Clinical trial NCT02777970
Conditions: Acute Pain
Keywords: Acute pain Acute moderate to severe pain Postoperative pain Dexketoprofen Tramadol Dexketoprofen trometamol Tramadol hydrochloride Multimodal analgesia Third molar extraction Fixed drug combination Paracetamol Analgesics
Sponsor: Menarini Group
Start date: 2016-04-01; Completion date: 2017-02-14
Enrollment: 654 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study is aimed to evaluate the analgesic efficacy of TRAM.HCl/DKP.TRIS 75mg/25mg oral fixed drug combination in comparison with TRAM.HCl /paracetamol 75mg/650mg in the treatment of moderate to severe acute pain.

Detailed description:
The present phase IV study is a randomised, double-blind, placebo and active-controlled, parallel group study in moderate to severe acute pain after removal of impacted lower third molar.

In this single-dose clinical trial patients are randomized to the following 3 treatment arms in a 2:2:1 ratio:

* TRAM.HCL/DKP.TRIS
* Paracetamol/TRAM.HCL
* Placebo.

Arms: arm 1: Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg film-coated tablet oral single dose;

Placebo matching Tramadol Hydrochloride/Paracetamol 75 mg/650mg, as 2 x \[37.5mg/325mg\] film-coated tablets, oral single dose. arm 2: Tramadol Hydrochloride/Paracetamol 75 mg/650 mg, as 2 x \[37.5mg/325mg\] film-coated tablets, oral single dose;

Placebo matching Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg film-coated tablet oral single dose.

. arm 3: Placebo matching one film-coated tablet of Tramadol Hydrochloride/Dexketoprofen Trometamol 75mg/25mg oral single dose;

Placebo matching two film-coated tablets of Tramadol Hydrochloride/Paracetamol 37.5mg/325mg oral single dose.
Interventions: intervention 1: Tramadol Hydrochloride/Dexketoprofen Trometamol intervention 2: Tramadol Hydrochloride/Paracetamol intervention 3: Placebo
Intervention descriptions: intervention 1: None intervention 2: None intervention 3: None

Protocol documents:
Prot_000.pdf: 
Clinical Trial Protocol 
EudraCT No.: 2015-004152-22 
 
 
Study Code DEX-TRA-06
Final Version 2.0, 24 NOV 2015
 
 
 
 
Confidential 
Menarini Ricerche S.p.A 
 
 
 
 
 
 
Dexketoprofen Analgesic eVolution wIth tramaDol- DAVID Study 
 
CLINICAL TRIAL PROTOCOL 
FINAL VERSION 2.0*, 24 NOV  2015 
Analgesic efficacy of oral dexketoprofen trometamol/tramadol hydrochloride versus 
tramadol hydrochloride/paracetamol: a randomised, double-blind, placebo and active-
controlled, parallel group study in moderate to severe acute pain after removal of impacted 
lower third molar.  
Study code 
DEX-TRA-06 
EudraCT-Number  
2015-004152-22 
Investigational Medicinal Product 
Dexketoprofen  trometamol 25mg /Tramadol hydrochloride 
75mg 
Development phase of study  
III b 
Sponsor 
MENARINI RICERCHE SpA 
Via Sette Santi 1, 
50131 Firenze (Italy) 
Co-ordinating Investigator 
  
 
  
 
 
 
 
STATEMENT OF CONFIDENTIALITY
The information in this document contains trade secrets and proprietary commercial information of Menarini Group 
that is privileged or confidential and may not be disclosed unless such disclosure is required by law. In any case, 
persons to whom the information is disclosed must be informed that the information is privileged or confidential and 
may not be further disclosed without written authorisation by Menarini Group. 
*version 2.0 represents an editorial upgrade of version 1.0 which has never been submitted to any Competent Authority


Clinical Trial Protocol 
EudraCT No.: 2015-004152-22 
 
Study Code DEX-TRA-06
Final Version 2.0, 24 NOV  2015 
 
Page 2 of 82 
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1. SIGNATURES 
 
The signatories have read the clinical trial protocol titled “Analgesic efficacy of oral 
dexketoprofen trometamol/tramadol hydrochloride versus tramadol hydrochloride/paracetamol: 
a randomised, double-blind, placebo and active-controlled, parallel group study in moderate to 
severe acute pain after removal of impacted lower third molar. (Dexketoprofen Analgesic 
eVolution wIth tramaDol - DAVID Study)” - Final Version 2.0, 24 NOV 2015 - carefully and 
agree to adhere to its provisions. Changes to the protocol have to be stated by the sponsor in 
amendments to the clinical trial protocol which, if they are substantial, have to be authorised by 
the Competent Authorities and Ethics Committees before translating them into action. 
 
Sponsor’s Representative 
Signature 
Date 
  
  
  
.............................................. 
.............................. 
 
Co-ordinating Investigator 
Signature 
Date 
 
 
  
  
 
 
 
 
................................................ 
.............................. 
 
 
 


Clinical Trial Protocol 
EudraCT No.: 2015-004152-22 
 
Study Code DEX-TRA-06
Final Version 2.0, 24 NOV  2015 
 
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1.1 
Principal Investigator’s Statement 
 
My signature below documents my agreement with the contents of this clinical trial protocol titled 
“Analgesic efficacy of oral dexketoprofen trometamol/tramadol hydrochloride versus tramadol 
hydrochloride/paracetamol: a randomised, double-blind, placebo and active-controlled, parallel 
group study in moderate to severe acute pain after removal of impacted lower third molar. 
(Dexketoprofen Analgesic eVolution wIth tramaDol - DAVID Study)” - Final Version 2.0, 24 
NOV 2015 - with regard to the execution of the study and the required documentation/data 
collection. I agree to comply with this clinical trial protocol in its entirety and with the ICH 
guidelines for Good Clinical Practice (GCP). 
 
Principal Investigator  
Signature 
Date 
............................................................. ............................................................. ..............................
 (printed name) 
 
 
 
 


Clinical Trial Protocol 
EudraCT No.: 2015-004152-22 
 
Study Code DEX-TRA-06
Final Version 2.0, 24 NOV  2015 
 
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2. PROTOCOL SYNOPSIS 
Study Title,  Study Code 
and Nick name 
/Acronym 
Analgesic efficacy of oral dexketoprofen trometamol/tramadol 
hydrochloride versus tramadol hydrochloride/paracetamol: a 
randomised, double-blind, placebo and active-controlled, parallel 
group study in moderate to severe acute pain after removal of impacted 
lower third molar. (Dexketoprofen Analgesic eVolution wIth tramaDol 
- DAVID Study) 
 
Study code: DEX-TRA-06  
Phase 
Phase IIIb 
Indication 
Moderate to severe acute pain following impacted lower third molar 
extraction. 
No. of sites &countries 
Approximately 20 sites among Europe and Turkey. 
Investigational 
Medicinal Product 
(IMP) 
Dexketoprofen  trometamol 25mg /Tramadol hydrochloride 
75mg film-coated tablet (DKP.TRIS/TRAM.HCl 25mg/75mg). 
Reference therapy 
− Tramadol hydrochloride 75mg/paracetamol 650mg film-coated 
tablet, as 2 x [37.5mg/325mg] (TRAM.HCl/paracetamol 75 mg/650 
mg) 
− Matching placebo  
Treatment regimen 
All study treatments will be administered as single oral dose; double 
dummy technique will be applied to ensure double-blind condition. 
Rescue medication (RM) 
Ibuprofen 400mg tablets.  
Design 
Multicentre, randomised, double-blind, double-dummy, parallel-group, 
placebo and active-controlled, single-dose study. 
Eligible patients will be randomised in a 2:2:1 ratio to one of the 3 
possible treatment arms: 
− DKP.TRIS/TRAM.HCl 
− TRAM.HCl/paracetamol 
− Placebo 
Primary objective 
To 
assess 
the 
comparability 
of 
DKP.TRIS/TRAM.HCl 
and 
TRAM.HCl/paracetamol in terms of analgesic efficacy on moderate to 
severe pain following impacted lower third molar extraction. 
Secondary objectives 
To confirm the safety and tolerability profile of DKP.TRIS/TRAM.HCl 
following single dose administration. 
Study duration 
 
The individual study participation will last approximately 3 weeks, 
including:  
− Screening period, for study eligibility assessment (within 2 weeks 
prior to randomisation), which includes the prior to surgery, 
surgery, and qualification steps. 


Clinical Trial Protocol 
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Study Code DEX-TRA-06
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− Randomisation, treatment administration and efficacy assessment 
period (day 1). 
− End of study visit (6±1 days after randomisation). 
The overall clinical phase is planned to start in 1H 2016 and to be 
completed within the Q4 2016. 
The enrolment will be competitive. 
Inclusion criteria 
To be eligible for this study, EACH of the following criteria must be 
satisfied: 
1. Properly executed written informed consent. 
2. Male or female patients aged more than 18 years. 
3. Scheduled for outpatient surgical extraction -under local 
anaesthesia (i.e. 2% lidocaine with 1:80,000 epinephrine) - of 
lower third molar teeth, with at least one of which fully or partially 
impacted in the mandible requiring bone manipulation (e.g. level B 
or C plus class II or III of the Pell-Gregory scale). 
4. Females participating in the study must be either: 
− Females of non-childbearing potential, defined as any woman 
who had undergone surgical sterilization or is more than 2 years 
post-menopausal; 
− Females of childbearing potential provided that they have a 
negative pregnancy test at baseline (screening and qualification 
period) and are routinely using an effective method of birth 
control resulting in a low failure rate (i.e. hormonal 
contraception, intrauterine device, condoms in combination with 
a spermicidal cream, male partner sterilization –vasectomy– or 
total sexual abstinence). 
5. Mentally competent, able to understand and give written informed 
consent prior to study entry.  
6. Compliant to undergo all visits and procedures scheduled in the 
study, including recording of pain assessments on the electronic 
diary (e-Diary) as required by protocol. 
After surgery, patients will be eligible to progress with randomisation 
ONLY if the following criterion is also met: 
7. Pain of at least moderate intensity in the first 4 hours after the end 
of surgery (NRS score > 4). 
Exclusion criteria 
To be eligible for this study, NONE of the following criteria must be 
satisfied: 
1. Patients who are judged by the Investigator not to be suitable 
candidates for the study treatments and the RM based on their 
medical history, physical examination, concomitant medication 
(CM) and concurrent systemic diseases.  
2. Clinically significant abnormalities in the vital signs (VS) and / or 
safety laboratory tests, as per investigator’s judgement. 


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3. History of allergy or hypersensitivity to the study treatments, RM 
or to any other NSAIDs, opioids and acetyl salicylic acid. 
4. History of peptic ulcer, gastrointestinal disorders by NSAIDs or 
gastrointestinal bleeding or other active bleedings. 
5. History of severe asthma.  
6. Moderate to severe renal dysfunction, severe hepatic dysfunction or 
severe cardiac dysfunction. 
7. Coagulation disorders. 
8. History of, or current epilepsy.  
9. Patients with Crohn’s disease or ulcerative colitis. 
10. Patients using and not suitable for withdrawing analgesics within 
12 hours before surgery (5 days prior to the surgery day in case of 
COX-2 inhibitors) and for 8 hours post-dose [analgesics other than 
those specified in the protocol (namely study treatments and RM)]. 
11. Patients using and not suitable for withdrawing alcohol, sedatives 
(e.g. benzodiazepines) and hypnotic agents within 12 hours before 
surgery and for 8 hours post-dose. 
12. Chronic opioid treatment (major opioids and tramadol). 
13. Patients using and not suitable for withdrawing the following 
prohibited medications, within 48 hours or 5 half-lives (whichever 
the longer) prior to the start of surgery and for 24 hours post-dose: 
− Anticoagulants, thrombolytic and antiplatelet agents  
− Corticosteroids (with the exception of inhalers or topical agents); 
− Monoamine oxidase (MAO) inhibitors (a minimum of 14 days 
must elapse prior to the start of surgery);  
− Antiepileptics; 
− Antipsychotics; 
− Serotonin reuptake inhibitors and tricyclic antidepressants; 
− Lithium; 
− Methotrexate; 
− Antibacterial sulfonamides. 
14. Participation in other clinical studies in the previous 4 weeks.  
15. History of drug or alcohol abuse. For the purpose of the study, 
alcohol abuse is defined as regularly intake of more than 4 units of 
alcohol per day (1 unit corresponds approximately to 125 ml wine, 
200 ml beer, 25 ml spirit). 
16. History of any illness or condition that, in the opinion of the 
Investigator might pose a risk to the patient or confound the 
efficacy and safety results of the study. 
17. Pregnant and breastfeeding women. NOTE: a pregnancy test will 
be performed to all women of childbearing potential at Screening 
and another one on the day of surgery prior to randomisation. 


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After surgery, patients will not be eligible to progress with 
randomisation if the following criterion is also met: 
18. Surgical complication that, in the opinion of the Investigator, 
advises against their inclusion in the study. 
Study procedures and 
Efficacy and Safety 
assessments 
 
Prior to any study-related procedure, the patient’s written informed 
consent form (ICF) must be obtained.  
Screening period (within 2 weeks prior to randomisation) 
 Prior to surgery  
The following procedures/assessments must be completed during the 
screening period and prior to the surgery day (day 1):   
− Collection of demographic data. 
− Recording of medical history. 
− Recording of prior and concomitant medications (CMs). 
− Physical examination including body weight (BW), height (H), 
and vital signs (VS) (blood pressure [BP], heart rate [HR]). 
− Laboratory safety tests (haematology, clinical chemistry, 
coagulation test and urinalysis). 
− Pregnancy test (if applicable). 
− Instructions regarding how to complete patient’s pain and 
analgesia assessments, RM intake and 
 functionality on 
e-Diary. 
− Recording of adverse events (AEs) occurred since the ICF 
signature, if any.  
− Check of inclusion and exclusion criteria. 
 Surgery  
The surgical procedure will be performed under local anaesthetic block 
using 2% lidocaine with 1:80,000 epinephrine up to a total volume of 
5.4 mL per molar. 
Surgery shall be performed at least one day apart pre-surgery 
procedures have been completed. 
 Qualification  
After completion of surgery (last suture), patients will be followed for 
a period of up to 4 hours and the following will be performed/assessed: 
− Instruct patients to inform the investigator when they experience 
pain.  
− Dispensing of the e-Diary and testing its main functions.  
− VS measurement.  
− Pregnancy test (if applicable).  
− Recording of AEs and changes in CM, if any, since the last 
assessment. 
− Review/Check of inclusion/exclusion criteria.  
 
Patients reporting pain within 4 hours after the end of surgery will be 
asked to rate their pain intensity (PI) on the e-Diary to assess their 


Clinical Trial Protocol 
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eligibility for randomisation. Patients must describe their PI in 
response to the question: ‘How do you rate the intensity of your pain?’ 
using an 11-point Numerical Rating Scale (NRS) ranging from 0 (no 
pain) to 10 (worst pain). 
 
NOTES:  
1. Only patients experiencing pain of moderate or higher intensity 
(NRS score ≥4) within the first 4 hours after the end of surgery will 
be eligible for randomisation.  
2. A patient can be screened a maximum of 2 times, provided that 
he/she was not already randomised and all the inclusion and none 
of the exclusion criteria are met.  
3. Pregnancy test should not be repeated during the qualification 
period if it was performed the day before as screening procedure. 
 
Randomisation, treatment administration and efficacy assessment 
period (day 1, t0 - t8h) 
 Randomisation and treatment administration (t0) 
Patients successfully completing the qualification period will be 
randomised through IxRS to one of the three possible treatment arms 
(DKP.TRIS/TRAM.HCl, TRAM.HCl/paracetamol or placebo) and the 
corresponding study treatment will be given, as one single oral dose. 
NRS-PI immediately prior to the administration of the study 
treatment will be recorded as baseline PI (t0h). 
 
A box of RM (ibuprofen 400mg tablets) will be assigned by IxRS and 
provided to the patients that will be instructed about its usage. A paper 
diary for RM recording intake will be also given to patients, with the 
request to return it to the site at the End of Study visit. 
 
 8-hour pain and analgesic effect assessment period (t0 – t8h) 
After the study treatment administration, patients will remain under 
observation at site for two hours (up to t2h). 
Pain and analgesia assessment by patients will be performed either at 
site (from t15min to t2h) and out of the site (from t4h to t8h) by e-Diary 
recording. 
The following items will be recorded by the patients on the e-Diary: 
− Pain relief (VRS-PAR): at t15min, t30min, t1h, t1.5h, t2h, t4h, t6h and t8h. 
Patients will be asked to answer the question ‘How do you rate your 
pain relief?’ using a 5-point verbal rating scale (VRS), where 0 = 
‘no relief’, 1 = ‘a little (perceptible) relief’, 2 = ‘some (meaningful) 
relief’, 3 = ‘lot of relief’, 4 = ‘complete relief’. 
− Pain Intensity (NRS-PI): at t15min, t30min, t1h, t1.5h, t2h, t4h, t6h and t8h,  
using the 11-point NRS. 
− First intake of RM, if any.  


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− Onset of analgesia: The two-
 method will be used to 
assess the onset of analgesia within the first two hours (from t0 to 
t2h): the first stop upon the experience of “first perceptible” PAR 
(FPPAR) and the second stop when PAR is considered 
“meaningful” (MPAR). 
− Patient Global Evaluation (PGE): at the end of the assessment 
period (t8h), or immediately before RM intake, if any. Patients will 
be asked to answer the question: ‘How would you rate the 
medication received for your pain?’ using a 5-point VRS, where: 1 
= ‘poor’, 2 = ‘fair’, 3 = ‘good’, 4 = ‘very good’, 5 = ‘excellent’.  
Occurrence of any AE as spontaneous reporting and changes in CM, if 
any, will be collected by study staff while the patients are at the site.  
 
Rescue medication 
At any time during the 8-hour post-dose period, patients will be 
allowed to take RM if they have not achieved adequate pain relief after 
receiving the study medication; however, they will be encouraged to 
wait for at least 60 minutes after dosing to allow time for the study 
treatment effect to take place. Patients will be duly instructed by the 
investigator that during the 8-hour post dose period a maximum of 2 
tablets of RM will be allowed, each one separated by a minimum 
interval of 4 hours. Patients will be also instructed to bring back the 
remaining RM at the End of Study visit. 
 
NOTE: After first intake of RM, patients will stop using the e-Diary 
including the 
 functionality. Only the first intake of RM will 
be recorded on the e-Diary. 
Time of each intake of RM, if any, will be recorded by the patients in a 
paper booklet (RM diary). The Investigator or designee will be 
responsible for entering RM diary data into the e-CRF. 
 
End of Study visit (6 ± 1 days after randomisation)  
− Return of e-Diary, RM diary and unused RM by patients. 
− RM accountability. 
− Physical examination. 
− VS measurement. 
− Pregnancy test (if applicable). 
− Recording of AEs and changes in CM, if any, since the last visit. 
NOTE: 
For the study purposes, patients will be required to attend the study 
centre to accomplish the procedures from Screening to End of study. 
Unscheduled surgical follow-up visits may be requested by the surgeon 
at an earlier timepoint; however they will not be considered as part of 
this study. 


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Efficacy endpoints 
Primary endpoint: 
Total pain relief (TOTPAR), calculated as the weighted sum of the 
PAR scores (measured according to a 5-point VRS from 0=no relief to 
4=complete relief), over 6 hours post-dose (TOTPAR6). 
Secondary endpoints: 
−
−Percentage of patients achieving at least 50% of maximum
TOTPAR over 
 8 hours post-dose.
−
−Percentage of patients who achieved at least 30% of PI reduction
versus baseline at each pre-specified time point over the 8-hour
post-dose period.
−
−Time to confirmed FPPAR (time to onset of analgesia) - i.e. time to
FPPAR if confirmed by experiencing MPAR
−
−
PGE of the study medication (measured according to a five-point
VRS from 1 = poor to 5 = excellent), at 8 hours post-dose or
whenever the patient uses RM.
−
−Percentage of patients who required RM within 
 8
hours post-dose.
Safety endpoints 
−Incidence, intensity (severity), seriousness and treatment-causality
of treatment-emergent AEs (TEAEs, reported starting from the
study medication intake).
−Frequency of clinically significant changes in physical examination,
and VS, post-dose versus baseline. (NOTE: for physical
examination screening period values will be used as baseline; for
VS, the values collected during the qualification period will be used
as baseline).


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Sample size 
A sample size of 230 patients per active arm is considered adequate to 
demonstrate the non-inferiority of DKP.TRIS/TRAM.HCl oral fixed 
combination compared to TRAM.HCl/paracetamol assuming a non-
inferiority margin of 20%, a power of 80%  and an overall significance 
level of 2.5 % (1-side). The mean TOTPAR6 for TRAM.HCl/ 
paracetamol is assumed equal to 7.4 (SD 6.30). 
115 patients in placebo arm are sufficient to demostrate the superiority 
of both TRAM.HCl/paracetamol and DKP.TRIS/TRAM.HCl vs 
placebo  for model sensitivity. 
Assuming about 10% of major protocol violators, and 20% of 
screening failure rate a total of  640 patients need to be randomised 
and  approximately 800 patients are expected to be screened. 
Analysis populations 
The following analysis populations will be considered: 
− Intention-to-treat (ITT) population: All patients randomised.  
− Safety population: All patients who have received at least one dose 
of the study treatment.  
− Per protocol (PP) population: All patients of the ITT population 
who did not experience relevant protocol violations related to the 
efficacy endpoints of primary interest. 
Statistical analysis 
Primary efficacy analysis  
The primary efficacy variable (TOTPAR6) will be used to assess the 
non-inferiority 
of 
DKP.TRIS/TRAM.HCl 
versus 
TRAM.HCl/ 
paracetamol using analysis of covariance (ANCOVA), with treatment 
as main effect and adjusted for the baseline PI level with one-sided 
significance level of 2.5%. 
Non-inferiority hypothesis will be satisfied if the lower limit of the 
confidence interval is greater than a non-inferiority margin of 20%. 
In case the non-inferiority will be confirmed, the superiority of 
DKP.TRIS/TRAM.HCl versus  TRAM.HCl/paracetamol will be tested.
Non-inferiority will be tested on the PP and ITT populations, while 
superiority only on the ITT population. 
Superiority of DKP.TRIS/TRAM.HCl and TRAM.HCl/paracetamol 
versus placebo will be tested in order to confirm the model sensitivity 
on the ITT population. 
 
Secondary efficacy analysis 
SPID6 will be analyzed for non inferiority with the possibility to switch 
for superiority analogously to the primary efficacy variable. 
All the other secondary efficacy variables will be descriptively 
analysed. The superiority for DKP.TRIS/TRAM.HCl will be tested on 
the secondary endpoints when applicable, through an ad hoc inferential 
analysis, as reported below: 
− NRS -PI, SPID (excluded SPID6), %max SPID, TOTPAR (excluded 
TOTPAR6), %max TOTPAR (continue variables) will be analyzed 
by ANCOVA model 


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− PGE and VRS-PAR (categorical variables) will be analyzed by 
Wilcoxon rank-sum test. 
− Percentage of patients who required rescue medication, and 
percentage of patients achieving at least 30% of PI reduction, 
achieving at least 50% max TOTPAR, confirmed FPPAR, MPAR 
will be tested using a Chi²-Test. 
− Time to use RM, time to FPPAR, confirmed FPPAR and MPAR 
will be assessed using a Log-rank test. 
 
Safety analysis 
Adverse events will be coded using the MedDRA dictionary. The 
incidence of each TEAEs will be summarized by system organ class 
(SOC), preferred term (PT) and treatment. 
Clinically significant abnormal findings in VS and physical 
examination will be listed by treatment. 
Safety variables will be analysed only by descriptive statistics and will 
be run on the safety population. 
NOTES:  
− All through the document, any mention to the dosage of 25mg dexketoprofen trometamol (DKP.TRIS) 
refers to the amount of dexketoprofen. The corresponding weight for the active ingredient expressed as 
trometamol salt (DKP.TRIS) is 36.90mg. 
− All through the document, with DKP.TRIS/TRAM.HCl 25mg/75mg, DKP 25mg TRIS/TRAM.HCl 75mg 
and DKP+TRAM is made reference to dexketoprofen 25mg trometamol/tramadol hydrochloride 75mg 
fixed dose combination.  
 
 


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2.1 
SCHEMATIC STUDY DESIGN 
 
 
T0   T+15’ T+30’ T+1h T+1.5h T+2h         T+4h                      T+6h                     T+8h         
Screening 
 
Pre-Surgery  
 
Single oral administration of: 
 
-DKP.TRIS/TRAM.HCl 25mg/75mg
-TRAM.HCl/paracetamol 75mg/650mg 
-Placebo 
  At the centre                               Out of centre 
< 4h 
6±1days 
Randomisation 
(day 1) 
≤ 2 weeks 
IC 
End of 
study 
visit 
Qualification 
        
Surgery 
(day 1) 
≥ 1day before 
surgery 


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2.2 
STUDY FLOW- CHART 
Study procedures 
Screeninga 
Randomisation, treatment administration and efficacy assessment period 
End of Study  
 
Prior to 
 surgery 
Qualification  
(day 1) 
At the centre (day 1)h 
Out of centre (day 1)i 
(6± 1 days after 
randomisation) 
T-0 h 
T+15’ 
T+30’ 
T+1h 
T+1.5h 
T+2h 
T+4h 
T+6h 
T+8h 
Check of Informed 
consentb 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics and 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion /   Exclusion 
criteria 
X 
X  
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
X 
Vital sign 
 (BP, HR) 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Safety Laboratory 
Tests    
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy test (if 
applicable) 
X  
Xc  
 
 
 
 
 
 
 
 
 
X 
e-Diary Instruction 
X 
 
 
 
 
 
 
 
 
 
 
 
e-Diary dispensing & 
testing of its main 
functions 
 
X 
 
 
 
 
 
 
 
 
 
 
Randomisation to 
treatment and Dosing 
 
 
X 
 
 
 
 
 
 
 
 
 
PI assessment (NRS)g  
 
Xd  
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
 
PAR assessment (VRS)g  
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient’s Global 
Evaluation  
 
 
 
 
 
 
 
 
 
 
Xf 
 
FPPAR and MPARg 
 
 
As soon as they are experienced 
 
 
 
 
Dispensing of RM and 
RM diary  
 
 
X 
 
 
 
 
 
 
 
 
 
RM and RM diary Return 
/ Accountability 
 
 
 
 
 
 
 
 
 
 
 
X 


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Study procedures 
Screeninga 
Randomisation, treatment administration and efficacy assessment period 
End of Study  
 
Prior to 
 surgery 
Qualification  
(day 1) 
At the centre (day 1)h 
Out of centre (day 1)i 
(6± 1 days after 
randomisation) 
T-0 h 
T+15’ 
T+30’ 
T+1h 
T+1.5h 
T+2h 
T+4h 
T+6h 
T+8h 
Return of e-Diary  
 
 
 
 
 
 
 
 
 
 
 
X 
AEs/CM recording 
X 
X 
While patients are at site 
 
X 
a The entire screening period, including the pre-surgery evaluations, the surgical procedure and the qualification period, must be completed within 2 weeks prior to randomisation 
bIC must be signed before any other study procedure is performed 
c To be repeated on day 1 before randomisation if not performed the day before as screening procedure 
dNRS-PI > 4 is required for randomisation 
eNRS-PI at T0 is recorded as baseline PI 
f Or immediately before RM intake 
g To be completed upon RM intake, if any 
h E-Diary recording is allowed within a ±3 minutes time window at T+15’, T+30’, T+1h, T+1.5h and T+2h  
i E-Diary recording is allowed within a ±10 minutes time window at T+4h, T+6h and T+8h 
 
 


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3. INVESTIGATOR(S) AND STUDY ADMINISTRATIVE STRUCTURE 
 
Co-ordinating Investigator 
 
 
  
 
 
 
 
  
   
 
 
Sponsor 
Menarini Ricerche S.p.A. 
Clinical Research Department 
Via Sette Santi, 1 
50131 Florence, Italy 
Corporate Director of Clinical 
Research / 
Sponsor’s Representative 
 
 
 
 
 
Clinical Research Physician  
 
 
 
  
 
 
 
Study Manager  
 
    
 
 
Biostatistician  
  
 
 
Data Manager   
 
    
 
 
  
 


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Sponsor’s Pharmaceutical 
Manufacturer of the IMP 
A. Menarini Research & Business Service GmbH 
Pharmaceutical Development Department 
Glienicker Weg 125 D-12489 Berlin, Germany  
Head of the Pharmaceutical 
Development Department 
 
      
 
 
 
Packaging, Labelling, and Distribution 
of the IMP 
 
 
 
 
Sponsor’s Pharmacovigilance Unit 
 
 
,
 
 
Drug Safety Manager 
 
     
 
 
 
  
 
 
 
Quality Assurance  
 
 
 
Head of Quality Assurance & GXP 
Compliance 
 
  
 
 
 
 
CRO  
 
  
 
Vice President Operations – General 
Partner 
 
 
 
   
 
 
 
 
 
 
 
  
 
 


