onset of first perceptible pain relief (Stopwatch 1).
•
Time to onset of meaningful pain relief (Stopwatch 2).
•
Time to achieve a 50% reduction in baseline pain (pain at least half gone).
•
Time to request the first dose of rescue medication.
•
Time to first intake of rescue medication.
•
Subject’s global evaluation of the treatment (5-point Likert scale) 8 hours or before first 
intake of rescue medication (whatever the first) and 24 hours after the first dose of IMPs.
14.5.5
Missing data
Diligent attempts will be made to limit the amount of missing data in the pain relief assessments 
used to determine the primary efficacy endpoint. Efforts will be made to encourage but not to 
enforce subjects to not start rescue medication intake if not needed. 
Primary analysis
For the primary analysis, missing pain relief assessments in the first 4 hours after first dose as well 
as pain relief assessments after start of intake of rescue medication will be imputed by LOCF for 
intermittent missing data, and substitution by δ for missing data after premature discontinuation 
from the trial or disregarded pain relief assessments after start of rescue medication intake.
The value of parameter δ will depend on the reason for discontinuation and treatment arm. The 
following 3 categories of reason for discontinuation will be distinguished: Discontinuation due to 
LoE, adverse events, and other, non-drug related reasons. The parameter will be
•
δ = 0:
For missing data after discontinuation due to LoE, discontinuation due to 
adverse events and for disregarded pain relief assessments after start of rescue 
medication intake for subjects in the tramadol HCl/diclofenac sodium FDC 
combination arms.
•
δ = 0.375:
For missing data after discontinuation due to LoE, discontinuation due to 
adverse events and for disregarded pain relief assessments after start of rescue 
medication intake for subjects in the monotherapy arms diclofenac sodium 
50 mg and tramadol HCl 50 mg.
•
δ = 0:
For missing data after discontinuations due to other, non-drug related, 
reasons. 
The size of parameter δ is chosen to result in a TOTPAR4 penalty of Δ/2 in case the trial 
discontinuation/start of rescue medication intake occurs 2 hours after first dose, with non-inferiority 
margin Δ =1.5 points (TOTPAR4) as determined in Section 18.2. 
Sensitivity analysis 1: Full Analysis Set, single imputation methods
To investigate the constancy assumption, missing and disregarded pain relief assessments will be 
imputed with the following single imputation methods used in historical trials of the active 
comparators as well:
•
Last Observation Carried Forward. 
•
Last Observation Carried Forward for intermittent missing data, and substitution by Zero 
(no relief from starting pain) for missing data after premature discontinuation from the trial 
or disregarded pain relief assessments after start of rescue medication intake.
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14.5.6
Subgroup analyses
Subgroup analyses will be performed for subjects with a moderate pain intensity at baseline (with 
scores of 5 or 6 on the 11-point NRS) and for subjects with a severe pain intensity at baseline (with 
scores of 7 to 10 on the 11-point NRS). Furthermore, subgroup analyses will be performed per site.
14.6
Analysis of safety data
The analysis of safety data will be performed for the Safety Set and will be listed with all 
corresponding information.
14.6.1
Adverse events
A definition of adverse event is given in Section 12.3.1. 
The original terms used by the investigators in the CRFs to identify adverse events will be coded 
using the most recent version of the MedDRA at the time of database lock.
Any adverse event which occurs after first administration of the IMPs or pre-existing adverse event
which worsens (adverse change in intensity, frequency, or quality) after first administration of the 
IMPs compared to the complaint present before first intake of the IMPs is considered as a treatment 
emergent adverse event.
Treatment emergent adverse events will be summarized for each treatment group by System Organ 
Class and Preferred Term. Additional summaries by time to onset, duration, intensity, relationship 
to IMP, outcome, expectedness, and countermeasures will also be produced.
Subjects with SAEs will be summarized and additionally listed. Special attention will be given to 
those subjects who discontinue treatment due to an adverse event or who experience a severe 
adverse event or SAE.
The incidence of adverse events and adverse events leading to premature discontinuation from 
treatment will be presented descriptively.
14.6.2
Clinical laboratory parameters and urinalysis
Clinical laboratory parameter data (clinical chemistry, hematology, and coagulation) and urinalysis 
results will be descriptively summarized by type of laboratory test and time point and descriptive 
statistics will be presented. 
14.6.3
Vital signs
Descriptive statistics will be calculated for each parameter of the vital signs collected at Visit 1 and 
Visit 2.
