Clinical trial NCT05170841
Conditions: Low Back Pain
Sponsor: Menarini International Operations Luxembourg SA
Start date: 2020-09-17; Completion date: 2022-05-04
Enrollment: 538 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A randomized, double-blind, study to evaluate the analgesic efficacy and safety of Dexketoprofen trometamol and Tramadol hydrochloride combination versus placebo on moderate to severe acute pain in patients with acute low back pain.

Detailed description:
This is a multicenter, randomized, double-blind, double-dummy, parallel group, placebo-controlled study encompassing 2 study phases: a single-dose phase (first 8 hours) and a multiple-dose phase starting after the single-dose phase (from 8h until day 5).

Study population will be of male or female patients aged 18 years to 65 years with acute low back pain of moderate to severe intensity, whose onset of the current acute low back pain episode is within 48 hours prior to Screening. Patients with or without radiculopathy will be included, excluding those with neurological signs, according to the Quebec Task Force classification. Patients experiencing a new episode of low back pain will be eligible only if preceded by a period of at least 2 months without any low back pain. Patients should be free from analgesic due to previously administered pain killer (immediate or slow release formulations), according to exclusion criteria.

Approximately 612 patients will be screened to achieve 510 patients randomly assigned to study treatment.

In the single-dose phase patients will receive a single-dose treatment, consisting of 1 film-coated tablet and 2 capsules which have to be orally administered together at the same time (Day 1). The multiple-dose phase will begin 8 hours after the first dose. The patients assigned to Dexketoprofen/Tramadol fixed combination or Tramadol 100 milligram (mg) during the single-dose phase will continue to receive the same treatment during the multiple-dose phase; however, the patients assigned to receive placebo during the single-dose phase will either receive Dexketoprofen/Tramadol fixed combination or Tramadol 100 mg during the multiple-dose phase.

Arms: arm 1: Two phase intervention. Single Dose Phase (time 0 - time 8h) and Multiple Dose phase (time 8h - Day 5) In this arm patients will receive during each phase film coated tablets (administered as one tablet) arm 2: Two phase intervention. Single Dose Phase (time 0 - time 8h) and Multiple Dose Phase (time 8h - Day 5) In this arm patients will receive during each phase (administered as 2 capsules of Tramadol 50 mg) arm 3: Two phase intervention. Single dose phase (time 0 - time 8h) and Multiple Dose Phase (time 8h - Day 5).

SINGLE DOSE PHASE: Placebo film-coated tablets matching Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg MULTIPLE DOSE PHASE: Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg film coated tablets (administered as one tablet) arm 4: Two phase intervention. Single Dose Phase (time 0 - time 8h) and Multiple Dose Phase (time 8h - Day 5).

SINGLE DOSE PHASE: Placebo capsules matching active comparator (administered as 2 capsules of Tramadol 50 mg) MULTIPLE DOSE PHASE: Tramadol Hydrochloride 100 mg (administered as 2 capsules of Tramadol 50 mg)
Interventions: intervention 1: Dexketoprofen Trometamol 25 mg/Tramadol Hydrochloride 75 mg intervention 2: Tramadol Hydrochloride 100 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Administered as one single tablet to be taken every 8 hours intervention 2: Administered as two capsules with 50 mg each to be taken every 8 hours intervention 3: Administered as one tablet if matching Dexketoprofen Trometamol 25 mg and Tramadol Hydrochloride 75 mg or two capsules if matching Tramadol Hydrochloride 100 mg

Protocol documents:
Prot_000.pdf: 
Corporate Medical Department 
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1 
CLINICAL STUDY PROTOCOL 
A randomized, double-blind, placebo-controlled, parallel arm group study to evaluate the 
analgesic efficacy and safety of Dexketoprofen trometAmol aNd Tramadol hydrochloride oral 
fixEd dose combination on moderate to severe acute pain in patients with acute low back pain 
DANTE study 
Sponsor name and address 
Menarini International Operations Luxembourg SA. 
1, Avenue de la Gare L-1611 Luxembourg. 
Ph. (+352) 2649761 - Fax (+352) 26497649 
Protocol Code 
MEIN/18/DEX-LBP/001 
EudraCT (or National Clinical 
Trial Identified Number) 
2019-003656-37 
Protocol Phase (if applicable) 
IV 
Study type and design: 
Multicenter, randomized, double-blind, 
double-dummy, parallel group, placebo-controlled 
study encompassing 2 study phases: a single-dose 
phase (first 8 hours) and a multiple-dose phase 
starting after the single-dose phase. 
Protocol Version Number 
Version 2 (Amendment 1) 
Protocol Version Date 
13 September 2021 
Coordinating Investigator 
Prof. Giustino Varrassi 
CRO 
IQVIA 
NCT05170841


 
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CONFIDENTIAL                                                                                                                                               2 
 
Summary of Changes from Previous Version 
Document History 
Document 
Date 
Substantial 
Region 
Amendment 1 
13 September 2021 
Yes 
Global 
 
The overall rationale for this amendment is to update the change in the sample size as per the 
re-estimation of sample size and to incorporate the changes provided in erratum dated 
19 May 2020. 
 
Affected Section(s) 
Summary of Revisions Made 
Rationale 
Section 2. Protocol 
Synopsis 
 
Section 14.2. 
Determination of Sample 
Size 
The statistical power of the study has 
been revised in order to achieve a 
desired power level of 80%. The 
original study power was set at 90%.  
The sample size for the study has 
been reduced accordingly from 680 
to 510 and the number of patients to 
be randomized in each treatment 
arm has been updated (204 patients 
each in TRAM.HCl  and 
DKP.TRIS/TRAM.HCl treatment 
groups and 102 patients in Placebo 
groups). The total number of patients 
to be screened is changed to 612 
patients from 816 patients  
The text related to the sample size 
determination and study schema is 
updated accordingly. 
The protocol changes have been 
implemented to compensate the 
issues and delays caused by 
COVID-19 Pandemic situation 
(patients limited access to 
hospitals and healthcare workers). 
We have proposed a sample size 
re-estimation in order to achieve a 
desired power level of 80%. The 
original study power was set at 
90%. The estimation of effect 
size, population variance and 𝛼-
level were the same used to 
calculate the original sample size. 
The power of 80% is deem 
sufficient to keep the scientific 
integrity of the study results 
Section 2. Protocol 
Synopsis 
 
In inclusion criterion 6, the reference 
to exclusion criterion 14 is changed 
to exclusion criterion 15. 
Reference to the correct exclusion 
criterion has been updated 


 
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CONFIDENTIAL                                                                                                                                               3 
 
Section 8.1.1 
Inclusion Criteria 
To correct the incorrect reference 
to exclusion criterion 
Section 2. Protocol 
Synopsis 
 
Section 8.1.2 
Exclusion Criteria 
Added examples for other analgesics 
in exclusion criterion 15. 
 
For exclusion criterion 16 added 
selective serotonin reuptake 
inhibitors and serotonin 
norepinephrine reuptake inhibitors in 
parenthesis for serotonin reuptake 
inhibitors. 
Examples of medication added for 
clarification  
 
 
Examples of medication added for 
clarification  
Section 10.2 
Assessment of Safety 
 
Section 12 Withdrawal 
Criteria 
Creatinine clearance value defining 
abnormal renal function is corrected 
from ≥60 mL/min to ≤60 mL/min. 
To correct the error in definition of 
abnormal renal function. 
Abnormal renal function for the 
study is defined as ≤60 mL/min 
Section 10.2 
Assessment of Safety 
Removed the word “locally” with 
reference to urinalysis. 
To remove the reference to local 
laboratory. All the laboratory 
evaluations will be performed in 
central laboratory. 
Section 2. Protocol 
Synopsis  
 
Section 7 
Exclusion Criteria 
The number of countries where the 
study is conducted is reduced to 6 
from 8; Italy and Lithuania are 
removed from the list. 
Administrative change 
 
CONFIDENTIALITY STATEMENT 
The information in this document contains information that are privileged or confidential and may not 
be disclosed unless such disclosure is required by law. In any event, persons to whom the information 
is disclosed must be informed that the information is privileged or confidential and may not be further 
disclosed by them. These restrictions on disclosure will apply equally to all future information supplied 
to you which is indicated as privileged or confidential. 


 
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4 
 
T AB L E  O F  C O N T E N T S  
A randomized, double-blind, placebo-controlled, parallel arm group study to evaluate the 
analgesic efficacy and safety of Dexketoprofen trometAmol aNd Tramadol hydrochloride oral 
fixEd dose combination on moderate to severe acute pain in patients with acute low back 
pain ................................................................................................................................................ 1 
DANTE study ................................................................................................................................. 1 
1. 
RESPONSIBILITIES ............................................................................................................... 8 
2. 
PROTOCOL SYNOPSIS ....................................................................................................... 10 
Inclusion Criteria .......................................................................................................................14 
Exclusion Criteria ......................................................................................................................15 
3. 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS .................................................. 24 
4. 
STUDY SCHEME .................................................................................................................. 26 
4.1 
Study Flow Chart ..................................................................................................... 27 
5. 
STUDY RATIONALE AND BACKGROUND INFORMATION ............................................... 29 
5.1 
Low Back Pain ......................................................................................................... 29 
5.2 
Investigational Medicinal Product: Dexketoprofen Benefits ...................................... 29 
5.2.1. Pre-clinical data on the co-administration of dexketoprofen trometamol and tramadol 
Hydrochloride ...........................................................................................................................32 
5.2.2. Clinical development of dexketoprofen trometamol and tramadol hydrochloride fixed 
combination ..............................................................................................................................33 
5.3 Assessment of Potential Risks and Benefits ................................................................ 45 
6. 
TRIAL OBJECTIVES AND ENDPOINTS .............................................................................. 47 
7. 
STUDY DESIGN. ................................................................................................................... 50 
7.1 
Procedures and Study Visits .................................................................................... 51 
8. 
SELECTION OF SUBJECTS ................................................................................................ 55 
8.1 
Inclusion and Exclusion Criteria ............................................................................... 56 
8.1.1 
Inclusion Criteria .........................................................................................................56 
8.1.2. 
Exclusion Criteria ........................................................................................................57 
8.1.3. Screening Failures ..........................................................................................................59 
9. 
STUDY TREATMENT ........................................................................................................... 59 
9.1 
Study Treatment Formulation, Appearance, Packaging, and Labeling ..................... 60 
9.2 
Study Treatment Distribution and Return/Destruction .............................................. 62 


 
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CONFIDENTIAL                                                                                                                                               5 
 
9.3 
Product Storage and Stability .................................................................................. 62 
9.4 
Study Product Compliance ...................................................................................... 63 
9.5 
Concomitant Therapy/ies ......................................................................................... 63 
9.6 
Not Permitted Medications ....................................................................................... 63 
9.7 
Rescue Medicine ..................................................................................................... 64 
10. 
STUDY ASSESSMENT AND PROCEDURES ................................................................... 65 
10.1 
Assessment of Efficacy ........................................................................................ 65 
10.2 
Assessment of Safety .......................................................................................... 66 
11. 
SAFETY DATA MANAGEMENT ....................................................................................... 67 
11.1 
Adverse Event (AE).............................................................................................. 67 
11.2 
Drug Relationship ................................................................................................ 67 
11.3 
Adverse Drug Reaction (ADR) ............................................................................. 68 
11.4 
Seriousness ......................................................................................................... 68 
11.5 
Adverse Event/Adverse Drug Reaction Intensity .................................................. 69 
11.6 
Adverse Event/Adverse Drug Reaction Expectedness ......................................... 69 
11.7 
Serious Unexpected Adverse Drug Reaction (SUSAR) ........................................ 69 
11.8 
Individual Case Safety Report (ICSR) .................................................................. 70 
11.9 
Collection, Recording and Reporting of AEs ........................................................ 70 
11.10 
Management of Serious AEs (SAEs) including laboratory abnormalities .............. 71 
 
Reporting Duties of the Investigator ...................................................................................71 
 
Reporting Duties of the Sponsor ........................................................................................71 
11.11 
Management of Non-serious AEs (NSAEs) including laboratory abnormalities .... 72 
 
Reporting Duties of the Investigator ...................................................................................72 
11.12 
Management of any laboratory abnormality ......................................................... 72 
11.13 
Management of pregnancy exposure cases ......................................................... 73 
12. 
WITHDRAWAL CRITERIA ................................................................................................ 73 
13. 
LOST TO FOLLOW-UP ..................................................................................................... 74 
14. 
STATISTICS ...................................................................................................................... 74 
14.1 
Statistical Methods (Blinding and Randomization) ................................................ 75 
14.2 
Determination of Sample Size .............................................................................. 76 


 
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14.3 
Analysis Populations ............................................................................................ 77 
14.4 
Analysis Variables ................................................................................................ 78 
14.5 
STATISTICAL ANALYSIS .................................................................................... 81 
.Descriptive statistics ................................................................................................................81 
Primary (efficacy) analysis ........................................................................................................81 
Sensitivity analysis ....................................................................................................................82 
Secondary (efficacy) analysis ...................................................................................................82 
Exploratory (efficacy) analysis ..................................................................................................83 
Subgroup analysis ....................................................................................................................83 
Safety analysis .........................................................................................................................83 
Interim analysis and stopping rules ...........................................................................................84 
Data imputations .......................................................................................................................84 
14.6 
Protocol Deviations and Protocol Amendments .................................................... 84 
14.7 
Statistical Analysis Plan ....................................................................................... 85 
15. 
STUDY DISCONTINUATION AND CLOSURE .................................................................. 86 
16. 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTS ..................................................... 86 
17. 
QUALITY CONTROL AND QUALITY ASSURANCE ........................................................ 86 
17.1 
Study Monitoring/Data Quality Control ................................................................. 86 
17.2 
Case Report Forms .............................................................................................. 87 
17.3 
Quality Assurance ................................................................................................ 87 
18. 
ETHICS ASPECTS ............................................................................................................ 87 
18.1 
Ethics Committees ............................................................................................... 87 
18.2 
Subject’s Insurance .............................................................................................. 88 
19. 
DATA PROTECTION LAWS COMPLIANCE ..................................................................... 88 
19.1 
Acknowledgment .................................................................................................. 88 
19.2 
Data Controllers and Data Processors ................................................................. 89 
19.3 
Duties of the Parties involved in the performance of the study ............................. 89 
19.4 
Data Breach ......................................................................................................... 92 
19.5 
Information Notice on Personal Data Protection and Pseudo-anonymization ....... 94 
19.6 
Genetic Data ........................................................................................................ 95 