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4. TABLE OF CONTENTS 
 
1. 
SIGNATURES ............................................................................................................................. 2 
1.1 
Principal Investigator’s Statement......................................................................................... 3 
2. 
PROTOCOL SYNOPSIS ............................................................................................................. 4 
2.1 
Schematic Study Design ...................................................................................................... 13 
2.2 
Study Flow- Chart ............................................................................................................... 14 
3. 
INVESTIGATOR(S) AND Study ADMINISTRATIVE STRUCTURE .................................. 16 
4. 
TABLE OF CONTENTS ........................................................................................................... 18 
4.1 
Glossary ............................................................................................................................... 22 
5. 
ETHICAL AND LEGAL ASPECTS ......................................................................................... 24 
5.1 
General Aspects ................................................................................................................... 24 
5.2 
Independent Ethics Committee and Legal Requirements ................................................... 24 
5.3 
Patient Information and Declaration of Consent ................................................................. 24 
5.4 
Patient Insurance ................................................................................................................. 25 
5.5 
Documentation of Study-related Data and Record Retention ............................................. 25 
5.6 
Confidentiality ..................................................................................................................... 26 
5.7 
Protocol Modifications ........................................................................................................ 26 
5.8 
Study Commencement ........................................................................................................ 26 
5.9 
Patient’s Safety .................................................................................................................... 26 
5.10 Data Property/Publication Policy ........................................................................................ 27 
6. 
BACKGROUND INFORMATION .......................................................................................... 28 
6.1 
Pain ...................................................................................................................................... 28 
6.2 
Investigational Medicinal Product: DEXKETOPROFEN TROMETAMOL AND 
TRAMADOL HYDROCHLORIDE FIXED COMBINATION .................................................... 28 
Dexketoprofen trometamol .................................................................................................................. 29 
Tramadol hydrochloride ...................................................................................................................... 30 
6.2.1 
Data on the co-administration of dexketoprofen trometamol and tramadol 
hydrochloride ............................................................................................................................. 31 
6.2.1.1 
Pre-clinical studies ............................................................................................................... 31 
6.2.1.2 
Published data from non-sponsored clinical studies ............................................................ 31 
6.2.1.3 
Post-marketing clinical experience ...................................................................................... 32 
6.2.2 
Clinical development of dexketoprofen trometamol and tramadol hydrochloride fixed 
combination ................................................................................................................................ 32 
6.2.2.1 
Phase I study (DEX-TRA-PK) ............................................................................................ 33 


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6.2.2.2 
Phase II study (DEX-TRA-02) ............................................................................................ 33 
6.2.3 
Phase III confirmatory studies ..................................................................................... 36 
6.2.3.1 
DEX-TRA-04: the abdominal hysterectomy pain model .................................................... 37 
6.2.3.2 
DEX-TRA-05: the hip arthroplasty pain model .................................................................. 39 
6.2.4 
DEX-TRA-06: Phase IIIb new study in dental pain model ......................................... 41 
6.3 
Risk-Benefit Assessment ..................................................................................................... 41 
7. 
STUDY OBJECTIVES .............................................................................................................. 42 
7.1 
Primary Objective................................................................................................................ 42 
7.2 
Secondary Objectives .......................................................................................................... 42 
8. 
INVESTIGATIONAL PLAN .................................................................................................... 43 
8.1 
Overall Study Design And Plan Description ....................................................................... 43 
8.2 
Discussion Of Study Design, Including The Choice Of Control Group ............................. 44 
8.3 
Selection Of Study Population ............................................................................................ 44 
8.3.1 
Inclusion criteria .......................................................................................................... 44 
8.3.2 
Exclusion criteria ......................................................................................................... 45 
8.3.3 
Study restrictions.......................................................................................................... 47 
8.3.4 
Withdrawal of patients from therapy or assessment .................................................... 47 
8.4 
Identity of the Investigational Product(s) ............................................................................ 48 
8.4.1 
Description of Investigational Medicinal Product(s) ................................................... 48 
8.4.2 
Packaging, labelling, and storage ................................................................................. 48 
8.4.3 
Rescue medication ....................................................................................................... 49 
8.4.4 
Drug accountability ...................................................................................................... 50 
8.4.5 
Destruction of surplus medication ............................................................................... 50 
8.5 
Treatments ........................................................................................................................... 50 
8.5.1 
Treatment administration - frequency and duration of application.............................. 50 
8.5.2 
Randomisation and blinding ........................................................................................ 51 
8.5.3 
Treatment compliance .................................................................................................. 51 
8.5.4 
Concomitant Medication .............................................................................................. 52 
8.5.5 
Anaesthetics for Surgery .............................................................................................. 52 
8.5.6 
Prohibited Medication .................................................................................................. 52 
8.6 
Study Procedures And Assessments.................................................................................... 53 
8.6.1 
Study schedule ............................................................................................................. 53 
8.6.1.1 
Informed consent process .................................................................................................... 53 
8.6.1.2 
Screening period (within 2 weeks prior to randomisation) .................................................. 53 
8.6.1.3 
Randomisation, treatment administration and efficacy assessment period (day 1, t0 - t8h) .. 54 


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8.6.1.4 
End of Study visit (6 ± 1 days after randomisation) ............................................................ 55 
8.6.2 
Surgical Assessment .................................................................................................... 57 
8.6.2.1 
Surgical Trauma Rating Scale ............................................................................................. 57 
8.6.2.2 
Other Surgery Parameters .................................................................................................... 57 
8.6.3 
Assessments of Efficacy .............................................................................................. 57 
8.6.3.1 
Pain Intensity Numerical Rating Scale ................................................................................ 58 
8.6.3.2 
Pain relief Verbal Rating Scale ........................................................................................... 58 
8.6.3.3 
Use of rescue medication ..................................................................................................... 58 
8.6.3.4 
Time to onset of analgesia ................................................................................................... 59 
8.6.3.5 
Patient’s Global Evaluation ................................................................................................. 59 
8.6.4 
Assessment of Safety ................................................................................................... 60 
8.6.4.1 
Medical History ................................................................................................................... 60 
8.6.4.2 
Physical Examinations and Vital signs ................................................................................ 60 
8.6.4.3 
Clinical Laboratory Evaluation............................................................................................ 60 
8.6.4.4 
Adverse Events/Serious Adverse Events – Definitions ....................................................... 61 
8.6.4.5 
Monitoring and Recording of Adverse Events .................................................................... 64 
8.6.5 
Efficacy and Safety Endpoints ..................................................................................... 64 
8.6.5.1 
Primary Endpoint ................................................................................................................. 64 
8.6.5.2 
Secondary Endpoints ........................................................................................................... 64 
8.6.5.3 
Safety Endpoints .................................................................................................................. 65 
8.7 
Management And Reporting Of Adverse Events ................................................................ 66 
8.7.1 
Reporting of Serious Adverse Events to the Sponsor .................................................. 66 
8.7.2 
Management of Suspected Unexpected Serious Adverse Reactions ........................... 67 
8.7.3 
Annual Safety Reporting .............................................................................................. 68 
8.7.4 
Breaking of the Randomisation Code .......................................................................... 68 
8.7.5 
Serious and Non-serious Adverse Events Follow-up .................................................. 68 
8.8 
Management Of Positive Pregnancy Test ........................................................................... 69 
9. 
STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE .......................... 69 
9.1 
Determination Of Sample Size ............................................................................................ 69 
9.2 
Analysis Populations ........................................................................................................... 69 
9.3 
Statistical Analysis .............................................................................................................. 70 
9.3.1 
Descriptive statistics .................................................................................................... 70 
9.3.2 
Primary (efficacy) analysis .......................................................................................... 70 
9.3.2.1 
Sensitivity analysis .............................................................................................................. 71 
9.3.3 
Secondary (efficacy) analysis ...................................................................................... 71 


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9.3.4 
Exploratory (efficacy) analysis .................................................................................... 71 
9.3.5 
Subgroup analysis ........................................................................................................ 71 
9.3.6 
Safety analysis.............................................................................................................. 71 
9.3.6.1 
AEs ...................................................................................................................................... 71 
9.3.6.2 
Other Safety Variables ......................................................................................................... 72 
9.3.7 
Interim analysis and stopping rules .............................................................................. 72 
9.3.8 
Data imputations .......................................................................................................... 72 
9.4 
Protocol Violations And Blind Review ............................................................................... 72 
9.5 
Statistical Analysis Plan ...................................................................................................... 73 
10. 
DATA QUALITY MANAGEMENT ..................................................................................... 73 
10.1 Data Collection .................................................................................................................... 73 
10.1.1 Case Report Forms ....................................................................................................... 73 
10.1.2 IVRS/IWRS ................................................................................................................. 74 
10.1.3 Patient diary ................................................................................................................. 74 
10.2 Clinical Data Management .................................................................................................. 75 
10.3 Source Data ......................................................................................................................... 75 
10.4 Quality Control/Quality Assurance ..................................................................................... 76 
10.4.1 Study Monitoring ......................................................................................................... 76 
10.4.2 Quality Assurance ........................................................................................................ 76 
11. 
PREMATURE TERMINATION OF THE WHOLE STUDY ............................................... 76 
12. 
END OF CLINICAL TRIAL AND ARCHIVING ................................................................. 77 
12.1 Archiving Of Electronic Documentation/Date .................................................................... 77 
13. 
REFERENCES........................................................................................................................ 78 
 
 
 


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4.1 
GLOSSARY 
ß-HCG 
ß-Human Chorionic Gonadotropine 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALAT 
Alanine Aminotransferase 
a.m. 
From Latin ante meridiem, before-noon 
ANCOVA 
Analysis of Covariance 
ASA 
American Society of Anaesthesiologists 
ASAT 
Aspartate Aminotransferase 
AUC 
Area Under the Curve 
BDRM 
Blind Data Review Meeting 
BOCF 
Baseline Observation Carried Forward 
BP 
Blood Pressure 
CA 
Competent Authority 
CI
Confidence Interval
CM 
Concomitant Medication 
Cmax 
Maximum Plasma Concentration 
CPK 
Creatine Phosphokinase 
CRF 
Case Report Form 
CRO 
Clinical Research Organisation 
COX  
Cyclooxygenase  
CYP2D6 
Cytochrome P450 2D6 
CYP3A4 
Cytochrome P450 3A4 
DKP.TRIS 
Dexketoprofen Trometamol 
DSM 
Drug Safety Manager 
DSUR 
Development Safety Update Report 
EC 
Ethics Committee 
ECG 
Electrocardiogram 
e-CRF 
Electronic Case Report Form 
e-Diary 
Electronic Diary 
FPPAR 
First Perceptible Pain Relief 
G6PD 
glucose-6-phosphate dehydrogenase 
GCP 
Good Clinical Practice 
GGT 
Gamma-Glutamyl Transpeptidase 
Hb 
Haemoglobin 
HCT 
Haematocrit 
HR 
Heart rate 
IASP 
International Association for the Study of Pain 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
i.m. 
Intramuscular 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
ITT 
Intention-to-treat 
i.v. 
Intravenous 
IxRS (IVRS/IWRS) 
Interactive Voice/Web Response System 
LDH 
Lactate Dehydrogenase 
LOCF 
Last Observation Carried Forward 
M1 
O-demethyltramadol  
MAO 
Monoamine oxidase 
MCH 
Mean Corpuscular Haemoglobin 
MCHC 
Mean Corpuscular Haemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MIA 
Monosodium Iodoacetate 


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MPAR 
Meaningful Pain Relief 
N 
Number of Non-missing Observations 
NRS 
Numerical Rating Scale 
NSAID 
Non-Steroidal Anti-Inflammatory Drug  
PAR 
Pain Relief 
PCA 
Patient Controlled Analgesia 
PGE 
Patient Global Evaluation 
PI 
Pain Intensity 
PID 
Pain Intensity Difference 
PK 
pharmacokinetics 
PP 
Per-protocol 
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time
QA 
Quality Assurance 
RBC 
Red Blood Cell 
RM 
Rescue Medication 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SmPC 
Summary of Product Characteristics 
SOC 
System Organ Class 
SPID 
Sum of Pain Intensity Differences 
SOP 
Standard Operating Procedure 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TEAEs 
Treatment Emergent Adverse Events 
t1/2,ß 
Elimination half-life 
tmax 
Time to Maximum Plasma Concentration 
TMF 
Trial Master File 
TOTPAR 
Total Pain Relief 
TRAM.HCl 
Tramadol Hydrochloride  
VRS 
Verbal Rating Scale 
VS 
Vital Signs 
WBC 
White Blood Cell 
 
 


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5. ETHICAL AND LEGAL ASPECTS 
5.1 
GENERAL ASPECTS 
This study will be carried out in compliance with the study protocol, the recommendations on 
biomedical research on human subjects of the Declaration of Helsinki1, International Conference of 
Harmonisation, and national requirements of the participating countries. 
The Sponsor has contracted the Contract Research Organisation (CRO) to perform some of the 
Sponsor’s trial related duties and functions like site selection and monitoring. Medical monitoring, 
safety management, data management, statistical analysis and medical writing will be performed by the 
Sponsor. The ultimate responsibility for the quality and the integrity of the study resides with the 
Sponsor. The study will be conducted in agreement with Sponsor’s or CRO’s Standard Operating 
Procedures’ (SOP) requirements as agreed. 
All clinical work conducted under this protocol is subject to GCP rules. This includes 
audits/inspections by the Sponsor and/or its delegate (e.g. CRO), and/or by national/international 
Health Authority representatives at any time. All Investigators must agree to the audits/inspection of 
the study site, facilities, and of study-related records by the Health Authority representatives and/or by 
the Sponsor, and/or its delegates, which must be performed in accordance with national laws 
concerning personal data protection. 
5.2 
INDEPENDENT ETHICS COMMITTEE AND LEGAL REQUIREMENTS 
Before starting the study in a study site, study protocol and relevant documentation must be submitted 
to and approved by the Competent Authorities (CAs) and the Independent Ethics Committees (IEC) of 
the participating Countries/Centres. 
In addition, all local national legal requirements for the conduct of a clinical study have to be followed 
prior to the start of the study. The CAs and IECs of the participating centres will be informed about any 
changes in the study protocol, the end of the study, or the premature study termination as appropriate, 
and within the requested time period.  
5.3 
PATIENT INFORMATION AND DECLARATION OF CONSENT 
Before any study-related procedures may be performed, informed consent must be obtained from the 
patient by means of a signed declaration. 
The Informed Consent Form (ICF) must be approved in the corresponding local language and in 
accordance with local laws and regulations by the IEC prior to be submitted to the patient.  
In the patient information leaflet, patients will be given information and fully comprehensive 
explanation in easily understandable terms of the study procedures, regarding the benefits, restrictions, 
discomforts, and risks in taking part in the study, the properties of the Investigational Medicinal 
Product (IMP), the method of assignment to treatments, and any medically accepted and readily 
available treatment other than the IMP.  


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Patients will also be informed about the measures taken to ensure their confidentiality according to the 
pertinent legislation.  
After being duly informed and interviewed by the Investigator, the patient freely has to date and sign 
the ICF before being enrolled into the study and before undergoing any study procedure. The 
Investigator must store the original of the signed ICF in the Investigator’s File, and the patient will be 
provided with a copy of it. The process of obtaining the ICF has to be documented in the source 
documents. 
If a protocol amendment would affect the terms of the ICF, it will be revised to reflect the protocol 
change and submitted to IEC for approval. The Investigator will ensure that this new ICF is signed by 
all patients who subsequently enter in the study and those who are currently in the study, before the 
changes take effect on their participation in the trial. 
5.4 
PATIENT INSURANCE 
For patients participating in the study, the Sponsor Menarini Ricerche S.p.A. has stipulated an 
insurance policy in accordance with local regulatory requirements. 
Details on the insurance company, the insurance number and conditions will be reported in the ICF 
and/or provided as a separate document, in accordance with national requirements. 
A copy of the insurance certificate will be provided to each Investigator and will be filed in the 
Investigator’s File at the sites and in the study’s Trial Master File (TMF). 
5.5 
DOCUMENTATION OF STUDY-RELATED DATA AND RECORD RETENTION  
It is the responsibility of the Investigator to document all study-related data for each patient and record 
them in a case report form (CRF). For this study, an electronic CRF (e-CRF) will be used. The 
Investigator has to guarantee the accuracy of the documented data and has to comment any missing or 
spurious data. 
In addition to the e-CRF the Investigator will maintain adequate records that fully document the 
participation of the patient in the clinical study including the study assessments (patient source data 
documentation). Details on the source data documentation are provided in section 10.3. As required by 
ICH-GCP guidelines, the Investigator will keep patients’ records and essential documents until at least 
two years after the last approval of a marketing application in an ICH region, or until there are no 
pending or contemplated marketing applications in an ICH region, or at least two years have elapsed 
since the formal discontinuation of clinical development of the IMP.  
Patients’ data (e.g. e-CRFs, safety laboratory data) have to be archived for the same period of time. 
These documents should be retained for a longer period however, if required by the applicable 
regulatory requirements or by an agreement with the Sponsor. No study documents should be 
destroyed without prior written agreement between Sponsor and Investigator. Should the Investigator 
wish moving the study record to another location, he/she must notify the Sponsor in writing.  


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Details on the archiving of electronic documents/data are provided in section 12.1.  
5.6 
CONFIDENTIALITY 
By signing the study protocol, the Investigator affirms that any information provided by the Sponsor 
will be maintained in confidence, and that such information will be divulged to IECs or CAs only 
under an appropriate understanding of confidentiality with such a committee or institution. 
In order to maintain the patient’s confidentiality, all data collected by the Investigator will be recorded 
pseudonymously in the e-CRF. Patient’s data will be identified by a unique patient number. The 
Investigator agrees that within national regulatory restrictions and ethical considerations, 
representatives of the Sponsor, any regulatory agency, and IEC may consult study source documents in 
order to verify data in the e-CRF. Patient medical records pertinent to the study will be reviewed by the 
study monitor to assure adequate source documentation, accuracy, and completeness of e-CRFs. The 
review will be conducted in accordance with relevant SOPs and with strict adherence to professional 
standards of confidentiality, GCP, and the relevant data protection legislation. 
5.7 
PROTOCOL MODIFICATIONS 
The protocol must be read thoroughly by everybody whom the information therein concerns and the 
instructions must be exactly followed. 
Changes in the study protocol will require a protocol amendment. Such amendments will be agreed 
upon and approved in writing by all signatories of the protocol. If amendments are substantial, i.e. are 
likely to have an impact on the safety of the patients, or to change the interpretation of the scientific 
documents in support of the conduct of the study, or if they are otherwise significant, the IECs and the 
CAs in the participating countries have to approve these amendments before implementation unless 
urgent safety measures need to be implemented (see section 5.9).  
Changes which have no significant impact on medical or scientific validity of the study will be agreed 
upon and approved in writing by all signatories of the protocol and the IECs and the CAs will be 
notified of this protocol amendment. 
Any substantial amendments of the protocol will be integrated in an updated study protocol. The 
principal investigator must ensure full compliance with the updated study protocol. 
5.8 
STUDY COMMENCEMENT 
The study can commence in an individual study site only after all prerequisites are fulfilled according 
to ICH/GCP guidelines, any local regulatory requirements, and the Sponsor/CRO’s SOPs. 
5.9 
PATIENT’S SAFETY 
If any event(s) related to the conduct of the study or to the IMP affects the safety of the study 
participants, the Sponsor and the Investigator will take appropriate urgent safety measures to protect 
the patients against any immediate hazard. The CAs and IECs will be informed forthwith about these 
new events and the measures taken. 


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5.10 DATA PROPERTY/PUBLICATION POLICY 
All data generated in the study (e.g. e-CRFs, patient diaries, the structured data files in the clinical 
database system, the results of the statistical evaluation, and medical interpretation as well as the final 
clinical study report) are the property of Menarini Ricerche S.p.A. 
It is intended that study design and main results will be published on www.clinicaltrials.gov. In 
addition, the results of the study may be published as scientific literature. Results may also be used in 
submissions to CAs. The conditions mentioned below are intended only to protect confidential 
commercial information (patents, etc.), and not to restrict publication. 
All information concerning dexketoprofen trometamol/tramadol hydrochloride fixed dose combination 
–abbreviated as DKP.TRIS/TRAM.HCl- (such as patent applications, formulae, manufacturing 
processes, basic scientific data, or formulation information supplied to the investigator by Menarini 
Ricerche S.p.A. and not previously published) is considered confidential by Menarini Ricerche S.p.A. 
and will remain the sole property of Menarini Ricerche S.p.A. The investigator agrees not to use it for 
other purposes without written consent from Menarini Ricerche S.p.A. 
Menarini Ricerche S.p.A. will use the information obtained in this clinical study in connection with the 
development of DKP.TRIS/TRAM.HCl and therefore may disclose it to other investigators or concerned 
CAs and IECs in the European Union or abroad. In order to allow for the use of information derived 
from this clinical study, the Investigator has an obligation to provide Menarini Ricerche S.p.A. with 
complete test results and all data recorded during this study. 
Prior to submitting the results of this study for publication or presentation, the Investigator will allow 
Menarini Ricerche S.p.A. at least 60 days time to review and comment upon the publication 
manuscript. Menarini Ricerche S.p.A. will provide any manuscript of the results of this study at least 
60 days before publishing to the authors for a complete review. In accordance with generally 
recognised principles of scientific collaboration, co-authorship with any Menarini Ricerche S.p.A. 
personnel will be discussed and mutually agreed upon before submission of a manuscript to a 
publisher. 
It is agreed, that the results of the study will not be submitted for presentation, abstract, poster 
exhibition, or publication by the Investigator until Menarini Ricerche S.p.A. has reviewed/commented 
and agreed to any publication. 
 
 


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6. BACKGROUND INFORMATION 
6.1 
PAIN 
Pain is the most common symptom for which patients seek medical attention. It can be defined as 
an unpleasant sensory and emotional experience associated with actual or potential tissue damage, 
or described in terms of such damage (International Association for the Study of Pain, IASP)2. 
Pain can be either acute or chronic. Acute pain typically is associated with recent tissue injury and 
has a short duration. Tissue injury causes a cascade of events, including peripheral inflammation, 
that release various mediators into the local environment. These mediators activate the primary 
afferent nerves or sensitize local nerve receptors, which, in turn, can evoke changes at the level of 
the spinal cord, a process referred to as ‘peripheral sensitization’. This process is responsible for the 
development of hyperalgesia beyond the damaged site. If acute pain is not properly treated, 
prolonged activation of the pain pathways can lead to further neurophysiologic changes collectively 
called ‘central sensitization’ which may prolong recovery and in some cases convert acute pain into 
a chronic condition. Proper analgesic treatment can reduce this risk3. Pain due to tissue damage is 
referred to as nociceptive. The response to nociceptor sensory input is a multifactorial process, with 
both central and peripheral mechanisms involved4. Nociceptive pain usually responds to non-
steroidal anti-inflammatory drugs (NSAIDs) and opioids. 
In spite of the great variety of analgesics available, the management of patients suffering from pain 
still continues to be inadequate5, 6, 7. Due to the subjective component of pain, the problems 
associated to a correct diagnosis or the fear of the adverse reactions associated to some drugs, 
patients are frequently undertreated for acute and chronic situations2. One study on the prevalence 
of post-operative pain in surgical inpatients stated that 41% of 1490 surgical patients reported 
moderate to severe pain despite an acute pain protocol8. 
Clinical experience has proven that in patients with moderate to severe pain, it is difficult to obtain 
an effective analgesia with a single drug (monotherapy) and therefore, analgesic drugs are 
commonly combined (multimodal analgesia) in order to obtain an optimal control of pain. 
Multimodal analgesia has shown its benefits in treating different kinds of acute and chronic pain in 
humans. However, extemporaneous combinations of available analgesics are often used 
empirically, without knowing the mechanism of interaction and/or the best dose ratio of the 
analgesics to be combined in order to achieve optimal efficacy and safety9, 5, 6, 7.  
6.2 
INVESTIGATIONAL MEDICINAL PRODUCT: DEXKETOPROFEN 
TROMETAMOL AND TRAMADOL HYDROCHLORIDE FIXED COMBINATION 
Menarini Ricerche is developing a combination of DKP.TRIS and TRAM.HCl, two analgesics with 
different mechanism of action, for the treatment of moderate to severe acute pain, based on the 
rationale that multimodal analgesia is necessary in most patients suffering from acute and chronic 
pain, particularly of moderate to severe intensity.  


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DKP.TRIS and TRAM.HCl are well-known and widely used analgesics which have been present in 
the market of most European countries for a very long time. 
The rationale for combining DKP.TRIS and TRAM.HCl relies on the following: 
(i) DKP.TRIS and TRAM.HCl have different mechanisms of action; the former exerts its 
antinociceptive activity mainly at the peripheral level, whereas the latter is a centrally acting 
analgesic;  
(ii) DKP.TRIS and TRAM.HCl have different pharmacokinetic profiles; their combination is 
expected to be characterized both by quick onset (typical of DKP.TRIS) and long duration 
(peculiar to TRAM.HCl) of the analgesic effect. 
This pharmacodynamic and pharmacokinetic rationale is supported by preclinical and clinical 
evidence. Data on the single components are reported below. 
Dexketoprofen trometamol 
DKP.TRIS is the tromethamine salt of the S-(+) enantiomer of ketoprofen, an analgesic, anti-
inflammatory and antipyretic drug, which belongs to the NSAIDs group (M01AE). 
The mechanism of action of NSAIDs is related to the reduction of prostaglandin synthesis by the 
inhibition of cyclooxygenase (COX) pathway. DKP.TRIS has been demonstrated to be an inhibitor 
for COX-1 and COX-2 activities in experimental animals and humans. It has been shown in 
different studies that the enantiomer S-(+) of ketoprofen suppresses the synthesis of prostaglandins, 
whereas the enantiomer R-(-) is inactive or almost inactive10, 11.  
Clinical studies performed on several pain models demonstrated effective analgesic activity of 
DKP.TRIS. The onset of its analgesic activity was shown to be approximately at 30 minutes post-
administration, with analgesic effect persisting for 4 to 6 hours12, 13, 14 ,15, 16, 17. 
After oral administration of DKP.TRIS to humans, the maximum plasma concentration (Cmax) is 
reached at 30 minutes (range 15 to 60 minutes). The elimination half-life value of DKP.TRIS is 
1.65 hours. The main elimination route for DKP.TRIS is glucuronide conjugation followed by renal 
excretion. After administration of DKP.TRIS, only the S-(+) enantiomer is obtained in urine, 
demonstrating that no conversion to the R-(-) enantiomer occurs in humans18. 
When administered concomitantly with food, the area under the curve (AUC) does not change, 
however the Cmax of DKP.TRIS decreases and its absorption rate is delayed (increased time to 
maximum plasma concentration, tmax)19. 
In multiple-dose pharmacokinetic studies, it was observed that the AUC after the last administration 
is not different from that obtained following a single dose, indicating that no drug accumulation 
occurs18. 
Oral DKP.TRIS (as 12.5mg and 25mg film-coated tablets) is currently approved in all European 
countries and in several non-European countries (for a total of 62 countries world-wide), with a 


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large cumulative experience of use. It is indicated for the symptomatic treatment of pain of mild to 
moderate intensity, such as musculo-skeletal pain, dysmenorrhoea and dental pain. According to the 
nature and severity of pain, the recommended dosage is generally 12.5mg every 4-6 hours or 25mg 
every 8 hours. The total daily dose should not exceed 75mg20.  
DKP.TRIS is also available on the market as a 50mg/2ml injectable formulation –to be 
administered either by intramuscular (i.m.) or by intravenous (i.v.) route–, which is indicated for the 
symptomatic treatment of acute pain of moderate to severe intensity, such as post-operative pain, 
renal colic and low back pain. The recommended dose is 50mg every 8 - 12 hours. If necessary, the 
administration can be repeated 6 hours apart. The total daily dose should not exceed 150mg21. 
Tramadol hydrochloride 
TRAM.HCl is a centrally acting analgesic (NO2A X 02). (+)-Tramadol and its main metabolite (+)-
O-demethyltramadol [(+)-M1] are non-selective pure agonist at mu (µ), delta (δ) and kappa (κ) 
opioid receptors with a higher affinity for the µ receptor. Other mechanisms which contribute to its 
analgesic effect are inhibition of neuronal re-uptake of noradrenaline [(-)-tramadol] and 
enhancement of serotonin release [(+)-tramadol]22, 23. 
In contrast to morphine, analgesic doses of TRAM.HCl over a wide range have no respiratory 
depressant effect; gastrointestinal motility is also less affected, and effects on the cardiovascular 
system tend to be slight. The potency of TRAM.HCl is reported to be 1/10 (one tenth) to 1/6 (one 
sixth) that of morphine22 23 . The mean absolute bioavailability is approximately 70%, irrespective 
of the concomitant intake of food. Following a single oral dose administration of TRAM.HCl 
100mg to young healthy volunteers, plasma concentrations are detectable within approximately 15 
to 45 minutes with a mean tmax of 1.6 to 2 hours. Elimination half-life (t1/2,ß) is approximately 6 
hours. In humans TRAM.HCl is mainly metabolised by means of N- and O-demethylation and 
conjugation of the O-demethylation products with glucuronic acid. Among 11 metabolites found in 
the urine, only M1 is pharmacologically active and animal experiments have shown that it is more 
potent than the parent substance by the factor 2 - 4. Its half-life (t1/2,ß) is 7.9 hours (range 5.4 - 9.6 
hours), approximating that of TRAM.HCl. The inhibition of one or both types of the isoenzymes 
cytochrome P450 3A4 (CYP3A4) and cytochrome P450 2D6 (CYP2D6) involved in the 
biotransformation of TRAM.HCl may affect the plasma concentration of TRAM.HCl or its active 
metabolite. TRAM.HCl and its metabolites are almost completely excreted via the kidneys. 
TRAM.HCl has a linear pharmacokinetic profile within the therapeutic dosage range22 23. 
Oral TRAM.HCl is currently authorised over 90 countries as 50mg to 400mg different formulations 
(capsules, tablets and extended-release formulations). It is indicated for the treatment of moderate to 
severe pain. The start dose in case of acute pain is 100mg, and the recommended unitary dose is 
between 50 and 100mg not taken more frequently than every 4 hours, with a maximum of 
400mg/day23. 