15
QUALITY SYSTEM, AUDIT AND INSPECTION
15.1
Quality system
The sponsor is responsible for implementing and maintaining quality assurance and quality control 
systems with written SOPs.
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15.2
Data quality assurance
The accuracy and reliability of the trial data will be assured by careful CRO/investigator selection 
and oversight by the performance of a combination of trial site visits, training, monitoring visits, 
remote verification by the sponsor or appropriate use of electronic tools by the trial site, data 
cleaning, and audits.
Trial site monitoring as defined in GCP will be performed by sponsor personnel or by authorized 
sponsor delegates at pre-defined intervals depending on the progress of the trial.
Corrections, amendments, or clarifying statements resulting from monitoring visits should be made 
by the investigator where necessary. 
Appropriate checking against source documents must be done by the sponsor. 
Audits as defined by GCP should be performed for this trial. The auditors will be independent of the 
trial and its performance.
15.3
Inspections 
The principal investigator, any investigators, the sponsor, or personnel at other establishments, must
cooperate with any inspection of the documents, facilities, records, and other resources deemed 
appropriate by the inspecting authorities to be related to the trial and that may be located at the trial 
site, at the sponsor, or at other establishments. 
The sponsor must be notified as soon as possible about any upcoming regulatory authority 
inspection.
16
GENERAL CONDITIONS AND AGREEMENTS
16.1
Insurance
If required by applicable regulatory requirements, the sponsor will arrange suitable insurance for the 
subjects included in this trial and provide the investigator with the relevant terms and conditions of 
this insurance. The investigator must inform all subjects about this insurance and (if requested) be 
prepared to explain the relevant terms and conditions of this insurance to the subject.
If changes to the trial are implemented after the initial insurance was arranged, e.g., due to protocol 
amendments, the sponsor will notify the insurance company of these changes in accordance with 
the insurance conditions. If changes to insurance arise, the sponsor will inform the investigators 
who will then inform their subjects about relevant changes.
16.2
Legal regulations
This trial will be carried out in compliance with any applicable regulatory requirements with respect 
to the use of narcotics.
Before initiating the trial, if required by the applicable regulatory requirements, the sponsor or its 
authorized legal representative and/or the investigator will submit any required documents to the 
appropriate authorities for review, acceptance, and/or permission to begin the trial. 
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16.3
Contracts
Specific contracts between the relevant parties, i.e., between the investigator/other parties at the trial 
sites and the sponsor or its local offices or CRO or its affiliates authorized by the sponsor, will be 
used to set out any arrangements on delegation and distribution of tasks and obligations and, if 
appropriate, on financial matters. This protocol and other documentation may serve as the basis of 
such contracts. In case of discrepancies with other contracts, the provisions of the protocol prevail.
In addition, responsibility for insurance or indemnity to cover any liability of the investigator that 
may arise directly or indirectly from the investigator’s participation in the trial will be specified in a 
contract between the investigator and sponsor, if applicable.
16.4
Subject data and data protection
Subject trial data will be stored in a manner maintaining confidentiality in accordance with 
applicable regulatory requirements.
The investigator should ensure that any documents or data given to the sponsor or authorized 
sponsor representatives do not contain information that would affect the confidentiality of the 
subject’s identity.
The investigator will obtain permission for direct access to original subject data from the subject as 
part of the written informed consent procedure (see Section 4.2). This gives permission to examine, 
analyze, verify, and reproduce any records and reports that are important to the evaluation of the 
trial. Any party (e.g., domestic and foreign regulatory authorities, sponsor personnel or its 
representatives, and auditors) with direct access must take all reasonable precautions within the 
constraints of the applicable regulatory requirement(s) to maintain the confidentiality of the 
subject’s identity and sponsor’s proprietary information.
16.5
Public disclosure
The results of this trial will be publically disclosed in accordance with the sponsor’s disclosure 
policy, the European Federation of Pharmaceutical Industries and Associations (EFPIA) Principles 
for Responsible Clinical Trial Data Sharing and applicable regulatory guidance (e.g., on 
www.cofepris.gob.mx). 
The results (or parts thereof) of this trial may be published as a full publication (e.g., journal 
publication) or at a congress (e.g., as a poster or presentation). The sponsor reserves the right to 
review any proposed full publication or poster or presentation of the results of this trial by the 
coordinating investigator before they are submitted for publication or public disclosure. 