 
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CONFIDENTIAL                                                                                                                                               7 
 
19.7 
Transfer of subjects’ data outside the European Union ........................................ 95 
19.8 
Exercise of subjects’ data privacy rights ............................................................... 95 
19.9 
Future research .................................................................................................... 96 
20. 
DATA HANDLING AND RECORDS KEEPING ................................................................. 96 
21. 
PUBLICATION POLICY AND RESULTS .......................................................................... 97 
22. 
REFERENCES .................................................................................................................. 98 
23. 
Protocol Approval Page ................................................................................................. 101 
24. 
Investigator’s approval Page ......................................................................................... 102 
25. 
APPENDICES .................................................................................................................. 103 
25.1 
Appendix 1: Declaration of Helsinki .................................................................... 103 
 
 


 
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CONFIDENTIAL                                                                                                                                               8 
 
1. RESPONSIBILITIES 
 
Sponsor:  
Name: Menarini International Operations 
Luxembourg SA 
Address: 1, Avenue de la Gare L-1611 
Luxembourg 
Phone: +352 2649761 
Clinical Trial Coordinator (CTC): 
Name: Manuella Mendes Martins  
Address: Via Sette Santi 1-3, 50131, Firenze 
Phone: +39 055 56807394 
e-mail: mmendesmartins@menarini.it  
Study Medical Expert (SME): 
Name: Deniz Coskunsever  
Address: Via Sette Santi 1-3, Firenze 
Phone: +90 538 5440052 
e-mail: dcoskunsever@menarini.com.tr  
Study Drug Safety Manager (SDSM):  
Name: Francesca Ricupito 
Address: Via Sette Santi 1-3, 50131, Firenze 
Phone: +39 055 56809379 
e-mail: fricupito@menarini.it 
Coordinating Investigator  
Name: Prof. Giustino Varrassi 
Address: Frazione San Vittorino, Via Colle 
Rignano 1, 67100 L’Aquila, Italy  
Phone: +39 3486068472 
e-mail: giuvarr@gmail.com  
CRO  
Name: IQVIA Ltd 
Address: Forbury Place, 23 Forbury Road, 
Reading 
RG1 3JH, UK 
Phone: +44 118 450 8000 
Statistician  
Name: Aswin Nair 
 


 
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CONFIDENTIAL                                                                                                                                               9 
 
Address: IQVIA, World Trade Center  
Tower A, 7th Floor Infopark, Kusumagiri 
Phone: +914847113757 
e-mail: aswin.nair@iqvia.com  
Any other relevant Person/Organisation: 
Sponsor QC Statistician  
Name: Giorgio Reggiardo 
Address: Medi Service – Genoa 
Phone: 0039 0108990125 
e-mail: giorgio.reggiardo@mediservice.it 
 
 


 
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CONFIDENTIAL                                                                                                                                               10 
 
2. PROTOCOL SYNOPSIS 
 
Title 
Acronym  
Sponsor Study Code  
A randomized, double-blind, placebo-controlled, parallel arm group study 
to evaluate the analgesic efficacy and safety of Dexketoprofen 
trometAmol aNd Tramadol hydrochloride oral fixEd dose combination on 
moderate to severe acute pain in patients with acute low back pain – DANTE 
study. 
Study product, Dosage 
and Regimen:  
-Investigational Product 
 
-Reference Therapy 
(comparator) 
 
Dexketoprofen trometamol (DKP.TRIS) 25 mg/Tramadol hydrochloride 
(TRAM.HCl) 75 mg film-coated tablet administered orally as a single tablet, 
every 8 hours. 
Placebo as one tablet matching DKP.TRIS 25 mg/TRAM.HCl 75 mg. 
Placebo as two capsules matching TRAM.HCl. 
Tramadol (TRAM.HCl) 100 mg, as two capsules with 50 mg every 8 hours. 
Study Type and Design 
This is a multicenter, randomized, double-blind, double-dummy, parallel 
group, placebo-controlled study encompassing 2 study phases: a 
single-dose phase (first 8 hours) and a multiple-dose phase starting after the 
single-dose phase (from t8 h until day 5). 
510 eligible patients will be randomized in a 4:4:1:1: ratio to 1 of the 4 
possible treatment arms: 
 
Single-dose phase (t0-t8) 
Multiple-dose phase (t8-day5) 
DKP.TRIS/TRAM.HCl n=204 
DKP.TRIS/TRAM.HCl 
TRAM.HCl n=204 
TRAM.HCl 
Placebo n=51 
DKP.TRIS/TRAM.HCl 
Placebo n=51 
TRAM.HCl 
Phase 
IV 
Objectives 
Primary objective: 
 
To evaluate the analgesic efficacy of DKP.TRIS/TRAM.HCl fixed 
combination versus placebo in moderate to severe acute low back 
pain after the first dose (first 8 hours). 


 
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Secondary objectives: 
 
To evaluate the analgesic efficacy of DKP.TRIS/TRAM.HCl fixed 
combination versus TRAM.HCL 100 mg in moderate to severe acute 
low back pain after the first dose (first 8 hours). 
 
To evaluate the analgesic efficacy of DKP.TRIS/TRAM.HCl fixed 
combination in moderate to severe acute low back pain versus 
TRAM.HCl 100 mg after multiple doses (from t8h until day 5).  
 
To assess the safety and tolerability of DKP.TRIS/TRAM.HCl fixed 
combination after single and multiple doses. 
Endpoints 
Primary endpoint: 
Time to first achieve a numeric rating scale-pain intensity (NRS-PI) score of 
<4 or a pain intensity reduction ≥30% from drug intake till 8 hours after the 
first dose (t8h). 
Secondary endpoints: 
Single-dose phase: Day 1; t0-t8h 
 
Pain relief (PAR) – verbal rating scale (VRS) scores at each 
prespecified time point (t15m, t30m, t1h, t1.5h, t2h, t4h, t6h, t8h) over 
the 8 hours after the first dose. 
 
Total pain relief (TOTPAR) at 4, 6, and 8 hours (TOTPAR4, 
TOTPAR6, TOTPAR8) after the first dose. 
 
Percentage of maximum TOTPAR (% max TOTPAR) at 4, 6 and 
8 hours after the first dose. 
 
Percentage of patients achieving at least 50% of maximum TOTPAR 
at 4, 6, and 8 hours after the first dose. 
 
Mean Pain Intensity (PI) - visual analogue scale (VAS) scores at 
each prespecified time points (t15m, t30m, t1h, t1.5h, t2h, t4h, t6h, 
t8h) over the 8 hours after the first dose. 
 
Summed pain intensity difference (SPID) at 4, 6, and 8 hours (SPID4, 
SPID6, SPID8) after the first dose. 


 
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 
Percentage of maximum SPID (% max SPID) at 4, 6, and 8 hours 
after the first dose. 
 
Percentage of patients achieving at least 30% of pain intensity 
reduction versus baseline at 4, 6, and 8 hours after the first dose. 
 
Patient global evaluation (PGE) of the study medication at 8 hours 
after the first dose. 
 
Time to rescue medication (RM): Time elapsed between treatment 
administration and the first dose of RM from baseline till 8 hours after 
the first dose. 
 
Percentage of patients who required RM within the first 4, 6, or 
8 hours after the first dose. 
Multiple-dose phase: from t8h to 8 hour after last dose intake on Day 5 
 
PAR-VRS scores at each prespecified time point over the multiple-
dose phase. 
 
TOTPAR at 24, 48, 72, and 96 hours (TOTPAR24, TOTPAR48, 
TOTPAR72, TOTPAR96) of the multiple-dose phase. 
 
Percentage of maximum TOTPAR (% max TOTPAR) at 24, 48, 72, 
and 96 hours of the multiple-dose phase. 
 
Percentage of patients achieving at least 50% of maximum TOTPAR 
at 24, 48, 72, and 96 hours of the multiple-dose phase. 
 
Pain intensity (PI)- VAS scores at each prespecified time point over 
the multiple-dose phase. 
 
SPID at 24, 48, 72, and 96 hours (SPID24, SPID48, SPID72, 
SPID96) of the multiple-dose phase. 
 
Percentage of maximum SPID (% max SPID) at 24, 48, 72, and 
96 hours of the multiple-dose phase. 
 
Percentage of patients achieving at least 30% of PI reduction versus 
baseline at 24, 48, 72, and 96 hours of the multiple-dose phase. 
 
PGE at 96 hours of the multiple-dose phase. 


 
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CONFIDENTIAL                                                                                                                                               13 
 
 
Percentage of patients who required RM within 24, 48, 72, and 
96 hours of the multiple-dose phase. 
 
Roland Morris Disability Questionnaire (RMQ) at 96 hours of the 
multiple-dose phase. 
 
Treatment Satisfaction Questionnaire for Medication (TSQM) at 
96 hours of the multiple-dose phase. 
Complete treatment and assessment period: from t0 on Day 1 to 8 hour after 
last dose intake on Day 5 
 
Time to first achieve an NRS score <4 or a pain intensity reduction of 
≥30% from the first drug intake till 5 days after the first dose, 
excluding patients assigned to the placebo treatment arms during the 
single-dose phase. 
 
TOTPAR at 104 hours from the first drug intake till 5 days after the 
first dose (TOTPAR104), excluding patients assigned to the placebo 
treatment arms during the single-dose phase. 
 
SPID at 104 hours from the first drug intake till 5 days after the first 
dose (SPID104), excluding patients assigned to the placebo 
treatment arms during the single-dose phase. 
 
Time to RM: Time elapsed between the first drug intake till 5 days 
after the first dose, excluding patients assigned to the placebo 
treatment arms during the single-dose phase. 
Exploratory endpoint: 
Time to first achieve an NRS-PI score <4 AND a pain intensity reduction of 
≥30% from drug intake till 8 hours after the first dose. 
Study Population: 
Subject’s characteristics 
 
 
 
 
Male or female patients aged 18 years to 65 years with acute low back pain 
of moderate to severe intensity, whose onset of the current acute low back 
pain episode is within 48 hours prior to Screening. Patients with or without 
radiculopathy will be included, excluding those with neurological signs, 
according to the Quebec Task Force classification. Patients experiencing a 
new episode of low back pain will be eligible only if preceded by a period of 


 
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CONFIDENTIAL                                                                                                                                               14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
at least 2 months without any low back pain. Patients should be free from 
analgesic due to previously administered pain killer (immediate or slow 
release formulations), according to exclusion criteria. 
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 will be excluded.  
Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all 
of the following criteria: 
1. Properly executed written informed consent. 
2. Male or female patients aged 18 years to 65 years. 
3. Patients with acute low back reporting pain of at least moderate 
intensity at Screening (NRS score ≥ 5). The onset of the current 
acute low back pain episode is within 48 hours prior to Screening. 
4. Patients with or without radiculopathy will be included, excluding 
those with neurological signs, according to the Quebec Task Force 
classification. 
5. Naïve patients to any low back pain or patients with previous 
history of low back pain experiencing a new episode, preceded by 
a period of at least 2 months without any low back pain prior to 
Screening. 
6. Patients free from analgesic (as per exclusion criterion 15) due to 
previously administered pain killer (immediate or slow release 
formulations), according to physician’s judgment. 
7. Females participating in the study must be either: 
- 
Females of nonchildbearing potential, defined as any 
woman 
who 
had 
undergone 
surgical 
sterilization 


 
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CONFIDENTIAL                                                                                                                                               15 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
(documented hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy) or is more than 2 years 
postmenopausal (defined as no menses for 12 months); 
- 
Females of childbearing potential (following menarche until 
menopause unless permanently sterile) provided that they 
have a negative pregnancy test at Screening and are 
routinely using an effective method of birth control resulting 
in a low failure rate (ie, combined hormonal contraception, 
intrauterine device, condoms in combination with a 
spermicidal cream, male partner sterilization (vasectomy), 
bilateral tubal occlusion or total sexual abstinence) during 
the study treatment. 
8. Mentally competent and able to understand and give written 
informed consent prior to Screening. 
9. Compliant to undergo all visits and procedures scheduled in the 
Study. 
Exclusion Criteria 
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, CM and concurrent systemic diseases. 
2. Clinically significant abnormalities in the vital signs as per 
Investigator’s judgment. 
3. Patients with acute low back pain and radiation to limb with presence 
of neurologic signs (focal weakness, asymmetry of reflexes, sensory 
loss in a dermatome, or loss of bowel, bladder, or sexual function) 
according to Quebec Task Force Classification. 
4. History of hypersensitivity to the study treatments, RM or to any other 
nonsteroidal anti-inflammatory drugs (NSAIDs), or opioids. 
5. Known photoallergic or phototoxic reactions during treatment with 
ketoprofen or fibrates. 