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6.2.1 
Data on the co-administration of dexketoprofen trometamol and tramadol 
hydrochloride 
6.2.1.1 Pre-clinical studies 
Previous pre-clinical studies performed in mice showed that the co-administration of DKP.TRIS 
with TRAM.HCl produces an additive-synergistic anti-nociception, which seems to be modulated 
by opioid receptors. The results also showed that DKP.TRIS antagonises the effects of TRAM.HCl 
on the inhibition of gastrointestinal transit, a fact that could be clinically beneficial since the 
incidence or intensity of constipation on the TRAM.HCl treated patients could diminish24. 
The analgesic effects of the oral co-administration of DKP.TRIS with TRAM.HCl in comparison 
with the same drugs administered individually have also been investigated in rats on a knee-
osteoarthritis model induced by intra-articular injection of monosodium iodoacetate (MIA). The co-
administration of DKP.TRIS with TRAM.HCl demonstrated a statistically significant improvement 
of analgesia and a more prolonged effect as compared to the single drug administration25. 
6.2.1.2 Published data from non-sponsored clinical studies 
Published clinical evidence particularly supports the rationale for developing a combination of an 
analgesic opioid such as TRAM.HCl and a NSAID. 
A review on the multimodal analgesia for post-operative pain control showed that neither opioids 
nor NSAIDs alone can have an effective analgesic effect without producing side effects such as 
nausea, vomiting, sedation and intestinal bleeding. The same review reported that most clinical 
studies (either double or single blind) testing the association of NSAIDs and opioids showed that 
patients experience lower pain scores, need fewer analgesics, and have a prolonged time to 
requiring analgesics after surgery26. 
The results of two clinical studies evaluating the effects of oral DKP.TRIS co-administered with 
TRAM.HCl i.v. via a Patient Controlled Analgesia (PCA) device on post-operative pain showed 
that DKP.TRIS provided a significant analgesic benefit and reduced post-operative TRAM.HCl 
consumption. Study objectives included the evaluation of the efficacy of two different multimodal 
analgesia protocols (with or without oral DKP.TRIS in addition to standard-practice TRAM.HCl 
i.v.) in terms of post-operative pain relief, TRAM.HCl consumption during PCA and side effects 
after abdominal hysterectomy (n = 50) or total hip replacement surgery (n = 36). In both studies, the 
two tested analgesia protocols including TRAM.HCl in monotherapy or in combination with 
DKP.TRIS were effective in relieving pain with no significant differences between groups in 
sedation scores, adverse effects or patient satisfaction. It was concluded that the administration of 
DKP.TRIS provided a significant analgesic benefit and decreased the opioid requirements in the 
treatment of moderate to severe post-operative pain27, 28. 


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In addition, in a double-blind randomised clinical trial in order to assess the efficacy of ketoprofen 
(the racemic drug of dexketoprofen) in association with TRAM.HCl in post-operative pain 
treatment after major abdominal surgery, it was shown that the total dose of TRAM.HCl needed to 
obtain a better analgesic quality was lower in the group treated with TRAM.HCl combined with 
ketoprofen (193mg/24h i.v.) than in the group treated only with TRAM.HCl (235mg/24h i.v.). It 
was concluded that ketoprofen, used as an adjuvant to TRAM.HCl, significantly improved the 
quality of post-operative analgesia after major abdominal surgery29.  
6.2.1.3 Post-marketing clinical experience 
IMS Health data on DKP.TRIS (Enantyum®) non-hospital prescriptions in Spain in 2009 for the 
two marketed oral forms (tablets and sachets) and for the injectable formulation showed that 
DKP.TRIS was prescribed concomitantly with TRAM.HCl in around 125.000 cases (oral forms) 
and 6.400 cases (injectable formulation) over a total of 5.695.476 prescriptions.  
These numbers indicated that the use of the two drugs in combination is well established in the 
medical practice as a part of the therapeutic armamentarium in the field of analgesia. Moreover, it is 
worthy of note that these data excluded hospital prescriptions, thus underestimating the real extent 
of use of the combination.  
Overall, available data indicate that co-dispensation of DKP.TRIS and TRAM.HCl is part of current 
clinical practice, which supports the medical need for the development of a fixed-dose combination 
of these two products. 
6.2.2 
Clinical development of dexketoprofen trometamol and tramadol hydrochloride fixed 
combination 
The clinical development of the the DKP.TRIS/TRAM.HCl fixed-combination started with a phase 
I safety and pharmacokinetics (PK) study (DEX-TRA-PK)30, aimed at investigating the potential 
drug-drug interactions between the products as well as their tolerability when concomitantly 
administered as a single oral dose to healthy subjects. The study results indicated that there was no 
drug-drug interaction between DKP.TRIS and TRAM.HCl and that the concomitant administration 
was well tolerated. A phase II dose-finding study (DEX-TRA-02)31 32was performed in the most 
frequently used model of acute nociceptive pain of moderate-severe intensity (impacted third 
mandibular molar tooth extraction), aimed at evaluating the analgesic efficacy and safety of 
DKP.TRIS (12.5mg and 25mg) and TRAM.HCl (37.5mg and 75mg) given as 4 different 
combinations and as single components. Results from DEX-TRA-02 allowed for the selection of 
DKP.TRIS/TRAM.HCl 25mg/75mg as the optimum combination of doses then evaluated in the 
subsequent phase III registration studies.  
DEX-TRA-04 33 and DEX-TRA-0534 were two phase III registration studies aimed at evaluating the 
analgesic efficacy and safety of the DKP.TRIS/TRAM.HCl 25/75mg oral fixed-dose combination 
in comparison with each single component (tramadol given at a higher dose, 100mg), following 


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single and repeated-dose administration, in two recognised models of visceral and somatic moderate 
to severe acute pain, namely abdominal hysterectomy and hip arthroplasty, respectively. The study 
results provided robust evidence of the superiority of DKP.TRIS/TRAM.HCl 25mg/75mg over the 
single components in the management of moderate to severe acute pain. 
6.2.2.1 Phase I study (DEX-TRA-PK)  
The DEX-TRA-PK was an open, randomised, three-sequence, three-session, cross-over, phase I 
study, conducted in one single investigational site in Italy. A total of 30 Caucasian healthy subjects 
(17 men and 13 women, aged 18-54 years, who had previously tolerated a test dose of DKP. TRIS 
12.5mg + TRAM.HCl 50mg), divided in 3 cohorts of 10 subjects, were assigned to receive, 
according to a cross-over design, one single oral dose of DKP.TRIS 25mg, TRAM.HCl 100mg and 
of both drugs given as extemporaneous combination, in 3 different study sessions separated by a 
minimum 7-day wash-out period. On each study session, serial blood samples were withdrawn from 
the subjects for (PK) assessment. Standard safety parameters were measured during each of the 3 
study sessions, with a final safety follow-up visit performed 7-10 days after the last treatment 
intake.  
The study results showed that DKP.TRIS and TRAM.HCl pharmacokinetic parameters were similar 
when comparing both drugs administered as single agents and in combination. The rate and the 
extent of availability (Cmax and AUC) of DKP.TRIS, (+)-tramadol, (–)-tramadol and (+)-M1 was 
unaffected by the co-administration. Therefore, it was concluded that there was no drug-drug 
interaction between TRAM.HCl 100mg and DKP.TRIS 25mg when concomitantly orally 
administered to healthy subjects. Moreover, the concomitant administration was well tolerated 
without raising any safety concerns. 
6.2.2.2 Phase II study (DEX-TRA-02) 
The DEX-TRA-02 was a multicentre, randomised, double-blind, double-dummy, parallel, placebo 
and active-controlled, single-dose phase II, dose-finding study aimed at evaluating the analgesic 
efficacy and safety of DKP.TRIS (12.5mg and 25mg) and TRAM.HCl (37.5mg and 75mg) given as 
4 different combinations and as single components, in comparison to placebo, on moderate to 
severe acute pain following impacted third mandibular molar tooth extraction. An active control 
(ibuprofen 400mg) was included in order to validate the pain model, in compliance with the 
regulatory guidelines on clinical investigation of medicinal products for treatment of nociceptive 
pain (CPMP/EWP/612/00)2. 
The design included a total of 10 balanced treatment arms, with the 4 combinations of 
DKP.TRIS/TRAM.HCl (12.5mg/37.5mg, 12.5mg/75mg, 25mg/37.5mg and 25mg/75mg), the 4 
corresponding single treatments, placebo and ibuprofen 400mg.  
A total of 611 patients (247 males and 364 females, aged 18-64 years) experiencing moderate to 
severe pain (Visual Analogue Scale, VAS ≥ 40mm and Verbal Rating Scale, VRS ≥ 2) after the 


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extraction of at least one impacted third mandibular molar tooth were randomised and received one 
single oral dose of the assigned study treatment. Rescue medication (RM) consisting of paracetamol 
(1g, every 6-8 hours) was available on request during the 24-hour post-dose period.  
The analgesic efficacy evaluation was based on the patients’ electronic diary (e-Diary) scores of 
pain intensity (PI) and pain relief (PAR) measured on VRS at regular intervals over a 24-hour post-
dosing period, the patient global evaluation (PGE) at the end of the assessment period and the use of 
RM. After use of RM, PI returned to its baseline level and PAR to zero for all subsequent time 
points (baseline observation carried forward, BOCF). 
Safety was assessed by evaluation of any change in the physical examination, vital signs (VS), 12-
lead ECG, and laboratory safety tests post-dose versus baseline. Recording and monitoring of AEs 
were conducted during the entire study period.  
The efficacy analysis was run on the Intention-to-treat (ITT) population, which included 606 
patients (with balanced allocation into the 10 treatment arms).  
The percentage of responders (achievement of at least 50% maximum total pain relief, max 
TOTPAR) over the 6-hour post-dosing period (primary endpoint; figure 1) was significantly 
superior to placebo for all DKP.TRIS/TRAM.HCl combinations (p < 0.0001 for each comparison, 
except p = 0.0009 for DKP12.5/TRAM37.5); with the highest percentage of responders achieved in 
the DKP.TRIS/TRAM.HCl 25mg/75mg group (72% versus 10% in the placebo group). The 
percentage of responders was also statistically superior to placebo for all combinations over 4 hours 
and it remained statistically superior (except for DKP.TRIS/TRAM.HCl 12.5mg/37.5mg) over 8 
and 12 hours. 


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Figure 1: Primary Endpoint - Percentage of responders 
(achievement of at least 50% max TOTPAR) over 6 hours; max 
TOTPAR corresponded to the theoretical maximum weighted sum of 
the PAR scores, according to a 5-point VRS (0 = ‘none’ to 4 = 
‘complete’); (p < 0.0001 for each comparison; except p = 0.0009 for 
DKP.TRIS/ TRAM.HCl 12.5mg/37.5mg). 
 
The analysis of SPID (Sum of Pain Intensity Differences), TOTPAR and derived variables (% max 
SPID and % max TOTPAR) over 4, 6, 8 and 12 hours showed that all combinations were 
significantly superior to placebo, with the best results achieved with DKP.TRIS/TRAM.HCl 
25mg/75mg. The time to RM was significantly longer for all combinations than for placebo, with 
DKP.TRIS/TRAM.HCl 12.5mg/75mg and DKP.TRIS/TRAM.HCl 25mg/75mg presenting the 
longest time to RM [median time (95% confidence interval, CI)]: 8.5 (5.9 to 13.0) hours and 8.1 
(6.3 to 13.4) hours respectively, versus 1.4 (1.2 to 1.8) hours in the placebo group. The percentage 
of patients using RM over 6 hours was significantly inferior in the groups DKP.TRIS/TRAM.HCl 
12.5mg/75mg, DKP.TRIS/TRAM.HCl 25mg/37.5mg and DKP.TRIS/TRAM.HCl 25mg/75mg than 
in the placebo group (46.8%, 39.7% and 37.7% respectively versus 72.6%), with the 
DKP.TRIS/TRAM.HCl 25mg/75mg group presenting the lowest percentage. The difference was 
still significant for DKP.TRIS/TRAM.HCl 25mg/75mg over 8 hours (47.5% versus 72.6%). The 
analysis of PGE showed the superiority of all combinations versus placebo, with the higher scores 
also in the DKP.TRIS/TRAM.HCl 25mg/75mg group.  
The study results indicated that all combinations were effective in the treatment of moderate to 
severe acute pain at 4 and 6 hours post-dose, with DKP.TRIS/TRAM.HCl 25mg/75mg, 
DKP.TRIS/TRAM.HCl 12.5mg/75mg and DKP.TRIS/TRAM.HCl 25mg/37.5mg remaining also 
effective over 8 and 12 hours, thus confirming the value of combining the fast active DKP.TRIS 
with the long lasting TRAM.HCl efficacy. DKP.TRIS/TRAM.HCl 25mg/75mg presented consistent 
superior efficacy in all parameters of analgesia tested. All combinations were well tolerated, 
72%
60%
56%
55%
45%
37%
27%
25%
10%
10%
0%
10%
20%
30%
40%
50%
60%
70%
80%
DKP25 + TRAM75
DKP12.5 + TRAM75
DKP25 + TRAM37.5
DKP25
Ibuprofen
DKP12.5 + TRAM37.5
DKP12.5
TRAM75
TRAM37.5
Placebo


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presenting a safety and tolerability profile fully in line with that previously known for DKP.TRIS 
and TRAM.HCl as single agents. 
The DEX-TRA-02 study results also allowed for the selection of DKP.TRIS/TRAM.HCl 
25mg/75mg as the optimum combination of doses to be further investigated in the subsequent phase 
III pivotal studies. Based on the analysis of the percentage of responders over 4, 6, 8 and 12 hours 
and conversely the median time to RM (and also taking into account the recommended doses for the 
single agents, based on their pharmacokinetic profiles), the necessity of re-dosing with 
DKP.TRIS/TRAM.HCl 25mg/75mg in order to maintain an adequate analgesic effect was expected 
to be every 8 hours. Therefore, the posology/regimen selected for progressing into the confirmatory 
phase III trial was DKP.TRIS/TRAM.HCl 25mg/75mg to be administered every 8 hours. 
 
6.2.3 
Phase III confirmatory studies  
DEX-TRA-04 and DEX-TRA-05 were two multicentre, randomised, double-blind, double-dummy, 
parallel, placebo- and active-controlled, phase III, registration studies, aimed at evaluating the 
superior analgesic efficacy and safety of the selected dexketoprofen/tramadol 25mg/75mg oral 
fixed-combination in comparison with the single components (dexketoprofen 25mg and tramadol 
100mg) following single and repeated-dose administration, on moderate to severe acute pain after 
abdominal hysterectomy (DEX-TRA-04) and total hip arthroplasty (DEX-TRA-05), two recognised 
models of visceral and somatic moderate to severe acute pain (CPMP/EWP/612/00), frequently 
used in the clinical evaluation of analgesic drugs. 
Both studies were conducted in parallel and according to similar design and objectives. On the day 
after surgery, after cessation of the post-operative analgesia, a total of 606 patients (DEX-TRA-04) 
and 641 patients (DEX-TRA-05) experiencing pain of moderate to severe intensity (VAS ≥40) were 
randomised and received the first dose of the assigned study treatment. The treatment period 
consisted of a single-dose phase (first eight hours after the first dose) followed by a multiple-dose 
phase (subsequent six doses, in case of DEX-TRA-04 or subsequent 12 doses, in case of DEX-
TRA-05). Each dose of study medication was separated by an eight-hour interval. During the 
single-dose phase, patients received one of four possible treatments (dexketoprofen/tramadol 
25mg/75mg, dexketoprofen 25mg, tramadol 100mg or placebo), according to a 3:3:3:1:1:1 
randomisation ratio. During the multiple-dose phase, patients assigned to active treatment remained 
on the same treatment arm while patients assigned to placebo were re-allocated to receive one of the 
three possible active treatments (dexketoprofen/tramadol 25mg/75mg, dexketoprofen 25mg or 
tramadol 100mg). Overall, patients received seven consecutive doses of study drug within a three-
day period (DEX-TRA-04) or 13 consecutive doses within a five-day period (DEX-TRA-05). RM 
(metamizole 500mg, with a maximum recommended daily dose of 2g) was available on request 
during the entire treatment period. 


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Following treatment administration, patients were requested to make multiple assessments of PI (at 
rest and on movement) and of PAR on an e-Diary over a period of three or five days, with the last 
assessment to be recorded eight hours after the last dose of study drug. Patients also had to make an 
overall assessment of the study medication (PGE) at the end of each study phase. The amount and 
the time when RM was used were also recorded. For both studies, the primary efficacy endpoint 
was the mean SPID at rest over eight hours after the first dose (SPID8). 
The safety evaluation was based on the incidence of AEs, which were assessed throughout the 
entire study. Furthermore, safety was also evaluated by the assessment of clinically significant 
changes post-dose versus baseline in physical examination, vital signs, 12-lead ECG and laboratory 
safety tests (haematology, biochemistry and urinalysis). 
6.2.3.1 DEX-TRA-04: the abdominal hysterectomy pain model 
Demography and baseline characteristics of the different treatment groups were comparable. The 
overall mean age was 48 years (range 25 to 73 years). Initial pain was moderate in 38% patients and 
severe in 62% patients.  
The results of the primary analysis (mean SPID8, Fig. 2) confirmed the superiority of 
dexketoprofen/tramadol 
over 
the 
single 
components 
(mean 
[SD]: 
242 
[139] 
for 
dexketoprofen/tramadol versus 185 [139] for dexketoprofen and 157 [151] for tramadol; p<0.001 
for both comparisons). In addition, the comparisons of dexketoprofen and tramadol versus placebo 
(117 [122]) were both statistically significant (p<0.001 and p=0.010, respectively), confirming 
model sensitivity. Analyses on the PP population confirmed the primary efficacy results.


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There was statistical evidence favouring dexketoprofen/tramadol over the single agents for all PI 
variables (mean PI, mean SPID, mean %max SPID and response to treatment) at rest during the 
single dose phase of the study.  
Superiority of dexketoprofen/tramadol over the single agents was also seen for all PI variables at 
rest and on movement during the multiple-dose phase of the study. However, for mean PI (at rest 
and on movement) and for mean SPID on movement statistical significance was only achieved over 
dexketoprofen. 
Statistically significant superiority of dexketoprofen/tramadol over the single agents was shown for 
the PAR endpoints (mean PAR, mean TOTPAR and response to treatment) over 4, 6 and 8 hours. 
There was evidence of a longer overall time to first use of RM on dexketoprofen/tramadol 
compared to the single agents. Dexketoprofen/tramadol was found to be superior to the single 
agents with regards to the time to use of RM during the single-dose. 
The percentage of patients using RM over 24 hours during the multiple-dose phase was statistically 
significantly lower with dexketoprofen/tramadol than with the single agents. Results were 
mantained over 48 hours and overall during the multiple-dose phase, but the differences did not 
reach statistical significance.  
Dexketoprofen/tramadol was found to be statistically significantly superior to both single agents in 
terms of PGE scores for the single-dose phase, whereas the superiority was not mantained for the 
multiple dose phase of the study. 
Overall, 76 (13%) patients reported a total of 100 adverse reactions (ADRs), of which 51 were mild, 
42 were moderate and seven were severe. The most frequent ADRs (≥2% amongst the treatment 
group) were nausea (4.6% patients; 29 events), vomiting (2.3% patients; 14 events), abdominal 
distension (1.5% patients; nine events), platelet count increased (1.3% patients; eight events) and 
Figure 2 - Mean SPID8 (Primary Endpoint). PI 
measured on a 0-100 VAS, with the left end labeled “no 
pain” and the right end labeled “worst possible pain”. 
0
50
100
150
200
250
Placebo
DKP/TRAM 
25/75mg
DKP 25mg
TRAM 100mg
117
242
185
157
Mean SPID8 at rest


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blood lactate dehydrogenase increased (1.0% patients; six events). The dexketoprofen/tramadol 
group presented a lower incidence of ADRs (9.4% patients) in comparison with the dexketoprofen 
(15% patients) and tramadol groups (13% patients). Overall, 11 (1.8%) patients reported a total of 
15 serious adverse events (SAEs), of which only one (psychotic disorder; in the 
dexketoprofen/tramadol group) was considered to be treatment-related. There were no marked 
differences between treatment groups in terms of safety outcomes, including vital signs, physical 
examination, 12-lead ECG or laboratory safety parameters. It was concluded that the study 
treatments were safe and well tolerated and that the dexketoprofen/tramadol combination showed a 
safety profile fully in line with that previously known for the single agents. 
6.2.3.2 DEX-TRA-05: the hip arthroplasty pain model 
Demography and baseline characteristics of the different treatment groups were comparable. The 
overall mean age was 62 years (range 29 to 80). Baseline pain was moderate in 51% patients and 
severe in 49% patients.  
For the primary endpoint (mean SPID8, Fig. 3), the highest mean (SD) value was reported in the 
dexketoprofen/tramadol group [247 (157)]; values reported by dexketoprofen and tramadol groups 
were very similar, [209 (155)] and [205 (146)], respectively, and the lowest value was reported in 
the placebo group [151 (159)]. The combination was significantly better than dexketoprofen 
[p=0.019; 95% confidence interval (CI): 6.4 to 73] and tramadol (p=0.012; 95% CI: 9.5 to 76). In 
addition, both single agents were superior to placebo (p<0.05), thus confirming model sensitivity. 
Analyses on the PP population showed generally similar results, although the differences between 
dexketoprofen/tramadol and both single components were slightly inferior to those observed in the 
ITT population and did not reach statistical significance at the 5% level. 
 
 
 
 
 
 
 
 
 
When assessed by PI (mean PI, mean SPID, mean % max SPID, response to treatment), 
dexketoprofen/tramadol was more effective than either dexketoprofen monotherapy or tramadol 
Figure 3 - Mean SPID8 (Primary Endpoint). PI 
measured on a 0-100 VAS, with the left end labeled “no 
pain” and the right end labeled “worst possible pain”. 
0
50
100
150
200
250
Placebo
DKP/TRAM 
25/75mg
DKP 25mg
TRAM 100mg
151
247
209
205
Mean SPID8 at rest


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monotherapy during both the single- and multiple-dose phases of the study. Superiority was 
generally established after the 2-hour time point following the first dose. 
The highest mean TOTPAR and percentage of responders with regards to PAR during the single-
dose phase were reported in dexketoprofen/tramadol group when compared to the single agents, 
although the differences did not reach statistical significance. 
Similarly, the highest PGE scores were reported in the dexketoprofen/tramadol group during the 
single- and multiple-dose phases of the study; however, no statistically significant differences were 
observed in comparison to the single components.  
There was evidence of a longer overall time to first use of RM for dexketoprofen/tramadol 
compared with dexketoprofen monotherapy and tramadol monotherapy.  
In terms of percentage of patients using RM, the fixed dose combination was also found to be 
superior to both single components over 24 and 48 hours and overall during the multiple dose 
phase.  
The percentage of patients using RM over 24 and 48 hours and overall during the multiple-dose 
phase, were statistically significantly lower in the dexketoprofen/tramadol group than in the 
dexketoprofen group and in the tramadol group.  
The worst pain score whilst moving was slightly lower on average for the dexketoprofen/tramadol 
group than for the dexketoprofen group and the tramadol group on Day 2 and Day 3 during the 
multiple dose phase. 
Overall, 27 (4.2%) patients experienced a total of 39 ADRs during the active treatment, of which 16 
were mild, 18 were moderate and five were severe. The most frequent ADRs (≥1% amongst the 
treatment group) were nausea (0.9% patients; 6 events) and vomiting (0.6% patients; four events).  
The dexketoprofen/tramadol group presented a lower incidence of ADRs (2.8% patients) in 
comparison with the dexketoprofen group (4.7% patients) and the tramadol group (5.1% patients). 
Two patients reported a total of five serious ADRs. One patient in the dexketoprofen group 
experienced duodenal ulcer. Another patient in the dexketoprofen/tramadol group experienced 
periorbital oedema, face oedema, laryngeal oedema and haematuria. These events were resolved on 
the same day (haematuria resolved within two days).There were no marked differences between 
treatment groups in terms of safety outcomes, including HR, BP, physical examination, 12-lead 
ECG or laboratory safety parameters. 
In summary, the results from the phase III studies provided robust evidence of the efficacy of the 
dexketoprofen/tramadol 25mg/75mg fixed-dose combination in the management of moderate to 
severe acute pain, as confirmed by the single dose efficacy, the repeated-dose sustained effect, and 
the good safety profile observed. 


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6.2.4 DEX-TRA-06: Phase IIIb new study in dental pain model 
The present phase IIIb study is aimed to evaluate the analgesic efficacy, safety and tolerability of 
DKP.TRIS/TRAM.HCl 25mg/75mg in comparison with TRAM.HCl /paracetamol 75mg/650mg, an 
oral fixed-combination indicated in the treatment of moderate to severe acute pain and already 
present in the market. 
The surgical removal of impacted lower third molar is a well-recognised model of moderate to 
severe pain commonly used in the development of analgesic drugs (it has already been used in 
DEX-TRA-02 study) that offers considerable advantages from a methodological point of view: a) 
the incidence of such procedures in young adults is relatively high and the patient population is 
healthy and generally free from complications; b) the surgical procedure is fairly uniform and the 
nature and extent of tissue trauma are limited and comparable among patients; c) the postoperative 
pain typically begins within 1 to 3 hours after surgery, ranges from moderate to severe in intensity 
and requires the use of analgesics. These characteristics reduce variability in the study population 
and allow reasonable sample size to detect differences between treatments35 36  37 38 39  
6.3 
RISK-BENEFIT ASSESSMENT 
In this study, patients will receive one single oral dose of DKP.TRIS/TRAM.HCl 25mg/75mg, 
TRAM.HCl/paracetamol 75mg/650mg or placebo (in a 2:2:1 ratio).  
RM consisting of ibuprofen 400mg (a maximum of 2 tablets, each one separated by a minimum 
interval of 4 hours) will be available on request during the 8-hour post-dose period. Ibuprofen 
400mg is a safe and effective drug for the treatment of dental and post-operative pain (Ibuprofen 
SmPC)40. 
According to the results from the previous phase I to III studies (§ 6.2.2 and § 6.2.3), 
dexketoprofen/tramadol 25mg/75mg is expected to provide adequate pain relief for the participating 
patients without raising any safety concerns. In addition, both dexketoprofen and tramadol will be 
administered within the higher unitary dose (25mg and 100mg, respectively) and well below the 
maximum daily dose (75mg and 400mg, respectively) recommended by the respective authorised 
Summary of Product Characteristics (SmPC)20, 23.  
The selected active comparator (TRAM.HCl/paracetamol 75mg/650mg) is indicated for the 
symptomatic treatment of moderate to severe pain. According to the authorised41 SmPC, an initial 
dose of 75mg/650mg is recommended, with additional doses to be taken as needed, not exceeding 
300 mg tramadol and 2600 mg paracetamol per day. 
The inclusion of the placebo arm is considered appropriate from the ethical point of view, taking 
into account the self-limiting nature of the post-operative dental pain, the single-dose nature of the 
study and the availability of RM.  


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None of the study procedures or requested examinations (such as blood draws) is associated with 
any specific risks. AEs, if any will be recorded during the entire study period. Upon discharge from 
the study site, patients will be instructed to contact the site immediately in case of any medical 
emergency. 
7. STUDY OBJECTIVES  
7.1 
PRIMARY OBJECTIVE 
To assess the comparability of DKP.TRIS/TRAM.HCl and TRAM.HCl/paracetamol in terms of 
analgesic efficacy on moderate to severe pain following impacted lower third molar extraction. 
7.2 
SECONDARY OBJECTIVES 
To confirm the safety and tolerability profile of DKP.TRIS/TRAM.HCl following single dose 
administration. 
 


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8. INVESTIGATIONAL PLAN 
8.1 
OVERALL STUDY DESIGN AND PLAN DESCRIPTION 
DEX-TRA-06 is designed as a multicentre, randomised, double-blind, double-dummy, parallel-
group, placebo and active-controlled, single dose, phase IIIb study, intended to be conducted in 
approximately 20 sites among Europe and Turkey. 
The study design includes a total of 3 treatment arms, with a 2:2:1 randomisation ratio: 
− DKP.TRIS/TRAM.HCl 
− TRAM.HCl/paracetamol 
− Placebo 
Male or female patients, aged more than 18 years, scheduled to undergo surgical extraction (under 
local anaesthesia) of at least one impacted lower third molar and who are otherwise healthy will be 
enrolled in the study.  
Upon completion of the surgical extraction, those patients experiencing moderate to severe pain 
(Numerical Rating Scale, NRS ≥4) within 4 hours after the end of surgery will be considered 
eligible to progress with randomisation and to receive one single oral dose of the assigned study 
treatment. 
Rescue medication (RM) consisting of ibuprofen 400mg (a maximum of 2 tablets, each one 
separated by a minimum interval of 4 hours) will be available on request during the 8-hour post-
dose period. 
The analgesic efficacy evaluation will be based on patients’ e-Diary scores of pain intensity (PI) 
and pain relief (PAR) at pre-defined intervals during the 8-hour post-dose period; the patient global 
evaluation (PGE) of the study medication at the end of the assessment period; the time to onset of 
the analgesic effect within two hours post-dose and the first use of RM. The safety evaluation will 
include a physical examination, vital signs (VS) and recording of adverse events (AEs). 
The individual study participation will have duration of approximately 3 weeks, encompassing: 
- Screening period, for study eligibility assessment (within 2 weeks prior to randomisation), 
including the pre-surgery procedures to be completed at least one day prior to surgery and ending 
with the 4-hour qualification post-surgery.  
- Randomisation and treatment administration (day 1, t0) followed by a 8-hour pain and analgesic 
effect assessment period as follows: 
- 
from t0 to t2h, at the study centre. 
- 
from t2h to t8h, out of the study centre.  
- End of study visit (6 ± 1 days after randomisation). 