Neither the sponsor nor the coordinating investigator has the right to prohibit publication or public 
disclosure unless it can be shown to affect possible patent rights.
16.6
Trial results reporting
A final report integrating clinical and statistical results will be prepared by the sponsor. The
coordinating investigator will approve the final report on behalf of the participating investigators. 
The sponsor will provide the competent authority/ies and relevant IECs with a summary of the trial
results in accordance with applicable regulatory requirements. 
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All principal investigators will be provided with a summary of the trial results.
16.7
Approval
16.7.1
Sponsor 
This protocol has been approved in accordance with sponsor SOPs. 
16.7.2
Coordinating investigator 
This protocol has been approved by the coordinating investigator.
17
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18
APPENDIX
18.1
List of potentially important medical concepts – classified by System 
Organ Class
Blood and lymphatic system disorders
Agranulocytosis
Aplastic anaemia
Blast cell proliferation 
(myeloproliferative and 
lymphoprolipherative disorders)
Bone marrow depression
Disseminated intravascular 
coagulation (DIC)
Haemolytic anaemia 
Histiocytosis
Loss of anticoagulation control 
Pancytopenia 
Splenic haemorrhage, infarction or
thrombosis
Thrombocytopenia (<30000)
Thrombotic thrombocytopenic 
purpura
Cardiac disorders
Angina unstable
Atrial flutter
Atrioventricular block complete
Cardiac arrest
Cardiac failure acute
Cardiac fibrillation
Cardiac tamponade 
Cardiogenic shock 
Cardiomyopathy acute 
Coronary artery spasm
Cor pulmonale decompensated
Myocardial infarction
Torsade de pointes
Ventricular fibrillation
Ventricular tachycardia 
Ear and labyrinth disorders
Deafness
Vestibular ataxia
Endocrine disorders
Adrenocortical insufficiency acute
Eye disorders
Cataract/lens opacity
Glaucoma
Keratitis/corneal opacification
Macular degeneration 
Optic neuropathy, atrophy 
Papilloedema 
Ptosis 
Retinal artery/vein occlusion 
Retinitis 
Scotoma
Sudden visual loss
Uveitis
Vitreous detachment
Gastrointestinal disorders
Colitis haemorrhagic
Gastric ulcer haemorrhage
Gastric ulcer perforation
Haematemesis
Haemoperitoneum
Ileus 
Intestinal ischaemia 
Intestinal perforation 
Melaena 
Mesenteric occlusion 
Mesenteric vein thrombosis
Pancreatitis
Peritonitis
General disorders and administration site conditions
Malignant hyperthermia
Hepatobiliary disorders
Hepatic failure
Hepatitis fulminant
Hepatic necrosis
Hepatorenal syndrome
Portal hypertension
Reye’s syndrome
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Immune system disorders
Amyloidosis
Anaphylactic reaction
Anaphylactic shock
Graft versus host disease
Infections and infestations
Endotoxic shock
Sepsis
Toxic shock syndrome
Transmission of an infectious agent 
via a medicinal product
Injury, poisoning and procedural complications 
Transplant failure
Wound dehiscence
Metabolism and nutrition disorders
Diabetic coma
Failure to thrive 
Hypercalcaemia (CTC IV)
Hyperkalaemia (CTC IV)
Hypocalcaemia (CTC IV)
Hypokalaemia (CTC IV)
Lactic acidosis
Porphyria
Shock hypoglycaemic 
Tetany
Musculoskeletal and connective tissue disorders
Aseptic necrosis bone
Fracture pathological 
Muscle necrosis 
Osteomalacia 
Rhabdomyolysis
Systemic lupus erythematosus
Systemic sclerosis
Nervous system disorders
Amnesia
Anticholinergic syndrome
Aphasia
Cerebral oedema
Chorea
Coma
Convulsions
Demyelination
Encephalitis
Encephalopathy 
Epilepsy
Guillain-Barré syndrome
Hydrocephalus
Intracranial haemorrhage
Meningitis 
Multiple sclerosis
Myasthenia gravis
Myelitis
Neuroleptic malignant syndrome
Opisthotonus
Paralysis
Paresis
Parkinson’s syndrome
Serotonin syndrome
Stroke
Tunnel vision
Pregnancy, puerperium and perinatal conditions
Abortion
Eclampsia
Intra-uterine death
Psychiatric disorders
Anorexia nervosa
Delirium
Drug abuse
Drug dependence
Homicidal ideation
Intentional misuse
Self-injurious ideation/attempt
Suicidal ideation/attempt
Suicide completed