 
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CONFIDENTIAL                                                                                                                                               16 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
6. History of peptic ulcer, gastrointestinal disorders when taking NSAIDs, 
gastrointestinal bleeding, or other active bleeding. 
7. History of allergy (eg, precipitate attacks of asthma, bronchospasm, 
acute rhinitis, or cause nasal polyps, urticaria or angioneurotic 
oedema) to the study treatments, RM or to any other NSAIDs, or 
opioids. 
8. Anamnestic mild to severe renal dysfunction, mild to severe hepatic 
dysfunction, as per Investigator’s judgment. 
9. Patients with chronic dyspepsia. 
10. Patients with severe heart failure (Class III and Class IV of New York 
Heart Association [NYHA] Classification). 
11. History of hemorrhagic diathesis and other coagulation disorders. 
12. History of or current epilepsy or convulsions. 
13. Patients with Crohn’s disease or ulcerative colitis. 
14. Patients receiving monoamine oxidase (MAO) inhibitors (a minimum 
of 14 days of washout must elapse prior to the Screening). 
15. Treatment with topical preparations/medications within 4 hours prior to 
Screening, anesthetics and muscle r2elaxants within 8 hours prior to 
Screening, short-acting analgesics (eg, paracetamol) within 4 hours 
prior to Screening, other analgesics (NSAIDs [eg, ketoprofen 
ibuprofen, diclophenac]) within 5 half-lives prior to Screening or use of 
an opioid within the 14 days preceding Screening. 
16. Treatment with high doses of salicylates (≥3 g/day), anticoagulants, 
thrombolytic and antiplatelet agents, heparins, corticosteroids (except 
inhalers and topical agents), lithium methotrexate, used at high doses 
of 15 mg/week or more, hydantoins (including phenytoin) and 
sulphonamides, antiepileptics, antipsychotics, serotonin reuptake 
inhibitors (selective serotonin reuptake inhibitors [SSRIs] and 
serotonin norepinephrine reuptake inhibitors [SNRIs]) and tricyclic 


 
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CONFIDENTIAL                                                                                                                                               17 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of Subjects 
antidepressants, and analgesics within 48 hours or 5 half-lives 
(whichever is the longer) prior to Screening. 
17. Patients using sedatives (eg, benzodiazepines) and hypnotic agents 
within 8 hours before Screening. 
18. Any chronic or acute painful condition other than the study indication 
that may interfere with the assessment of the efficacy of the study 
treatment. 
19. Any non-pharmacological interventional therapy for low back pain 
(physical therapy, acupuncture, massage etc.) one month before 
Screening. 
20. Patients with litigation related to work. 
21. Patients with severe dehydration (caused by vomiting, diarrhea, or 
insufficient fluid intake) within one month prior to Screening. 
22. Severe respiratory depression according to physician’s judgment. 
23. Participation in other clinical studies in the previous 4 weeks. 
24. 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). 
25. 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. 
26. Pregnant and breastfeeding women. NOTE: a pregnancy test will be 
performed on all women of childbearing potential at Screening. 
27. Patients presenting any of the contraindications reported for 
dexketoprofen/tramadol, tramadol or paracetamol (according to the 
SmPC). 
28. Known or suspected serious spinal pathology (eg, metastatic, 
inflammatory or infective diseases of the spine, cauda equine 
syndrome, trauma, spinal fracture). 


 
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CONFIDENTIAL                                                                                                                                               18 
 
29. Spinal surgery within the preceding 6 months. 
 
Approximately 612 patients will be screened to achieve 510 patients 
randomly assigned to study treatment given an expected 20% screen failure 
rate. 
Clinical Sites 
Number of Centers  
The study will be conducted in primary care and hospital setting in 6 
European countries. 
Number of centers: 50-60 
List of Countries 
Croatia, Estonia, Hungary, Latvia,  Poland, and Spain. 
 
 
 
Study Duration (specify 
different study phases): 
First Pts In (FPI) 
Last Pts Out (LPO) 
 
 
 
 
 
 
 
 
Study Description 
The individual study participation will last up to 8 days, including: 
Visit 1 (Day 1): screening phase, randomization and first study treatment 
administration. 
Complete treatment and assessment period: from Day 1 to Day 5. After the 
last dose intake on Day 5, the “follow-up period” will last until Visit 2 (Day 6 
+2 days). 
Visit 2: (Day 6 with an allowed time-window of +2 days): end of study visit.  
A follow up phone call after Visit 1 and Visit 2 will be performed within 24 hours 
from results only in case of abnormality and clinically relevant laboratory test 
according to the investigator judgement. 
 
In the single-dose phase patients will receive a single-dose treatment, 
consisting of 1 film-coated tablet and 2 capsules which have to be orally 
administered together at the same time (Day 1) and according to 
Investigator’s instructions. The multiple-dose phase will begin 8 hours after the 
first dose. The patients assigned to DKP.TRIS/TRAM.HCl fixed combination 
or TRAM.HCL 100 mg during the single-dose phase will continue to receive 
the same treatment during the multiple-dose phase; however, the patients 
assigned to receive placebo during the single-dose phase will either receive 
DKP.TRIS/TRAM.HCl fixed combination or TRAM.HCL 100 mg during the 
multiple-dose phase. 


 
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CONFIDENTIAL                                                                                                                                               19 
 
The overall clinical phase is planned to start in Q3/2020 and to be completed 
within Q2/2022. 
Statistical Assumptions 
 
Sample size calculation: 
A sample size of 510 patients is required to detect the difference between 
DKP.TRIS/TRAM.HCl and placebo and to demonstrate the non-inferiority of 
DKP.TRIS/TRAM.HCl versus TRAM.HCl for the time to first achieve an 
NRS-PI score <4 or a pain intensity reduction of ≥30% from drug intake till 
8 hours after the first dose. 
A sample size of a total number of 204 patients (102 for each treatment arm) 
was considered appropriate for detecting the superiority of 
DKP.TRIS/TRAM.HCl versus Placebo, assuming a power of 80%, alpha of 
0.05, and a hazard ratio of 1.5 with a relative Wald confidence interval of 
1.17 to 1.97 and the probability of event of 0.961 and 0.835 in the treatment 
and placebo groups, respectively (based on previous studies).. 
Additionally, a total number of 408 patients (204 for each treatment arm) is 
sufficient for assessing the non-inferiority of DKP.TRIS/TRAM.HCl versus 
TRAM.HCl, assuming a hazard ratio of 1.06, a non-inferiority margin of 0.8, 
a power of 80%, alpha of 0.025, and proportions of events of 96.1% and 
94.7%, respectively (based on previous studies). 
The 510 patients will be randomized in a 4:4:1:1 ratio (204 for 
DKP.TRIS/TRAM.HCl, 204 for TRAM.HCl and 102 for placebo - 51 switching 
to DKP.TRIS/TRAM.HCl and 51 switching to TRAM.HCl in the multiple dose 
phase). 
Assuming an approximately 20% screen failure rate, 612 patients are 
expected to be screened. 


 
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CONFIDENTIAL                                                                                                                                               20 
 
Analysis populations: 
The following populations will be considered for the statistical analysis: 
 
Safety population: All patients randomized who have received at 
least 1 dose of the study treatment. 
 
Intention-to-treat (ITT) population: All patients randomized. 
 
Per-protocol (PP) population: All patients of the ITT population who 
have not experienced major protocol violations. 
Efficacy analyses will be performed using the ITT population or PP 
population as defined in the SAP. The PP population will be used to perform 
confirmatory analyses and to assess non-inferiority. 
Primary efficacy analysis: 
The primary efficacy variable, time to first achieve an NRS-PI score <4 or a 
pain intensity reduction of ≥30% from drug intake till 8 hours after the first 
dose, will be analyzed for the superiority of DKP.TRIS/TRAM.HCl versus 
placebo on the ITT population using a Cox Proportional Hazard (CPH) 
model with treatment, baseline PI categories, and baseline radiculopathy 
categories as covariates. 
A two-sided significance level of 5% will be used. 
In the case where the proportional hazard assumption is not satisfied, 
additional analyses that permit relaxation of the assumption will be 
implemented. 
Secondary efficacy analyses: 
The primary efficacy variable, time to first achieve an NRS-PI score <4 or a 
pain intensity reduction of ≥30% from drug intake till 8 hours after the first 
dose, and all the secondary endpoints will be used to assess the 


 
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CONFIDENTIAL                                                                                                                                               21 
 
non-inferiority of DKP.TRIS/TRAM.HCl versus TRAM.HCl 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 pre-specified non-inferiority margin. 
In the case where non-inferiority is confirmed on the PP set, the superiority 
of DKP.TRIS/TRAM.HCl versus TRAM.HCl will be also tested on the ITT. 
All the secondary endpoints related to the single phase will be also analyzed 
for the superiority of DKP.TRIS/TRAM.HCl versus placebo. 
Non-inferiority will be tested on the PP population and in addition for the 
secondary endpoints of primary interest (TOPAR24, TOTPAR48) also on the 
ITT populations. Superiority will only be tested on the ITT population, 
providing that non-inferiority is confirmed on the PP population. 
All the secondary endpoints will be tested through an ad hoc inferential 
analysis, as reported below: 
 
Time to first achieve an NRS-PI score <4 and/or a pain intensity 
reduction of ≥30% will be analyzed analogously to the primary 
efficacy variable. 
 
Secondary efficacy variables with quantitative outcome: 
o NRS-PI, SPIDs, %max SPIDs, TOTPARs, %max TOTPARs, 
and TSQM will be analyzed by an analysis of covariance 
(ANCOVA) with treatment and the baseline PI-NRS as 
covariates. 
o Roland Morris Disability Questionnaire will be analyzed using 
ANCOVA with treatment and the baseline RMQ score as 
covariates. 
o PGE and PAR-VRS (ordinal variables) will be analyzed by 
Wilcoxon rank-sum test. 


 
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CONFIDENTIAL                                                                                                                                               22 
 
 
Secondary efficacy variables with binary outcomes will be tested 
using a Chi-squared test. 
 
Time to first use of RM will be assessed using a Log-rank test. 
 
The amount of RM consumption and the number of patients using 
RM will be descriptively analyzed. 
Missing values will be handled using different strategies: 
 
Single imputation methods: single missing values between 
measurements will be linearly interpolated; if more consecutive data 
are missed, a last observation carried forward (LOCF) method will be 
applied. 
 
Multiple imputation approach: if a Missing At Random (MAR) pattern 
of missing data is detected, missing values will be replaced by using 
a multiple imputation approach. 
 
No imputation: missing values will not be replaced. 
In order to minimize and evaluate the impact of RM on efficacy assessment, 
values collected after the RM intake will be imputed by using different 
strategies: 
 
Single imputation methods: during the single-dose phase, PI will 
return to its baseline level and PAR to zero (Baseline Observation 
Carried Forward [BOCF]). During the multiple-dose phase, PI and 
PAR recorded during the 6 hours after the intake of RM will be 
replaced with the LOCF or worst observation carried forward 
(WOCF) in case the assessment immediately before intake is 
missed. 
 
Estimated approach: 


 
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CONFIDENTIAL                                                                                                                                               23 
 
o Treatment Policy Strategy: values collected are used 
regardless of whether or not the RM is taken without any 
imputation. 
o Hypothetical Strategy: a scenario is envisaged in which the 
intake of RM would not occur. Values collected for the 
6 hours after the RM intake will be considered as missed, and 
they will be imputed by using a multiple imputation approach. 
Safety analyses: 
 
Adverse events will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary. The incidence of each 
treatment emergent adverse events (TEAEs) will be summarized by 
system organ class (SOC), preferred term (PT) and treatment. 
 
Reasons for early treatment termination will be summarized by 
treatment. 
 
Laboratory findings will be summarized as shift tables by treatment. 
 
Clinically significant abnormal findings in vital signs and physical 
examination will be listed by treatment. 
 
Safety analyses will be run on the safety population. 


 
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CONFIDENTIAL                                                                                                                                               24 
 
3. LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
ABBREVIATION DEFINITION 
ADR 
Adverse drug reaction 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
AUC 
Area under the curve 
BOCF 
Baseline observation carried forward 
CM 
Concomitant medication 
DKP.TRIS 
Dexketoprofen trometamol 
EC 
Ethics committee 
ECG 
Electrocardiogram 
eCRF 
Electronic case report forms 
GCP 
Good Clinical Practice 
HA 
Health Authority 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation  
IMP 
Investigational medicinal product 
ITT 
Intention-to-treat 
LBP 
Low back pain 
LOCF 
Last observation carried forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
NRS 
Numerical Rating Scale 
NSAID 
Nonsteroidal anti-inflammatory drugs 
PAR 
Pain relief 
PGE 
Patient Global Evaluation 
PI 
Pain intensity 
PP 
Per-protocol 
RM 
Rescue medication 
RMQ 
Roland Morris Disability Questionnaire 


 
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CONFIDENTIAL                                                                                                                                               25 
 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SOP 
Standard operating procedures 
SPID 
Summed Pain Intensity Difference 
TEAE 
Treatment emergent adverse event 
TOTPAR 
Total pain relief 
TRAM.HCl 
Tramadol hydrochloride 
TSQM 
Treatment Satisfaction Questionnaire for Medication 
VAS 
Visual Analogue Scale 
VRS 
Verbal rating scale 


 
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4.  STUDY SCHEME  
 


 
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4.1 
Study Flow Chart 
 
PROCEDURE 
 
VISIT 1 
Eligibility 
Checka 
COMPLETE TREATMENT AND ASSESSMENT 
PERIOD 
VISIT 2 
END OF 
STUDYc 
Single-Dose Phase 
Day 1 
Multiple-Dose Phase 
Day 1 to Day 5b 
Screening  
(Day 1) 
t0 
t15m, 
t30m, t1h, 
t1.5h, t2h, 
t4h, t6h 
t8h 
From 2nd Dose 
to Last Dose 
on Day 5 
8h After 
Last Study 
Dose 
Day 6 +2 
Days 
(Allowed 
Window) 
Informed consent  
X 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
Inclusion/Exclusion 
criteria 
X 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
Physical examination 
X 
 
 
 
 
 
X 
Height and weight 
X 
 
 
 
 
 
 
Vital signs (HR, BP) 
X 
 
 
 
 
 
X 
Safety laboratory tests 
X 
 
 
 
 
 
X 
Pregnancy test 
X 
 
 
 
 
 
X 
e-Diary instructions, 
dispensing and training 
X 
 
 
 
 
 
 
Return of e-Diary, IMP, 
RM and empty blister 
 
 
 
 
 
 
X 
IMP and RM 
dispensation 
X 
 
 
 
 
 
 
Randomization to 
treatment 
X 
 
 
 
 
 
 
NRS- PI 
X 
X 
X 
X 
X 
(every day BEFORE 
and 2h AFTER every 
dose intake) 
X 
 
PAR-VRS 
 
 
X 
X 
X 
(every day BEFORE 
and 2h AFTER every 
dose intake) 
X 
 
PGE 
 
 
 
X 
 
X 
 
Roland Morris 
Disability 
Questionnaire 
 
X 
 
 
 
X 
 


 
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PROCEDURE 
 
VISIT 1 
Eligibility 
Checka 
COMPLETE TREATMENT AND ASSESSMENT 
PERIOD 
VISIT 2 
END OF 
STUDYc 
Single-Dose Phase 
Day 1 
Multiple-Dose Phase 
Day 1 to Day 5b 
Screening  
(Day 1) 
t0 
t15m, 
t30m, t1h, 
t1.5h, t2h, 
t4h, t6h 
t8h 
From 2nd Dose 
to Last Dose 
on Day 5 
8h After 
Last Study 
Dose 
Day 6 +2 
Days 
(Allowed 
Window) 
Treatment Satisfaction 
Questionnaire 
 
 
 
 
 
X 
 
IMP and RM return and 
accountability 
 
 
 
 
 
 
X 
Concomitant/prohibited 
medication 
Throughout the study period 
Adverse Events 
Throughout the study period 
a A follow up phone call after Visit 1 will be performed within 24 hours from results only in case of abnormality and clinically 
relevant laboratory test according to the investigator judgement. 
b After the last dose intake on Day 5, the “follow-up period” will last until Visit 2. 
c A follow up phone call after Visit 2 will be performed within 24 hours from results only in case of abnormality and clinically 
relevant laboratory test according to the investigator judgement. 