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The design contemplates a sample size of 640 randomised patients. It is anticipated that 
approximately 800 patients will be needed to be screened in order to obtain 640 randomised 
patients, under the assumption that approximately 20% of the screened patients will not satisfy the 
eligibility criteria for randomisation.  The enrolment will be competitive. 
The overall clinical phase is planned to start in 1H 2016 and to be completed within the Q4 2016. 
8.2 
DISCUSSION OF STUDY DESIGN, INCLUDING THE CHOICE OF CONTROL 
GROUP 
The 
DEX-TRA-06 
study 
has 
been 
designed 
to 
compare 
the 
efficacy 
between 
dexketoprofen/tramadol 25mg/75mg and TRAM.HCl/paracetamol on moderate to severe pain 
following impacted lower third molar extraction.  
Tramadol/paracetamol has been selected as the active control as it has proven to be an effective 
analgesic for the treatment of moderate to severe painful conditions, such as postoperative dental 
pain, and it appears to be generally well tolerated42. 
A placebo arm has been included due to the high and variable placebo response rate, and is intended 
to validate the model of pain. 
A single-dose trial design has been selected since it is regarded as sensitive and precise, constituting 
the cornerstone of the determination of analgesic efficacy 43, 44.  
The parameters selected for the efficacy evaluation (PI, PAR, PGE, time to onset of analgesia and 
use of RM) are typical of studies with analgesics 35, 45, 46, 47, 48, 49. 
Ibuprofen 400mg has been chosen as RM because, in accordance with published literature, it is a 
reference standard for the treatment of dental pain 50, 51. 
The baseline observation carried forward (BOCF) method52 will be applied after use of RM in order 
to minimize the impact of its use on efficacy assessments. 
8.3 
SELECTION OF STUDY POPULATION 
After providing informed consent, the eligibility of the patients to enter this study will be assessed 
based on the inclusion and exclusion criteria, which will be checked during the screening period 
with a re-checked to be done after the surgery during the qualification period.  
Patients will be included only if they meet all of the inclusion criteria (§ 8.3.1), do not meet any of 
the exclusion criteria (§ 8.3.2) and if they agree to accept the restrictions that come with 
participating in this study (§ 8.3.3). 
8.3.1 Inclusion criteria 
To be eligible for this study, EACH of the following criteria must be satisfied: 
1. Properly executed written informed consent. 
2. Male or female patients aged more than 18 years. 


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3. Scheduled for outpatient surgical extraction -under local anaesthesia (i.e. 2% lidocaine with 
1:80,000 epinephrine) - of lower third molar teeth, with at least one of which fully or partially 
impacted in the mandible requiring bone manipulation (e.g. level B or C plus class II or III of 
the Pell-Gregory scale). 
4. Females participating in the study must be either: 
− Females of non-childbearing potential, defined as any woman who had undergone surgical 
sterilization or is more than 2 years post-menopausal; 
− Females of childbearing potential provided that they have a negative pregnancy test at 
baseline (screening and qualification period) and are routinely using an effective method of 
birth control resulting in a low failure rate (i.e. hormonal contraception, intrauterine device, 
condoms in combination with a spermicidal cream, male partner sterilization –vasectomy– or 
total sexual abstinence). 
5. Mentally competent, able to understand and give written informed consent prior to study entry. 
6. Compliant to undergo all visits and procedures scheduled in the study, including recording of 
pain assessments on the electronic diary (e-Diary) as required by protocol. 
After surgery, patients will be eligible to progress with randomisation ONLY if the following 
criterion is also met: 
7. Pain of at least moderate intensity in the first 4 hours after the end of surgery (NRS score > 4). 
8.3.2 Exclusion criteria 
To be eligible for this study, NONE of the following criteria must be satisfied: 
1. Patients who are judged by the Investigator not to be suitable candidates for the study treatments 
and the RM based on their medical history, physical examination, concomitant medication (CM) 
and concurrent systemic diseases.  
2. Clinically significant abnormalities in the vital signs (VS) and / or safety laboratory tests, as per 
investigator’s judgement. 
3. History of allergy or hypersensitivity to the study treatments, RM or to any other NSAIDs, 
opioids and acetyl salicylic acid. 
4. History of peptic ulcer, gastrointestinal disorders by NSAIDs or gastrointestinal bleeding or 
other active bleedings. 
5. History of severe asthma.  
6. Moderate to severe renal dysfunction, severe hepatic dysfunction or severe cardiac dysfunction. 
7. Coagulation disorders. 
8. History of, or current epilepsy.  
9. Patients with Crohn’s disease or ulcerative colitis. 


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10. Patients using and not suitable for withdrawing analgesics, , within 12 hours before surgery (5 
days prior to the surgery day in case of COX-2 inhibitors) and for 8 hours post-dose [for 
analgesics other than those specified in the protocol (namely study treatments and RM)]. 
11. Patients using and not suitable for withdrawing alcohol, sedatives (e.g. benzodiazepines) and 
hypnotic agents within 12 hours before surgery and for 8 hours post-dose. 
12. Chronic opioid treatment (major opioids and tramadol). 
13. Patients using and not suitable for withdrawing the following prohibited medications, within 48 
hours or 5 half-lives (whichever the longer) prior to the start of surgery and for 24 hours post-
dose: 
− Anticoagulants, thrombolytic and antiplatelet agents  
− Corticosteroids (with the exception of inhalers or topical agents); 
− Monoamine oxidase (MAO) inhibitors (a minimum of 14 days must elapse prior to the start of 
surgery);  
− Antiepileptics; 
− Antipsychotics; 
− Serotonin reuptake inhibitors and tricyclic antidepressants; 
− Lithium; 
− Methotrexate; 
− Antibacterial sulfonamides. 
14. Participation in other clinical studies in the previous 4 weeks.  
15. History of drug or alcohol abuse. For the purpose of the study, alcohol abuse is defined as 
regularly intake of more than 4 units of alcohol per day (1 unit corresponds approximately to 
125 ml wine, 200 ml beer, 25 ml spirit). 
16. History of any illness or condition that, in the opinion of the Investigator might pose a risk to 
the patient or confound the efficacy and safety results of the study. 
17. Pregnant and breastfeeding women. NOTE: a pregnancy test will be performed to all women of 
childbearing potential at Screening and another one on the day of surgery prior to 
randomisation. 
After surgery, patients will not be eligible to progress with randomisation if the following criterion 
is also met: 
18. Surgical complication that, in the opinion of the Investigator, advises against their inclusion in 
the study. 


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8.3.3 Study restrictions  
Patients will be asked to adhere to the following study restrictions during their study participation, 
which are also listed and explained in the ICF: 
− Patients must attend the site in fasting conditions on the day of laboratory tests. 
− On the morning of Day 1, patients might have a light breakfast no less than 2 hours before 
surgery. After surgery, they will not be allowed food for at least 2 hours post-dose. 
− Intake of alcohol is restricted within 12 hours before surgery and for 8 hours post-dose. 
− Smoking and intake of caffeine are restricted within the 2 hours before surgery and for 8 hours 
post-dose. 
− Local application of ice is not permitted during the 8-hour post-dose period. 
For study restrictions on concomitant medication, refer to § 8.5.6. 
NOTE: During the study, antibiotic prophylaxis is permitted, at the Investigator’s discretion. The 
use of alcohol-free mouthwashes with chlorhexidine or similar agents is also allowed. 
8.3.4 Withdrawal of patients from therapy or assessment 
Participation in the study is strictly voluntary and patients have the right to withdraw from the study at 
any time without explanation. This will not affect their rights for future medical care. Patients may also 
be withdrawn at the Investigator's discretion or at specific Sponsor’s request at any time. In the event 
that the patient withdraws from the study for whatever reason, the Investigator must be informed 
immediately and the date, reasons, and circumstances for premature discontinuation will be 
documented in the corresponding section of the e-CRF. Patients have to discontinue the study if they 
experience: 
• 
An AE, including clinically significant abnormal laboratory value(s) which request study 
termination according to the Investigator’s judgement. 
• 
Protocol violation (e.g. prohibited medication, poor compliance with study procedures). 
• 
Patient’s request. 
Any patient who prematurely terminates participation after having received the dose of the IMP, will 
be encouraged to undergo the End of Study examinations according to the procedures described under 
section 8.6.4.1. 
NOTE: If study participation is terminated due to an AE the patient has to be followed-up, for details 
see section Adverse Events Follow-up (§ 8.7.5). 
If a patient prematurely terminates the study, data already collected will be used and analysed for the 
purpose of the study. In regard to biological samples already collected, the patient will be asked if 
samples already obtained but not yet analysed shall be destroyed or analysed.  


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8.4 
IDENTITY OF THE INVESTIGATIONAL PRODUCT(S)  
8.4.1 Description of Investigational Medicinal Product(s) 
Test drug: 
 
Dexketoprofen Trometamol/Tramadol Hydrochloride fixed combination of: 
Dexketoprofen Trometamol  
Chemical name: S-(+)-2-(3-benzoylphenyl) propionate of 1,1,1-tris (hydroxymethyl) 
methylammonium 
Generic name: Dexketoprofen trometamol 
Molecular formula: C20H25NO6  
Tramadol Hydrochloride  
Chemical name: (1RS,2RS)-2-[(Dimethylamino) methyl]-1-(3-methoxyphenyl) cyclohexanol 
hydrochloride 
Generic name: Tramadol hydrochloride 
Molecular formula: C16H25NO2 . HCl 
Dose for combination:  
 
DKP.TRIS/TRAM.HCl 25mg/75mg film-coated tablets (as one tablet) 
Reference drug: 
 
− TRAM.HCl /paracetamol 75 mg/650 mg, as 2 x [37.5 mg/325 mg] film-coated tablets  
− Placebo matching DKP.TRIS/TRAM.HCl 25mg/ 75mg  
− Placebo matching active comparator  
Dosage form of the treatments: oral film-coated tablets.  
Regimen: one single oral dose.   
Double 
dummy 
technique 
will 
be 
applied 
to 
ensure 
double 
blind 
condition 
of 
DKP.TRIS/TRAM.HCl 25mg/75mg vs. TRAM.HCl/paracetamol 75mg/650mg vs. placebo 
administration.  
8.4.2 Packaging, labelling, and storage 
The packaging and labelling of IMP will be performed by the Sponsor’s Pharmaceutical 
Development Department 
 
 which is also responsible for IMP distribution directly to the study sites or 
through local depots. 
Packaging: The IMP will be provided in treatment boxes (blister cards) to be dispensed at 
randomisation. The IMP will be packaged in Al-Al blister (primary packaging) which are 


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permanently fixed in blister cards (secondary packaging) containing 3 film-coated tablets each (as 
per double-dummy technique). 
Labelling: The IMP will be labelled in compliance with the current valid international and 
corresponding national requirements. The treatment box (blister card) labels will have a peel-off 
section which has to be attached to the corresponding section in the drug accountability log upon 
dispensing of the IMP. The peel-off part reports the treatment kit number to identify the treatment 
as assigned through IxRS. The fixed section of the label will report (blinded) the contents of the 
treatment box and the instructions how to administer and store the IMP. 
Storage: At the study site, the IMP has to be stored at controlled room temperature. The following 
storage recommendations are in place: “Do not store above 30 °C” and “Store in the original 
package in order to protect from light”. The IMP must be kept in a secure area, out of reach of 
children and inaccessible to unauthorized individuals. 
8.4.3 Rescue medication  
Ibuprofen as 400 mg tablets is allowed as RM during the 8-hours assessment post-dose period. 
Ibuprofen will be provided using the commercial 
 
 
 RM will be re-packaged in blister cards (1 blister card containing 10 tablets) and re-labelled 
according to national/international requirements (including at minimum a RM box number and the 
note “For clinical trial use only”) by the Sponsor’s Pharmaceutical Development Department. RM 
will be centrally distributed as described for the IMP (i.e. either by the Sponsor’s Pharmaceutical 
Development Department or by a local depot).  
The RM has to be stored in a secure area and below 25 °C, it should be kept out of reach of children 
and inaccessible to unauthorised individuals.  
After randomisation, patients will be provided with the box assigned by IxRS and asked to use it as 
follows:  
At any time during the 8-hour post-dose period, patients will be able to choose to receive RM if 
they have not achieved adequate pain relief after receiving the study medication; however, they will 
be encouraged to wait for at least 60 minutes after dosing to allow time for the study treatment 
effect to take place. Patients will be duly instructed by the Investigator that during the 8-hour post 
dose period a maximum of 2 tablets of RM will be allowed, each one separated by a minimum 
interval of 4 hours. Patients will be also instructed to bring back the remaining RM at the End of 
Study visit. 
NOTE: In accordance to the authorised SmPC, the total daily dose of ibuprofen must not exceed 
2400 mg. 


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8.4.4 Drug accountability  
Upon receipt of all IMP and RM, study site personnel or designed pharmacist will open the 
shipment package, verify the contents as stated on the enclosed shipping form, and confirm the 
receipt through the IxRS. 
The IxRS will be used to record the IMP/RM delivery to the study site, the inventory at the site, 
including dates, quantities, batch/serial numbers, expiry dates. The assignment of the IMP/RM to 
each patient through the unique code numbers assigned to the IMP/RM (treatment box number) and 
to the patients (patient number) will be also done through IxRS. 
The Investigator will be responsible for documenting the dispensing of the IMP/RM to the patient 
by entering the treatment box number in the source documents and in the e-CRF from 
randomisation (day 1). 
Patients will be instructed to return used or unused RM box at the End of Study visit.  
A RM patient diary will be used by the patient for documentation of RM consumption (as described 
under 10.1.3) which has to be checked by the Investigator at the End of Study visit in order to 
document the RM consumption by each patient. The use of RM, as reported in RM patient diary 
(source document), will be recorded by the Investigator in the e-CRF. 
In addition, study sites will maintain drug accountability forms to document the dispensed IMP/RM 
and returned RM. The peel-off labels of IMP/RM will be stuck on the drug accountability paper 
forms. 
8.4.5 Destruction of surplus medication 
At the end of the study, at the latest, all remaining IMP/RM will be reconciled under the 
responsibility of the Investigator at the site. No later than at the close out visit, the IMP/RM will be 
returned for destruction to the Sponsor’s Pharmaceutical Development Department, or local depots, 
provided this is not in conflict with any national export legislation. If in any country participating in 
the study, the return of IMP/RM should require an export licence, the IMP/RM could be locally 
destroyed there.  
8.5 
TREATMENTS  
8.5.1 Treatment administration - frequency and duration of application 
After confirmation of eligibility, patients will be randomly allocated to one of the following 3 arms: 
− DKP.TRIS/TRAM.HCl 25mg/75mg as 1 film-coated tablet 
− TRAM.HCl/paracetamol 75 mg/650 mg, as 2 x [37.5mg/325mg] film-coated tablets  
− Placebo matching DKP.TRIS/TRAM.HCl 25mg/75mg (1 film-coated tablet) and active 
comparator (2 film-coated tablets) 


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One single-dose treatment, consisting of three oral film-coated tablets to ensure the double-dummy 
technique, has to be orally administered together with approximately 150 ml of still/tap water. 
8.5.2 Randomisation and blinding 
The study will be performed according to a double-blind, double dummy, randomised, parallel-
group design. 
Patients will be randomised only after confirmation of their eligibility criteria on day 1 within 4 
hours after the surgery, to one out of the 3 treatment arms (see section 8.5.1), as per treatment code 
delivered through IxRS in accordance with the randomisation list. To keep blinded the conditions, 
placebo tablets matching the DKP.TRIS/TRAM.HCl or TRAM.HCl/paracetamol will be 
administered as per double-dummy design (fig. 4).  
 
 
Figure 4. Representation of double dummy design 
The Sponsor’s delegate will be responsible for generating the randomisation list that will assign the 
treatment to each patient.  
In order to preserve the double-blind conditions of the study, persons who are involved in the 
preparation or the handling of the randomisation list will not be involved in the study conduct and 
statistical analysis. This will remain in effect until the database is completed and locked.  
A packaging randomisation list will be prepared; one set will be used for programming the IxRS 
and one set will be provided to Pharmaceutical Development Department of A. Menarini Research 
& Business Service GmbH, 
. 
8.5.3 Treatment compliance 
Study drugs will be dispensed only under the restricted conditions defined in the present protocol at 
the study centre and will be administered by the clinical Investigator or under his/her direct 
supervision.  
P
P
P
P
P
P
1 tablet DKP.TRIS/TRAM.HCl25mg/75mg
2 tablets placebo matching TRAM.HCl/Paracetamol 37.5mg/325mg
1 tablet placebo matching DKP.TRIS/TRAM.HCl25mg/75mg
2 tablets TRAM.HCl/Paracetamol37.5mg/325mg
1 tablet placebo matching DKP.TRIS/TRAM.HCl25mg/75mg
2 tablets placebo matching TRAM.HCl/Paracetamol 37.5mg/325mg


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8.5.4 Concomitant Medication 
The use of prior and concomitant medication has to be carefully monitored, since the use of certain 
drugs represents an exclusion criterion for participation in the study (see § 8.3.2). For this reason, 
medications taken within 4 weeks of the screening day (prior medication) have to be recorded at 
screening, while the regular and occasional use of any CM (starting from the screening) has to be 
recorded at each visit. In order to facilitate recording of medication history, patients will be asked to 
bring their medication, preferably in their original packaging. 
8.5.5 Anaesthetics for Surgery 
Surgery will be conducted under local anaesthetic block using 2% lidocaine (with 1:80.000 
epinephrine) up to a total volume of 5.4 mL per molar. No sedation is permitted.  
Other agents that are not allowed during the surgery include (see also Proibited Medication section): 
- 
Opioids (including meperidine, fentanyl, sufentalin, alfentalin, remifentalin), 
- 
Benzodiazepines (e.g. diazepam), 
- 
All other sedative and hypnotic agents, 
- 
All other local anaesthetics. 
8.5.6 Prohibited Medication 
- 
Analgesics, , are prohibited within 12 hours before surgery (5 days prior to the surgery day in 
case of COX-2 inhibitors) and for 8 hours post-dose [analgesics other than those specified in the 
protocol (namely study treatments and RM)]. Patients have to agree to take only the defined RM 
(ibuprofen 400mg) until 8-hour post-dose period. 
- 
Sedatives (e.g. benzodiazepines) and hypnotic agents are prohibited within 12 hours before 
surgery and for 8 hours post-dose. 
- 
The following medications are prohibited within 48 hours or 5 half-lives (whichever is longer) 
prior to the start of surgery and for 24 hours post-dose: 
o Anticoagulants, thrombolytic and antiplatelet agents; 
o Corticosteroids; 
o MAO inhibitors - a minimum of 14 days had to elapse prior to the start of surgery; 
o Antiepileptics; 
o Antipsychotics; 
o Serotonin reuptake inhibitors and tricyclic antidepressants; 
o Lithium; 
o Metotrexate; 
o Antibacterial Sulphonamides. 


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8.6 
STUDY PROCEDURES AND ASSESSMENTS 
8.6.1 Study schedule 
The Study Flowchart reported under § 2.2 displays each of the study assessments and procedures 
together with the scheduled time of occurrence.  
Each patient will undergo the study procedures described below, which include at least 3 visits to 
the study site.  
In addition, patients will be asked to record data, during the 8-hour post-dosing period, using the e-
Diary provided.  
8.6.1.1 Informed consent process 
Eligible patients may only be included in the study after they had provided the written informed 
consent. The informed consent must be obtained before conducting any study-specific procedures 
(i.e. any of the procedures described in the protocol). The process of obtaining the informed consent 
shall be documented in the patient source documents. 
8.6.1.2 Screening period (within 2 weeks prior to randomisation) 
 Prior to surgery  
The following procedures/assessments must be completed during the screening period and prior to 
the surgery day (day 1):   
− Collection of demographic data. 
− Recording of medical history. 
− Recording of prior and concomitant medications (CMs). 
− Physical examination including body weight (BW), height (H), and vital signs (VS) (blood 
pressure [BP], heart rate [HR]). 
− Laboratory safety tests (haematology, clinical chemistry, coagulation test and urinalysis). 
− Pregnancy test (if applicable). 
− Instructions regarding how to complete patient’s pain and analgesia assessments, RM intake 
and 
functionality on e-Diary. 
− Recording of adverse events (AEs) occurred since the ICF signature, if any.  
− Check of inclusion and exclusion criteria. 
 Surgery  
The surgical procedure will be performed under local anaesthetic block using 2% lidocaine with 
1:80,000 epinephrine up to a total volume of 5.4 ml per molar. 
Surgery shall be performed at least one day apart pre-surgery procedures have been completed. 
 Qualification  
After completion of surgery (last suture), patients will be followed for a period of up to 4 hours and 


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the following will be performed/assessed: 
− Instruct patients to inform the investigator when they experience pain.  
− Dispensing of the e-Diary and testing its main functions.  
− VS measurement.  
− Pregnancy test (if applicable).  
− Recording of AEs and changes in CM, if any, since the last assessment. 
− Review/Check of inclusion/exclusion criteria.  
Patients reporting pain within 4 hours after the end of surgery will be asked to rate their pain 
intensity (PI) on the e-Diary to assess their eligibility for randomisation. Patients must describe their 
PI in response to the question: ‘How do you rate the intensity of your pain?’ using an 11-point 
Numerical Rating Scale (NRS) ranging from 0 (no pain) to 10 (worst pain). 
NOTES:  
1. Only patients experiencing pain of moderate or higher intensity (NRS score ≥4) within the first 
4 hours after the end of surgery will be eligible for randomisation.  
2. A patient can be screened a maximum of 2 times, provided that he/she was not already 
randomised and all the inclusion and none of the exclusion criteria are met.  
3. Pregnancy test should not be repeated during the qualification period if it was performed the day 
before as screening procedure. 
8.6.1.3 Randomisation, treatment administration and efficacy assessment period (day 1, t0 - t8h) 
 Randomisation and treatment administration (t0) 
Patients successfully completing the qualification period will be randomised through IxRS and the 
corresponding study treatment will be given, as one single oral dose. NRS-PI immediately prior to 
the administration of the study treatment will be recorded as baseline PI (t0h). 
A box of RM (ibuprofen 400mg tablets) will be assigned by IxRS and provided to the patients that 
will be instructed about its usage. A paper diary for RM recording intake will be also given to 
patients, with the request to return it to the site at the End of Study visit. 
 
8-hour pain and analgesic effect assessment period (t0 – t8h) 
After the study treatment administration, patients will remain under observation at site for two 
hours (up to t2h). 
Pain and analgesia assessment by patients will be performed either at site (from t15min to t2h) and out 
of the site (from t4h to t8h) by e-Diary recording. 
The following items will be recorded by the patients on the e-Diary: 
− Pain relief (VRS-PAR): at t15min, t30min, t1h, t1.5h, t2h, t4h, t6h and t8h. Patients will be asked to 
answer the question ‘How do you rate your pain relief?’ using a 5-point verbal rating scale 


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(VRS), where 0 = ‘no relief’, 1 = ‘a little (perceptible) relief’, 2 = ‘some (meaningful) relief’, 3 = 
‘lot of relief’, 4 = ‘complete relief’. 
− Pain Intensity (NRS-PI): at t15min, t30min, t1h, t1.5h, t2h, t4h, t6h and t8h, using the 11-point NRS. 
− First intake of RM, if any.  
− Onset of analgesia: The two
 method will be used to assess the onset of analgesia 
within the first two hours (from t0 to t2h): the first stop upon the experience of “first perceptible” 
PAR (FPPAR) and the second stop when PAR is considered “meaningful” (MPAR). 
− Patient Global Evaluation (PGE): at the end of the assessment period (t8h), or immediately 
before RM intake, if any. Patients will be asked to answer the question: ‘How would you rate the 
medication received for your pain?’ using a 5-point VRS, where: 1 = ‘poor’, 2 = ‘fair’, 3 = 
‘good’, 4 = ‘very good’, 5 = ‘excellent’. 
Occurrence of any AE as spontaneous reporting and changes in CM, if any, will be collected by 
study staff while the patients are at the site.  
NOTE: Patient will be allowed to complete the scheduled assessments on e-Diary within a ±3 
minutes time window for t15min, t30min, t1h, t1.5h, and t2h time points, and a ±10 minutes time window 
for t4h, t6h and t8h time points. 
 
Rescue medication 
At any time during the 8-hour post-dose period, patients will be allowed to take RM if they have not 
achieved adequate pain relief after receiving the study medication; however, they will be 
encouraged to wait for at least 60 minutes after dosing to allow time for the study treatment effect to 
take place. Patients will be duly instructed by the investigator that during the 8-hour post dose 
period a maximum of 2 tablets of RM will be allowed, each one separated by a minimum interval of 
4 hours. Patients will be also instructed to bring back the remaining RM at the End of Study visit. 
NOTE:  
After first intake of RM, patients will stop using the e-Diary including the 
 functionality. 
Only the first intake of RM will be recorded on the e-Diary,  
Time of each intake of RM, if any, will be recorded by the patients in a paper booklet (RM diary). 
The Investigator or designee will be responsible for entering diary data into the e-CRF. 
8.6.1.4 End of Study visit (6 ± 1 days after randomisation)  
− Return of e-Diary, RM diary and unused RM by patients. 
− RM accountability. 
− Physical examination. 
− VS measurement. 


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− Pregnancy test (if applicable). 
− Recording of AEs and changes in CM, if any, since the last visit. 
 
NOTE: 
For the study purposes, patients will be required to attend the study centre to accomplish the 
procedures from Screening to End of Study. Unscheduled surgical follow-up visits may be requested 
by the surgeon at an earlier timepoint; however they will not be considered as part of this study.


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8.6.2 Surgical Assessment 
8.6.2.1 Surgical Trauma Rating Scale 
The following surgical trauma rating scale53 will be used to rate the degree of difficulty of the 
surgical procedure for each molar tooth removed by the oral surgeon: 
 
Rating 
Characteristics 
1 
Tooth in vertical position, not covered by bone, simple root anatomy without 
root deviation 
Operating time less than 5 minutes 
2 
Mesioangulated tooth in high position, partly impacted in bone, simple root 
anatomy without root deviation 
Operating time 5-10 minutes 
3 
Tooth in mesioangulated or deep horizontal position, fully impacted in bone 
with or without root deviation 
Operating time up to 20 minutes 
4 
Tooth in distoangulated or deep horizontal position, root deviations, close 
relation to inferior alveolar nerve 
Operating time usually more than 20 minutes 
The corresponding numerical rating for each molar extracted and the total rating will be recorded on 
the patient’s source record and on the e-CRF. 
8.6.2.2 Other Surgery Parameters 
The following information will be recorded by the Investigator or designee: 
- 
Time of local anaesthetic (i.e. beginning of surgery) 
- 
Time of completion of last suture (i.e. end of surgery) 
- 
Duration of surgery (i.e. time elapsed between the time of local anaesthetic and time of 
completion of last suture).  
- 
Complications, if any - NOTE: Complications may represent exclusion criteria (see section 
8.3.2) 
- 
Number of teeth extracted 
8.6.3 Assessments of Efficacy 
The analgesic efficacy evaluation will be based on patients’ e-Diary scores of PI and PAR at pre-
defined intervals during the 8-hour post-dose period; the PGE at the end of the assessment period; 


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the time to onset of the analgesic effect (limited to the 2-hour post-dose period) and the first use of 
RM. 
8.6.3.1 Pain Intensity Numerical Rating Scale  
An 11-point numerical rating scale (ranging from 0 [no pain] to 10 [worst pain], as represented in 
figure 5) will be used for the subjective assessment of PI54, 55, 56, 57. Patients will be asked to select 
the number that best represents their PI at the time of the assessment. 
 
Figure 5. The NRS 
NRS-PI will be measured: 
- 
During the qualification period, in order to confirm eligibility, namely moderate or higher 
PI (NRS ≥4); 
- 
immediately prior to the treatment administration (t0h), 
- 
at pre-specified time points during the 8-hour post-dose period, (i.e:  at t15min, t30min, t1h, t1.5h, 
t2h, t4h, t6h and t8h). 
8.6.3.2 Pain relief Verbal Rating Scale  
A 5-point VRS will be used for the 8-hour post-dose PAR subjective assessment 35, 58. 
Patients will be asked to answer the question ‘How do you rate your pain relief?’ and to select the 
adjective that best describes the level of pain relief on the e-Diary. The number associated with the 
adjective chosen by the patient will constitute the experienced pain relief as reported below:  
Score 
Pain Relief 
0 
No relief 
1 
A little (perceptible) relief 
2 
Some (meaningful) relief 
3 
Lot of relief 
4 
Complete relief 
VRS-PAR will be measured at pre-specified time points during the 8-hour post-dose period, i.e. at  
t15min, t30min, t1h, t1.5h, and t2h, t4h, t6h and t8h. 