Renal and urinary disorders
Anuria
Goodpasture’s syndrome
Haemolytic uraemic syndrome
Nephritis/nephritic syndrome
Nephrotic syndrome
Oliguria
Renal failure acute
Renal tubular necrosis
Urinary obstruction/retention
Reproductive system and breast disorders
Metrorrhagia/uterine heamorrhage
Priapism
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Respiratory, thoracic and mediastinal disorders
Acute respiratory failure
Adult respiratory distress syndrome 
Alveolitits allergic
Asphyxia
Bronchospasm
Laryngeal oedema
Pulmonary fibrosis
Pulmonary haemorrhage
Pulmonary infarction
Pulmonary vasculitis
Respiratory arrest
Status asthmaticus
Pulmonary oedema
Skin and subcutaneous tissue disorders
Angioneurotic oedema
Erythema nodosum 
Pemphigus
Stevens-Johnson syndrome
Toxic epidermal necrolysis
Vascular purpura
Vascular disorders
Acute circulatory failure 
Embolism
Malignant hypertension
Necrosis ischaemic
Thrombosis
Status: Jul 2012
CTC = Common Toxicity Criteria also referred to as the Common Terminology Criteria for Adverse Events (CTCAE).
18.2
Justification of non-inferiority margin
On 30 Mar 2016, an updated literature search in PubMed yielded 7 publications, none of which 
provided elements that could serve to identify a rationale for a non-inferiority margin.
The search string used was ((((third molar removal) OR third molar extraction) OR third molar 
surgery)) AND ((non-inferiority) OR clinically relevant difference).
Farrar (2000) has pointed out that the absence of taking a next dose or a dose of rescue medication, 
under the assumption that these can be taken freely, can be seen as the patient’s most unambiguous 
way to express that his/her perceived pain relief is evaluated by him/her as sufficient. In a series of 
repeated experiments mainly in cancer breakthrough pain, Farrar has concluded that a mean 
TOTPAR equal to 33% of the maximum possible TOTPAR has the optimal combination of 
sensitivity and specificity to predict that a patient does not feel the need to take another dose of 
analgesic (Farrar et al. 2010). Because the maximum value for TOTPAR4 = 16 and following 
Farrar’s approach, a TOTPAR4 = 5.33 would be a clinically relevant effect, though not necessarily 
a minimum clinically relevant effect.
Clinical trials in pain are known for their relevant placebo effect which has to be taken into account 
when proposing a clinically relevant difference to placebo. A mean TOTPAR4 value of 2.37 was 
found for placebo by pooling across all trials in pain after third molar removal with diclofenac 
50 mg, as available in the public domain (Bakshi et al. 1994), or with any dose of tramadol 
available at Grünenthal in-house (Reports ICSR031-00, ICSR033-00, TRAMAP-ANAG-02, 
TRAMAP-ANAG-07, TRAMAP-ANAG-10, TRAMAP-ANAG-12, TRAMAP-ANAG-13, 
CAPSS-128). Thus, a difference to placebo in TOTPAR4 value by 5.33-2.37 = 2.96 ≈ 3 can be 
assumed to represent a clinically relevant difference, although not necessarily a minimum clinically 
relevant difference. 
We believe that a choice of a non-inferiority margin = 0.5*3 = 1.5 (½ of the clinically meaningful 
effect of 3 points TOTPAR4) reflects the largest loss of effect that would still be clinically acceptable.
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18.3
Previous clinical trials with a combined treatment of tramadol and 
diclofenac
The benefits of the diclofenac and tramadol combination have been shown in previous clinical trials 
using various formulations (Table 2). 
Table 2:
Previous clinical trials with combination of tramadol and diclofenac
Author
Indication
Design
Number 
of 
subjects
Treatment groups 
and dosage
Results
Auad Saab et 
al. 2009
Postoperative 
pain (orthopedic 
surgery)
Prospective, 
double-blind, 
randomized, 
controlled, 
single-dose 
Phase IIIb 
pilot trial
30
- T/D FDC 
25 mg/25 mg po, 
1 tablet + placebo
- T/D FDC 
25 mg/25 mg po, 
2 tablets
- D 50 mg + placebo
T/D 25 mg/25 mg 
(2 tablets) provided the 
best pain relief at 
3 hours and at 6 hours 
and the shortest time to 
achieve a 20% decrease 
in the pain intensity 
(0.75 hours).