 
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CONFIDENTIAL                                                                                                                                               29 
 
5. 
STUDY RATIONALE AND BACKGROUND INFORMATION  
5.1 
Low Back Pain 
According to the National Institute for Health and Care Excellence (NICE) guidelines, low back pain 
(LBP) is defined as tension, soreness, and/or stiffness in the lower back region (bottom of rib cage to 
buttock creases) for which no specific cause can be identified1. Low back pain is the leading 
contributor to years lived with disability. The estimated point prevalence of nonspecific LBP is 18%. 
Low back pain imposes an enormous economic burden on healthcare systems and affects individuals’ 
daily lives. Hence, there is a need for effective strategies to minimize the impact of LBP. 
 
A search including 15 clinical practice guidelines for the management of LBP in primary care were 
performed for the period from 2008 to 2017 in electronic databases. For acute LBP, most guidelines 
endorsed recommendations for patient education, reassurance about the favourable prognosis and 
advice on returning to normal activities, avoiding bed rest, and the use of nonsteroidal 
anti-inflammatory drugs (NSAIDs) and weak opioids for short periods where necessary.2 
 
In 
the 
literature, 
several 
NSAIDs 
and 
opioids 
(diclofenac3, 
piroxicam4, 
paracetamol5, 
oxycodone/acetaminophen, naproxen with cyclobenzaprine6, tramadol/paracetamol7) were evaluated 
for their efficacy in an acute LBP model in comparison with placebo with conflicting results. 
 
In spite of the great variety of analgesics available, the management of patients suffering from pain 
still continues to be inadequate. Due to the subjective component of pain, the problems associated 
with making a diagnosis or the fear of the adverse drug reactions (ADRs) associated with some drugs, 
patients are frequently undertreated for acute and chronic situations.8,9,10,11 Clinical experience has 
shown that in patients with moderate to severe pain, it is difficult to obtain effective analgesia with a 
single drug (monotherapy); and therefore, analgesic drugs are commonly combined (multimodal 
analgesia) in order to obtain optimal control of pain. 
 
5.2 
Investigational Medicinal Product: Dexketoprofen Benefits 
Menarini Ricerche has developed a fixed combination of dexketoprofen trometamol (DKP.TRIS) and 
tramadol hydrochloride (TRAM.HCl), two analgesics with different mechanisms of action, for the 


 
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CONFIDENTIAL                                                                                                                                               30 
 
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. DKP.TRIS and TRAM.HCl are well-known and widely used analgesics and have been 
available in European countries for a very long time. 
 
The rationale for combining DKP.TRIS and TRAM.HCl relies on the following: 
 
The drugs have a different mechanism of action. The former exerts its antinociceptive 
activity mainly at the peripheral level, whereas the latter is a centrally acting analgesic. 
 
The drugs have a different and complementary pharmacokinetic profile: 
− 
DKP.TRIS is characterized by a fast absorption and a quick onset of action 
− 
TRAM.HCl maintains a long analgesic effect (especially over multiple dose). 
 
Consequently, the combination of these substances is expected to result in an improved effectiveness 
above the level achieved by each single substance. This pharmacodynamic and pharmacokinetic 
rationale is supported by nonclinical and clinical evidence. Data on the single components are reported 
below. 
 
Dexketoprofen trometamol 
Dexketoprofen trometamol 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 inactive.12,13 
 
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 after 
administration, with analgesic effect persisting for 4 to 6 hours.14,15,16,17,18,19 
 


 
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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 humans. 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]).20 
 
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 
occurs.21 
 
Oral DKP.TRIS (as 12.5 mg and 25 mg 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 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 12.5 mg every 4 to 6 hours or 25 mg every 8 
hours. The total daily dose should not exceed 75 mg.22 
 
DKP.TRIS is also available on the market as a 50 mg/2 mL injectable formulation to be administered 
either by intramuscular or by intravenous route, which is indicated for the symptomatic treatment of 
acute pain of moderate to severe intensity, such as post-operative pain, renal colic and LBP. The 
recommended dose is 50 mg every 8 to 12 hours. If necessary, the administration can be repeated 6 
hours apart. The total daily dose should not exceed 150 mg.23 
 
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 


 
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CONFIDENTIAL                                                                                                                                               32 
 
effect are inhibition of neuronal re-uptake of noradrenaline [(-)-tramadol] and enhancement of 
serotonin release [(+)-tramadol]. 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 morphine. The mean absolute bioavailability is approximately 70%, 
irrespective of the concomitant intake of food. Following a single oral dose administration of TRAM.HCl 
100 mg 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 range.24,25 
 
Oral TRAM.HCl is currently authorised over 90 countries as 50 mg to 400 mg different formulations 
(capsules, tablets and extended-release formulations). It is indicated for the treatment of moderate to 
severe pain. The starting dose in case of acute pain is 100 mg, and the recommended unitary dose is 
between 50 mg and 100 mg not taken more frequently than every 4 hours, with a maximum of 
400 mg/day.25 
 
5.2.1. Pre-clinical data on the co-administration of dexketoprofen trometamol and 
tramadol Hydrochloride 
The relevant nonclinical evidence of the fixed combination of DKP.TRIS and TRAM.HCl for the 
treatment of acute pain of moderate to severe intensity has been established for the two separate 
products as well as in pharmacological and toxicological studies of the combination of DKP.TRIS and 
TRAM.HCl performed by Menarini or reported in the literature. In order to further support the rationale 
and to provide data on the safety use of the combination of DKP.TRIS and tramadol, 


 
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CONFIDENTIAL                                                                                                                                               33 
 
pharmacodynamic, safety pharmacology, toxicokinetic, and toxicological studies have been carried 
out. The co-administration of DKP.TRIS with TRAM.HCl demonstrated a statistically significant 
improvement of analgesia and a more prolonged effect compared with the single drug administration. 
 
Safety pharmacology studies indicate that DKP.TRIS alone and in association with TRAM.HCl has no 
significant effect on hERG current and on the electrocardiogram (ECG) in conscious dogs and 
consequently do not possess any liability for QT prolongation. The effects of dexketoprofen, 
TRAM.HCl and their combination on gastrointestinal transit (GIT) were investigated in male mice. The 
results showed that DKP.TRIS antagonized in a dose-dependent fashion the inhibition of the GIT 
induced by TRAM.HCl. Also, the repeated (13-weeks) oral concomitant administration of DKP.TRIS 
and TRAM.HCl does not indicate new significant toxicological effects in the rat. Toxicokinetic 
evaluation shows that the pharmacokinetic parameters of dexketoprofen, tramadol and M1 
(O-desmethyltramadol) are similar following their administration as single agents or when combined. 
5.2.2. Clinical development of dexketoprofen trometamol and tramadol 
hydrochloride fixed combination 
The clinical development of the DKP.TRIS/TRAM.HCl fixed combination started with a Phase I safety 
and pharmacokinetics study (DEX-TRA-PK) that indicated that there were no drug-drug interactions 
between DKP.TRIS and TRAM.HCl and that the concomitant administration, as a single oral dose in 
healthy subjects, was well tolerated. 
 
A Phase II dose-finding study (DEX-TRA-02) performed in the most frequently used model of acute 
nociceptive pain of moderate to severe intensity (impacted third mandibular molar tooth extraction), 
indicated that DKP.TRIS (12.5 mg and 25 mg) and TRAM.HCl (37.5 mg and 75 mg) given as 4 different 
combinations and as single component were all effective in the treatment of moderate to severe acute 
pain at 4 and 6 hours post dosing, thus confirming the value of combining the fast active DKP.TRIS 
with the long-lasting TRAM.HCl efficacy. The study results also allowed for the selection of 
DKP.TRIS/TRAM.HCl 25 mg/75 mg as the optimum combination of doses to be further evaluated in 
the subsequent Phase III pivotal studies. 
 
The Phase III studies (DEX-TRA-04 and DEX-TRA-05) results provided robust evidence of the 
superiority of DKP.TRIS/TRAM.HCl 25 mg/75 mg over the single components, dexketoprofen 25 mg 


 
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CONFIDENTIAL                                                                                                                                               34 
 
and tramadol at higher dose (100 mg) (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 good safety profile observed was fully in line with 
that previously established for these agents in monotherapy. 
 
The Phase IIIB study (DEX-TRA-06) results provided robust evidence of the superiority of 
DKP.TRIS/TRAM.HCl 25 mg/75 mg over PARACETAMOL/TRAM.HCL 650 mg/75 mg (a fixed dose 
combination already available in the market) in the well-known model of acute nociceptive pain of 
moderate to severe intensity (impacted third mandibular molar tooth extraction). In this single-dose 
study, the good safety profile observed was fully in line with that previously established. 
 
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 to 54 years, who had previously tolerated a test dose of DKP. TRIS 
12.5 mg + TRAM.HCl 50 mg), divided in 3 cohorts of 10 subjects, were assigned to receive, according 
to a cross-over design, one single oral dose of DKP.TRIS 25 mg, TRAM.HCl 100 mg 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 
pharmacokinetic assessment. Standard safety parameters were measured during each of the 3 study 
sessions, with a final safety follow-up visit performed 7 to 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 100 mg and DKP.TRIS 25 mg when concomitantly orally administered to healthy subjects. 
Moreover, the concomitant administration was well tolerated without raising any safety concerns. 
 


 
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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 (12.5 mg and 25 mg) and TRAM.HCl (37.5 mg and 75 mg) 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 400 mg) 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). 
 
The design included a total of 10 balanced treatment arms, with the 4 combinations of 
DKP.TRIS/TRAM.HCl (12.5 mg/37.5 mg, 12.5 mg/75 mg, 25 mg/37.5 mg and 25 mg/75 mg), the 
4 corresponding single treatments, placebo and ibuprofen 400 mg. A total of 611 patients (247 males 
and 364 females, aged 18 to 64 years) experiencing moderate to severe pain (Visual Analogue Scale, 
[VAS] ≥ 40mm and Verbal Rating Scale, [VRS] ≥ 2) after the 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 consisting of paracetamol (1 g, every 6 to 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 postdosing 
period, the patient global evaluation (PGE) at the end of the assessment period and the use of rescue 
medication (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, 12- lead 
ECG, and laboratory safety tests post-dose versus baseline. Recording and monitoring of adverse 
events (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 


 
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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 25 mg/75 mg 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 12.5 mg/37.5 mg) over 8 and 
12 hours. 
 
The analysis of sum of pain intensity differences (SPID), 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 25 mg/75 mg. The time 
to RM was significantly longer for all combinations than for placebo, with DKP.TRIS/TRAM.HCl 12.5 
mg/75 mg and DKP.TRIS/TRAM.HCl 25 mg/75 mg 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 12.5 mg/75 mg, DKP.TRIS/TRAM.HCl 
25 mg/37.5 mg and DKP.TRIS/TRAM.HCl 25 mg/75 mg than in the placebo group (46.8%, 39.7% and 
37.7% respectively versus 72.6%), with the DKP.TRIS/TRAM.HCl 25 mg/75 mg group presenting the 
lowest percentage. The difference was still significant for DKP.TRIS/TRAM.HCl 25 mg/75 mg over 


 
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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 25 mg/75 mg 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 25 mg/75 mg, 
DKP.TRIS/TRAM.HCl 12.5 mg/75 mg and DKP.TRIS/TRAM.HCl 25 mg/37.5 mg 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 25 mg/75 mg presented consistent superior 
efficacy in all parameters of analgesia tested. All combinations were well tolerated, 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 25 mg/75 mg 
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 25 mg/75 mg 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 25 mg/75 mg to be administered every 8 hours. 
 
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 25 mg/75 mg oral 
fixed-combination in comparison with the single components (dexketoprofen 25 mg and tramadol 
100 mg) 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. 


 
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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 
DEXTRA-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 
25 mg/75 mg, dexketoprofen 25 mg, tramadol 100 mg 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 25 mg/75 mg, dexketoprofen 25 mg or 
tramadol 100 mg). 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 500 mg, with a maximum recommended daily dose of 2 g) was available on request 
during the entire treatment period. 
 
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). 
 


 
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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, Figure 2) confirmed the superiority of 
DKP.TRIS/TRAM.HCl over the single components (mean [SD]: 242 [139] for DKP.TRIS/TRAM.HCl 
versus 185 [139] for DKP.TRIS and 157 [151] for TRAM.HCl; 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 per-protocol (PP) population confirmed the primary efficacy results. 
 
There was statistical evidence favouring DKP.TRIS/TRAM.HCl 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 DKP.TRIS/TRAM.HCl 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. 
 


 
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Statistically significant superiority of DKP.TRIS/TRAM.HCl 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 DKP.TRIS/TRAM.HCl compared to 
the single agents. The DKP.TRIS/TRAM.HCl combination 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 
DKP.TRIS/TRAM.HCl than with the single agents. Results were maintained over 48 hours and overall 
during the multiple-dose phase, but the differences did not reach statistical significance. Overall, 
DKP.TRIS/TRAM.HCl 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 maintained for the multiple 
dose phase of the study. 
 
Overall, 76 (13%) patients reported a total of 100 ADRs, of which 51 were mild, 42 were moderate 
and 7 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; 9 
events), platelet count increased (1.3% patients; 8 events) and blood lactate dehydrogenase 
increased (1.0% patients; 6 events). The DKP.TRIS/TRAM.HCl group presented a lower incidence of 
ADRs (9.4% patients) in comparison with the DKP.TRIS (15% patients) and TRAM.HCl groups (13% 
patients). Overall, 11 (1.8%) patients reported a total of 15 serious adverse events (SAEs), of which 
only 1 (psychotic disorder; in the DKP.TRIS/TRAM.HCl 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 
DKP.TRIS/TRAM.HCl combination showed a safety profile fully in line with that previously known for 
the single agents. 
 
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. 