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8.6.3.3 Use of rescue medication 
Time of first intake of rescue medication will be recorded on the e-Diary. After this, patients will 
stop using the e-Diary. 
8.6.3.4 Time to onset of analgesia 
The
 
  will be used to assess the onset of analgesia, within the first 2 
hours post dose (i.e.: while the patient is still at site).  
Patients will be instructed to stop the first 
 by pressing the 'first perceptible pain relief' 
button when the relief from pain is first perceptible (i.e. at the moment they first feel any pain relief 
whatsoever) (FPPAR) and then to stop the second 
 by pressing the 'meaningful pain relief' 
button when the relief from pain becomes meaningful to them (MPAR).  
In case of RM use during the first 2 hours, the patient will be no longer required to use the 
 and they will be considered as censored. 
FPPAR and MPAR are assessed by
 or the time when the patients report for the first 
time a pain relief score >1 and >2 respectively, whichever happens first.  
Time to confirmed FPPAR (time to onset of analgesia) is defined as the time to FPPAR for those 
patients who achieve meaningful pain relief (MPAR).  
8.6.3.5 Patient’s Global Evaluation 
Patients will be asked to give a subjective overall assessment (PGE) of the study medication by 
using a 5-point VRS35, 59. 
Patients will be asked to answer the question: ‘How would you rate the medication received for 
your pain?’ and to select the adjective that best rate the study medication that they received for pain 
relief on the e-Diary. The number associated with the adjective chosen by the patient will constitute 
the global evaluation score, as reported below: 
 
Score 
PGE 
1 
Poor 
2 
Fair 
3 
Good 
4 
Very Good 
5 
Excellent 
 
The PGE will be recorded at the end of the assessment period (at 8 hours post-dose or whenever the 
patient uses RM). 
 


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8.6.4 Assessment of Safety 
Assessment of safety will be based on the evaluation of the following variables: 
• Incidence, intensity (severity), seriousness and treatment-causality of TEAEs, i.e. AEs that 
occurred after study drug intake. 
• Frequency of clinically significant changes in: 
− 
Physical examination  
− 
VS 
NOTE: for physical examination, the screening period values will be used as baseline; for VS, the 
values collected during the qualification period will be used as baseline. 
8.6.4.1 Medical History 
A complete medical history will be registered during the Screening period in the subject’s source 
record and reported on the e-CRF, including: 
o A thorough review of systems, including any past or current acute conditions (e.g. urinary 
tract infection), intermittent conditions (e.g. migraine), and chronic conditions (e.g. 
hypertension). 
o Prior surgical procedures. 
o Pharmacotherapy and chronic or recent (within 4 weeks of screening) use of any medication 
(prior medications). 
o Allergies or idiosyncrasies to drugs. 
o Substance abuse (including alcohol abuse). 
Past conditions that no longer affect the subject should not be recorded.  
8.6.4.2 Physical Examinations and Vital signs  
Physical examination (review of body systems) will be performed during the Screening period and 
at the End of study visit. Measurement of height (in whole centimetres) and weight (in kilograms to 
one decimal place) will be performed during the Screening period only. 
Vital signs (i.e. BP [systolic and diastolic, mmHg] and HR [beats/min]) will be measured 1) during 
the screening period, 2) during the qualification period and, 3) at the End of Study visit.  
Out of range measures will be repeated at the Investigator’s discretion. 
The collected data will be registered in the subject’s source record and reported on the e-CRF. 
8.6.4.3 Clinical Laboratory Evaluation 
Blood laboratory safety tests will be performed locally, with blood samples (8ml approximately) 
collected in fasting conditions during the Screening period. The following parameters will be 
analysed: 


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o Haematology: Red blood cell (RBC) count, haematocrit (HCT), haemoglobin (Hb), mean 
corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular 
haemoglobin concentration (MCHC), platelet count, white blood cells (WBC) count, and 
differential WBC count (neutrophil, lymphocyte, monocyte, eosinophil and basophil counts, 
absolute and %). 
o Serum biochemistry: Sodium, potassium, chloride, total calcium, glucose, creatinine, urea, total 
protein, albumin, alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), aspartate 
aminotransferase (ASAT), alanine aminotransferase (ALAT), total bilirubin, direct bilirubin, 
lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). 
o Coagulation test: prothrombin time, partial thromboplastin time (PTT), INR. 
Urinalysis will be performed during the Screening period, using Roche Combur-10® dipsticks. The 
following parameters will be analysed: Specific gravity, pH, leucocytes, nitrite, protein, glucose, 
ketones, urobilinogen, bilirubin, blood (erythrocytes/haemoglobin). 
Pregnancy tests (when appropriate) will be performed during the Screening period, during the 
qualification period and at the End of Study visit, by determination of the urine β human chorionic 
gonadotropine (ß-HCG), using locally available commercial dipsticks. 
Unscheduled re-tests can be performed as required according to the investigator’s judgement. 
The reference ranges of laboratory parameters described in this study will be submitted by each 
centre to the sponsor prior to beginning of this study and will be updated as appropriate.  
The lab print-outs should be identified with the laboratory requisition number, patient number, 
patient’s age, gender, and site number, as well as with the date and time of sample collection. All 
results should be reviewed by the Investigator with print-outs being dated and signed by the 
investigator and stored in the patient’s record. Out of range values will be judged by the 
Investigator as “abnormal clinically significant” or as “abnormal not clinically significant” and 
stored in the patient’s record. Note: abnormal evaluation can be repeated at the Investigator’s 
discretion. Records will be transferred on the e-CRF. 
8.6.4.4 Adverse Events/Serious Adverse Events – Definitions 
8.6.4.4.1 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical trial subject administered a 
medicinal product and which does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavourable and unintended sign (including an abnormal laboratory 
finding, for example), symptom or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not considered related to the medicinal (investigational) 
product. 


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NOTE: abnormal laboratory findings considered by the Investigator as not clinically significant are 
not considered AEs.  
Treatment-Emergent Adverse Events 
 AEs will be categorized as Treatment-Emergent Adverse Events (TEAE) or Non-TEAE. If an AE 
occurs for the first time or if it worsens in terms of seriousness or severity after the first study drug 
intake it will be classified as TEAE, otherwise it will be classified as non-TEAE. 
8.6.4.4.2 Adverse Drug Reaction (ADR) 
All untoward and unintended responses to an IMP related to any dose administered. The definition 
covers also medication errors and uses outside what is foreseen in the protocol, including misuse 
and abuse of the product. The definition implies a “reasonable possibility of a causal relationship” 
between the event and the IMP. This means that there are facts (evidence) or arguments to suggest a 
causal relationship. For causality assessment of AEs, see section 8.6.4.4.6. 
8.6.4.4.3 Intensity (Severity) of an Adverse Event/Adverse Drug Reaction 
It will be assessed based on the following definitions: 
• 
Mild: It does not interfere with routine activities; 
• 
Moderate: It interferes with routine activities; 
• 
Severe: It makes it impossible to perform routine activities. 
NOTE: The term ‘severe’ is used here to describe the intensity of a specific event. This has to be 
distinguished from the term ‘serious’ (see section 8.6.4.4.4). 
8.6.4.4.4 Serious Adverse Event (SAE)/Serious Adverse Drug Reaction (SADR) 
A Serious Adverse Event is any untoward medical occurrence or effect that at any dose: 
• results in death;  
• is life-threatening; 
• requires hospitalization or prolongation of existing hospitalization;  
• results in persistent or significant disability or incapacity;  
• is a congenital anomaly or birth defect; 
• is an ‘important medical event’ that may jeopardise the patient or may require an 
intervention to prevent one of the above characteristics/consequences. 
These characteristics/consequences have to be considered at the time of the event. For example, 
regarding a life-threatening event, this refers to an event in which the patient was at risk of death at 
the time of the event; it does not refer to an event which hypothetically might have caused death if it 
were more severe.  


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NOTE: The term ‘hospitalization’ refers here to inpatient admission lasting more than 24 hours. 
Any other AE/ADR which is not included in the above definitions will be considered as non 
serious. 
The Investigator has to immediately report all SAEs to the Sponsor, according to the procedures and 
timelines described in section 8.7.1. The seriousness must be confirmed by the Investigator or a 
delegated physician. 
8.6.4.4.5 Unexpected Adverse Drug Reactions  
An ADR, the nature or intensity of which is not consistent with the applicable product’s safety 
reference information. Any other ADR which is not included in the above definition will be 
considered as expected. 
In this study, the ‘safety reference information’ will be the safety section included in the last version 
of the IMP’s Investigator’s brochure (IB). 
8.6.4.4.6 Algorithm for Causality Assessment of Adverse Events  
The causality (causal relationship to the study drug) of AEs will be assessed based on the following 
algorithm: 
1. Certainly related: An AE is considered certainly related to a drug when it occurs with a plausible 
time sequence to the administration of the drug, and which 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 definitive pharmacologically or phenomenologically, using a 
satisfactory rechallenge procedure if necessary. 
2. Probably related: An AE is considered probably related to a drug when it occurs with a 
reasonable time sequence to the administration of the drug, is unlikely to be attributed to concurrent 
disease or other drugs or chemicals, and which follows a clinically reasonable response on 
withdrawal (dechallenge). Rechallenge information (AE reappearance after drug reintroduction) is 
not required to fulfil this definition. 
3. Possibly related: An AE is considered possibly related to a drug when it occurs with a reasonable 
time sequence to the administration of the drug, but could also be explained by concurrent disease 
or other drugs or chemicals. Information on drug withdrawal (dechallenge) may be lacking or 
unclear. 
4. Unlikely related: An AE is considered unlikely related to a drug when the temporal relationship 
to the drug administration makes a causal relationship improbable (but not impossible) and/or other 
drugs, chemicals or underlying disease provide plausible explanations. 
5. Not related: An AE is considered not related to the use of a drug in case of existence of a clear 
alternative explanation and/or unreasonable temporal relationship, and/or non plausibility. 


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6. Unassessable/unclassifiable: The relationship between drug and AE is considered 
unassessable/unclassifiable when a report, suggesting an adverse reaction, cannot be judged because 
information is insufficient or contradictory and cannot be supplemented or verified. NOTE: It is the 
responsibility of the study team to obtain all available information before an AE is definitively 
classified as ‘unassessable / unclassifiable’. 
An AE in which the relationship is ranked 1, 2, 3 or 6 will be considered as an ADR. AEs ranked 4 
or 5 will not be considered as ADRs. 
8.6.4.5 Monitoring and Recording of Adverse Events 
At every study visit patients will be asked a standard question to elicit medically related changes in 
their well-being. They will be asked if they have been hospitalized, have had any accident, have 
used any new medication, or have changed concomitant medication regimens (both prescription and 
over the counter medication). 
In addition to the patient observations, AEs may be collected from other sources, e.g. physical 
examination findings, or other documents that are relevant to patient safety, and recorded in the AE 
page of the e-CRF.  
The Investigator is responsible for the detection and documentation of events meeting the definition 
of AE, as provided in this protocol (see section 8.6.4.4).  
All AEs, whether or not thought to be drug related, must be recorded by the Investigator (or 
designee) in the source documents and in the appropriate section of the e-CRF throughout the whole 
study duration, from the Informed Consent signature until the End of Study visit. 
In addition any relevant AE Information could be recorded by the investigator in e-CRF only until 
the last visit of last patient. 
8.6.5 Efficacy and Safety Endpoints 
8.6.5.1 Primary Endpoint 
Total pain relief (TOTPAR), calculated as the weighted sum of the PAR scores (measured 
according to a 5-point VRS from 0=no relief to 4=complete relief), over 6 hours post-dose 
(TOTPAR6). 
8.6.5.2 Secondary Endpoints 
− 
 
 
  
 
  
− Percentage of patients achieving at least 50% of maximum TOTPAR over 
 8 hours post-
dose.  
− 
 
  


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− Percentage of patients who achieved at least 30% of PI reduction versus baseline at each pre-
specified time point over 8 hours post-dose period. 
− 
 
  
 
  
 
 
− Time to confirmed FPPAR (time to onset of analgesia) - i.e. time to FPPAR if confirmed by 
experiencing MPAR.  
− 
 
 
  
 
  
−  PGE of the study medication (measured according to a five-point VRS from 1 = poor to 5 = 
excellent), at 8 hours post-dose or whenever the patient uses RM.  
−
  
− Percentage of patients who required RM within 
 8 hours post-dose.  
8.6.5.3 Safety Endpoints 
− 
Incidence, intensity (severity), seriousness and treatment-causality of treatment-emergent AEs 
(i.e. TEAEs, reported starting from the study medication intake). 
− 
Frequency of clinically significant changes in physical examination and VS, post-dose versus 
baseline. (NOTE: for physical examination, screening period values will be used as baseline; 
for VS the values collected during the qualification period will be used as baseline). 
 
 
 


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8.7 
MANAGEMENT AND REPORTING OF ADVERSE EVENTS 
8.7.1 Reporting of Serious Adverse Events to the Sponsor 
All SAEs, whether or not deemed drug-related or expected, must be recorded in the corresponding 
section of the e-CRF within 24 hours (one calendar day) of awareness. Once the information is 
saved, a notification e-mail will be automatically generated and sent to the Sponsor’s Drug Safety 
Manager (DSM).  
SAE Report Forms in paper support will be provided as a backup, to be used only in case of 
breakdown of the e-CRF System. Whenever paper SAE Report Forms are used, they must be 
submitted by fax or e-mail to the Sponsor’s DSM, within the same required timeframe. 
Sponsor’s DSM contact details: 
  
 
 
 
  
  
 
 
  
 
 
   
 
 
  
 
The Sponsor’s confirmation of reception of the SAE Report Form must be kept in the patient’s 
records. 
The initial SAE entry should include at least the following data: 
- A short description of the AE. 
- Reason why the event is categorised as serious (seriousness assessment), according to 
criteria described in section 8.6.4.4.4. 
- Causality assessment (according to the algorithm described in section 8.6.4.4.6). 
- Study code and patient number (if paper SAE Report Form is used). 
- Reporter’s name and telephone number for clarifications (if paper SAE Report Form is 
used). 
If not already reported, the full description of the event and outcome must follow within 1 working 
day. 


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Any questions arising during the processing and medical review of the SAE will be managed by 
means of electronic queries (i.e. queries in the e-CRF). In case of breakdown of the e-CRF System, 
queries will be sent by fax or e-mail. 
In case of breakdown of the e-CRF System and the paper SAE Report Form has been sent, the 
Investigator will be responsible for entering the data in the e-CRF as soon as the system works 
again. 
Any additional information provided by the Investigator as a query reply or as a SAE follow-up will 
be processed in the same way as the initial SAE report within the same required timeframe.  
SAEs occurred after the End of Study visit should be also recorded in e-CRF, if feasible. Otherwise, 
the paper SAE report form should be completed and sent to the Sponsor’s DSM (see section 8.7.5).  
8.7.2 Management of Suspected Unexpected Serious Adverse Reactions 
For each SAE, assessment of seriousness (according to section 8.6.4.4.4) and causality (according 
to section 8.6.4.4.6) will be provided by both the reporting Investigator and the Sponsor. The 
assessment of expectedness (according to section 8.6.4.4.5) will be done by the Sponsor. 
NOTE: The causality assessment given by the Investigator will not be downgraded by the Sponsor. 
If the Sponsor disagrees with the Investigator’s causality assessment, the opinions of both, the 
Investigator and of the Sponsor, will be provided. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) are AEs which, cumulatively: 
− have a reasonable possibility of causal relationship to the IMP. 
− are serious.  
− are unexpected. 
The Sponsor will ensure that all SUSARs occurred during the study are reported on an expedited 
basis (7 days or 15 days) to the concerned national CAs and ECs, according to European and/or 
country-specific legal requirements: 
- For fatal or life-threatening SUSARs the Sponsor will report at least the minimum information, 
as soon as possible, and in any case no later than 7 days after being made aware of the case. If 
the initial report is incomplete, the Sponsor will submit a completed report based on the initial 
information within an additional 8 days.  
- SUSARs which are not fatal and not life-threatening will be reported within 15 days. 
- The clock for expedited initial reporting (day zero) starts as soon as the information containing 
the minimum reporting criteria has been received by the Sponsor (or the Sponsor’s delegate). 


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- If significant new information on an already reported case is received by the Sponsor, the clock 
starts again at day zero (i.e. the date of receipt of new information). This information will be 
reported as a follow-up report within 15 days. 
The Sponsor will also inform all Investigators. Whenever practicable, the information will be 
aggregated in a ‘line listing’ of SUSARs in 6 monthly periods.  
Events associated with placebo will usually not satisfy the criteria for a SUSAR and therefore for 
expedited reporting. However, where SUSARs are associated with placebo (e.g. reaction due to an 
excipient or impurity), the Sponsor will report such cases. 
SUSARs identified after the end of the trial will be reported to the CAs by the Sponsor. 
8.7.3 Annual Safety Reporting 
Once a year throughout the clinical trial, the Sponsor will provide the concerned national CAs and 
ECs with a safety report (Development Safety Update Report, DSUR), taking into account all new 
safety information received during the reporting period.  
8.7.4 Breaking of the Randomisation Code 
Breaking of the treatment code for a specific patient can be requested by the Sponsor’s DSM or by 
the Investigator, by contacting the IxRS.  
The Investigator should unblind the treatment allocation in the course of the clinical trial only if this 
is relevant to the safety of the patient (e.g. in order to offer adequate care for the patient’s 
immediate condition).  
If possible, prior to breaking of the code, the Sponsor’s DSM and/or the site monitor should be 
contacted. The Investigator has to document the reason for breaking the code in the IxRS. 
As regards the Sponsor, when an event may be a SUSAR, the blind will be broken by the Sponsor’s 
DSM only for that specific patient. The blind will be maintained for persons responsible for the 
ongoing conduct of the study (such as the management, monitors, Investigators) and those 
responsible for data analysis and interpretation of study results, such as biometrics personnel. 
8.7.5 Serious and Non-serious Adverse Events Follow-up 
Non-serious AEs will be recorded until the End of Study visit. 
If a patient is withdrawn from the study due to an AE or if a patient has an ongoing SAE at the End 
of Study visit, the patient has to be followed-up until the event is resolved or until the patient’s 
condition stabilises.  


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After the last study visit, the Investigator is not requested to actively follow-up the patient (unless 
ongoing SAEs are present at the End of Study visit). However, if after the end of the trial, the 
Investigator becomes aware of any SAEs, they should be duly reported to the Sponsor. 
If indicated, safety blood tests, urinalysis, and/or any other clinical investigation can be performed 
to follow-up AEs. 
8.8 
MANAGEMENT OF POSITIVE PREGNANCY TEST 
The Investigator has to inform the Sponsor, within 1 week of awareness, about any unexpected case 
of pregnancy occurring during the study, monitor the pregnancy until delivery and report whatever 
outcome to the Sponsor  
A specific form (“Pregnancy Exposure Report Form”) will be distributed to the sites to be used for 
this purpose.  
The Investigator must immediately (within 24 hours of awareness) report to the Sponsor’s DSM 
any case of pregnancy resulting in an abnormal outcome (miscarriage or newborn with congenital 
abnormality and/or stillbirth) according to the procedures described for SAEs in section 8.7.1.  
9. STATISTICAL METHODS AND DETERMINATION OF SAMPLE SIZE 
9.1 
DETERMINATION OF SAMPLE SIZE 
A sample size of 230 patients per active arm is considered adequate to demonstrate the non 
inferiority of DKP.TRIS/TRAM.HCl oral fixed combination compared to TRAM.HCl/paracetamol 
assuming a non-inferiority margin of 20%, a power of 80%  and an overall significance level of 2.5 
% (1-side). The mean TOTPAR6 for TRAM.HCl/paracetamol is assumed equal to 
 
115 patients in placebo arm are sufficient to demostrate the superiority of both 
TRAM.HCl/paracetamol and DKP.TRIS/TRAM.HCl vs placebo for model sensitivity. 
Assuming about 10% of major protocol violators, and 20% of screening failure rate a total of  640 
patients need to be randomised and approximately 800 patients are expected to be screened.  
9.2 
ANALYSIS POPULATIONS 
The following analysis populations will be considered:  
− Intention-to-treat (ITT) population: All patients randomised.  
− Safety population: All patients who have received at least one dose of the study treatment.  
− Per protocol (PP) population: All patients of the ITT population who did not experience relevant 
protocol violations related to efficacy endpoints of primary interest  


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9.3 
STATISTICAL ANALYSIS 
9.3.1 Descriptive statistics 
All study variables will be presented by treatment and overall using the appropriate descriptive 
statistics according to the variable nature, unless otherwise specified: 
- Continuous variables: number of non-missing observations, arithmetic mean, standard deviation 
(SD), minimum, median, maximum; 
- Categorical variables: number of non-missing observations and column percentages (N, %). 
The behavior over time of study variables will be summarized by treatment as follows: 
- Continuous variables: descriptive statistics for each time point and for the absolute differences to 
baseline; 
- Discrete variables: descriptive statistics for each time point and shift tables to baseline (where 
applicable and/or requested). 
9.3.2 Primary (efficacy) analysis  
The primary efficacy variable will be analyzed on the PP and ITT populations to assess the non-
inferiority hypothesis using analysis of covariance (ANCOVA) for testing the differences in 
treatment efficacy, as quantified by TOTPAR6, between DKP.TRIS/TRAM.HCl and 
TRAM.HCl/paracetamol. 
The ANCOVA model will include terms of treatment and the baseline PI level with one-sided 
significance level of 2.5%.  The following hypothesis will be tested: 
 
δ
µ
µ
≥
−
HCl
TRAM
TRIS
DKP
l
paracetamo
HCl
TRAM
H
.
/
.
/
.
0 :
 
against 
 
δ
µ
µ
<
−
HCl
TRAM
TRIS
DKP
l
paracetamo
HCl
TRAM
H
.
/
.
/
.
1:
 
 
with δ of 20% as non-inferiority limit. 
In case the non-inferiority is confirmed, the superiority of DKP.TRIS/TRAM.HCl versus 
TRAM.HCl/paracetamol will be tested on the ITT population. 
Comparison of DKP.TRIS/TRAM.HCl and TRAM.HCl/paracetamol versus placebo will be 
performed in order to confirm the model sensitivity on the ITT population. 


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9.3.2.1 Sensitivity analysis  
In case non-inferiority is confirmed the primary efficacy endpoint will be also evaluated on the ITT 
population using other methods of imputation respect to the one described under section 9.3.8 and 
they will be described in detail in the Statistical Analysis Plan (SAP). 
9.3.3 Secondary (efficacy) analysis 
SPID6 will be analyzed for non-inferiority with the possibility to switch for superiority analogously 
to the primary efficacy variable. 
All the other secondary efficacy variables will be descriptively analysed. The superiority for 
DKP.TRIS/TRAM.HCl will be tested on the secondary endpoints when applicable, through an ad 
hoc inferential analysis, as reported below: 
− NRS -PI, SPID, (excluded SPID6), %max SPID, TOTPAR (excluded TOTPAR6), %max 
TOTPAR (continue variables) will be analyzed analogously to the primary efficacy variable. 
− PGE and VRS-PAR (categorical variables) will be analyzed by Wilcoxon rank-sum test. 
− Percentage of patients who required rescue medication, and percentage of patients achieving at 
least 30% of PI reduction, achieving at least 50% max TOTPAR, confirmed FPPAR, MPAR will 
be tested using a Chi²-Test. 
− Time to use RM, time to FPPAR, confirmed FPPAR and MPAR will be assessed using a Log-
rank test. 
9.3.4 Exploratory (efficacy) analysis 
Exploratory analysis, if any, will be fully described in the SAP.  
9.3.5 Subgroup analysis 
Subgroup analysis, if any, will be fully described in the SAP.  
9.3.6 Safety analysis 
The safety analysis will be run on the safety population. Safety analysis will consider AEs, 
laboratory values, physical examination, VS data. All safety endpoints will be analysed using 
descriptive statistics. 
9.3.6.1  AEs 
Adverse Events occurring after treatment administration (TEAEs), will be summarised by primary 
System Organ Class (SOC) and Preferred Term (PT). For each PT/SOC, the number of TEAEs, the 
number of patients with TEAEs, and the percentage of patients with TEAE will be given.  
TEAEs will be listed by treatment arm, overall and stratified by intensity (mild, moderate, and 
severe), relationship to the treatment intake (certainly related / probably related / possibly related / 
unlikely related / not related / unessessable-unclassifiable) and for those leading to study 
discontinuation. 


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Serious TEAEs will be analysed analogously as TEAEs.  
AEs/SAEs which are not considered TEAE will be included in a separate listing. 
All  serious TEAEs which have an onset date after the patient's study completion will be included in 
a separated listing. 
Any TEAEs serious or not serious with a relationship to the treatment intake other than “not 
related” or “unlikely related” will be considered as treatment-related AEs/SAEs (i.e. 
ADRs/SADRs).  
9.3.6.2 Other Safety Variables 
Descriptive statistics on vital signs, haematology, serum biochemistry, and urine tests will be 
presented on the safety population. 
Change in vital signs and laboratory values will be also evaluated descriptively.  
9.3.7 Interim analysis and stopping rules 
No interim analysis is planned for this study.  
9.3.8 Data imputations 
The method of last observation carried forward (LOCF) will be applied among patients who missed 
more than one consecutive, otherwise the missing value will be replaced by the mean of the two non 
missing data collected respectively before and after the missing one. This procedure will be applied to 
all efficacy outcomes. If PI is missed at t0h the value recorded during qualification procedure will be 
used as baseline. 
After rescue medication intake, PI will return to its baseline (t0h) level and PAR to zero (“no relief”) for 
all subsequent time points (i.e. baseline observation carried forward, BOCF). Different approaches 
might be applied for sensitivity analysis, as described in section 9.3.2.1 
9.4 
PROTOCOL VIOLATIONS AND BLIND REVIEW 
Categories of protocol violations will be assigned to each potential protocol violation defined before 
the treatment unblinding and will be integrated in the SAP. 
A blind data review meeting (BDRM) will take place at the end of the study in order to evaluate and 
accept the data management report, discuss remaining issues (outstanding queries, unresolved 
errors) and to confirm and approve relevant protocol violations. Patients who experience relevant 
protocol violations will be excluded from the PP population (eg: patient did not confirm adequate 
baseline PI (i.e. ≥4), missing PI and/or PAR assessment in the first 6 hours, study treatment not 
taken). 
After final BDRM take place and the database is considered cleaned, the database will be locked 
and unblinded. 


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9.5 
STATISTICAL ANALYSIS PLAN 
The SAP will be finalised before the unblinding of the study. 
The SAP will describe in detail study endpoints and the statistical analyses to be performed, 
including also additional endpoints and analyses not planned in the protocol.  
In case major deviations from the original primary endpoint or from the original primary analyses 
will occur during the study, these changes will be the subject of a substantial protocol amendment.  
No major deviations from the original analysis plan will take place after data unblinding.  
Minor deviations (e.g. not involving changes in the primary endpoint and analysis) which might 
occur during the study will be detailed only in the SAPs.  
10. DATA QUALITY MANAGEMENT 
10.1 DATA COLLECTION 
Data collection activities will be carried out under the responsibility of Sponsor.  
Patient data will be collected using various data capture systems described below.  
A list of the data capture system versions used and the validation documentation of each version 
will be maintained. The list and the validation documentation will be provided to the site at the site 
initiation visit (SIV), filed in the Investigator’s file, and will be updated whenever any data capture 
system version changes.  
Patients will be identified by the patient number (patient ID), assigned at the Screening visit. 
The patient ID will be a number composed of 8-digits 
  
 
 
 
  
The data will be collected, processed, evaluated, and stored in anonymous form in accordance with 
applicable data protection regulations. 
10.1.1 Case Report Forms 
Clinical data collected during the study at sites will be recorded in an electronic CRF (e-CRF) using 
 which is a validated system. The e-CRF will be developed based on this study 
protocol under the responsibility of Sponsor that will also perform user acceptance test of the e-
CRF in order to ensure the protocol adherence.  
The e-CRF will be made available to the study personnel by means of the 
interface which 
is a validated system. The accounts will be individual and password-protected.  


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The Investigator or designee (see section 5.5) will be responsible for entering study data into the e-
CRF in accordance to the e-CRF Completion Guidelines provided by Sponsor. In order to improve 
the quality of data collection and cleaning, data shall be entered into the e-CRF as closely as 
possible to the time when they become available and not later than within 5 working days. 
The e-CRF data will never be considered as source data. The definition of the source data can be 
found in section 10.3. 
Investigators will ensure the accuracy, completeness and consistency of data entered signing 
electronically the e-CRF using the personal password. An audit trail within the system will track all 
changes made to the data. 
10.1.2 IVRS/IWRS 
IxR system 
, is a validated system used by 
the site personnel for the registration of IMP, patient screening (including assignment of the patient 
ID), patient randomisation, kit assignment, patient status change and code break. Site staff will be 
provided with a personal user name and password to access to IxRS.  
Further details will be reported in a separate IxRS user manual specifying the system that will be 
used (i.e. voice and/or web). The manual will be prepared by 
 and provided 
to site personnel by CRO. Some data (e.g. patient numbers and gender) collected through IxR 
system could be automatically integrated in e-CRF (the integration process will be detailed in a 
specific integration document created by Menarini in collaboration with 
). 
10.1.3 Patient diary  
Efficacy variables (Pain relief [PAR], Pain intensity [PI], first intake of RM, onset of analgesia 
[FPPAR, MPAR] and Patient’s Global Evaluation [PGE]) will be collected with a validated 
system, using an electronic device (smartphone) provided by the dedicated vendor at site. Patient 
will complete the questionnaires/recording at site (t0h – t2h) and out of the site (t4h – t8h) at each 
time point as per protocol. The patient has to return the electronic device to the site at the end of 
study visit.  
Data will be automatically transferred, as soon as saved by the patient to a central database 
managed by the dedicated vendor and then automatically integrated in the e-CRF, according to a 
specific integration document created by Menarini and the dedicated vendor.   
Moreover, patients are required to record their use of RM (including the time of each RM intake) 
for the whole study duration in a paper booklet (RM diary). The patient has to bring the diary to the 
site at the end of study visit and the completed diary pages have to be checked and collected by the 
Investigator. The Investigator or designee is responsible for entering RM data from the ad hoc RM 
diary into the e-CRF. 