Auad et al. 
2009
Postoperative 
pain 
(bunionectomy)
Prospective, 
randomized, 
controlled, 
single-dose, 
double-blind, 
multi-site, 
multinational  
Phase III trial
110
- T/D FDC 
25 mg/25 mg po, 
1 tablet + placebo
- T/D FDC 
25 mg/25 mg po, 
2 tablets
- D 50 mg + placebo
Both T/D FDC groups 
had a greater total pain 
relief at 4 h and 8 h 
when compared to the 
D 50 mg control group.
At 90 min, there were 
significant differences 
in pain intensity in favor 
of the T/D 50 mg/50 mg 
group. T/D FDC groups 
had an earlier onset of 
effect, an earlier peak of 
maximum pain relief, 
and a longer time to 
administer the first dose 
of rescue medication 
compared to D 50 mg.
Mok et al. 
1996
Postoperative 
pain (abdominal 
surgery)
Randomized, 
double-blind
80
- T 50 mg IV + 
D 50 mg IM
- T 50 mg IV + 
placebo IM
- Meperidine 50 mg 
IV + placebo IM
- Placebo IV + 
D 50 mg IM
T+D provided the best 
pain relief with a 1 h 
peak, lasting 6 h.
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Author
Indication
Design
Number 
of 
subjects
Treatment groups 
and dosage
Results
Filippi et al. 
1999
Postoperative 
pain after disc 
surgery
Randomized 
open label
60
Group 1: no standard
pain therapy, subjects 
received on demand 
different analgesics
Group 2: standardized 
pain therapy, oral D
up to 75 mg per dose 
+ oral T up to 200 mg 
per dose
Subjects in the T+D 
group had lower pain 
levels than the control 
group at 24, 48, and 
72 h.
Wilder-Smith 
et al. 2003
Post Cesarean 
pain
Randomized, 
double-blind, 
placebo-
controlled, 
single dose
120
- T 100 mg IM + 
placebo IM
- D 75 mg IM + 
placebo IM
- T 100 mg IM + 
D 75 mg IM
- Placebo IM + 
Placebo IM
The T+D group had the 
longest median time to 
the first rescue 
medication dosage.
Hussain et al. 
2008
Post 
hysterectomy 
pain
Randomized, 
double-blind,
placebo-
controlled
70
- Placebo supp. + 
T 317 mg PCA
- D 100 mg supp. + 
T 258 mg PCA
The group with the 
placebo suppository 
used more T to relieve
pain.
Vasallo-
Comendeiro 
and Arjona 
Fonseca 2011
Gynecological 
and obstetric 
surgery
Analytical, 
observational, 
prospective, 
cohort trial
50
- T 1 mg/kg IV + 
D 75 mg IV
- Pethydine 1 mg/kg 
IV + dipyrone 
600 mg IV
Analgesia of T+D 
combination was 
superior to the one with 
pethydine + dipyrone.
De Sousa 
Santos et al. 
2012
Third molar 
surgery, 
postoperative 
pain
Randomized, 
double-blind, 
crossover, 
split mouth
30
- T 50 mg po + 
dexamethasone 4 mg 
po 1 h before 
surgery
- T 50 mg po + 
D 50 mg po 1 h 
before surgery
Tramadol + 
dexamethasone group 
presented lower pain 
scores.
Mitra et al. 
2012
Pain after 
Cesarean section
Randomized, 
double–blind, 
parallel, 
controlled
204
- D 100 mg 64up. 
Every 8 h for 24 h 
plus either
- Acetaminophen IV 
1 g every 6 h
- T 75 mg IV every 
6 h
Pain intensity scores as 
an area under the curve 
(AUC) was lower in the 
T+D group. The use of 
rescue medication was 
similar in both groups. 
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Author
Indication
Design
Number 
of 
subjects
Treatment groups 
and dosage
Results
Shareef et al. 
2014
Post Cesarean 
pain
Randomized
90
- T 100 mg IM x2
- D 75 mg IM x2
- (T 50 mg IM + 
D 50 mg IM) x2
T+D combination 
achieved earlier 
analgesia compared 
with montherapies.