 
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For the primary endpoint (mean SPID8, Figure 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), 
DKP.TRIS/TRAM.HCl was more effective than either DKP.TRIS monotherapy or TRAM.HCl 
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 DKP.TRIS/TRAM.HCl group when compared to the single agents, although 
the differences did not reach statistical significance. Similarly, the highest PGE scores were reported 
in the DKP.TRIS/TRAM.HCl group during the single- and multiple-dose phases of the study; however, 
no statistically significant differences were observed in comparison to the single components. 
 


 
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There was evidence of a longer overall time to first use of RM for DKP.TRIS/TRAM.HCl compared 
with DKP.TRIS monotherapy and TRAM.HCl 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 
DKP.TRIS/TRAM.HCl group than in the DKP.TRIS group and in the TRAM.HCl group. The worst pain 
score whilst moving was slightly lower on average for the DKP.TRIS/TRAM.HCl group than for the 
DKP.TRIS group and the TRAM.HCl 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 DKP.TRIS/TRAM.HCl group presented a lower incidence of ADRs (2.8% patients) in comparison 
with the DKP.TRIS group (4.7% patients) and the TRAM.HCl group (5.1% patients). Two patients 
reported a total of five serious ADRs. One patient in the DKP.TRIS group experienced duodenal ulcer. 
Another patient in the DKP.TRIS/TRAM.HCl 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 heart rate, blood pressure, 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 
DKP.TRIS/TRAM.HCl 25 mg/75 mg 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. 
 
Phase IIIB study: DEX-TRA06 (dental pain model) 
This was a multicentre, randomised, double-blind, double-dummy, parallel-group, placebo and active-
controlled, single-dose, Phase IIIb study aimed to evaluate the analgesic efficacy, safety and 
tolerability of DKP.TRIS/TRAM.HCl 25 mg/75 mg in comparison with TRAM.HCl/paracetamol 


 
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CONFIDENTIAL                                                                                                                                               43 
 
75 mg/650 mg, in moderate to severe pain following surgical removal of impacted lower third molar. 
Participation in the study lasted for approximately 3 weeks for each patient and was made up of: a 
screening period, (within 2 weeks before randomisation), including the pre-surgery procedures to be 
completed at least 1 day prior to surgery and ending within the 4 hours qualification post-surgery; 
randomisation and treatment administration (day 1, t0) followed by an 8-hour assessment period 
during which patients recorded efficacy data followed by an end of study visit (6±1 days after 
randomisation). 
 
Healthy adult patients (>18 years of age) scheduled for surgical extraction of at least one fully/partially 
impacted lower third molar requiring bone manipulation. A total of 654 patients were randomised and 
653 were eligible for analysis. Surgery was performed under local anaesthetic using 2% lidocaine 
(with 1:80.000 epinephrine) up to a total volume of 5.4 mL per molar. No sedation was permitted. 
 
Patients rated PI using an 11-point NRS (0 no pain; 10 worst pain). Participants experiencing 
moderate/severe pain (≥4) within 4 hours of surgery were randomised (2:2:1 ratio) to a single oral 
dose of TRAM.HCL/DKP.TRIS 75/25 mg, TRAM.HCL/paracetamol 75/650 mg or placebo. 
 
Analgesia and pain were recorded by using the following measures: PAR on a 5-point VRS (0=‘no 
relief’, 1=‘a little (perceptible) relief’, 2=‘some (meaningful) relief’, 3=‘lot of relief’, 4=‘complete relief’) 
at the predefined postdose time points t15 min, t30 min, t1 hour, t1.5 hour, t2 hour, t4 hour, t6 hour 
and t8 hour and PI on the 11-point NRS at t0 and at the same predefined postdose time points. The 
primary efficacy endpoint was TOTPAR, calculated as the weighted sum of the PAR scores measured 
according to a 5-point VRS, over 6 hours postdose (TOTPAR6). 
 


 
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The primary efficacy variable was analysed on the PP and ITT populations to assess the non-inferiority 
hypothesis. Since non-inferiority was confirmed, the ITT population was used to perform superiority 
analyses on the primary endpoint, as prespecified. The mean (SD) TOTPAR6 reported by patients in 
the TRAM.HCL/DKP.TRIS group was 13 (7.0), while those in TRAM.HCL/paracetamol and placebo 
groups were 9.2 (7.7) and 1.9 (3.9), respectively, demonstrating that the combination 
TRAM.HCL/DKP.TRIS was statistically superior (p<0.0001) to TRAM/paracetamol. 
 
Secondary efficacy endpoints included the time course of mean PAR and PI scores over 8 hours; 
TOTPAR over 2, 4, and 8 hours postdose and the percentage of maximum calculated TOTPAR 
(% max TOTPAR) over 2, 4, 6, and 8 hours; sum of pain intensity difference (SPID) and the 
percentage of maximum calculated SPID (% max SPID) over 2, 4, 6, and 8 hours; percentage of 
responders in terms of PAR or PI reduction, namely subjects who achieved at least 50% of max 
TOTPAR or at least 30% of PI reduction versus baseline at prespecified time points over the 8 hours, 
respectively; time to FPPAR; time to confirmed FPPAR (ie, time to FPPAR if confirmed by 
experiencing MPAR) and time to MPAR; percentage of patients who achieved FPPAR, confirmed 


 
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FPPAR and MPAR within 30 min, 1 hour and 2 hours; PGE at 8 hours or whenever the patient used 
RM; time of first intake of RM since study drug intake; percentage of patients using RM at 2, 4, 6, or 
8 hours. 
 
Superiority of TRAM.HCL/DKP.TRIS overactive comparator and placebo was observed at all 
secondary endpoints. Overall, 53 patients (8.1%) experienced one or more ADRs (97 ADRs in total) 
but none of the ADRs were considered to be serious. No clinically relevant differences were identified 
in ADRs incidences between treatment groups. Overall, the most common ADRs were vomiting 
(3.8%), nausea (3.4%), dizziness (2.9%) and somnolence (2.1%). No deaths or other significant ADRs 
occurred. There were no clinically relevant changes in the vital signs or physical examination versus 
baseline. 
 
Overall, the study confirmed that TRAM HCL/ DKP TRIS 75/25 mg oral fixed combination is effective 
and superior over TRAM HCL/paracetamol 75/650 mg in relieving moderate to severe acute pain 
following removal of impacted lower third molar. TRAM HCL/DKP TRIS 75/25 mg oral fixed 
combination shows faster onset of effect, greater and durable analgesia, together with a favourable 
safety profile. 
 
DKP.TRIS/TRAM.HCl has already been compared to TRAM100 mg in several pain models (dental 
pain, abdominal laparotomic hysterectomy, and total hip arthroplasty) in order to evaluate 
DKP.TRIS/TRAM.HCl efficacy versus single agents (even at higher doses) in both visceral and 
somatic nociceptive pain.27,28 
 
The aim of this study is to investigate the efficacy of DKP.TRIS/TRAM.HCl in moderate to severe 
acute LBP. 
5.3 Assessment of Potential Risks and Benefits 
The use of the 2 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. 


 
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Overall, available data indicate that co-dispensation of DKP.TRIS and TRAM.HCl is part of current 
clinical practice. 
 
Most of the patients in this study may derive a direct benefit from being treated with 
DKP.TRIS/TRAM.HCl, which has already demonstrated favorable efficacy at the doses tested. All 
participants taking part in the study may derive general medical benefit from careful and close 
monitoring by medical personnel during the study. Safety will be ensured by assessing participants 
for AEs and laboratory test results. 
 
The inclusion of the single agents as active comparators has been deemed necessary in agreement 
with the Guideline on Clinical Development of Fixed Combination Medicinal Products 
(CPMP/EWP/240/95).29 A placebo-controlled design has been selected for the single-dose phase (the 
first 8 hours after randomization) of the study, in agreement with both the Note for Guidance on Clinical 
Investigation of Medicinal Products for Treatment of Nociceptive Pain (CPMP/EWP/612/00)30 and 
Guideline on Clinical Medicinal Products Intended for the Treatment of Neuropathic Pain 
(CPMP/EWP/252/03)31 taking into account that the primary efficacy endpoint is evaluated in this 
period. The inclusion of the placebo arm during the single-dose phase is considered acceptable from 
an ethical point of view, considering the availability of RM and the fact that the use of placebo is limited 
to the first dose intake. After the first administration of study medication, placebo-assigned patients 
will be allocated to receive an active treatment such as TRAM.HCl 100 or DKP.TRIS/TRAM.HCl 
25/75 mg. (see Section 7) 
 
The placebo arm is included in the study to demonstrate analgesic effect of DKP.TRIS/TRAM.HCl 
compared with placebo as the primary objective. The patients assigned to the placebo arm will receive 
only one dose of placebo in the single-dose phase. These patients will later receive either 
DKP.TRIS/TRAM.HCl or TRAM.HCl in the multiple-dose phase. The availability of RM allows patients 
to take RM if they have not achieved adequate pain relief after receiving the assigned study drug. 
Paracetamol (acetaminophen) has been chosen as a RM as it is a safe and effective drug for the 
treatment of acute LBP, in addition it does not have interactions with the study medications.32,33,34 


 
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CONFIDENTIAL                                                                                                                                               47 
 
The most commonly observed AEs associated with DKP.TRIS are gastrointestinal in nature. Peptic 
ulcers, perforation or gastrointestinal bleeding, sometimes fatal, particularly in the elderly, may occur. 
Nausea, vomiting, diarrhea, flatulence, constipation, dyspepsia, abdominal pain, melena, 
hematemesis, ulcerative stomatitis, exacerbation of colitis and Crohn’s disease have been reported 
following administration. Less frequently, gastritis has been observed. 
 
The most commonly reported ADRs associated with TRAM.HCl are nausea and dizziness, both 
occurring in more than 10% of patients. In the completed clinical studies performed with 
DKP.TRIS/TRAM.HCl, the most commonly observed ADRs were vomiting, nausea and dizziness 
(2.9%, 2.7%, and 1.1% of patients, respectively). 
 
This study will be conducted in compliance with the protocol, Good Clinical Practice (GCP), and the 
applicable regulatory requirements. 
6. 
TRIAL OBJECTIVES AND ENDPOINTS 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
PRIMARY 
 
 
To 
evaluate 
the 
analgesic efficacy of 
DKP.TRIS/TRAM.HCl 
fixed 
combination 
versus 
placebo 
in 
moderate 
to 
severe 
acute low back pain 
after the first dose (first 
8 hours). 
Endpoints of primary interest: 
 
Time to first achieve an NRS-PI score <4 
or a pain intensity reduction of ≥30% 
from drug intake till 8 hours after the first 
dose (t8h). 
Other endpoints: 
Pain Relief (PAR)- VRS scores at each 
prespecified time point (t15m, t30m, t1h, 
t1.5h, t2h, t4h, t6h, t8h) over the 8 hours 
after the first dose. 
 
Mean TOTPAR at 4, 6, and 8 hours 
(TOTPAR4, TOTPAR6, TOTPAR8) after 
the first dose. 
 
Percentage of maximum TOTPAR (% 
max TOTPAR) at 4, 6, and 8 hours after 
the first dose. 
The NRS is widely used 
clinically for the assessment 
of pain. This scale is a valid 
and reliable scale to measure 
pain intensity. High test-retest 
reliability has been observed 
for NRS in all kinds of 
patients. 
 
 
Efficacy endpoints of PAR, 
TOTPAR, SIPD, and PGE 
are well characterized and 
accepted endpoints both in 
the 
literature 
and 
by 
Regulatory 
authorities 
for 
evaluation of the analgesic 


 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
 
Percentage of patients achieving at least 
50% of maximum TOTPAR at 4, 6, and 
8 hours after the first dose. 
 
Mean Pain Intensity (PI) - VAS scores at 
each prespecified time points (t15m, 
t30m, t1h, t1.5h, t2h, t4h, t6h, t8h) over 
the 8 hours after the first dose. 
 
SPID at 4, 6, and 8 hours (SPID4, 
SPID6, SPID8) after the first dose. 
 
Percentage of maximum SPID (% max 
SPID) at 4, 6, and 8 hours after the first 
dose. 
 
Percentage of patients achieving at least 
30% of PI reduction versus baseline at 
4, 6, and 8 hours after the first dose. 
 
PGE of the study medication at 8 hours 
after the first dose. 
 
Time to RM: Time elapsed between 
treatment administration and the first 
dose of RM from baseline till 8 hours 
after the first dose. 
 
Percentage of patients who required RM 
within the first 4, 6, or 8 hours after the 
first dose. 
benefits 
of 
investigational 
medications. 
SECONDARY 
 
 
To 
evaluate 
the 
analgesic efficacy of 
DKP.TRIS/TRAM.HCl 
fixed 
combination 
versus 
TRAM.HCL 
100 mg in moderate to 
severe acute low back 
pain after the first dose 
(first 8 hours). 
 
 
Same 
endpoints 
related 
to 
the 
single-dose phase as included for the 
primary objective will also be used to 
evaluate the analgesic efficacy of 
DKP.TRIS/TRAM.HCl 
versus 
TRAM.HCL in moderate to severe acute 
low back pain after the first dose (first 8 
hours) 
 
To 
evaluate 
the 
analgesic efficacy of 
DKP.TRIS/TRAM.HCl 
fixed combination in 
moderate 
to 
severe 
Endpoints of primary interest:  
 
TOTPAR 
at 
24 
and 
48 
hours 
(TOTPAR24, 
TOTPAR48) 
of 
the 
multiple-dose phase. 
 


 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
acute low back pain 
versus 
TRAM.HCl 
100 mg after multiple 
doses (from t8h until 
Day 5). 
Other endpoints: 
 
Pain Relief (PAR)-VRS scores at each 
prespecified time point over the multiple-
dose phase. 
 
TOTPAR 
at 
72, 
and 
96 hours 
(TOTPAR72, 
TOTPAR96) 
of 
the 
multiple-dose phase. 
 
Percentage 
of 
maximum 
TOTPAR 
(% max TOTPAR) at 24, 48, 72, and 
96 hours of the multiple-dose phase. 
 
Percentage of patients achieving at least 
50% of maximum TOTPAR at 24, 48, 72, 
and 96 hours of the multiple-dose phase. 
 
Pain Intensity (PI)-VAS scores at each 
prespecified time point over the multiple-
dose phase. 
 
SPID at 24, 48, 72, and 96 hours 
(SPID24, SPID48, SPID72, SPID96) of 
the multiple-dose phase. 
 