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10.2 CLINICAL DATA MANAGEMENT 
Data Management will be carried out under the responsibility of Sponsor.  
e-CRF data will be electronically verified through the use of on-line and off-line checks. 
Discrepancies in the data will be resolved by means of electronic queries. Data will be frozen after 
source data verification by the monitor, and they will be locked by the data manager when all 
activities for the trial, including medical revision of the data, are complete and no more entries are 
expected.  
Data from sources other than e-CRF will be provided to the data manager on an agreed scheduled 
basis. The data manager has the responsibility to reconcile data captured in the e-CRF, with external 
data sources. Discrepancies found in the reconciliation of the data, will be addressed by means of 
queries.  
A clear overview of all clinical data management activities will be given in the data management 
plan. 
10.3 SOURCE DATA 
Source data are defined as all data in original records and certified copies of original records of 
clinical findings, observations or other activities that are necessary for the reconstruction and 
evaluation of the trial. 
Original documents and data records include, but are not limited to, hospital/patients’ medical 
records, laboratory notes, patients’ identification forms, and pharmacy dispensing records, if 
applicable. 
Study sites will also maintain a paper drug accountability forms for the IMP and the RM to 
document dispensed and returned IMP/RM per patient.  
Source data should be held available for perusal by the Sponsor representatives for the study or to 
other authorised persons such as auditors and inspectors of Regulatory Authorities.  
Direct access to source data is defined as the permission to examine, analyse, verify and reproduce 
any records and reports that are important for evaluation of a clinical trial. Any party allowed to 
direct access to study source data and documents should take all reasonable precautions within the 
constraints of the applicable regulatory requirements to maintain the confidentiality of patient 
identities and sponsor proprietary information. 
Data should be consistent with the source documents and discrepancies, if any, should be explained 
in writing.  
All the original documentation pertinent to the study procedures must be available for review in 
each patient’s record. 


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10.4 QUALITY CONTROL/QUALITY ASSURANCE 
10.4.1 Study Monitoring 
This trial will be monitored in accordance with the ICH Note for Guidance on GCP. Monitoring 
will be carried out by the appointed CRO. The site monitor will perform visits to the trial sites along 
the study conduct according to the monitoring plan. Facilities, study drug, storage area, e-CRF, 
patient’s source data, and all other study documentation will be inspected/reviewed by the site 
monitor for adherence to the protocol and GCP. At each site visit, the monitor will review the e-
CRFs for completion and accuracy. Accuracy will be checked by performing source data 
verification that is a direct comparison of the entries made onto the e-CRFs against the appropriate 
source documentation. Any resulting discrepancies will be reviewed with the Principal Investigator 
and site staff. 
The Investigator agrees to allow access to all study related materials needed for the proper review of 
study conduct and to assist the monitor during the monitoring visits and the data cleaning process. 
All monitoring activities will be described in detail in the study-specific monitoring plan. 
10.4.2 Quality Assurance 
Independent study audit(s) and/or inspection(s) may take place at any time during or after the trial. 
The independent audit/inspection can be carried by the Quality Assurance (QA) Department of the 
CRO, the independent QA Department 
 or a 
Competent Authority. At all times, the confidentiality of subject related documents will be 
maintained. 
11. PREMATURE TERMINATION OF THE WHOLE STUDY 
The whole trial may be discontinued at the discretion of the Sponsor in the event of any of the 
following: 
• New information leading to unfavourable risk-benefit judgement of the investigational products 
due to: 
- 
Occurrence of significantly previously unknown AEs or unexpectedly high intensity or 
incidence of known AEs 
- 
New evidence of unfavourable safety or efficacy findings (from clinical or non-clinical 
examinations, e.g. toxicology) 
• The Sponsors decision that continuation of the trial is unjustifiable for medical or ethical 
reasons 
• Discontinuation of development of the IMP 
Competent Authorities and IECs will be informed about the discontinuation of the trial in 
accordance with applicable regulations. 


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12. END OF CLINICAL TRIAL AND ARCHIVING 
The clinical trial will end with the collection and analysis of study data and the issue of the clinical 
study report. All essential documents will be finally archived by the Sponsor according to the 
relevant SOP. 
12.1 ARCHIVING OF ELECTRONIC DOCUMENTATION/DATE  
Duplicate electronic media such CDs/DVDs (one for routine access and one for back-up) containing 
the patient data in PDF format (e.g. e-CRFs, e-Diary) for each site will be prepared by the Sponsor 
or a delegate for archiving purposes. The electronic media, of a (not re-printable type) will be 
appropriately labelled recording the files/data included. The files should contain at least the e-data 
copy clearly reporting the study code and the e-CRF/e-Diary version used; for e-CRF data also the 
electronic signature and the associated audit trails have to be included.  
Patient data relevant for each site will be distributed to the Investigator, who has to confirm the 
receipt of the material, verify whether the provided electronic media represent a copy of data 
generated during the study and sign a dedicate form provided by the Sponsor, the signed form has to 
be collected and archived at the Sponsor. 
Two copies of the same electronic media prepared for the sites or cumulative electronic media with 
the same content will be archived by the Sponsor. In addition the Sponsor is responsible to create 2 
electronic media (one for routine access and one for back-up) containing an integrated SAS 
database with all study data (eg: e-CRF, e-Diary, IxRS), following appropriate refreshment 
procedures.  
Investigators and Sponsor will be also responsible to refresh their electronic media approximately 
every 7 years to ensure long term archiving of files/data. 
 


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13. REFERENCES 
                                                 
 
1WMA Declaration of Helsinki- Ethical Principles for Medical Research involving Human 
Subjects. 64th WMA General Assembly, Fortaleza, Brazil, October 2013. 
2Committee for Proprietary Medicinal Products (CPMP). Note for guidance on clinical 
investigation of medicinal products for treatment of nociceptive pain (CPMP/EWP/612/00); 
November 2002. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SAP_001.pdf: 
 
 
 
 
 
Dexketoprofen Analgesic eVolution wIth tramaDol- DAVID Study 
 
Statistical Analysis Plan  
Version 1.0  
Date: 14 February 2017 
 
 
Study code 
DEX-TRA-06 
EudraCT-Number  
2015-004152-22 
Investigational Medicinal Product 
Dexketoprofen  trometamol 25mg /Tramadol hydrochloride 
75mg 
Development phase of study  
III b 
Sponsor 
MENARINI RICERCHE SpA 
Via Sette Santi 1, 
50131 Firenze (Italy) 
Co-ordinating Investigator 
  
 
  
 
 
 
 
 
  


Menarini Ricerche S.p.A. 
 
          Study DEX-TRA-06 
 
Statistical Analysis Plan 
Version 1.0, 14 FEB 2017 
 
Page 2 of 49 
 
 
SIGNATURE PAGE 
 
 
Prepared by:  
_________________________ 
 
_______________ 
 
  
 
          
 
 
Senior Biostatistician 
 
 
 
Menarini Ricerche S.p.A. 
 
 
Approved by: 
_________________________ 
 
_______________ 
 
 
 
 
 
Date 
 
Head of Data Management & Biostatistics 
 
 
Menarini Ricerche S.p.A. 
 
 
                                   
 
 
 
 
 
 
            Date 
 
Study Physician 
 
 
Menarini Ricerche S.p.A. 
 
 
 
 


Menarini Ricerche S.p.A. 
 
          Study DEX-TRA-06 
 
Statistical Analysis Plan 
Version 1.0, 14 FEB 2017 
 
Page 3 of 49 
 
 
TABLE OF CONTENTS 
 
1        INTRODUCTION ........................................................................................................................ 6 
2 
STUDY OBJECTIVES ................................................................................................................. 7 
2.1 
Primary Objective .................................................................................................................. 7 
2.2 
Secondary Objective .............................................................................................................. 7 
3 
INVESTIGATIONAL PLAN ....................................................................................................... 8 
3.1 
Overall Study Design and Plan .............................................................................................. 8 
3.2 
Efficacy and Safety Variables .............................................................................................. 12 
3.2.1 
Efficacy Variables ............................................................................................................. 12 
3.2.2 
Safety Variables ................................................................................................................. 14 
4 
STATISTICAL METHODS....................................................................................................... 16 
4.1 
Data Quality Assurance ....................................................................................................... 16 
4.2 
General Presentation Considerations ................................................................................... 16 
4.3 
Analysis Populations ............................................................................................................ 17 
4.4 
Study Patients ...................................................................................................................... 17 
4.4.1 
Disposition of Patients ....................................................................................................... 17 
4.4.2 
Protocol Deviations ........................................................................................................... 18 
4.5 
Demographic and Other Baseline Characteristics ............................................................... 18 
4.6 
Efficacy Evaluation .............................................................................................................. 20 
4.6.1 
Analysis and Data Conventions......................................................................................... 20 
4.6.2 
Handling of Dropouts or Missing Data ............................................................................. 22 
4.6.3 
Multiplicity ........................................................................................................................ 23 
4.6.4 
Examination of Subgroups ................................................................................................ 23 
4.6.5 
Primary Efficacy Variable – Mean TOTPAR (TOTPAR6) ............................................... 23 
4.6.6 
Secondary Efficacy Variables ........................................................................................... 26 
4.7 
Safety Evaluation ................................................................................................................. 36 
4.7.1 
Adverse Events .................................................................................................................. 36 
4.7.2 
Deaths, Serious Adverse Events, and Other Significant Adverse Events ......................... 37 
4.7.3 
Clinical Laboratory Evaluation ......................................................................................... 38 
4.7.4 
Vital Signs, Physical Findings and Other Observations Related to Safety ....................... 38 
4.8 
Determination of Sample Size ............................................................................................. 39 
4.9 
Changes in the Conduct of the Study or Planned Analysis ................................................. 39 
5 
GENERAL DEFINITIONS ........................................................................................................ 39 
5.1 
Data validation ..................................................................................................................... 39 
5.2 
Computer systems and software to be used in the analysis ................................................. 39 
5.3 
Coding systems used ............................................................................................................ 40 
5.3.1 
Clinical Terms ................................................................................................................... 40 
5.3.2 
Drugs ................................................................................................................................. 40 
5.4 
Report type, language and format ........................................................................................ 40 
6 
TABLES FIGURES AND LISTINGS ....................................................................................... 41 
6.1 
Statistical analysis report (TFL) .......................................................................................... 41 
6.2 
Tables, headings, and footnotes ........................................................................................... 41 
6.3 
List of Tables and Figures ................................................................................................... 41 
6.4 
Patient data listing ................................................................................................................ 46 
7 
REFERENCES ............................................................................................................................ 48 


Menarini Ricerche S.p.A. 
 
          Study DEX-TRA-06 
 
Statistical Analysis Plan 
Version 1.0, 14 FEB 2017 
 
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LIST OF ABBREVIATIONS 
 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ALAT 
Alanine Aminotransfetrase 
ANCOVA 
Analysis of Covariance 
ASAT 
Aspartate Aminotransferase 
ß-HCG 
Human Chorionic Gonadotropine
BDRM 
Blinded Data Review Meeting 
BOCF 
Baseline Observation Carried Forward 
BP 
Blood Pressure 
CI 
Confidence Interval 
CM 
Concomitant Medication 
CPK 
Creatine Phosphokinase 
CRF 
Case Report Form 
CS 
Clinically Significant 
DKP.TRIS 
Dexketoprofen Trometamol 
ECG 
Electrocardiogram 
EOS 
End of Study 
ET 
Early Termination/Withdrawal 
GEE 
General Estimating Equations 
GGT 
Gamma-Glutamyl Transpeptidase  
Hb 
Haemoglobin 
HCT 
haematocrit 
HR 
Heart Rate 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
INR 
International Normalized Ratio 
ITT 
Intention-to-Treat 
LDH 
Lactate Dehydrogenase 
LOCF 
Last Observation Carried Forward 
MAO 
Monoamine Oxidase  
MCH 
Mean Corpuscular Haemoglobin 
MCHC 
Mean Corpuscular Haemoglobin Concentration 
MCV 
Mean Corpuscular Volume 
MMRM 
Mixed Models Repeated Measures 
NCS 
Not Clinically Significant 
NSAID 
Non-Steroidal Anti-Inflammatory Drug 
PAR 
Pain Relief 
PCA 
Patient Controlled Analgesia 
PGE 
Patients Global Evaluation 
PI 
Pain Intensity 
PID 
Pain Intensity Differences 


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          Study DEX-TRA-06 
 
Statistical Analysis Plan 
Version 1.0, 14 FEB 2017 
 
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PP 
Per Protocol 
PT 
Preferred Term 
PTT 
Partial Thromboplastin Time 
RBC 
Red Blood Count 
RM 
Rescue Medication 
SAE 
Serious Adverse Event 
SADR 
Serious Adverse Drug Reaction 
SD 
Standard Deviation 
SE 
Standard Error 
SOC 
System Organ Class 
SPID 
Sum of Pain Intensity Differences 
TEAE 
Treatment Emergent Signs and Symptoms 
TOTPAR 
Total Pain Relief 
TRAM.HCI Tramadol Hydrochloride 
VAS 
Visual Analogue Scale 
VRS 
Verbal Rating Scale 
VS 
Vital Signs 
WBC 
White Blood Count 
WHO 
World Health Organization 
WOCF 
Worst Observation Carried Forward 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Statistical Analysis Plan 
Version 1.0, 14 FEB 2017 
 
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1 
INTRODUCTION 
The purpose of this document is to provide further details about the statistical analysis methods 
specified in study protocol for the Phase III-b study of dexketoprofen trometamol (DKP.TRIS) and 
tramadol hydrochloride (TRAM.HCI) fixed-combination in patients with moderate to severe acute 
pain after removal of impacted lower third molar.  The study is sponsored by Menarini Ricerche 
S.p.A.  A brief description of the study objectives and study design are given in sections 2 and 3 
respectively.  Subsequent sections include the definition of analysis populations, efficacy and safety 
endpoints including details about statistical methods and hypotheses. 
 
Menarini Ricerche is developing a combination of DKP.TRIS and TRAM.HCI, two analgesics with 
different mechanisms of action, for the treatment of moderate to severe acute pain, based on the 
rationale that multimodal analgesia is necessary in most patients suffering from acute and chronic 
pain, particularly of moderate to severe intensity. 
 
Pain is the most common symptom for which patients seek medical attention.  Acute pain is 
typically associated with recent tissue injury and has a short duration.  If not properly treated, 
prolonged activation of the pain pathways can lead to further neurophysiologic changes collectively 
called ‘central sensitization’ which may prolong recovery and in some cases convert acute pain into 
a chronic condition.  Proper analgesic treatment can reduce this risk. 
 
DKP.TRIS and TRAM.HCI are well-known and widely used analgesics which have been present in 
the market of most European countries for a very long time.  The clinical development of the 
DKP.TRIS and TRAM.HCl fixed combination started with a phase I safety and pharmacokinetics 
(PK) study (DEX-TRA-PK), aimed at investigating the potential drug-drug interactions between the 
products as well as their tolerability when concomitantly administered as a single oral dose to 
healthy subjects.  The study results indicated that there was no drug-drug interaction between 
DKP.TRIS and TRAM.HCl and that the concomitant administration was well tolerated.  A phase II 
dose-finding study (DEX-TRA-02) was performed in the most frequently used model of acute 
nociceptive pain of moderate-severe intensity (impacted third mandibular molar tooth extraction) 
aimed at evaluating the analgesic efficacy and safety of DKP.TRIS (12.5 mg and 25 mg) and 
TRAM.HCl (37.5 mg and 75 mg) given as four different combinations and as single components.  
Results from DEX-TRA-02 allowed for the selection of DKP.TRIS 25 mg + TRAM.HCl 75 mg as 
the optimum combination of doses to be further evaluated in the subsequent phase III pivotal studies 
(DEX-TRA-04 and DEX-TRA-05). 
DEX-TRA-04 and DEX-TRA-05 were two phase III registration studies aimed at evaluating the 
analgesic efficacy and safety of the DKP.TRIS/TRAM.HCl 25/75mg oral fixed-dose combination in 
comparison with each single component (tramadol given at a higher dose, 100mg), following single 
and repeated-dose administration, in two recognised models of visceral and somatic moderate to 
severe acute pain, namely abdominal hysterectomy and hip arthroplasty, respectively. The study 
results provided robust evidence of the superiority of DKP.TRIS/TRAM.HCl 25mg/75mg over the 
single components in the management of moderate to severe acute pain. 
 
In this study, patients will receive one single oral dose of DKP.TRIS/TRAM.HCl 25mg/75mg, 
TRAM.HCl/paracetamol 75mg/650mg or placebo (in a 2:2:1 ratio).  


Menarini Ricerche S.p.A. 
 
          Study DEX-TRA-06 
 
Statistical Analysis Plan 
Version 1.0, 14 FEB 2017 
 
Page 7 of 49 
 
 
RM consisting of ibuprofen 400mg (a maximum of 2 tablets, each one separated by a minimum 
interval of 4 hours) will be available on request during the 8-hour post-dose period. Ibuprofen 
400mg is a safe and effective drug for the treatment of dental and post-operative pain (Ibuprofen 
SmPC). 
 
This SAP is based upon the following study documents: 
 Study Protocol, Version 2.0 (November 24, 2015) 
 electronic Case Report Form (eCRF), Version 2.0 (May 20, 2016) 
 
 
2 
STUDY OBJECTIVES 
 
 
2.1 
Primary Objective 
To assess the comparability of DKP.TRIS/TRAM.HCl and TRAM.HCl/paracetamol in terms of 
analgesic efficacy on moderate to severe pain following impacted lower third molar extraction. 
 
 
2.2 
Secondary Objective 
To confirm the safety and tolerability profile of DKP.TRIS/TRAM.HCl following single dose 
administration. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Statistical Analysis Plan 
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3 
INVESTIGATIONAL PLAN 
3.1 
Overall Study Design and Plan 
DEX-TRA-06 is designed as a multicentre, randomised, double-blind, double-dummy, parallel-
group, placebo and active-controlled, single dose, phase IIIb study, intended to be conducted in 
approximately 19 sites among Europe. 
The study design includes a total of 3 treatment arms, with a 2:2:1 randomisation ratio: 
 DKP.TRIS/TRAM.HCl 
 TRAM.HCl/paracetamol 
 Placebo 
Male or female patients, aged more than 18 years, scheduled to undergo surgical extraction (under 
local anaesthesia) of at least one impacted lower third molar and who are otherwise healthy will be 
enrolled in the study.  
Upon completion of the surgical extraction, those patients experiencing moderate to severe pain 
(Numerical Rating Scale, NRS ≥4) within 4 hours after the end of surgery will be considered 
eligible to progress with randomisation and to receive one single oral dose of the assigned study 
treatment. 
Rescue medication (RM) consisting of ibuprofen 400mg (a maximum of 2 tablets, each one 
separated by a minimum interval of 4 hours) will be available on request during the 8-hour post-
dose period. 
The analgesic efficacy evaluation will be based on patients’ e-Diary scores of pain intensity (PI) and 
pain relief (PAR) at pre-defined intervals during the 8-hour post-dose period; the patient global 
evaluation (PGE) of the study medication at the end of the assessment period; the time to onset of 
the analgesic effect within two hours post-dose and the first use of RM. The safety evaluation will 
include a physical examination, vital signs (VS) and recording of adverse events (AEs). 
The individual study participation will have duration of approximately 3 weeks, encompassing: 
- Screening period, for study eligibility assessment (within 2 weeks prior to randomisation), 
including the pre-surgery procedures to be completed at least one day prior to surgery and ending 
with the 4-hour qualification post-surgery.  
- Randomisation and treatment administration (day 1, t0) followed by a 8-hour pain and analgesic 
effect assessment period as follows: 
- 
from t0 to t2h, at the study centre. 
- 
from t2h to t8h, out of the study centre.  


Menarini Ricerche S.p.A. 
 
          Study DEX-TRA-06 
 
Statistical Analysis Plan 
Version 1.0, 14 FEB 2017 
 
Page 9 of 49 
 
 
- End of study visit (6 ± 1 days after randomisation). 
The design contemplates a sample size of 640 randomised patients. It is anticipated that 
approximately 800 patients will be needed to be screened in order to obtain 640 randomised 
patients, under the assumption that approximately 20% of the screened patients will not satisfy the 
eligibility criteria for randomisation.  The enrolment will be competitive. 
 
 
Figure 1:  Schematic Study Outline
      T0  T+15’ T+30’ T+1h T+1.5h T+2h     T+4h                 T+6h               T+8h         
Screening 
 
Pre-Surgery  
 
Single oral administration of: 
 
-DKP.TRIS/TRAM.HCl 25mg/75mg
-TRAM.HCl/paracetamol 75mg/650mg 
-Placebo 
  At the centre                               Out of centre 
< 4h 
Randomisation 
(day 1) 
 2 weeks 
IC 
End of 
study 
visit 
Qualification 
        
Surgery 
(day 1) 
≥ 1day before 
surgery 
6±1days 


Menarini Ricerche S.p.A. 
 
                          Study DEX-TRA-06 
 
 
 
Statistical Analysis Plan 
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Table 1:  Study Flow Chart 
 
Study procedures 
Screeninga 
Randomisation, treatment administration and efficacy assessment period
End of Study  
 
Prior to 
 surgery 
Qualification  
(day 1) 
At the centre (day 1)h 
Out of centre (day 1)i 
(6± 1 days after 
randomisation) 
T-0 h
T+15’ 
T+30’ 
T+1h 
T+1.5h 
T+2h 
T+4h 
T+6h 
T+8h
Check 
of 
Informed 
consentb 
X 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
and 
Medical History  
X 
 
 
 
 
 
 
 
 
 
 
 
Inclusion /   Exclusion
criteria 
X 
X  
 
 
 
 
 
 
 
 
 
 
Physical Examination 
X 
 
 
 
 
 
 
 
 
 
 
X 
Vital sign 
 (BP, HR) 
X 
X 
 
 
 
 
 
 
 
 
 
X 
Safety Laboratory 
Tests    
X 
 
 
 
 
 
 
 
 
 
 
 
Pregnancy 
test 
(if 
applicable) 
X  
Xc  
 
 
 
 
 
 
 
 
 
X 
e-Diary Instruction 
X 
 
 
 
 
 
 
 
 
 
 
 
e-Diary dispensing & 
testing of its main 
functions 
 
X 
 
 
 
 
 
 
 
 
 
 
Randomisation 
to 
treatment and Dosing 
 
 
X 
 
 
 
 
 
 
 
 
 
PI assessment (NRS)g  
 
Xd  
Xe 
X 
X 
X 
X 
X 
X 
X 
X 
 
PAR 
assessment 
(VRS)g  
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
Patient’s 
Global 
Evaluation  
 
 
 
 
 
 
 
 
 
 
Xf 
 
FPPAR and MPARg 
 
 
As soon as they are experienced 
 
 
 
 


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Study procedures 
Screeninga 
Randomisation, treatment administration and efficacy assessment period
End of Study  
 
Prior to 
 surgery 
Qualification  
(day 1) 
At the centre (day 1)h 
Out of centre (day 1)i 
(6± 1 days after 
randomisation) 
T-0 h
T+15’ 
T+30’ 
T+1h 
T+1.5h 
T+2h 
T+4h 
T+6h 
T+8h
Dispensing of RM and 
RM diary  
 
 
X 
 
 
 
 
 
 
 
 
 
RM and RM diary 
Return / Accountability 
 
 
 
 
 
 
 
 
 
 
 
X 
Return of e-Diary  
 
 
 
 
 
 
 
 
 
 
 
X 
AEs/CM recording 
X 
X 
While patients are at site 
 
X 
 
a The entire screening period, including the pre-surgery evaluations, the surgical procedure and the qualification period, must be completed within 2 weeks prior to randomisation 
bIC must be signed before any other study procedure is performed 
c To be repeated on day 1 before randomisation if not performed the day before as screening procedure 
dNRS-PI > 4 is required for randomisation
eNRS-PI at T0 is recorded as baseline PI 
f Or immediately before RM intake 
g To be completed upon RM intake, if any 
h E-Diary recording is allowed within a ±3 minutes time window at T+15’, T+30’, T+1h, T+1.5h and T+2h  
i E-Diary recording is allowed within a ±10 minutes time window at T+4h, T+6h and T+8h 
 
 
 


Menarini Ricerche S.p.A. 
 
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Statistical Analysis Plan 
Version 1.0, 14 FEB 2017 
 
Page 12 of 49 
 
 
3.2 
Efficacy and Safety Variables 
3.2.1 Efficacy Variables 
3.2.1.1 Pain Intensity - Numerical Rating Scale (NRS) 
 
An 11-point numerical rating scale (ranging from 0 [no pain] to 10 [worst pain], as represented in figure 
2) will be used for the subjective assessment of PI. Patients will be asked to select the number that best 
represents their PI at the time of the assessment. 
 
 
Figure 2:  Pain Intensity - Numerical Rating Scale (NRS) 
   
 
 
NRS-PI will be measured: 
 
- 
During the qualification period, in order to confirm eligibility, namely moderate or higher PI 
(NRS ≥4); 
- 
immediately prior to the treatment administration (t0h), 
- 
at pre-specified time points during the 8-hour post-dose period, (i.e:  at t15min, t30min, t1h, 
t1.5h, t2h, t4h, t6h and t8h). 
 
 
3.2.1.2 Pain Relief – Verbal Rating Scale (VRS)   
 
A 5-point VRS will be used for the 8-hour post-dose PAR subjective assessment. 
Patients will be asked to answer the question ‘How do you rate your pain relief?’ and to select the 
adjective that best describes the level of pain relief on the e-Diary. The number associated with the 
adjective chosen by the patient will constitute the experienced pain relief as reported below:  
 


Menarini Ricerche S.p.A. 
 
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Statistical Analysis Plan 
Version 1.0, 14 FEB 2017 
 
Page 13 of 49 
 
 
Score 
Pain Relief 
0 
No relief 
1 
A little (perceptible) relief 
2 
Some (meaningful) relief 
3 
Lot of relief 
4 
Complete relief 
 
VRS-PAR will be measured at pre-specified time points during the 8-hour post-dose period, i.e. at  
t15min, t30min, t1h, t1.5h, and t2h, t4h, t6h and t8h. 
 
 
 
3.2.1.3 Use of Rescue Medication  
 
Time of first intake of rescue medication ( Ibuprofen 400mg ) will be recorded on the e-Diary. After 
this, patients will stop using the e-Diary. 
 
 
3.2.1.4 Time to onset of analgesia 
 
The 
 method will be used to assess the onset of analgesia, within the first 2 hours post 
dose (i.e.: while the patient is still at site).  
Patients will be instructed to stop the first 
 by pressing the 'first perceptible pain relief' button 
when the relief from pain is first perceptible (i.e. at the moment they first feel any pain relief 
whatsoever) (FPPAR) and then to stop the second 
 by pressing the 'meaningful pain relief' 
button when the relief from pain becomes meaningful to them (MPAR).  
In case of RM use during the first 2 hours, the patient will be no longer required to use the 
 
and they will be considered as censored. 
FPPAR and MPAR are assessed by
 or the time when the patients report for the first time a 
pain relief score ≥1 and ≥2 respectively, whichever happens first.  
Time to confirmed FPPAR (time to onset of analgesia) is defined as the time to FPPAR for those 
patients who achieve meaningful pain relief (MPAR). 
 
 
3.2.1.5 Patient’s Global Evaluation 
 
Patients will be asked to give a subjective overall assessment (PGE) of the study medication by using a 
5-point VRS. 
Patients will be asked to answer the question: ‘How would you rate the medication received for your 
pain?’ and to select the adjective that best rate the study medication that they received for pain relief on 
the e-Diary. The number associated with the adjective chosen by the patient will constitute the global 
evaluation score, as reported below: 
 


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Statistical Analysis Plan 
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Score 
PGE 
1 
Poor 
2 
Fair 
3 
Good 
4 
Very Good 
5 
Excellent 
 
The PGE will be recorded at the end of the assessment period (at 8 hours post-dose or whenever the 
patient uses RM). 
 
3.2.2 Safety Variables 
Assessment of safety will be based on the evaluation of the following variables: 
 
 Incidence, intensity (severity), seriousness and treatment-causality of TEAEs, i.e. AEs that occurred 
after study drug intake. 
 
 Frequency of clinically significant changes in: 
 
Physical examination  (PE) 
 
Vital Signs (VS) 
 
NOTE: for PE, the screening period values will be used as baseline; for VS, the values collected 
during the qualification period will be used as baseline. 
 
 
 
3.2.2.1 Physical Examination, Height, Weight and Vital Signs 
 
Physical examination (review of body systems) will be performed during the Screening period and at the 
End of study visit. Measurement of height (in whole centimeters) and weight (in kilograms to one 
decimal place) will be performed during the Screening period only. 
Vital signs (i.e. BP [systolic and diastolic, mmHg] and HR [beats/min]) will be measured 1) during the 
screening period, 2) during the qualification period and, 3) at the End of Study visit.  
Out of range measures will be repeated at the Investigator’s discretion. 
The collected data will be registered in the subject’s source record and reported on the e-CRF. 
 