Chandanwale 
et al. 2014
Moderate to 
severe pain in: 
musculoskeletal 
conditions, 
osteoarthritis 
flare, rheumatoid 
arthritis flare, 
postoperative 
pain
Open label
204
- T 50 mg + D 75 mg 
FDC po, 1 tablet 
twice a day, 5 days
- T 37.5 mg + 
paracetamol 325 mg 
FDC po, 2 tablets, 
3-4 times a day, 
5 days  
Subjects on T+D FDC 
had a significant 
reduction in pain on 
Day 3 and Day 5 
compared to the 
tramadol + paracetamol 
group.
T = tramadol; D = diclofenac; h = hour; IM = intramuscular; IV = intravenous; po = oral; 65up. = suppository;
PCA = patient-controlled analgesia; FDC = fixed-dose combination.
18.4
Rescue medication and comparator prescribing information
The rescue medication (ibuprofen, ketorolac) and comparator (Voltaren [diclofenac], tramadol)
prescribing information provided with the protocol are examples. Copies of the versions used in the 
trial will be filed in the trial master file.
19
PROTOCOL AMENDMENTS
19.1
Protocol Amendment 01
Amendment rationale
This amendment has been implemented to change the following:
•
The Universal Trial Number was corrected.
•
The sponsor’s address was updated.
•
New exclusion criteria (9 and 10) concerning restrictions for dental surgery were added at 
Visit 1. Details on the reading of Exclusion Criterion 5 were provided. Two exclusion 
criteria were shifted to be assessed at Visit 1 instead of at Visit 2.
•
In sections referring to allowed and forbidden medication, it was added that systemic 
corticosteroids are not allowed during the trial.
•
Standardized anesthesia for dental surgery was changed from the administration of 
lidocaine only to lidocaine plus epinephrine. The anesthetic was added as trial treatment 
(Section 1.4.3 and Section 10.6 were added).
•
The use of cold compresses or ice bags is allowed from 4 hours after the first administration 
of IMP up to 30 minutes before each pain assessment.
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•
It was specified in Section 11.1.2.1 that that the postsurgical follow-up can be performed in 
a dental clinic or in an SMO’s research facilities. Every research facility must have a 
responsible clinical investigator. It was added, that emergency equipment has to be 
available at the site.
•
Dietary restrictions before and after surgery were added.
•
It was specified in the schedule of events and in Section 11.1.1 that only local safety 
laboratories will be used in this trial.
•
For the detection of safety signals and early safety reporting, a cross-reference to the 
sponsor’s Drug Safety procedures was added.
Detailed description of changes
Minor editorial changes, such as the correction of typing errors, are not specifically listed.
In the table below, deleted text is crossed out and new text is highlighted using italics.
Changes to this protocol include:
Formerly read:
Now reads: 
Section: Front Page
Grünenthal Group
Product Development Latin America
255 Alhambra Cir #435, 
Coral Gables 
FL 33134, United States
Grünenthal S.A.
Edificio Torres de las Américas
C-3100 Panama City
Panama
Trial sites:
Multi-site trial (approximately 8 
to 12 sites in Mexico)
Trial sites:
Multi-site trial (up to 8 sites in 
Mexico)
Universal Trial Number: U1111-1179-23333
Universal Trial Number: U1111-1179-2333
Section 1.3.2.1: Exclusion criteria at Visit 1
…
5. Known alcohol or drug abuse within
6 months or any history of seizures.
…
…
5. Known alcohol or drug abuse in the last
6 months or any history of seizures. Alcohol 
abuse is defined as the consumption of more 
than 3 ounces (about 90 mL) of liquor or 
spirits or 18 ounces (about 530 mL) of beer 
per day, for 5 consecutive days during the 
6-month period. Drug abuse is defined as 
the use of any recreational drug for 
5 consecutive days during the 6-month 
period.
…
7. Pregnant or lactating women.
8. Subjects who received systemic 
corticosteroids or opioid analgesics less 
than 2 weeks before surgery.
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Changes to this protocol include:
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Now reads: 
9. Subjects with molars linked to the
mandibular canal.
10. Subjects requiring immediate dental 
procedures other than third and fourth 
molars extraction.
Section 1.3.2.2: Exclusion criteria at Visit 2
7. Pregnant or lactating women.
12. Subjects who received systemic 
corticosteroids or opioid analgesics within 
2 weeks prior to surgery.
Note: Due to the shift of Exclusion Criteria 7 
and 12 to Section 1.3.2.1 and the addition of 
new exclusion criteria (9 and 10) to 
Section 1.3.2.1, the Exclusion Criteria 8-11 and 
13 listed for Visit 2 were renumbered to read 
Exclusion Criteria 11-15.