Percentage of maximum SPID (% max 
SPID) at 24, 48, 72, and 96 hours of the 
multiple-dose phase. 
 
Percentage of patients achieving at least 
30% of PI reduction versus baseline at 
24, 48, 72, and 96 hours of the 
multiple-dose phase. 
 
PGE at 96 hours of the multiple-dose 
phase. 
 
Percentage of patients who required RM 
at 24, 48, 72, and 96 hours of the 
multiple-dose phase. 
 
Roland Morris Disability Questionnaire 
at 96 hours of the multiple-dose phase. 
 
Treatment Satisfaction Questionnaire for 
Medication at 96 hours of the multiple-
dose phase. 
 
Time to first achieve an NRS score <4 or 
a pain intensity reduction of ≥30% from 
the 
first 
drug 
intake 
till 
5 
days 
posttreatment, 
excluding 
patients 


 
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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR 
ENDPOINTS 
assigned to the placebo treatment arms 
during the single-dose phase. 
 
TOTPAR at 104 hours from the first drug 
intake till 5 days after the first dose 
(TOTPAR104), 
excluding 
patients 
assigned to the placebo treatment arms 
during the single-dose phase. 
 
SPID at 104 hours from the first drug 
intake till 5 days after the first dose 
(SPID104), excluding patients assigned 
to the placebo treatment arms during the 
single-dose phase. 
 
Time to RM: Time elapsed between the 
first drug intake till 5 days after the first 
dose, excluding patients assigned to the 
placebo treatment arms during the 
single-dose phase. 
To assess the safety 
and 
tolerability 
of 
DKP.TRIS/TRAM.HCl 
fixed combination after 
single 
and 
multiple 
doses. 
 
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 
clinical 
laboratory 
evaluations, physical examination, and 
vital signs post-dose versus baseline. 
These are the most widely 
used endpoints for safety 
analysis. 
7. 
STUDY DESIGN. 
This is a Phase IV, multicenter, randomized, double-blind, double-dummy parallel group, 
placebo-controlled study encompassing 2 study phases: a single-dose phase (first 8 hours) and a 
multiple-dose phase starting after the single-dose phase (from t8 h until Day 5) aimed to investigate 
the efficacy of DKP.TRIS/TRAM.HCl fixed combination in moderate to severe acute LBP. 
 
The study will be conducted in primary care and hospital setting in 6 European countries in 50-60 
centers. The overall clinical phase is planned to start in Q3/2020 and to be completed within 
theQ2/2022. 


 
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Eligible patients will be randomized in a 4:4:1:1: ratio to 1 of the 4 possible treatment arms: 
Arm 
Single-dose phase (t0-t8) 
Multiple-dose phase (t8-Day 5) 
1 
DKP.TRIS/TRAM.HCl 
DKP.TRIS/TRAM.HCl 
2 
TRAM.HCl 
TRAM.HCl 
3 
Placebo 
DKP.TRIS/TRAM.HCl 
4 
Placebo 
TRAM.HCl 
 
In the single-dose phase the patients will receive a single dose treatment, consisting of 1 film-coated 
tablet and 2 capsules which must be orally administered together at the same time (Day 1) and 
according to Investigator’s instructions. The multiple-dose phase will begin 8 hours after the first dose. 
The patients assigned to DKP.TRIS/TRAM.HCl fixed combination or TRAM.HCL 100 mg during the 
single-dose phase will continue to receive the same treatment during the multiple-dose phase; 
however, the patients assigned to receive placebo during the single-dose phase will either receive 
DKP.TRIS/TRAM.HCl fixed combination or TRAM.HCL 100 mg during the multiple-dose phase. 
The study is considered completed when the last patient’s last study visit has occurred. 
7.1 
Procedures and Study Visits 
Patients will attend a total of 2 visits during the study. The description of the activities, procedures, and 
tests to be performed at each visit is detailed below. 
1. Visit 1 (Day 1, t0) 
The following procedures/assessments must be completed during the Screening: 
 
Obtaining informed consent. 
 
Patients will be asked to rate their PI on a paper to assess their eligibility for randomization. 
Patients must describe their PI in response to the question: ‘How do you rate the intensity of 
your pain?’ using an 11-point NRS ranging from 0 (no pain) to 10 (worst pain). 
 
Recording of prior and concomitant medications (CMs). 
 
Recording of medical history. 
 
Check of inclusion and exclusion criteria. 
 
Collection of demographic data. 
 
Physical examination including body weight, height and vital signs (blood pressure [BP], heart 
rate [HR]). 


 
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 
Safety laboratory tests. 
 
Pregnancy test (if applicable). 
 
Only patients experiencing pain of moderate or higher intensity (NRS score ≥5) and completing all 
screening procedures will be eligible for randomization. Randomization will be stratified according to: 
 
The baseline PI categories measured by the NRS scale in order to preserve the randomization 
ratio within each stratum: 
– 
≥ 5 to ≤7 (moderate pain) 
– 
˃7 (severe pain) 
 
The baseline radiculopathy categories measured by the Quebec Task Force classification35: 
– 
LBP without radiation 
– 
LBP+ radiation to extremity, proximally 
– 
LBP+ radiation to extremity, distally 
Randomized patient will receive: 
 
E-diary and related instructions about its usage 
 
A box with Investigation Medicinal Products (IMP) and RM and instructions about its usage. 
It will be required to the patients to record the NRS-PI and VRS-PAR to e-Diary before RM 
intake. 
 
Instructions regarding how to complete the patient’s pain and analgesia assessments. 
 
A follow up phone call after Visit 1 will be performed within 24 hours from results only in case of 
abnormality and clinically relevant laboratory test according to the investigator judgement. 
 
2. Complete treatment and Assessment Period (Day 1 to Day 5) 
Treatment and assessment period consists of a single-dose phase (t0 to t8h) and a multiple-dose 
phase (t8h to Day 5). Prior to the administration of the study treatment the following items will be 
recorded as baseline PI (t0h): 
 
NRS-PI; patients with NRS score ≥5 at the Screening, who could have NRS <5 between the 
period of Screening and before the first dose intake, will be randomized. 


 
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 
Roland Morris Disability Questionnaire (RMQ), patients will answer to 24 questions that enquire 
back pain on movement during daily life activities. The RMQ is a self-administered disability 
measure in which greater levels of disability are reflected by higher numbers on a 24-point 
scale. Each question is worth 1 point, so scores can range from 0 (no disability) to 24 
(severe disability). Clinical improvement over time can be graded based on the analysis of 
serial questionnaire scores. 
 
a. Single-dose phase (t0 – t8h) 
 
The single-dose phase corresponds to the first 8 hours after the first study treatment 
administration. 
 
The first dose should be taken by 16:00 on Day 1. 
 
After the first study treatment administration, patients will remain under observation at the site 
for 2 hours. 
 
The pain and analgesia assessments measured by NRS-PI and Verbal Rating Scale-Pain 
Relief (VRS-PAR) will be recorded by the patients on the e-Diary at t15min, t30min, t1h, t1.5h, 
t2h, at the clinical site, and at t4h, t6h and t8h and immediately before RM intake (if any) off the 
clinical site. 
 
Patient Global Evaluation (PGE): At the end of the single-dose phase (t8h), subjects 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’. 
 
First intake of RM, if any. 
 
Occurrence of any AE as spontaneous reporting and changes in CMs, if any, will be collected 
by study staff while the patients are at the site. 
 
b. Multiple-dose phase (t8h- day5) 
The multiple-dose phase will start on Day 1 with the second dose administration, when the single-dose 
phase is completed. 
 
Patients receiving DKP.TRIS/TRAM.HCl or TRAM.HCl during the first 8 hours will continue with 
the same treatment while patients who received placebo will switch to DKP.TRIS/TRAM.HCl or 
TRAM.HCl according to the randomization scheme specified above. During the multiple-dose 


 
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phase 12 doses of study treatment will be administered, with the last s t u d y  drug intake 
administered within Day 5. 
 
The frequency of the dosing is 8 hours. 
 
During this phase, patients will continue recording the following items on their e-Diaries: 
– 
NRS-PI, immediately prior to each dose of study treatment and 2 hours after each 
dose every day, with the last assessment to be completed on Day 5, 8 hours after 
the last dose intake. Within this period the NRS-PI shall be done also immediately 
before RM is taken, if any. 
– 
VRS-PAR, immediately prior to each dose of study treatment and 2 hours after each 
dose every day, with the last assessment to be completed on Day 5, 8 hours after 
the last dose. Within this period, the VRS-PAR shall be done also immediately 
before RM is taken, if any. 
– 
The RMQ will be assessed on Day 5, 8 hours after the last dose or whenever 
patients discontinue treatment. 
– 
PGE will be assessed on Day 5, 8 hours after the last dose or whenever patients 
discontinue treatment. 
– 
Treatment Satisfaction Questionnaire for Medication (TSQM) will be assessed on 
Day 5, 8 hours after the last dose or whenever patients discontinue treatment. It is 
comprised of 14 questions that provide scores on 4 scales: effectiveness (3 items), 
side effects (5 items), convenience (3 items) and global satisfaction (3 items). 
– 
During the multiple-dose phase, the study team will record AEs on spontaneous 
reporting. 
3. Visit 2: End of study (Day 6 +2 days) 
 
Return of e-Diary, unused IMP, unused RM and empty blisters by patients 
 
Physical examination 
 
Vital sign measurements 
 
Safety laboratory test 
 
Pregnancy test (if applicable) 
 
IMP accountability 


 
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 
RM accountability 
 
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 center to accomplish the 
procedures from Screening to End of study. 
 
After the last dose intake on Day 5, the “follow-up period” will last until Visit 2 (Day 6 +2 days). A 
follow-up phone call after Visit 2 will be performed within 24 hours from results only in case of 
abnormality and clinically relevant laboratory test according to the investigator judgement. 
8. 
SELECTION OF SUBJECTS 
Informed Consent Process 
Prior to the patient’s enrolment into the study and before performing any study-related procedures, 
the Investigator - or its authorized delegate - shall obtain the patient’s written, dated and signed 
informed consent to participate into the study and to the confidential disclosure, processing and 
transferring necessary documentation of the patient’s health and personal data to the contract 
research organization (CRO), Sponsor and its Affiliates, the competent Health Authorities (HA) and 
any other institutions, as legally required and in accordance with the local applicable privacy laws (for 
the Privacy information to be reported on the informed consent form (ICF) refer to Section 19). 
 
The institution and Investigator undertake to duly inform patients about personal data processing and 
the relevant applicable privacy rights before their participation in the study. 
 
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. If a protocol amendment would affect the terms of the ICF, it will be revised 
to reflect the protocol change and submitted to the Ethics Committee (EC) for approval. The 
Investigator will ensure that this new consent form is signed by all patients subsequently entered in 
the study and those currently in the study, if affected by the amendment. 


 
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CONFIDENTIAL                                                                                                                                               56 
 
8.1 
Inclusion and Exclusion Criteria 
8.1.1 Inclusion Criteria 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Properly executed written informed consent. 
2. Male or female patients aged 18 years to 65 years. 
3. Patients with acute low back reporting pain of at least moderate intensity at Screening 
(NRS score ≥ 5). The onset of the current acute low back pain episode is within 48 hours 
prior to Screening. 
4. Patients with or without radiculopathy will be included, excluding those with neurological 
signs, according to the Quebec Task Force classification. 
5. Naïve patients to any low back pain or patients with previous history of low back pain 
experiencing a new episode, preceded by a period of at least 2 months without any low 
back pain prior to Screening. 
6. Patients free from analgesic (as per exclusion criterion 15) due to previously administered 
pain killer (immediate or slow release formulations), according to physician’s judgment. 
7. Females participating in the study must be either: 
- 
Females of nonchildbearing potential, defined as any woman who had undergone 
surgical sterilization (documented hysterectomy, bilateral salpingectomy, or 
bilateral oophorectomy) or is more than 2 years postmenopausal (defined as no 
menses for 12 months); 
- 
Females of childbearing potential (following menarche until menopause unless 
permanently sterile) provided that they have a negative pregnancy test at 
Screening and are routinely using an effective method of birth control resulting in a 
low failure rate (ie, combined hormonal contraception, intrauterine device, condoms 
in combination with a spermicidal cream, male partner sterilization (vasectomy), 
bilateral tubal occlusion or total sexual abstinence) during the study treatment. 
8. Mentally competent and able to understand and give written informed consent prior to 
Screening. 
9. Compliant to undergo all visits and procedures scheduled in the Study. 


 
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CONFIDENTIAL                                                                                                                                               57 
 
8.1.2. Exclusion Criteria 
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, CM and 
concurrent systemic diseases. 
2. Clinically significant abnormalities in the vital signs as per Investigator’s judgment. 
3. Patients with acute low back pain and radiation to limb with presence of neurologic signs (focal 
weakness, asymmetry of reflexes, sensory loss in a dermatome, or loss of bowel, bladder, or 
sexual function, according to Quebec Task Force Classification). 
4. History of hypersensitivity to the study treatments, RM or to any other NSAIDs, or opioids. 
5. Known photoallergic or phototoxic reactions during treatment with ketoprofen or fibrates. 
6. History of peptic ulcer, gastrointestinal disorders when taking NSAIDs, gastrointestinal 
bleeding, or other active bleeding. 
7. History of allergy (eg, precipitate attacks of asthma, bronchospasm, acute rhinitis, or cause 
nasal polyps, urticaria or angioneurotic oedema) to the study treatments, RM or to any other 
NSAIDs, or opioids. 
8. Anamnestic mild to severe renal dysfunction, mild to severe hepatic dysfunction, as per 
Investigator’s judgment. 
9. Patients with chronic dyspepsia. 
10. Patients with severe heart failure (Class III and Class IV of New York Heart Association [NYHA] 
Classification). 
11. History of hemorrhagic diathesis and other coagulation disorders. 
12. History of or current epilepsy or convulsions. 
13. Patients with Crohn’s disease or ulcerative colitis. 
14. Patients receiving monoamine oxidase (MAO) inhibitors (a minimum of 14 days of washout 
must elapse prior to the first study drug dose). 
15. Treatment with topical preparations/medications within 4 hours prior to Screening, anesthetics 
and muscle relaxants within 8 hours prior to Screening, short-acting analgesics (eg, 
paracetamol) within 4 hours prior to Screening, other analgesics (NSAIDs [eg, ketoprofen, 
ibuprofen, diclofenac) within 5 half-lives prior to Screening, or use of an opioid within the 14 
days preceding Screening. 