 
 
 
 
 


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3.2.2.2 Clinical Laboratory Evaluation  
 
Blood laboratory safety tests will be performed locally, with blood samples (8ml approximately) 
collected in fasting conditions during the Screening period. The following parameters will be analysed: 
 
o Haematology: Red blood cell (RBC) count, haematocrit (HCT), haemoglobin (Hb), mean 
corpuscular volume (MCV), mean corpuscular haemoglobin (MCH), mean corpuscular haemoglobin 
concentration (MCHC), platelet count, white blood cells (WBC) count, and differential WBC count 
(neutrophil, lymphocyte, monocyte, eosinophil and basophil counts, absolute and %). 
 
o Serum biochemistry: Sodium, potassium, chloride, total calcium, glucose, creatinine, urea, total 
protein, albumin, alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), aspartate 
aminotransferase (ASAT), alanine aminotransferase (ALAT), total bilirubin, direct bilirubin, lactate 
dehydrogenase (LDH), and creatine phosphokinase (CPK). 
 
o Coagulation test: prothrombin time, partial thromboplastin time (PTT), INR. 
 
Urinalysis will be performed during the Screening period, using Roche Combur-10® dipsticks. The 
following parameters will be analysed: Specific gravity, pH, leucocytes, nitrite, protein, glucose, 
ketones, urobilinogen, bilirubin, blood (erythrocytes/haemoglobin). 
 
Pregnancy tests (when appropriate) will be performed during the Screening period, during the 
qualification period and at the End of Study visit, by determination of the urine  human chorionic 
gonadotropine (ß-HCG), using locally available commercial dipsticks. 
Unscheduled re-tests can be performed as required according to the investigator’s judgement. 
The reference ranges of laboratory parameters described in this study will be submitted by each centre to 
the sponsor prior to beginning of this study and will be updated as appropriate.  
The lab print-outs should be identified with the laboratory requisition number, patient number, patient’s 
age, gender, and site number, as well as with the date and time of sample collection. All results should 
be reviewed by the Investigator with print-outs being dated and signed by the investigator and stored in 
the patient’s record. Out of range values will be judged by the Investigator as “abnormal clinically 
significant” or as “abnormal not clinically significant” and stored in the patient’s record. Note: abnormal 
evaluation can be repeated at the Investigator’s discretion. Records will be transferred on the e-CRF. 
 
 
 
 
 
 
 
 
 
 
 
 


Menarini Ricerche S.p.A. 
 
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Statistical Analysis Plan 
Version 1.0, 14 FEB 2017 
 
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4 
STATISTICAL METHODS 
4.1 
Data Quality Assurance 
All tables, figures and data listings to be included in the report will be independently checked for 
consistency, integrity and in accordance with standard Menarini Ricerche procedures. 
 
 
4.2 
General Presentation Considerations 
‘Baseline’ is defined as the last available non-missing pre-treatment assessment (including unscheduled 
measurements if available and appropriate), unless otherwise specified.   
‘End of Study’ is defined as having completed the EOS visit.   
‘Duration of Treatment’ will be calculated relative to the date and time of randomization: 
 
Duration of Treatment (h) = Last Treatment Date/Time - Randomization Date/Time.   
 
The entire screening period comprehend the pre-surgery evaluation, the surgical procedure (Day 1 
Screening) and the qualification period. 
 
Continuous data will be summarized in terms of the mean, standard deviation (SD), median, minimum, 
maximum and number of observations, unless otherwise stated.  The minimum and maximum will be 
reported to the same number of decimal places as the raw data recorded in the database.  The mean, 
median, lower quartile and upper quartiles (if required) will be reported to one more decimal place than 
the raw data recorded in the database.  The SD will be reported to two more decimal places than the raw 
data recorded in the database.  In general, the maximum number of decimal places reported shall be four 
for any summary statistic. 
 
Categorical data will be summarized in terms of the number of patients providing data at the relevant 
time point (n), frequency counts and percentages.  Any planned collapsing of categories will be detailed 
in the SAP text and the data displays. 
 
Percentages will be presented to one decimal place and will be calculated using n as the denominator.   
 
P-values greater than or equal to 0.001, in general, will be presented to three decimal places.  P-values 
less than 0.001 will be presented as “<0.001”. 
 
Confidence intervals will be presented to one more decimal place than the raw data. 
 
All report outputs will be produced using SAS® version 9.3 or a later version in a secure and validated 
environment.   
 
 
 


Menarini Ricerche S.p.A. 
 
          Study DEX-TRA-06 
 
 
Statistical Analysis Plan 
Version 1.0, 14 FEB 2017 
 
Page 17 of 49 
 
 
4.3 
Analysis Populations  
The Safety Population is defined as all patients randomized who have received the study treatment. 
 
The Intention-to-treat (ITT) Population is defined as all patients randomized. 
 
The Per Protocol (PP) Population will include all patients from the ITT population who did not 
experience relevant protocol violations related to the efficacy endpoints of primary interest. 
 
The primary efficacy evaluation will be demonstrated on both PP and ITT populations in order to get 
major robustness in result of the non-inferiority study. Other efficacy analyses will be performed by 
using the ITT population, unless otherwise stated.  
 
For the ITT population, in the event that a patient is allocated the incorrect study treatment as per the 
study randomization list, patients will be summarized and analyzed ‘as randomized’ i.e. by randomized 
treatment arm.   
 
For the safety population, if a patient is allocated the incorrect study treatment as per the study 
randomization list, patients will be summarized and analyzed ‘as treated’ i.e. by allocated treatment arm. 
 
The following summaries on the analysis populations will be provided: 
 
 
The number and percentage of patients in each analysis population by treatment arm and overall. 
 
A by-patient listing of analysis population details presented by treatment arm and will include: 
country, center, patient identifier, and inclusion/exclusion flags for each population. All patients 
screened should appear on this listing.  If patient data has been partially excluded, visit should also 
appear on this listing. 
 
 
4.4 
Study Patients 
4.4.1 Disposition of Patients 
A clear accounting of the disposition of all patients who enter the study will be provided, from screening 
to study completion.  In the event that a patient prematurely discontinues the study for any reason before 
the end of the treatment period, a final assessment of PGE should be collected on the e-Diary.  An EOS 
visit will be completed for all patients who complete the study as well as those who prematurely 
terminate study participation after having received any dose of study treatment.  This visit will also be 
performed if the patient withdraws their consent. 
 
The number and percentage of patients screened, randomized, treated, terminating early (ET) and 
completing the study will be summarized by treatment arm and overall (Analysis population: All 
patients screened). 
 


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A by-patient listing of eligibility details, randomization details (including whether the blind was broken 
at discontinuation), visit dates and withdrawal/study completion details (including reason for 
discontinuation and duration of treatment prior to discontinuation) will be provided. 
 
 
4.4.2 Protocol Deviations 
Major or minor protocol deviations are defined as those deviations from the protocol likely to have an 
impact on the efficacy or safety of study treatments. The impact of major protocol deviations on the 
efficacy results will be investigated by assessing the robustness of the study results. 
Before any analyses of the data, a blinded data review meeting (BDRM) will take place to identify 
protocol deviations. The category list of potential protocol violators is reported in Appendix 1. 
Cases of major protocol violations will be discussed, and on a case-by-case basis it will be determined 
whether or not to exclude the patients from the PP population. The final decisions on which patients to 
include or exclude from the PP population will be finalized prior to unblinding. 
 
Major protocol deviations and any action to be taken regarding the exclusion of patients or affected data 
from specific analyses will be described in a separate document. 
 
The following protocol deviation summaries will be produced: 
 
 
The number and percentage of patients with a major protocol deviation by treatment arm and overall 
and by type of deviation (Analysis population: ITT) 
 
The number and percentage of patients with a major protocol deviation that brings to the exclusion 
from PP by treatment arm and overall and by type of deviation (Analysis population: ITT) 
 
The number and percentage of patients with a minor protocol deviation by treatment arm and overall 
and by type of deviation (Analysis population: ITT) 
 
A by-patient listing of all major protocol deviations.  
 
A by-patient listing of all minor protocol deviations. 
 
 
 
4.5 
Demographic and Other Baseline Characteristics 
The demographic and baseline characteristic variables identified below will be summarized by treatment 
arm and overall for the ITT, PP and/or Safety population: 
 
 
Demographic data (ITT population): 
 
o Age 
o Sex  
o Race 
o Country Childbearing potential 
o Height 
o Weight 
 


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 
Baseline characteristics (Safety population): 
 
o Physical examination  
o VS (HR, BP) 
o Laboratory safety tests (hematology, clinical chemistry, coagulation test, urinalysis) 
o Pregnancy test  
 
By-patient listings of all demographic data and baseline characteristics as stated above will be provided. 
 
Medical history will be classified using the Medical Dictionary for Regulatory Activities (MedDRA) 
Version 18.1, summarized by treatment arm and overall  and listed. 
 
Prior and concomitant medications as specified in the eCRF will be tabulated separately by treatment 
arm and overall. The proportion of patients receiving prior medications (medications ended within 4 
weeks of the screening date) will be summarized by preferred medication name.  A patient will be 
counted at most once for each prior preferred medication, even if the patient took the same medication 
on multiple occasions.  Concomitant medications (medications started on/after the screening date) and 
Prior and Concomitant medications (medications started prior to the screening date but ended after this 
date or still ongoing) will be summarized similarly. Prior and concomitant medications will be classified 
according to the World Health Organization (WHO) Drug Dictionary version September 2015 and 
presented by ATC code level 3. 
 
Medication start and stop dates/times will be compared to the date of screening date to allow 
medications to be classified as either prior only, both prior and concomitant, or concomitant only. Prior 
and concomitant and concomitant only medication will be summarized in the same table.   
 
If medication start and/or stop dates are missing or partial, the dates will be compared as far as possible 
with the date of screening date.  Medications will be assumed to be concomitant only, unless there is 
clear evidence (through comparison of partial dates) to suggest that the medication started within 4 
weeks prior to the screening date. If there is clear evidence of that, the medication will be assumed to be 
both prior and concomitant, unless there is clear evidence to suggest that the medication stopped prior to 
the screening date. If there is clear evidence to suggest that the medication stopped prior to the screening 
date, the medication will be assumed to be prior only. 
 
 
 
 
 
 
 
 
 


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4.6 
Efficacy Evaluation 
4.6.1 Analysis and Data Conventions 
4.6.1.1 Study Hypotheses 
 
The primary efficacy variable will be analyzed on the PP and ITT populations to assess the non-
inferiority hypothesis using  an analysis of covariance (ANCOVA) for testing the differences in 
treatment efficacy, as quantified by Total Pain Relief over 6 hours after treatment intake (TOTPAR6), 
between DKP.TRIS + TRAM.HCl and TRAM.HCl + Paracetamol arms. The Total Pain Relief has been 
selected as primary variable since for acute pain studies utilizing TOTPAR to assess pain relief may be 
more sensitive to treatment effects than utilizing SPID to assess pain intensity.  
 
ANCOVA is a statistical procedure that allows to include both categorical and continuous variables in a 
single model, and so is a general linear model which blends ANOVA and regression: 
 
 
where: 
 
 = jth replicate observation of response variable. 
    = mean value of response variable. 
   = 
. 
    = combined regression coefficient. 
  = covariate value for the jth replicate observation from the ith level of factor. 
     = mean value of covariate. 
   = unexplained error associated with the jth replicate observation from the ith level of factor. 
 
A non-inferiority test aims to demonstrate that results obtained from the test drug are not appreciably 
worse than the ones of standard drug. A non-inferiority margin () has to be specified in order to 
characterize the largest difference that you consider to be dismissible (Figure 3).  
  
 
Figure 3:  Hypotheses of Non-inferiority tests.  
 


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The ANCOVA model will include terms of treatment and the baseline PI (NRS) with one-sided 
significance level of 2.5%. The following hypothesis will be tested: 
 





HCl
TRAM
TRIS
DKP
l
paracetamo
HCl
TRAM
H
.
/
.
/
.
0 :
 
against 





HCl
TRAM
TRIS
DKP
l
paracetamo
HCl
TRAM
H
.
/
.
/
.
1:
 
 
with  of 20% as non-inferiority limit and μ as the respective mean. 
 
In case the non-inferiority is confirmed on PP and ITT populations, the superiority of DKP.TRIS + 
TRAM.HCl versus TRAM.HCl + Paracetamol will be tested on the ITT population by using the same 
ANCOVA model described above. 
 
Hence, the following hypotheses are tested: 
 
H(0): ( DKP.TRIS + TRAM.HCl) = ( TRAM.HCl + Paracetamol) 
against  
H(1): ( DKP.TRIS + TRAM.HCl) ≠ ( TRAM.HCl + Paracetamol) 
 
 
 
Comparison of DKP.TRIS + TRAM.HCl and TRAM.HCl + Paracetamol versus Placebo will be 
performed in order to confirm the model sensitivity on the ITT population. 
 
The following hypotheses are tested: 
 
H(0): ( DKP.TRIS + TRAM.HCl) = (Placebo) 
against  
H(1): ( DKP.TRIS + TRAM.HCl) ≠ (Placebo) 
 
H(0): ( TRAM.HCl + Paracetamol) = (Placebo) 
against  
H(1): ( TRAM.HCl + Paracetamol) ≠ (Placebo) 
 
 
 
4.6.1.2 Multi-center Studies 
 
The term ‘Center’ will be used to define each investigator site. As center is not a stratification variable 
for the randomization, it is not included in the main model for the primary analysis. The center effect, as 
random, will be investigated and reported, if significant,  in the final report as sensitivity and 
exploratory analysis.. 


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4.6.1.3 Adjustments for Covariates 
 
For the primary efficacy analysis the following variables are included as covariates in the ANCOVA 
model mentioned in §4.6.1.1 : 
 
 
Treatment (as the main effect). 
 
Baseline PI level. 
 
Treatment will be classed as being one of the following three treatment arms with a 2:2:1 ratio: 
 
 
Arm 
Single-dose phase 
1 
DKP.TRIS + TRAM.HCl 
2 
TRAM.HCl + Paracetamol 
3 
Placebo 
 
 
 
4.6.2 Handling of Dropouts or Missing Data 
For the primary analysis, the method of last observation carried forward (LOCF) will be applied among 
patients who missed more than one consecutive value, otherwise the missing value will be replaced by 
the mean of the two non missing data collected respectively before and after the missing one. If PI is 
missed at t0h the value recorded during qualification procedure will be used as baseline. 
After rescue medication intake, PI will return to its baseline (t0h) level and PAR to zero (“no relief”) for 
all subsequent time points (i.e. baseline observation carried forward, BOCF).  
 
In case non-inferiority is confirmed the primary efficacy endpoint will be also evaluated in the ITT 
population using other methods of imputation different from the ones described above as for sensitivity 
analysis:  
 
1. After RM intake the value will be handle with LOCF imputation method  instead of BOCF.  
2. For missed values any method of imputation will be implemented. 
3. For both missed values and values after RM intake any imputation will be used.   
 
If a discrepancy between the Rescue Medication reported in the eCRF and the one registered in the 
eDiary is present, the Rescue Medication collected in the eCRF will be considered as correct and used 
for the analysis since is confirmed by the source data verification. Sensitivity analyses considering only 
the Rescue Medication recorded in eDiary will be also implemented at least for the primary endpoint 
and the main secondary endpoints. 
 


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4.6.3 Multiplicity 
There is one primary endpoint comparison for non-inferiority (as detailed in Section 4.6.1.1) for this 
study.  For the switch from non-inferiority to superiority no multiplicity adjustment is needed, since, as 
stated in CPMP/EWP/482/99, the superiority interpretation of results corresponds to a simple closed test 
procedure.  
Other additional two comparisons between active treatments and placebo are planned in order to 
validate the study model. However as they are considered to be co-primary endpoints and they will 
therefore be interpreted together for purposes of the study, no adjustment for multiplicity is required. 
 
 
4.6.4 Examination of Subgroups 
The uniformity of the treatment effects for the primary efficacy variable will be examined for the 
following subgroups: 
 
1. Gender (Male, Female) 
2. Age (quartiles) 
3. Country 
 
The quartile values for age will be determined by examining the distribution of age at baseline. 
The results of the primary statistical analyses within each subgroup category will be presented.   
 
 
 
4.6.5 Primary Efficacy Variable – Mean TOTPAR (TOTPAR6) 
TOTPAR6 is calculated as the weighted sum of the PAR-VRS scores, over 6 hours after the treatment 
intake.  
 
The general formula for calculating TOTPARx is as follows: 
 
TOTPARx =  
 for i = 1, …, z 
  
where T(i) is the scheduled time, 
T(0) = 0, 
PAR(i) = PAR at time i. 
z is the number of timepoints from the first one after T(0) to T(x). 
 
 
This primary efficacy variable will be used for the assessment of the primary efficacy endpoint of non-
inferiority of DKP.TRIS + TRAM.HC1 versus TRAM.HCl + Paracetamol.  
 
 


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The following SAS program will be implemented: 
 
  
 
 
 
   
 
  
 
 
 
 
 
 
 
NB: Since the Placebo group is not considered in this efficacy analysis only the active treatment  arms 
need to be prior selected. 
 
The model uses the REML method (Restricted or Residual maximum likelihood) for the estimation of 
parameters. REML estimators are obtained by maximizing the part of the likelihood function that is 
invariant to the fixed effects part of the linear model. It requires the assumptions that the distribution of 
the dependent variable is normal, and the errors are normally distributed, uncorrelated and have an 
expected value of 0.  
 
To check assumptions the following tests will be done: 
 
To check the normal distribution of dependent variables within each treatment arm, QQplots and 
Histograms plots will be done as a graphical test. In addition the Shapiro-Wilk test will be performed. 
The null hypothesis of normal distribution, H0, will be tested by using a significance level of 5%. 
The following SAS procedure will be implemented: 
 
 
 
 
 
 
 
 
 
To check the homogeneity of the variance of the dependent variables the Bartlett test will be done. The 
null hypothesis, H0, is that all k population variances are equal. The alternative is that at least two are 
different. The null hypothesis is rejected at a significance level of 5% if the value of the Bartlett test 
statistic is greater than the corresponding critical value.  
 
 
 


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The following SAS procedure will be used: 
 
  
  
  
  
 
To check whether the residuals of the utilized mixed model have a multivariate normal distribution and 
if heteroscedasticity is present,  a graphical tests will be implemented by adding option “/ VCIRY” to 
the “MODEL” statement in the proc mixed reported above. For the multivariate normal distribution  
graph, the standardized residuals versus their ranks should form a straight line on the plot, which is 
visually assessed. For the  heteroscedasticity graph,  instead, if the points are equally distributed around 
the straight line and no trends are showed, the hypothesis of heteroscedasticity is rejected. 
 
As alternative, if the assumption required by the REML method are not fulfilled or if the likelihood 
function cannot be evaluated, the MIVQUE0 (Minimum Variance Quadratic Unbiased Estimation) 
method is used, as this method doesn’t require any particular assumptions. 
The results of model assumptions will be reported.  
 
Since, as explained in the §6.1.1.2, the ANCOVA model includes ANOVA and regression, it also 
assumes that the regression coefficients are homogeneous (the same) across the level of categorical 
independent variables. To check this assumption the interaction term of Treatment*PI at Baseline will 
be add to the covariates already included in the model as described in the §4.6.1.3.  
If the interaction term is not significant (associated p-value >0.05) it means that the regression 
coefficients can be considered homogeneous and the dependent variables can be analyzed as described 
in §4.6.5. If, alternatively, the interaction term of Treatment*PI at Baseline is significant (associated p-
value ≤ 0.05) it is not possible to interpret the relationship between the dependent variable and the 
treatment without referring also to the pain intensity at baseline. In this case a comparison of the 
treatment groups at different group levels of pain intensity (i.e. 5,7,10) needs to be done. The following 
SAS procedure will be implemented:  
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
To assess the non-inferiority hypothesis, the 95% Interval Confidence of the TOTPAR6 difference 
between the two active treatment arms (DKP.TRIS + TRAM.HC1 - TRAM.HCl + Paracetamol )  will 
be produced by including the “CL” option in the ‘estimate’ statement of Proc Mixed as showed above.  
If the lower limit of CI is higher than the predefined, then the Non-Inferiority can be claimed. 
Otherwise  DKP.TRIS + TRAM.HC1 has to be considered as inferior.  
As   , the 20% of the estimated mean of  TRAM.HCl + Paracetamol will be used.  
 


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In case the non-inferiority is confirmed in both PP and ITT populations, the superiority of DKP.TRIS + 
TRAM.HC1 versus TRAM.HCl + Paracetamol will be tested on the ITT population by using the same 
model and SAS Program described above. TOTPAR6 will be also analyzed by comparing the two active 
treatments versus the Placebo arm in order to validate the model sensitivity.  
 
 
4.6.6 Secondary Efficacy Variables 
All the secondary efficacy variables will be descriptively analysed. The superiority for DKP.TRIS + 
TRAM.HCl will be tested when applicable, through and ad hoc inferential analysis. 
The following treatment comparison will be presented: 
 
 DKP.TRIS + TRAM.HC1 vs TRAM.HCl + Paracetamol  
 
For the SPID6, as will be described in section 4.6.6.1.2,  also the Non-Inferiority is tested as for the 
primary variable.  
 
4.6.6.1 Pain Intensity 
 
4.6.6.1.1 PI-NRS Scores at Rest 
 
The PI-NRS score at rest will be analyzed by applying a longitudinal model with treatment, timepoint, 
the interaction between treatment and timepoint and baseline PI (NRS) as independent variables. 
 
The following SAS program will be used:  
 
 
  
  
  
  
 
 
  
 
 
 
 
 
 
 
The term trt*timepoint indicates the interaction between treatment and time. In clinical study where the 
hypothesis is that one method is non-inferior (or superior/equivalent) to the comparator method, an 
assessment of consistency over time for the treatment effect is often convenient. In practice there is an 
interaction whenever the effect of one factor depends on the level of another.  
Initially a plot for the mean of the interest variable over time and displayed by treatment arm can be 
useful. If no trt*timepoint interaction is detected this can be deleted from the model and the overall 
treatment effect can be assessed marginally by collapsing over time. 


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Within-subject correlation is another important issue that must be considered, since we can not assume 
all data points to be independent as when there is only one observation per subject. A 
variance/covariance matrix has to be indicated in the type statement and, to choose the more appropriate 
structure, the AIC/BIC criteria (lower is better) will be used. The rcorr option displays the correlation 
matrix that can be also useful for the selection.   
 
The underlying assumptions of normality of residuals will be examined by adding in the ‘model’ 
statement the residual option that produces an output containing the studentized residuals of the model. 
Then an univariate procedure will be applied to check the normality of them. A graph will be also 
produced by adding the VCIRY option in the ‘model’ statement.  
If the normality of residuals is not confirmed as required for the estimation by the REML method , the 
MIVQUE0 method is applied, as this method doesn’t require any assumptions. 
 
In addition an analysis by timepoint will be implemented in order to check the efficacy of analgesia in 
the first 8 hours after the treatment intake. 
The following SAS program will be used: 
 
 
 
 
 
 
   
 
  
 
 
 
 
The underlying assumption for the model above will be check in the same way as described in section 
4.6.5 . 
 
NB: Since the Placebo group is not considered in the efficacy analysis reported above only the active 
treatment  arms need to be prior selected. 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.6.6.1.2 SPIDs 
 
The mean of the secondary efficacy variable SPID6  (Sum of Pain Intensity Difference over 6 hours) 
will be analyzed for non-inferiority with the possibility to switch for superiority analogously to the 
primary efficacy variable. The same model and SAS program described in section 4.6.5 will be applied.   
The SPID6 at rest is calculated as the weighted sum of the PID values, over 6 hours after the treatment 
intake. 
 
The general formula for calculating SPIDj is as follows: 
 
SPIDj = 
 for i = 1, …, z 
 
where  T(i) is the scheduled time, 
T(0) = 0, 
PID(i) = PID at time i = PI (0) – PI (i). 
z is the number of timepoints from the first one after T(0) to T(j). 
 
  
The mean of SPID at rest over 2, 4 and 8 hours after the treatment intake (SPID2 SPID4 and SPID8) will 
be analyzed only for the superiority of DKP.TRIS + TRAM.HC1 vs TRAM.HCl + Paracetamol as 
described in section 4.6.5. Patients in the Placebo treatment arm will not be considered.  
Underlying assumptions will be examined in the same way as described in Section 4.6.5 . 
 
4.6.6.1.3 %max SPID 
 
 
 
 
 
 
 
 
 
 
 
4.6.6.1.4 Responders to treatment 
 
A responder will be defined as having achieved at least 30% of  PI-VAS at rest reduction versus 
baseline at each pre-specified time point. 
The frequencies and relative percentages will be calculated using the PI-VAS values at 2, 4, 6 and 8 
hours after the treatment intake. 
The percentage of responders will be summarized by treatment and the response will be analyzed using 
a Chi-square test by comparing the active treatment arms. 
 
 


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The following SAS code will be applied for this analysis: 
 
 
 
 
 
 
 
 
 
 
 
 
NB: Since the Placebo group is not considered in the efficacy analysis reported above only the active 
treatment  arms need to be prior selected. 
 
The underlying assumptions of adequate cell counts will be examined by reviewing data frequency and 
patterns using data the SAS procedure FREQ.  If inadequate expected cell counts are present (i.e. less 
than five), then either a correction to the Chi-square test or an alternative test will be applied (e.g. 
Fisher’s Exact Test). 
 
In addition, in order to have a general post-dose overview,  the percentage of responders over 8 hours 
after the treatment administration will be analysed using a general estimating equations (GEE) analysis.  
Response will be assessed for each of the following timepoints: 2, 4, 6 and 8 hours. 
The following SAS code will be applied for this analysis: 
 
 
 
                       
 
  
     
  
 
  
 
 
 
 
  
 
 
 
     
 
        
 
  
 
NB: Since the Placebo group is not considered in the efficacy analysis reported above only the active 
treatment  arms need to be prior selected. 


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4.6.6.2 Pain Relief 
 
4.6.6.2.1 VRS-PAR score 
 
The VRS-PAR score will be analyzed by timepoint by applying a Wilcoxon rank-sum test (or Mann–
Whitney–Wilcoxon test), that is a nonparametric test with the null hypothesis that the probability of an 
observation from the treatment X exceeding an observation from the second treatment Y is equal to the 
probability of an observation from Y exceeding an observation from X, against the alternative 
hypothesis that these probability are different.  
In an easily way  the set of hypothesis can be summarized saying that under H0 the distributions of both 
treatment populations are equal against the alternative hypothesis that they are not.  
 
Since the responses are assumed to be numeric discrete and the alternative is restricted to a shift in 
location, the Hodges-Lehmann estimate can be computed by comparing the median for each treatment.  
A Wilcoxon rank-sum test, so, can be interpreted as showing a difference in medians. Under this 
location shift assumption, we can also interpret the Wilcoxon rank-sum test as assessing whether 
the Hodges–Lehmann estimate of the difference in central tendency between the two populations differs 
from zero. 
 
 
The following SAS code will be applied for this analysis: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The underlying assumptions for the above analysis (independence of data and similar distributions in the 
groups being compared) will be examined by the Fisher exact test for the independence and by the 
Kolmogorov-Smirnov, with the relative Empirical Distribution Function (EDF) plot, to test the equality 
of distribution functions. In addition also the histogram plots for  the two group distributions, 
interpolated by the estimated Kernel function, will be reported. If  these examinations indicate that an 
assumption has been violated then an appropriate data transformation may be applied. 
 
 
 
 


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The following SAS procedure will be implemented:  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
4.6.6.2.2 TOTPARs 
  
 
 
 
Underlying assumptions will be examined in the same way as described in Section 4.6.5. 
 
4.6.6.2.3 %max TOTPAR 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.6.6.2.4 Percentage of responders 
 
A responder will be defined as having achieved at least 50% max TOTPAR.   
The mean will be calculated using the % max TOTPAR values at
 8 hours after the treatment 
intake. 
Responders will be analyzed by using the same statistical model and SAS syntax described in section 
4.6.6.1.4 . 
Since the Placebo group is not considered in the efficacy analysis reported above only the active 
treatment  arms need to be prior selected. 
 
 
4.6.6.3 Patient Global Evaluation  
 
 
The Patient Global Evaluation (PGE) scores will be collected 8 hours after the treatment intake or 
immediately prior the Rescue Medication intake. 
 
PGE scores will be analyzed using a Wilcoxon rank-sum test (or Mann–Whitney–Wilcoxon test) by 
applying the Hodges-Lehmann method as already described in section 4.6.6.2.1 .  
 
The following SAS code will be applied for this analysis: 
 
 
 
 
 
 
 
 
The underlying assumptions for the above analysis will be examined with the same techniques reported 
in section 4.6.6.2.1 (without ‘by’ statement) . 
 
NB: Since the Placebo group is not considered in the efficacy analysis reported above only the active 
treatment  arms need to be prior selected. 
 
 
4.6.6.4 First Perceptible Pain Relief and Meaningful Pain Relief 
 
4.6.6.4.1 Percentage of First Perceptible Pain Relief and Meaningful Pain Relief 
 
The First Perceptible Pain Relief (FPPAR)  and the Meaningful Pain Relief (MPAR) are assessed by 
pressing the specific stop-watch buttons or alternatively assessed when the Pain Relief score is, 
respectively,  ≥ 1 and   ≥  2 within the first 2 hours after the treatment intake. 
In case a patients declare a MPAR as first, then the FPPAR will be considered assessed as well and it 
will correspond in term of time with the MPAR.  
If the MPAR is assessed then the FPPAR is defined as confirmed.  