Section 1.4.3: Anesthetics for standardized surgery
New section
Commercially available cartridges containing 
36 mg of lidocaine hydrochloride plus 
0.018 mg of epinephrine in a total volume of 
1.8 mL will be provided by the sponsor.
Section 1.5: Prior/concomitant medications
The use of antibiotics and other concomitant 
medications except for analgesics is allowed at 
the discretion of the investigator…
The use of antibiotics and other concomitant 
medications except for analgesics and systemic 
corticosteroids is allowed at the discretion of 
the investigator…
Section 1.8: Schedule of events
…
Take blood samples for clinical laboratory 
parameter assessments and urine for 
urinalysis a
…
Take blood samples for clinical laboratory 
parameter assessments and urine for 
urinalysis a, b
…
b) Clinical laboratory parameter assessments
will be performed by contracted local certified 
clinical laboratories.
…
Section 3.1: Abbreviations
New abbreviation
SMO Site Management Organization
Section 5.1.1: Investigators
The trial may be conducted solely at a dental 
clinic, or management of a subject may be 
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Changes to this protocol include:
Formerly read:
Now reads: 
There must be an investigator at each trial site.
If the trial is conducted by a team of 
individuals at the trial site, the investigator 
leading and responsible for the team is called 
the principal investigator.
…
shared between a dental clinic and a local 
research facility of a Site Management 
Organization (SMO). The latter combination is 
considered a single trial site. 
There must be an investigator at each trial site. 
If the trial is conducted by a team of 
individuals at the trial site, the investigator 
leading and responsible for the team is called 
the principal investigator. For each of the local 
research facilities, a principal investigator will 
be designated and will have primary 
responsibility for compliance with the protocol 
and GCP at that site (see Section 5.1.2).
…
Section 10.2: Administration of investigational medicinal product
…
Subjects will stay at the clinic for at least for 
8 hours after the first IMP dose before they can 
leave the trial site facilities. They should take 
their last dose of IMPs as an outpatient 
16 hours (1 hour) after the first IMP dose.
…
…
Subjects will stay at the dental clinic or other 
research facility for at least for 8 hours after 
the first IMP dose before they can leave the 
trial site facilities. They should take their last 
dose of IMPs as an outpatient 16 hours 
(1 hour) after the first IMP dose.
…
Section 10.6: Lidocaine/epinephrine for anesthesia
New section
Details on the local anesthetic are provided in 
Section 1.4.3. The administration details are 
provided in Section 11.1.2.1.
Section 10.7 (formerly 10.6): Allowed and forbidden concomitant medications
…
Use of antibiotics and other concomitant 
medications except for analgesics is allowed by 
the protocol, according to the common practice 
of the investigator and the investigator’s 
brochure…
…
Use of antibiotics and other concomitant 
medications except for analgesics and systemic 
corticosteroids is allowed by the protocol, 
according to the common practice of the 
investigator and the investigator’s brochure…
Section 11.1.1: Enrollment Period (Visit 1)
…
Take blood samples for clinical laboratory 
parameter assessments and urine for urinalysis. 
…
Take blood samples for clinical laboratory 
parameter assessments and urine for urinalysis. 
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Changes to this protocol include:
Formerly read:
Now reads: 
If results of laboratory parameters deviate…
Clinical laboratory parameter assessments will 
be performed by contracted local certified 
clinical laboratories. If results of laboratory 
parameters deviate…
Section 11.1.2.1: Allocation Visit (Visit 2)
Standardized local anesthesia 
…To numb the mouth, blocking of the inferior 
alveolar, lingual, and buccal nerves will be 
carried out by using 1-3 shots of lidocaine per 
third molar not exceeding a maximum total 
amount of 300 mg per subject.
…
For restrictions concerning meals and fluid 
intake before and after surgery, please see 
Section 11.2.3.
Standardized local anesthesia 
…To numb the mouth, blocking of the inferior 
alveolar, lingual, and buccal nerves will be 
carried out by using 1-3 cartridges of lidocaine 
plus epinephrine per third molar not exceeding 
a maximum total amount of 300 mg of 
lidocaine per subject (8.3 cartridges). The 
anesthetics will be provided as cartridges of 
1.8 mL with 36 mg of lidocaine hydrochloride 
plus 0.018 mg of epinephrine. No other kind of 
anesthetic is allowed.