 
Corporate Medical Department 
 
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Previous Doc Number: 
CTWI10A 
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Study Code: MEIN/18/DEX-LBP/001 
Protocol Version 2 of 13/09/2021/  
 
 
 
  
 
CONFIDENTIAL                                                                                                                                               58 
 
16. Treatment with high doses of salicylates (≥3 g/day), anticoagulants, thrombolytic and 
antiplatelet agents, heparins, corticosteroids (except inhalers and topical agents), lithium 
methotrexate, used at high doses of 15 mg/week or more, hydantoins (including phenytoin) 
and sulphonamides, antiepileptics, antipsychotics, serotonin reuptake inhibitors (selective 
serotonin reuptake inhibitors [SSRIs] and serotonin norepinephrine reuptake inhibitors 
[SNRIs]) and tricyclic antidepressants, and analgesics within 48 hours or 5 half-lives 
(whichever is the longer) prior to Screening. 
17. Patients using sedatives (eg, benzodiazepines) and hypnotic agents within 8 hours before 
Screening. 
18. Any chronic or acute painful condition other than the study indication that may interfere with 
the assessment of the efficacy of the study treatment. 
19. Any non-pharmacological interventional therapy for low back pain (physical therapy, 
acupuncture, massage etc.) one month before Screening. 
20. Patients with litigation related to work. 
21. Patients with severe dehydration (caused by vomiting, diarrhea, or insufficient fluid intake) 
within one month prior to Screening. 
22. Severe respiratory depression according to physician’s judgment. 
23. Participation in other clinical studies in the previous 4 weeks. 
24. 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). 
25. 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. 
26. Pregnant and breastfeeding women. NOTE: a pregnancy test will be performed on all women 
of childbearing potential at Screening. 
27. Patients presenting any of the contraindications reported for dexketoprofen/tramadol, tramadol 
or paracetamol (according to the SmPC). 
28. Known or suspected serious spinal pathology (eg, metastatic, inflammatory or infective 
diseases of the spine, cauda equine syndrome, trauma, spinal fracture). 
29. Spinal surgery within the preceding 6 months. 


 
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CONFIDENTIAL                                                                                                                                               59 
 
8.1.3. Screening Failures 
Screen failures are defined as patients who consent to participate in the clinical study but are not 
subsequently entered in the study or assigned to the study product. The screen failures will not be 
continued in the study and re-screening is not allowed. 
9. 
STUDY TREATMENT  
The treatments administered during the study are: 
Dexketoprofen Trometamol/Tramadol Hydrochloride  
DKP.TRIS 25 mg/TRAM.HCl 75 mg film-coated tablets (as one film-coated tablet) 
Reference Therapy:  
– 
Placebo film-coated tablets matching DKP.TRIS 25 mg/TRAM.HCl 75 mg  
– 
Placebo capsules matching active comparator TRAM.HCl 100 mg (as 2 capsules of Tramadol 
50 mg) 
Active Comparator: 
TRAM.HCl 100 mg (as 2 capsules of Tramadol 50 mg) 
Dosage form of the treatments: 
Oral tablets and capsules. 
Regimen: every 8 hours, with maximum 13 consecutive doses within a 5-day period. 
– 
Double-dummy technique will be applied to ensure double-blind condition of DKP.TRIS 
25 mg/TRAM.HCl 75 mg versus TRAM.HCl 100 mg versus placebo administration. 
Individual study participation will last up to 8 days for each treatment group. For further details on the 
study design, please see Section 7.1. 
Treatments administered - posology schedule and duration 
Single-dose phase: 
The patients who are eligible will be randomly allocated to 1 of the 4 treatment groups. 
Patients will receive 1 of the 4 possible treatments: 
– 
DKP.TRIS 25 mg/TRAM.HCl 75 mg, as one film-coated tablet 
– 
TRAM.HCl 100 mg, as two capsules with 50 mg each 
– 
Placebo, as one film-coated tablet matching DKP.TRIS 25 mg/TRAM.HCl 75 mg  
– 
Placebo as two capsules matching TRAM.HCl 


 
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CONFIDENTIAL                                                                                                                                               60 
 
One single dose treatment, consisting of 1 film-coated tablet and 2 capsules, has to be orally 
administered together at the same time (Day 1) and according to Investigator’s instructions. 
 
Multiple-dose phase: 
Patients assigned to placebo treatment in the single-dose phase, will be allocated to receive 1 of the 
2 possible study active treatments, every 8 hours: 
– 
DKP.TRIS 25 mg/TRAM.HCl 75 mg, as one film-coated tablet 
– 
TRAM.HCl 100 mg, as two capsules with 50 mg each 
Conversely, patients who are already assigned to active treatment in the single-dose phase, will 
remain on the same active treatment. 
 
Multiple-dose treatment, each dose consisting of 1 film-coated tablet and 2 capsules, has to be orally 
administered together, every 8 hours, up to the end of Day 5, for a total of 12 drug administrations 
and according to Investigator’s instructions. 
9.1 
Study Treatment Formulation, Appearance, Packaging, and Labeling 
IMP Manufacturing: 
Placebo film-coated tablets matching DKP.TRIS 25 mg/TRAM.HCl 75 mg will be manufactured by A. 
Menarini Research & Business Service GmbH (Menarini Group), Glienicker Weg 125, 12489 Berlin, 
Germany. 
Placebo capsule matching active comparator Tramadol 50 mg will be manufactured by A. Menarini 
Manufacturing Logistics and Services S.R,L., (Menarini Group), Via Sette Santi, 3 50131- Florence 
(Italy). 
DKP.TRIS 25 mg/TRAM.HCl 75 mg film-coated tablets and TRAM.HCl 50 mg capsules will be sourced 
as authorized EU marketed products from commercial supplier in the European market. 
 
Packaging and Labelling: 
The packaging and labelling of IMP will be performed by A. Menarini Manufacturing Logistics and 
Services S.R,L., (Menarini Group), Via Sette Santi, 3 50131- Florence (Italy). 
All the IMPs will be provided in dedicated treatment boxes (Patient Box) to be dispensed at Day 1, 
upon randomization. The IMP will be packaged as described below: 


 
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CONFIDENTIAL                                                                                                                                               61 
 
 
IMP Primary packaging: 
PVC/PVDC//Aluminum blister. 
Each blister contains 1 (one) film-coated tablet or 2 (two) capsules, corresponding to randomized 
treatment. 
For each dose, patient must be instructed to intake together at the same time 1 (one) film-coated 
tablet and 2 (two) capsules, corresponding to dose of the randomized treatment. 
IMP Secondary packaging: 
One blister (containing 1 film-coated tablet) and 1 (one) blister (containing 2 capsules), corresponding 
to randomized treatment, will be packaged together in the same one labelled box. 
Each Patient Box will contain 15 labelled boxes (1 labelled box for the single-dose phase; 12 labelled 
boxes for the multiple-dose phase and 2 labelled boxes as “spare” doses). 
 
IMP Patient Box Secondary packaging:  
Each Patient box will contain 15 film-coated tablets (15 blisters) and 30 capsules (15 blisters), which 
suffice for a total of 13 treatment doses of the randomized treatment and 2 “spare” doses. 
 
IMP Labelling:  
The IMP will be labelled in compliance with all applicable regulatory requirements and Good 
Manufacturing Practice Guidelines, as well as any additional national requirement, and standard 
operating procedures (SOPs). 
The label content will be in local language for each country and will report the contents of the boxes 
and the instructions how to administer and store the IMP. 
 
Rescue Medication (RM): 
Paracetamol 500 mg tablets, oral administration. 
Paracetamol 500 mg tablets will be sourced from EU countries and as commercial product from 
authorized suppliers. 
Rescue medication will be provided in the same commercial primary packaging (blister with 
10 tablets). 


 
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CONFIDENTIAL                                                                                                                                               62 
 
Commercial blisters will be repackaged only in dedicated boxes (2 blister/box) and labelled. 
Rescue medication will be supplied to patients together the IMP in the same Patient box: each Patient 
Box will contain 1 RM box with 20 tablets (2 blister x 10 tablets). 
All repackaging and labelling operations will be performed by A. Menarini Manufacturing Logistics and 
Services S.R,L., (Menarini Group), Via Sette Santi, 3  50131- Florence (Italy). 
The label content will be in local language and will report the contents of the RM boxes and the 
instructions how to administer and store the RM. 
9.2 
Study Treatment Distribution and Return/Destruction 
Drug accountability: 
The Principal Investigator of each participating institution will be responsible for the management of 
all IMP/RM to be used for the clinical trial.  
An inventory will be maintained by the Principal Investigator (or designee) to include a signed account 
of all IMP/RM received, dispensed to and returned by each patient at the planned visits.  
An explanation will be given for any discrepancies. 
At the conclusion of the study, the Drug Accountability Form will be completed after a final IMP/RM 
supply inventory.  
 
Drug return: 
All used or unused IMP/RM must be returned, on agreed conditions, defined by the Sponsor. 
All used or unused IMPs must be accounted for and provided with relative return documentation duly 
filled in, signed and dated as appropriate. Any discrepancy (if any) must be investigated and 
satisfactorily explained. 
 
Drug destruction: 
Destruction of all IMP/RM (used or unused) will be carried out after written authorization of the 
Sponsor. 
9.3 
Product Storage and Stability 
The IMPs and rescue medication should be stored in the original packaging at a temperature below 
25°C, in a secure area, protected from light, and inaccessible to unauthorized personnel. 


 
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CONFIDENTIAL                                                                                                                                               63 
 
9.4 
Study Product Compliance 
Treatment compliance will be monitored from Visit 1 to end of study treatment. The Principal 
Investigator must instruct patients to return to clinical site IMP Patient box received. The amount of 
IMP/RM taken by the patient will be derived by counting the number of tablets/capsules in the blister 
returned and it will be recorded in the electronic case report form (eCRF). 
 
The patient compliance for study treatment period is calculated by the following formula: % compliance 
= number of tablets/capsules actually taken x 100 / expected number of tablets/capsules which should 
have been taken. 
𝐶𝑜𝑚𝑝𝑙𝑖𝑎𝑛𝑐𝑒 (%) = 
𝑢𝑛𝑖𝑡𝑠 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠/𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠  𝑎𝑐𝑡𝑢𝑎𝑙𝑙𝑦 𝑡𝑎𝑘𝑒𝑛
𝑢𝑛𝑖𝑡𝑠 𝑜𝑓 𝑡𝑎𝑏𝑙𝑒𝑡𝑠/𝑐𝑎𝑝𝑠𝑢𝑙𝑒𝑠 𝑒𝑥𝑝𝑒𝑐𝑡𝑒𝑑  𝑡𝑜 𝑏𝑒 𝑡𝑎𝑘𝑒𝑛∙100 
 
The overall patient compliance will be calculated as the percentage of the number of tablets/capsules 
actually taken by the patient over the number of tablets/capsules expected to be taken. 
The number of tablets/capsules actually taken will be calculated as the difference between the number 
of tablets/capsules handled out to the patient and the number of unused tablets/capsules returned or 
declared lost by the patient. 
 
The expected number of total tablets/capsules taken for each patient will be 39 based on 13 (thirteen) 
administrations with 3 tablets/capsules per administration. 
 A patient who has taken at least 80% and no more than 120% of the required IMPs intake since the 
last visit will be considered compliant 
9.5 
Concomitant Therapy/ies 
Any medication that the patient is receiving at the time of enrolment and the regular and occasional 
use of any CM during the study is to be recorded on the eCRF. If additional analgesia is needed during 
the treatment and assessment period, patients should take only the provided RM. 
9.6 
Not Permitted Medications 
The following drugs are prohibited according to the timeline provided and up to 24 hours after last 
intake of study medication: 


 
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CONFIDENTIAL                                                                                                                                               64 
 
 
Treatment with topical preparations/medications within 4 hours prior to Screening, 
anesthetics and muscle relaxants within 8 hours prior to Screening, short-acting analgesics 
(eg, paracetamol) within 4 hours prior to Screening (NSAIDs [eg, ketoprofen, ibuprofen, 
diclofenac]), other analgesics within 5 half-lives prior to Screening, and use of an opioid 
within the 14 days preceding Screening 
 
Any non-pharmacological therapy for low back pain (physical therapy, acupuncture, 
massage etc.) one month before Screening 
 
Sedatives (eg, benzodiazepines) and hypnotic agents within 8 hours before Screening 
 
The following drugs are prohibited within 48 hours or 5 half-lives (whichever is the longer) prior to the 
Screening and up to 24 hours after last intake of study medication: 
 
High doses of salicylates (≥3 g/day) 
 
Anticoagulants, thrombolytic, and antiplatelet agents 
 
Heparins 
 
Corticosteroids (except inhalers and topical agents) 
 
Lithium  
 
Methotrexate used at high doses of 15 mg/week or more 
 
Hydantoins (including phenytoin) and sulphonamides 
 
Monoamine oxidase (MAO) inhibitors in the 14 days prior to the use of the opioid. 
 
Antiepileptics 
 
Antipsychotics 
 
Serotonin reuptake inhibitors (SSRIs and SNRIs) and tricyclic antidepressants 
9.7 
Rescue Medicine 
Rescue medication can be taken at any time after the first dose if adequate pain relief is not achieved 
with the study treatment. However, the patients will be encouraged to wait for at least 60 minutes after 
dosing to allow time for the study treatment effect to take place. Paracetamol 500 mg for a maximum 
of 2 g per day is the recommended rescue medication. Patients will be duly instructed by the 
Investigator regarding the proper posology and method of administration and will be also instructed to 
bring back the remaining RM at Visit 2. The patients will be instructed to fill the RM accountability in 
e-Dairy appropriately to avoid overdosing and to control the RM intake. 