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Percentage of patients who achieved FPPAR, confirmed FPPAR and MPAR within 30 minutes, 1 hour 
and 2 hours will be reported and analyzed by using the same statistical methods and SAS syntax 
described in section 4.6.6.1.4 . Since the Placebo group is not considered in the efficacy analysis 
reported above only the active treatment  arms need to be prior selected. 
 
4.6.6.4.2 Time to First Perceptible Pain Relief and Meaningful Pain Relief 
 
The time to FPPAR and MPAR is defined as the time elapsed between treatment administration and the 
time of FPPAR and MPAR confirmation. 
In case a patient declares a Meaningful Pain Relief (MPAR) as first, then the FPPAR will be considered 
assessed as well and will correspond in term of time with the MPAR.  
If the MPAR is assessed then the FPPAR is defined as confirmed.  
The formula for the calculation is:  
 
Time to FPPAR/ MPAR = tFPPAR/MPAR – tTI  
 
where  t FPPAR/MPAR is the time (hours and minutes) of FFPAR/MPAR assessment, 
tTI is the time (hours and minutes) of  the study drug intake.  
 
In the case of no FPPAR and/or  MPAR assessment, time to FPPAR/ MPAR will be calculated as the 
time that occurred between tTI and the end of the time of interest (2 hours after the tTI) and the relative 
patient will be considered as censored. In case a Rescue Medication intake occurs or patient stops to use 
the e-diary within  two hours after the treatment intake, the corresponded patient will be considered as 
well  as censored with a time associated equal to the time of Rescue Medication intake or the time of last 
assessment available, respectively.  
 
Time to FPPAR/ MPAR will be compared using a log-rank test.  The 25th, 50th and 75th percentiles of 
the Kaplan-Meier estimate with associated 95% CI’s will be produced and presented with the log-rank 
p-value.  In addition, a Kaplan-Meier plot of will be presented. Time to confirmed FPPAR will be also 
analyzed in the same way.  
The following SAS code will be applied for this analysis: 
 
 
 
 
 
 
 
 
 
 


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The underlying assumptions for the above analysis will be examined by reviewing the data and checking 
the assumption of proportional hazards by analysing the interaction term ‘treatment*log(duration)’, 
where the logarithmic transformation is implemented to maintain the linearity. If the interaction term is 
not significant the hazards can be considered as proportional.  
In addition the estimated hazard functions plot by using the Epanechnikov kernel-smoothed estimates 
will be produced as a graphical check.  
Should these examinations indicate that an assumption has been violated then an alternative method of 
analysis (e.g. Wilcoxon Test) may be applied. 
 
The following SAS Syntax will be implemented:  
 
   
 
   
 
 
 
 
 
 
 
 
 
4.6.6.5 Rescue Medication  
 
4.6.6.5.1 Percentage of use of Rescue Medication 
 
Percentage of patients who required Rescue Medication within the first 2, 4, 6 and 8 hours after the 
treatment intake.  
Percentages will be analyzed by using the same method and SAS syntax described in section 4.6.6.1.4 . 
Underlying assumptions will be examined in the same way as described in Section 4.6.6.1.4 . 
- 
In order to handle some discrepancies between the Rescue Medications collected in the eCRF 
and the one recorded in the eDiary the following approaches will be adopted: The first RM 
between eCRF and eDiary 
- 
The RM recorded in eCRF 
- 
The RM recorded in eDiary 
 
4.6.6.5.2 Time to Rescue Medication 
 
The time to RM is defined as the time elapsed between treatment administration and RM intake.  The 
formula for calculating time to RM is: 
 
Time to RM = tRM – tTI 
 
where  tRM is the time (hours and minutes) of RM intake, 
tTI is the time (hours and minutes) of  study drug intake. 


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In the case of no rescue medication intake, time to RM will be calculated as the time that occurred 
between tTI and the end of the time period of interest (8 hours after tTI) and the relative patient will be 
considered as censored. Since the first RM intake have to be reported both in e-diary and in the paper 
diary if a patient stops to use the e-diary prematurely, he will not be considered as censored.  
In order to take into account any inconsistency between the electronic and the paper diaries, three type 
of time of first RM intake will be calculated by considering  the RM reported in the e-diary, the RM 
reported in the paper diary and the first reported RM between electronic and paper diaries.  
 
Time to RM will be analyzed by using the same method and SAS syntax reported in section 4.6.6.4.2 . 
Underlying assumptions will be examined in the same way as described in Section 4.6.6.4.2 . 
 
In order to handle some discrepancies between the Rescue Medications collected in the eCRF and the 
one recorded in the eDiary the following approaches will be adopted:  
- 
The first RM between eCRF and eDiary 
- 
The RM recorded in eCRF 
- 
The RM recorded in eDiary 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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4.7 
Safety Evaluation 
All safety summaries and analyses will be based upon the safety population as defined in Section 4.3.  
No formal statistical testing will be performed and only descriptive statistics provided unless otherwise 
noted.  The number of non-missing values and the mean with the respective SD (for continuous 
variables) or the percentage (for ordinal/categorical variables) will be reported.  Missing safety data will 
not be imputed. 
 
 
4.7.1 Adverse Events 
AEs will be coded using MedDRA Version 18.1. 
 
AEs will be summarized by primary System Organ Class (SOC), Preferred Term (PT) and treatment.  
An overview of AEs will be provided, with the number and percentage of patients reporting an event, 
presented for the following categories: 
 
 
 Any AEs 
 Any serious AEs 
 Any AEs leading to study discontinuation. 
 Any AEs leading to death 
 
Additionally, the following summaries of AEs will be presented by SOC and PT: 
 
 The number of AEs and the number and percentage of patients with AEs by treatment and 
overall. 
 
TEAE will be defined as those adverse events that occur for the first time or worsen in terms of intensity 
(severity)/ seriousness after the drug intake. 
 
Where dates are missing or partially missing, adverse events will be assumed to be treatment-emergent, 
unless there is clear evidence (through comparison of partial dates) to suggest that the adverse event 
started prior to the study treatment administration. 
 
TEAE will be summarized by primary System Organ Class (SOC), Preferred Term (PT) and treatment.  
An overview of TEAEs will be provided, with the number and percentage of patients reporting an event, 
presented for the following categories: 
 
 Any TEAE 
 Any serious TEAE 
 Any mild/moderate/severe TEAE 
 Any causally related TEAE (Adverse drug reaction [ADR]) 
 Any TEAE leading to study discontinuation. 
 Any TEAE leading to death 


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Additionally, the following summaries of TEAE will be presented by SOC and PT: 
 
 The number and percentage of patients with TEAE by treatment and overall. 
 The number and percentage of patients with TEAE by intensity (mild, moderate and severe). 
 The number and percentage of patients with TEAE by causality (related/not related). 
 
Any TEAE is defined as related (ADR) if the causality category falls into one of the following: certainly 
related, probably related, possibly related and unassessable/unclassifiable. Otherwise TEAE will be 
considered as not related.    
 
ADRs will be summarized by primary System Organ Class (SOC), Preferred Term (PT) and treatment.  
An overview of ADRs will be provided, with the number and percentage of patients reporting an event, 
presented for the following categories: 
 
 Any ADR 
 Any serious ADR 
 Any mild/moderate/severe ADR 
 Any ADR leading to study discontinuation. 
 Any ADR leading to death 
 
Additionally, the following summaries of ADR will be presented by SOC and PT: 
 
 The number and percentage of patients with ADR by treatment and overall. 
 The number and percentage of patients with ADR by intensity (mild, moderate and severe). 
 
For each patient and each event, the worst intensity recorded will be attributed and used in the by-
intensity summaries.  Similarly, the worst causality (most related to treatment) will be attributed and 
used in the by-causality summaries.  If intensity or causality is missing, the worst case will be assumed. 
 
A by-patient listing of all AEs (including non-TEAE) will be provided together with a listing of TEAE.   
 
4.7.2 Deaths, Serious Adverse Events, and Other Significant Adverse Events 
The number and percentage of deaths (if any) during the study by treatment arm (if numbers allow) will 
be reported. 
Serious AEs (SAEs) will be summarized by primary System Organ Class (SOC), Preferred Term (PT) 
and treatment.  An overview of SAEs will be provided, with the number and percentage of patients 
reporting an event, presented for the following categories: 
 
 Any SAE 
 Any mild/moderate/severe SAE 
 Any SAE leading to study discontinuation. 
 Any SAE leading to death 
 


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4.7.3 Clinical Laboratory Evaluation 
Each patient’s continuous hematology, biochemistry and coagulation  laboratory values will be flagged 
as “low”, “normal”, or “high” relative to the normal ranges provided by the laboratory, or “unknown”.  
Laboratory values will also be flagged for abnormality (normal, abnormal – not clinically significant 
[NCS] or abnormal-clinically significant [CS]).  
  
Urinalysis parameters are reported according to Roche Combur-10 dipstick leaflet. An overall 
investigator judgment for abnormality (normal, abnormal – not clinically significant [NCS] or 
abnormal-clinically significant [CS]) is also reported.  
 
The observed values (at screening) of haematology, serum biochemistry and coagulation test results will 
be summarized by treatment arm and overall, using descriptive statistics, including mean, SD, min and 
max values. Also the investigator judgment for each parameter will be summarized based on the 
following categories: normal, abnormal-NCS and abnormal-CS.  
 
 
The observed values (at screening) of urinalysis and pregnancy test (at screening and end of study) 
results will be presented in a frequency table by parameter, treatment arm and overall. For urinalysis , 
also the overall investigator judgment will be summarized based on the following categories: normal, 
abnormal-NCS and abnormal-CS. 
 
A by-patient listing of all laboratory data and pregnancy test data will be presented.  
 
Unscheduled laboratory values will only be presented in listings. 
 
 
4.7.4 Vital Signs, Physical Findings and Other Observations Related to Safety 
Vital signs (BP and HR) will be summarized by treatment arm and overall, for each time point, using 
descriptive statistics, including mean, SD, minimum and maximum values and also the abnormality 
categories: normal, abnormal-NCS and abnormal-CS. The change from baseline in each vital sign 
parameter will also be summarized.  
 
Physical examination (at screening and at end of study visit), will be summarized by treatment arm and 
overall, using descriptive statistics, including the abnormality categories: normal, abnormal-NCS and 
abnormal-CS. 
 
By-patient listings of all vital sign parameters, physical examination results and ECG results will be 
presented. 
 
Unscheduled values will only be presented in listings. 
 
 


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4.8 
Determination of Sample Size 
A sample size of 230 patients per active arm is considered adequate to demonstrate the non-inferiority 
of DKP.TRIS/TRAM.HCl oral fixed combination compared to TRAM.HCl/paracetamol assuming a 
non-inferiority margin of 20%, a power of 80%  and an overall significance level of 2.5 % (1-side). The 
mean TOTPAR6 for TRAM.HCl/ paracetamol is assumed 
 
Assuming about 10% of major protocol violators, and 20% of screening failure rate a total of  640 
patients need to be randomised and  approximately 800 patients are expected to be screened. 
 
128  patients in placebo arm are sufficient to demostrate the superiority of both 
TRAM.HCl/paracetamol and DKP.TRIS/TRAM.HCl vs placebo  for model sensitivity  
The sample size it is expected to be adequate to demostrate the superiority if a clinical 
significant benefit will be achieved by DKP.TRIS/TRAM.HCl  vs. TRAM.HCl/paracetamol. 
The following SAS procedure has been implemented for the calculation of sample size:  
  
 
      
 
 
 
 
 
4.9 
Changes in the Conduct of the Study or Planned Analysis 
N/A 
 
 
5 GENERAL DEFINITIONS 
5.1 Data validation 
 
 2016 4.1 will be used, as Electronic Data Capture system for data entry, by site 
personnel and for data cleaning and data locking by the Menarini Data Management team. 
5.2 Computer systems and software to be used in the analysis 
SAS v.9.3 by SAS Institute Inc., Cary, NC, USA. 
Database and SDTM and ADAM datasets will be created by using SAS Clinical Data Integration Studio 
version 4.9. 
All tables and listings will be produced using PROC REPORT or procedure specific output displays 
using output delivery system (ODS) within SAS version 9.3 and using SAS Office analytics.. 


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5.3 Coding systems used 
5.3.1 Clinical Terms  
Concomitant diseases, medical procedures, and AEs will be coded with MedDRA 18.1 
5.3.2 Drugs 
Drugs will be coded with WHODrug September 2015 
5.4 Report type, language and format  
The statistical output will be in Microsoft Word 2007 format and in English language.  
 Dates will be presented as DDMMMYY. 
 Numeric values will be decimal-point aligned. 
 Counts and percentages:  
<group 1> 
XXX (XX.X%) 
 Descriptive statistics:  
N 
 
XXX 
Mean  
XXX.X 
SD 
 
XXX.XX 
Median 
 
XXX.X 
 
Minimum 
XXX 
Maximum 
XXX 
 Character values will be left aligned. 


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6 TABLES FIGURES AND LISTINGS 
6.1 Statistical analysis report (TFL) 
The TFL (Tables, Listings and Figures) will follow the list of tables, plots, and listings of section 6.3 
and 6.4, which are intended to provide the overall idea of the general output and ordering of the TFL 
and will not necessarily be reproduced in the final TFL document. 
6.2 Tables, headings, and footnotes 
All tables stratified by treatment and gender will also contain the treatment overall column. The tables 
repeated for analysis population will be produced only once if the analysis populations are identical. All 
tables are provided for ITT population unless specified otherwise. 
Line 1: 
Study code: DEX-TRA-06 
Line 3: 
Table/Listing/Figure n: Table name (Study population) 
Line 4: 
Table/Listing/Figure n.n: Table name 
Line 5: 
Table/Listing/Figure n.n.n: Table name [if applicable] 
Line 6: 
Table/Listing/Figure n.n.n.n: Table name [if applicable] 
Line 7: 
Table/Listing/Figure n.n.n.n.n: Table name [if applicable] 
Footnote: 
Relevant notes (if any) 
 
6.3 List of Tables and Figures 
1 
Patient disposition 
Note: all tables by treatment/overall for ITT population (where applicable) 
1.1 
Overall patient disposition 
1.2 
Presence of patients at study visits 
1.3 
Protocol violations by category 
2 
Baseline and general characteristics 
Note: all tables by treatment/overall for ITT population  (otherwise specified) 
2.1 
Demographics and pregnancy test 
2.2 
Medical history by MedDRA SOC and PT 
2.3 
Pain Intensity at rest scores at Qualification and T0h 
2.4 
Physical examination results –investigator judgement Prior to Surgery  
2.5 
Vital Signs Prior to Surgery and at Qualification  
2.6 
Safety Laboratory Test Prior to Surgery 
2.7 
Prior and concomitant medication by ATC-Code  
2.7.1 
Prior medication by ATC-Code 
2.7.2 
Concomitant medication by ATC-Code 


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3 
Safety analysis 
Note: all analyses will be done on safety population by treatment/overall, unless otherwise stated 
3.1 
Consumption of rescue medication 
3.2 
AEs  
3.2.1 
Overview of AEs  
3.2.2 
AEs by MedDRA SOC, PT 
3.2.3 
AEs by MedDRA SOC, PT and intensity 
3.3 
TEAEs 
3.3.1 
Overview of TEAEs  
3.3.2 
TEAEs by MedDRA SOC, PT 
3.3.3 
TEAEs by MedDRA SOC, PT and intensity 
3.4 
ADRs 
3.4.1 
Overview of ADRs  
3.4.2 
ADRs by MedDRA SOC, PT 
3.4.3 
ADRs by MedDRA SOC, PT and intensity 
3.5 
Serious TEAEs 
3.5.1 
Overview of  Serious TEAEs by Investigator 
3.5.2 
Serious TEAE (by Investigator) by MedDRA SOC, PT 
3.5.3     Serious TEAE (by Investigator) by MedDRA SOC, PT and intensity 
3.5.4 
Overview of  Serious TEAEs by Sponsor 
3.5.5 
Serious TEAE (by Sponsor) by MedDRA SOC, PT 
3.5.6     Serious TEAE (by Sponsor) by MedDRA SOC, PT and intensity 
3.6 
Vital signs : 
3.6.1 
 Descriptive Statistics and Change Vs baseline at End of Study 
3.6.2 
Investigator Judgement at End of Study 
3.7 
Physical examination: 
3.7.1 
 Descriptive Statistics and Change Vs baseline at End of Study 
3.7.2 
  Investigator Judgement at End of Study 
3.8 
Pregnancy test at End of Study 
 
 
4 
Efficacy analysis 
Note: all tables by treatment/overall for ITT and PP population. For the estimation of non-inferiority the upper limit of  95% 
Confidence Interval of TOTPAR6 difference will be compared with δ = 20% of estimated mean of TRAM.HCl+Paracetamol. 
4.1 
Primary analysis  
4.1.1 
Descriptive statistics 
4.1.1.1 Descriptive statistics for TOTPAR6  
4.1.1.2 Descriptive statistics for TOTPAR6 (PP Population) 
4.1.2 
ANCOVA model for TOTPAR6  
4.1.2.1 Test of Fixed Effects 
4.1.2.1.1 Test of Fixed Effects for TOTPAR6 
4.1.2.1.2 Test of Fixed Effects for TOTPAR6 (PP Population) 
4.1.2.2 Estimation and difference of Least Squares Means   


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4.1.2.2.1 Estimation and difference of LSM for TOTPAR6 
4.1.2.2.2 Estimation and difference of LSM for TOTPAR6  (PP Population) 
 
4.2 
Secondary analysis  
4.2.1 
Continuous variables 
 
4.2.1.1 Pain Intensity score 
4.2.1.1.1 Descriptive statistics and change vs. Baseline by timepoint 
4.2.1.1.2  ANCOVA model  (longitudinal analysis) 
4.2.1.1.2.1 Test of fixed effect 
4.2.1.1.2.2 Estimation and difference  of LSM 
4.2.1.1.3   ANCOVA model (analysis by timepoint) 
4.2.1.1.3.1 Test of fixed effect 
4.2.1.1.3.2 Estimation and difference  of LSM 
 
4.2.1.2 SPIDs at 2, 4 ,6 and 8 hours   
Note: For SPID6 analysis will be performed also on the PP population to check non-inferiority as for TOTPAR6 
4.2.1.2.1 Descriptive statistics  for SPIDs 
4.2.1.2.2 ANCOVA model 
4.2.1.2.2.1 Test of fixed effect for SPID6 
4.2.1.2.2.2 Estimation and difference  of LSM for SPID6 
4.2.1.2.2.3 Test of fixed effect for SPID2,SPID4 and SPID8 
4.2.1.2.2.4 Estimation and difference  of LSM for SPID2,SPID4 and SPID8 
4.2.1.2.3 Descriptive statistics of SPID6 (PP Population) 
4.2.1.2.4 ANCOVA model (PP Population) 
4.2.1.2.4.1 Test of fixed effect for SPID6 
4.2.1.2.4.2 Estimation and difference  of LSM for SPID6 
 
4.2.1.3 %max SPIDs at 2, 4, 6 and 8  
4.2.1.3.1 Descriptive statistics  for %max SPIDs  
4.2.1.3.2 ANCOVA model   
4.2.1.3.2.1 Test of fixed effect   
4.2.1.3.2.2 Estimation and difference  of LSM 
 
4.2.1.4 TOTPARs at 2, 4 and 8 hours  
4.2.1.4.1 Descriptive statistics  for TOTPARs  
4.2.1.4.2 ANCOVA model   
4.2.1.4.2.1 Test of fixed effect   
4.2.1.4.2.2 Estimation and difference  of LSM 
 
4.2.1.5 %max TOTPARs at 2, 4, 6 and 8  
4.2.1.5.1 Descriptive statistics  for %max TOTPARs  
4.2.1.5.2 ANCOVA model   
4.2.1.5.2.1 Test of fixed effect   


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4.2.1.5.2.2 Estimation and difference of LSM 
 
 
4.2.2 
Categorical variables  
 
4.2.2.1 Pain Relief score 
4.2.2.1.1  Descriptive statistics and change vs. Baseline by timepoint 
4.2.2.1.2 Wilcoxon rank-sum test 
 
4.2.2.2 Patient Global Evaluation  
4.2.2.2.1 Descriptive statistics  
4.2.2.2.2 Wilcoxon rank-sum test 
 
4.2.3 
Binary variables  
 
4.2.3.1 Pain Intensity Responders at 2, 4, 6 and 8 hours 
4.2.3.1.1 Frequency table and percentage  
4.2.3.1.2 Chi-Square Test by timepoint 
4.2.3.1.3 GEE model  
4.2.3.1.3.1 
Test of fixed effect  
4.2.3.1.3.2 
Estimation and difference of LSM 
 
4.2.3.2 TOTPAR responders at 2, 4, 6 and 8 hours 
4.2.3.2.1 Frequency table and percentage  
4.2.3.2.2 Chi-Square Test by timepoint 
4.2.3.2.3 GEE model  
4.2.3.2.3.1 
Test of fixed effect  
4.2.3.2.3.2 
Estimation and difference of LSM 
 
4.2.3.3 FPPAR within 30 minutes, 1 hour and 2 hours 
4.2.3.3.1 Frequency table and percentage  
4.2.3.3.2 Chi-Square Test by timepoint 
 
4.2.3.4 Confirmed FPPAR within 30 minutes, 1 hour and 2 hours 
4.2.3.4.1 Frequency table and percentage  
4.2.3.4.2 Chi-Square Test by timepoint 
 
4.2.3.5 MPAR within 30 minutes, 1 and 2 hours 
4.2.3.5.1 Frequency table and percentage  
4.2.3.5.2 Chi-Square Test by timepoint 
 
4.2.3.6 Use of Rescue Medication within  2,4, 6 and 8 hours 
4.2.3.6.1 Frequency table and percentage  
4.2.3.6.2 Chi-Square Test by timepoint 


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4.2.4 
Time to Event analysis 
4.2.4.1 Time to FPPAR 
4.2.4.2 Time to Confirmed FPPAR 
4.2.4.3 Time to MPAR 
4.2.4.4 Time to Rescue Medication  
 
4.3 
Subgroup analysis  
4.3.1  Descriptive statistics of TOTPAR6 by subgroups [Age (Quartiles), gender and country] 
4.3.2 ANCOVA model for TOTPAR6  subgroups [Age (Quartiles), gender and country] 
4.3.2.1 Test of Fixed Effects for TOTPAR6 
4.3.2.2 Estimation and difference of LSM for TOTPAR6 
 
Figures 
 
Graph 1: Baseline Means Value of Pain Intensity Score at Qualification and T0h 
Graph 2: Time course of Pain Intensity Score over 8 hours 
Graph 3: SPIDs at 2, 4, 6 and 8 hours 
Graph 4: % max SPIDs at 2, 4, 6 and 8 hours 
Graph 5: Pain Intensity Responders at 2, 4, 6 and 8 hours 
Graph 6: Time course of Pain Relief Score over 8 hours 
Graph 7: TOTPARs at 2, 4, 6 and 8 hours 
Graph 8:  % max TOTPARs at 2, 4, 6 and 8 hours 
Graph 9: TOTPAR Responders at 2, 4, 6 and 8 hours 
Graph 10: Patient Global Evaluation  
Graph 11: FPPAR at 30 minutes, 1 and 2 hours 
Graph 12: Confirmed FPPAR at 30 minutes, 1 and 2 hours 
Graph 13: MPAR at 30 minutes, 1 and 2 hours 
Graph 14: Use of Rescue medication within 2,4, 6 and 8 hours 
Graph 15: Kaplan-Meier for FPPAR 
Graph 15: Kaplan-Meier for Confirmed FPPAR 
Graph 15: Kaplan-Meier for MPAR 
Graph 15: Kaplan-Meier for Rescue Medication  
Graph XX:Model assumption assessment  
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.4 Patient data listing 
 
Key variables (KV) are the variables present in each patient data listing: Subject number, age, gender, 
planned treatment, study population (Yes/No for Safety, ITT and PP). Screening Failures will be 
excluded from the listing.   
The following list is intended to provide the overall idea of the general output. 
 
L.1 
Patient disposition  
KV, date/time of informed consent,  date of screening, date/time of first study treatment, date of end of participation, 
reported term for the disposition event, standardized disposition term. 
L.2 
Demography  
KV, race, race specification, ethnicity, country, childbering potential (yes/no), actual treatment 
L.3 
Baseline characteristics  
KV, pain intensity at baseline, pain intensity at qualification.  
L.4 
Medical History  
KV, start date of medical history event, end date of medical history event, ongoing, body system or organ 
class/reported term for the medical history, HLGT, HLT, LLT. 
L.5 
Previous and Concomitant Medication  
KV, medication class, medication name, indication, dose form, dose, dosing frequency per interval, route of 
administration, start date of medication, end date of medication, ongoing, ATC1 (first level group) /ATC2 (second 
level group) /ATC3 (third level group), category (prior, concomitant, prior and concomitant) 
L.6 
Drug Exposure   
KV, actual treatment, box number planned, box number received, start date/time of treatment 
L.7 
All Adverse Events    
KV, date/time of first study treatment, actual treatment, treatment emergent analysis (yes/no), reported term for the 
adverse event, body system or organ class, causality, pattern of adverse event, concomitant or additional treatment 
given (yes/no), start date/time of adverse event, end date/time of adverse event, ongoing (yes/no), action taken with 
study treatment/outcome of adverse event, serious event (yes/no)/severity, lowest level term/high level term/high 
level group term 
L.8 
Laboratory results 


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KV, parameter, baseline (yes/no), category (coagulation test, haematology, serum chemistry, urinalysis), completion 
status, visit name (pre-surgery or unscheduled), investigator’s judgement (normal, abnormal NCS or abnormal CS), 
date/time of specimen collection, result in standard format, range in standard units. 
L.9 
Pregnancy Test Data 
KV, result test prior to surgery, date of specimen collection at baseline, result test at V1, date of collection at V1, 
result test at V4, date of collection at V4 
L.10 
Vital Signs Data 
KV, parameter, baseline (yes/no), visit name (pre-surgery, surgery, end of study), investigator’s judgement (normal, 
abnormal NCS or abnormal CS), actual treatment, date/time of measurements, result in standard units (standard 
units), change surgery-end of study. 
L.11 
Physical Examination Data 
KV, visit name (pre-surgery, unscheduled, end of study), date of examination,  actual treatment, investigator’s 
judgement (normal, abnormal NCS, abnormal CS or NOT DONE) 
L.12 
PI-NRS (Numerical Rating Scale) 
KV, PI value (original data),, timepoint, change from baseline, RMediary, RMeCRF, RMediaryLOCF, 
RMeCRFLOCF, missing. 
L.13 
All SPID Data 
KV, SPID2, derivation type SPID2, SPID4, derivation type SPID4, SPID6, derivation type SPID6, SPID8, 
derivation type SPID8. 
L.14 
All Mean % max of SPID Data 
KV,  Mean % max of SPID2, derivation type Mean % max of SPID2, Mean % max of SPID4, derivation type Mean 
% max of SPID4, Mean % max of SPID6, derivation type Mean % max of SPID6, Mean % max of SPID8, 
derivation type Mean % max of SPID8. 
L.15 
All TOTPAR Data   
KV, Total Pain Relief over 2 hours, derivation type TOTPAR2, Total Pain Relief over 4 hours, derivation type 
TOTPAR4, Total Pain Relief over 6 hours, derivation type TOTPAR6, Total Pain Relief over 8 hours, derivation 
type TOTPAR8. 


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L.16 
All Mean % max of TOTPAR Data   
KV, Mean % max of TOTPAR2, derivation type Mean % max of TOTPAR2, Mean % max of TOTPAR4, 
derivation type Mean % max of TOTPAR4, Mean % max of TOTPAR6, derivation type Mean % max of 
TOTPAR6, Mean % max of TOTPAR8, derivation type Mean % max of TOTPAR8.  
L.17 
PAR-VRS (Verbal Rating Scale)   
KV, parameter (PAR), PAR value (original value), timepoint, RMediary, RMeCRF, RMediaryLOCF, 
RMeCRFLOCF, missing. 
L.18 
Patient Global Evaluation   
KV, patient global evaluation, date/time of finding, actual treatment. 
L.19 
Rescue Medication   
KV, date/time of first exposure to treatment, rescue medication required within 4 hours (yes/no), rescue medication 
required within 6 hours (yes/no),  rescue medication required within 8 hours (yes/no), standardized medication 
name, ATC1, ATC3, dose form, start date/time of medication, end date/time of medication, comment. 
L.20 
FPPAR MPAR and CFPPAR 
KV, time to FPPAR, censor FPPAR(yes/no), censoring description FPPAR, time to MPAR, censor MPAR(yes/no), 
censoring description MPAR,  censor CFPPAR(yes/no), event or censoring description CFPPAR. 
L.21 
FSURG 
KV, first tooth ID, time anaesthetic, time last suture, duration of surgery, number of teeth, sum of surgical trauma 
rating scale, second tooth ID, third tooth ID, fourth tooth ID. 
 
 
 
 
 
 
 
 
 
7 
REFERENCES 
1. DEX-TRA 06 Study protocol, Final Version 2.0, November 24, 2015 , Menarini Ricerche, S.p.A   


Menarini Ricerche S.p.A. 
 
          Study DEX-TRA-06 
 
 
Statistical Analysis Plan 
Version 1.0, 14 FEB 2017 
 
Page 49 of 49 
 
 
2. International Conference on Harmonisation ICH Topic E9: Statistical principles for clinical 
trials. 1998.  
3. International Conference on Harmonisation ICH Topic E10: Choice of control group and related 
issues in clinical trials. 2001