…
Standardized surgery
…
Standardized surgery
…
Subjects requiring fourth molar extraction are 
allowed in the trial. Subjects with molars linked 
to the mandibular canal and those requiring 
immediate dental procedures other than third 
and fourth molar extraction must not be 
included in the trial.
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Changes to this protocol include:
Formerly read:
Now reads: 
Postoperative baseline examination and 
treatment allocation
…
The first dose of the IMPs (1 capsule or tablet 
with active treatment plus 3 placebos) will be 
administered as soon as subjects report a pain 
intensity 5 on the NRS. The time of dosing 
will be recorded.
…
Postoperative baseline examination and 
treatment allocation
…
The first dose of the IMPs (1 capsule or tablet 
with active treatment plus 3 placebos) will be 
administered as soon as subjects report a pain 
intensity 5 on the NRS. The time of dosing 
will be recorded. The use of cold compresses or 
ice bags on the cheeks of subjects is allowed 
4 hours after the administration of IMP; their 
use must be avoided in the 30-minute period 
before each pain assessment.
…
…
Subjects who undergo surgery and receive 
IMPs will stay in the clinic for at least 8 hours 
after the initial dose and will receive the second 
dose of IMPs at 8 hours (±10 minutes).
…
…
Subjects who undergo surgery and receive 
IMPs will stay in the dental clinic or other 
research facility for at least 8 hours after the 
initial dose and will receive the second dose of 
IMPs at 8 hours (±10 minutes). If pain 
assessments will take place in other research 
facilities, subjects must be transported to the 
facility between 15 minutes after the end of 
surgery and the first IMP administration; the 
commuting time may be up to 30 minutes. 
During transfer, subjects must be accompanied 
by a member of the SMO staff. Both must have 
written directions in the case of emergency.
…
---
…
Dental clinics must have an emergency kit 
according to local regulations (Norma Oficial 
Mexicana NOM-005-SSA3-2010). An 
emergency crash cart will be mandatory at 
each research facility any time an IMP is being 
administered.
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Changes to this protocol include:
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Now reads: 
Section 11.2.3: Meals and fluid intake restrictions
New section
Subjects may have a low-fat dinner the night 
before the surgery. They may have soft 
beverages like Ensure® up to 1 hour before 
surgery. Drinking water or juices (apple juice, 
orange juice) and low-fat milk are allowed 
after surgery. From 3 hours after IMP 
administration, subjects can have soft food 
(Jell-O™, mashed potatoes, milk shake, 
Ensure®). Water and soft food must be 
provided at room temperature. High-fat meals, 
ice creams, and sorbets must be avoided.
Section 12.3.1: Adverse events
Notification of serious adverse events
…
The investigator must comply with applicable 
regulatory requirement(s) related to the 
reporting of SAEs to the regulatory authorities 
and the relevant IECs.
Notification of serious adverse events
…
The investigator must comply with applicable 
regulatory requirement(s) related to the 
reporting of SAEs to the regulatory authorities 
and the relevant IECs. Based on the 
investigator SAE reports, the sponsor’s Drug 
Safety Department will generate Drug Safety 
Update Reports. They will monitor the 
Suspected Unexpected Serious Adverse 
Reaction reports to detect any possible safety 
signals and generate early safety alerts if 
necessary.
19.2
Protocol Amendment 02
Amendment rationale
This amendment has been implemented to change the following:
•
The planned number of trial sites was increased.
•
Changes in the sponsor’s signatory and the public contact point were made.
Detailed description of changes
Minor editorial changes, such as the correction of typing errors, are not specifically listed.
In the table below, deleted text is crossed out and new text is highlighted using italics.
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Changes to this protocol include:
Formerly read:
Now reads: 
Section: Front Page
Trial sites:
Multi-site trial (up to 8 sites in Mexico)
Documentation of the involved trial sites 
will be maintained.
Trial sites:
Multi-site trial (up to 10 sites in Mexico)
Documentation of the involved trial sites will be 
maintained.
Coordinating investigator a:
 DMD, PhD
…
Coordinating investigator a:
 DMD, PhD (
)
...
Sponsor’ signatory:
 PhD
Head of Clinical Product Development 
Latin America
Sponsor’s signatory a
 MD
Head of Clinical Product Development
Latin America
grunenthal.com
Public Contact:
grunenthal.com
Phone (+55) 
 Ext. 
Public Contact a:
Clinical Operations Project Manager
grunenthal.com
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