 
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CONFIDENTIAL                                                                                                                                               65 
 
10. STUDY ASSESSMENT AND PROCEDURES 
10.1 
Assessment of Efficacy 
The efficacy parameters will be used to test both the superiority of DKP.TRIS/TRAM.HCl versus 
placebo and the noninferiority of DKP.TRIS/TRAM.HCl when compared to TRAM.HCl. The following 
efficacy parameters will be used to assess the efficacy of the study treatment in the study: 
Numerical Rating Scale - Pain Intensity (NRS-PI) 
The NRS-PI is a 11-point rating scale to assess the pain intensity. The patients will be asked to rate 
their PI in response to the question: ‘How do you rate the intensity of your pain?’ ranging from 0 (no 
pain) to 10 (worst pain). Based on the rating scale, PI scores will be calculated at each pre-specified 
time points. The summed pain intensity difference (SPID [SPID24, SPID48, SPID72, SPID96]), 
percentage of maximum SPID (% max SPID) and percentages of patients achieving at least 30% of 
PI reduction versus baseline will be calculated at 4, 6, and 8 hours after first dose in the single-dose 
phase and 24, 48, 72, and 96 hours after the first dose of the multiple-dose phase of the study. 
Verbal Rating Scale - Pain Relief 
The VRS is a 5-point verbal rating scale to assess the pain relief. In this assessment, the patients will 
be asked to answer the question ‘How do you rate your pain relief?’, where 0 = ‘no relief’, 1 = ‘a little 
(perceptible) relief’, 2 = ‘some (meaningful) relief’, 3 = ‘lot of relief’, 4 = ‘complete relief’. Based on the 
rating scale, pain relief (PAR) scores, total pain relief (TOTPAR), percentage of maximum TOTPAR 
(% max TOTPAR) and percentage of patients achieving at least 50% of maximum TOTPAR will be 
calculated at prespecified time point points in the single and multiple-dose phases of the study. 
 
Roland Morris Disability Questionnaire (RMQ) 
The RMQ is a self-administered disability measure in which greater levels of disability are reflected by 
higher numbers on a 24-point scale. Each question is worth 1 point, so scores can range from 0 (no 
disability) to 24 (severe disability). The patients will have to answer 24 questions that inquire about 
back pain on movement during daily life activities. Clinical improvement over time can be graded 
based on the analysis of serial questionnaire scores. 
 
Patient Global Evaluation (PGE) 


 
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CONFIDENTIAL                                                                                                                                               66 
 
The PGE is a 5-point verbal rating scale where the patients will be asked to answer the question: ‘How 
would you rate the medication received for your pain?’ where 1= ‘poor’, 2 = ‘fair’, 3 = ‘good’, 4 = ‘very 
good’, 5 = ‘excellent’. The PGE will be assessed 8 hours after the first dose and 96 hours after the 
multiple-dose phase or whenever patients discontinue treatment. 
 
Treatment Satisfaction Questionnaire for Medication (TSQM) 
The TSQM comprises of 14 questions that provide scores on 4 scales: effectiveness (3 items), side 
effects (5 items), convenience (3 items), and global satisfaction (3 items). This will be assessed on 
Day 5, 8 hours after the last dose or whenever patients discontinue treatment. 
10.2 
 Assessment of Safety 
Safety will be assessed through collection of treatment-emergent AEs that started after the first dose 
of study treatment (incidence, severity, seriousness, treatment causality), clinical laboratory test 
evaluation, and physical examination (body weight, height, vital signs, blood pressure, and heart rate). 
Safety assessments will be performed at time points as described in Section 4.1. 
The following laboratory tests will be performed for evaluation of safety: 
 
Hematology: Red blood cell (RBC) count, hematocrit (HCT), hemoglobin (Hb), mean 
corpuscular volume (MCV), mean corpuscular hemoglobin (MCH), mean corpuscular 
hemoglobin concentration (MCHC), platelet count, white blood cell (WBC) count, and 
differential WBC count (neutrophil, lymphocyte, monocyte, eosinophil and basophil count, 
absolute and %). 
 
Serum biochemistry: Sodium, potassium, chloride, total calcium, glucose, creatinine, urea, 
total protein, albumin, alkaline phosphatase, gamma-glutamyl transpeptidase (GGT), 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), total bilirubin, direct 
bilirubin, lactate dehydrogenase (LDH), and creatine phosphokinase (CPK). 
Note: For patient who will discover an abnormal renal function (creatinine clearance 
≤ 60 mL/min) and/or an abnormal hepatic function (Child-Pugh class A to C) will be terminated 
from treatment and study. 
 
Coagulation test (only at Screening): prothrombin time, partial thromboplastin time (PTT), INR. 


 
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CONFIDENTIAL                                                                                                                                               67 
 
 
Urinalysis: Urinalysis will be performed using dipstick during the Screening and at the end of 
the study (Visit 2). The following parameters will be analyzed: specific gravity, pH, leucocytes, 
nitrite, protein, glucose, ketones, urobilinogen, bilirubin, blood (erythrocytes, hemoglobin). 
 
Pregnancy test: Pregnancy test, if appropriate, will be performed using stick pregnancy test 
during the Screening period and at the End of Study Visit. 
All the laboratory evaluations will be performed in the central laboratory (Q Squared Solutions). 
11. SAFETY DATA MANAGEMENT 
11.1 
Adverse Event (AE) 
Any untoward medical occurrence in a patient or clinical study patient administered a medicinal 
product and which does not necessarily have a causal relationship with this treatment. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal product, whether or 
not considered related to the medicinal product. 
11.2 
Drug Relationship 
The relationship between an AE and study drugs will be judged according to the following categories: 
1. Certain: The AE occurs in a plausible time relation to the administration of the drug and 
cannot be explained by a 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. Probable: The AE occurs in a reasonable time relation to the administration of the drug, it 
is unlikely to be attributed to a concurrent disease or other drugs or chemicals and it follows 
a clinically reasonable response on withdrawal (dechallenge). Rechallenge information (AE 
reappearance after drug reintroduction) is not required to fulfil this definition. 
3. Possible: The AE occurs with a reasonable time relation to the administration of the drug, 
but it could also be explained by a concurrent disease or other drugs or chemicals. 
Information on drug withdrawal (dechallenge) may be lacking or unclear. 
4. Unassessable: The relationship cannot be judged, because of the information is insufficient 
or contradictory and cannot be supplemented or verified. 


 
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CONFIDENTIAL                                                                                                                                               68 
 
5. Unlikely: A causal relationship cannot be definitively ruled out, but 
 
Other drugs, chemicals, or underlying disease provide plausible 
explanations and/or 
 
The temporal relation to the administration of the drug makes a causal 
relation improbable. 
6. Not Related: Any of the following are present: 
 
existence of a clear alternative explanation, and/or 
 
unreasonable temporal relationship between Drug and Event, and/or 
 
non-plausibility. 
11.3 
Adverse Drug Reaction (ADR) 
An ADR is any untoward and unintended response to an investigational medicinal product related to 
any dose administered. 
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. 
An ADR is considered any AE for which the relationship is considered as: 
1. Certain 
2. Probable 
3. Possible 
4. Unassessable. 
An AE is not considered as an ADR when the relationship is judged as: 
1. Unlikely 
2. Not related. 
11.4 
Seriousness 
An AE/ADR is considered serious when it: 
1. Results in death; 
2. Is life-threatening; 
Note: Life-threatening is considered any AE in which the patient was at risk of death at the time of 
the event; it does not refer to an event that hypothetically might have caused death if it were more 
severe. 


 
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Study Code: MEIN/18/DEX-LBP/001 
Protocol Version 2 of 13/09/2021/  
 
 
 
  
 
CONFIDENTIAL                                                                                                                                               69 
 
3. requires inpatient hospitalization or prolongation of existing hospitalization; 
4. results in persistent or significant disability/incapacity; 
5. is a congenital anomaly/birth defect; 
6. is another medically important condition that may jeopardize the patient or may require 
intervention to prevent 1 of the outcomes listed above. Any suspected transmission of an 
infectious agent via a medicinal product is considered serious and should be assessed under 
the category of medically important events in the absence of other seriousness criteria. 
An AE/ADR is considered Non-serious when it does not fulfill the conditions for the definition of 
Serious AE/ADR. 
11.5 
Adverse Event/Adverse Drug Reaction Intensity 
The intensity level of a Serious or a Non-serious AE or ADR is attributed according to the following 
definitions: 
 
Mild: does not interfere with routine activities; in case of laboratory tests, when there is a 
mild abnormality. 
 
Moderate: interferes with the routine activities; in case of laboratory tests, when there is a 
moderate abnormality. 
 
Severe: makes it impossible to perform routine activities; in case of laboratory tests, when 
there is a significant abnormality. 
11.6 
Adverse Event/Adverse Drug Reaction Expectedness 
An AE/ADR is considered Unexpected when the nature, severity, or outcome of the AE/ADR is not 
consistent with the information provided in the Reference Safety Document (Summary of Product 
Characteristics). 
11.7 
Serious Unexpected Adverse Drug Reaction (SUSAR) 
Any SAE judged by the Investigator or the Sponsor as drug-related (see Section 11.3) and 
considered as unexpected qualifies as a SUSAR. 
SUSARs are subject to expedited reporting, as specified in Section 11.10, as having a “Reasonable 
Possibility” of relationship with the IMP. 


 
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Protocol Version 2 of 13/09/2021/  
 
 
 
  
 
CONFIDENTIAL                                                                                                                                               70 
 
11.8 
Individual Case Safety Report (ICSR) 
Format and content provided to describe 1 or several AEs or a disease experience that occur to an 
individual patient at a particular point of time. 
11.9 
Collection, Recording and Reporting of AEs  
At each visit the Investigator will collect and assess any occurred subjective or objective AE 
occurred to each patient after his/her signature of the informed consent. 
 
The Investigator should manage as AE any laboratory test abnormality (newly occurring after the 
IMP administration or worsening of previously known abnormalities) considered as clinically 
relevant: ie, values significantly above or under normal range or which require an intervention or 
diagnostic tests or may result in the IMP discontinuation. 
 
Any AE communicated by the patient or by the patient’s relatives or delegates through phone calls, 
letters or e-mails will also be collected and assessed. 
 
The Investigator shall record on the respective eCRF AE recording pages any recognized AE 
identifying an ICSR, both serious and non-serious, whether or not thought to be drug-related, 
observed in or reported by the patient (or relatives/delegates), specifying the judgement on the 
causal relationship with the study treatment. 
 
Any available information and diagnostic measure (laboratory and instrumental tests, procedures, 
etc.) shall be recorded in and/or attached to the concerned eCRF pages/sections. 
The Investigator is expected to record also any AE occurring during the study follow-up period (up 
to Visit 2) after the administration of the last treatment dose. 
 
The Investigator is expected to follow-up any AE occurred during the study, including the follow-up 
period (period between the last drug intake and the visit 2), until the outcome of the AE has been 
determined. 
 


 
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Previous Doc Number: 
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Protocol Version 2 of 13/09/2021/  
 
 
 
  
 
CONFIDENTIAL                                                                                                                                               71 
 
The Investigator must report all the collected information on any ICSR with Serious and Nonserious 
AE (whether or not thought to be related to the investigational drug), providing the concerned 
eCRF-AE pages by alert e-mail, after the first knowledge of the occurrence of the case, to: 
 
 
When relevant, also the eCRF pages concerning medical history, CM, and laboratory tests will be 
placed at Sponsor disposal by e-mail. 
11.10 Management of Serious AEs (SAEs) including laboratory abnormalities 
 
Reporting Duties of the Investigator 
The Investigator must report all the collected information on any ICSR with SAE (whether or not 
thought to be related to the investigational drug), as above specified, no later than 24 hours after 
the first knowledge of the occurrence of the case. 
Any further information and supporting documentation that become available (copies of laboratory 
reports, tests, procedures, autopsy evidence of the cause of death, etc.) shall be provided no later 
than 24 hours after the knowledge, by the Investigator to the CRO by alert e-mail, to be forwarded 
to the Sponsor. 
The Investigator must also comply with the local applicable obligation(s) on the reporting of ADRs 
to the local concerned Regulatory Authority/EC. 
 
Reporting Duties of the Sponsor 
The Sponsor shall ensure that all relevant information about any suspected serious and 
unexpected adverse drug reaction (SUSAR), is expeditiously reported to the competent Authorities 
(including EudraVigilance Clinical Trial Module for clinical trials for which a EudraCT number has 
been assigned) and ECs (following general and local rules and procedures), with these deadlines 
after the first knowledge, intended as the day when the CRO receives the notification of the SUSAR: 
– Fatal and life-threatening unexpected cases, no later than 7 days; 
– Other unexpected serious cases, no later than 15 days. 
CRO Pharmacovigilance Officer: Vedran Stančić 
 
E-mail :  vedran.stancic@iqvia.com 
 
Fax : NA 
 
Mobile: +385 91 4171-128 


 
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Previous Doc Number: 
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Version Number: 
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Sponsor: Menarini Pharmaceutical 
Study Code: MEIN/18/DEX-LBP/001 
Protocol Version 2 of 13/09/2021/  
 
 
 
  
 
CONFIDENTIAL                                                                                                                                               72 
 
The Sponsor shall ensure that all relevant information and supporting documentation that 
subsequently becomes available, is also expeditiously reported as follow-up information according 
to the above-mentioned deadlines. 
Since this study is blinded, the patient’s code will be broken before the expedited reporting to the 
Competent Authorities and the ECs. 
Furthermore, the following safety issues will be subjected to expedited management for the 
identification of possible necessary actions: 
– SAEs associated with the study procedures 
– Potential clinically significant findings emerging from non-clinical studies 
– An anticipated end or suspension for safety reasons of another study with the same study 
drug. 
When appropriate and applicable the Sponsor will arrange the adequate information also to the 
Investigators. 
11.11  Management of Non-serious AEs (NSAEs) including laboratory 
abnormalities 
 
Reporting Duties of the Investigator 
The Investigator must report all the collected information on any ICSR with NSAE (whether or not 
thought to be related to the investigational drug), as above specified, no later than 5 Calendar days 
after the first knowledge of the occurrence of the case. 
Any further information and supporting documentation that become available (copies of laboratory 
reports, tests, procedures, etc.) shall be provided no later than 24 hours after the knowledge, by 
the Investigator to the CRO by e-mail or fax to be forwarded to the Sponsor. 
11.12  Management of any laboratory abnormality 
Any laboratory test abnormality which is considered by the Investigator as AE is to be managed as 
above detailed (refer to Section 11.9). 
However, all “out of range” values should be collected and reviewed periodically by the CRO 
medical team (medical data review team first reviews listings of laboratory values and send them 
to Therapeutic Medical Advisor for second review and approval). In case that the laboratory values 
deemed to be significant, but the site did not report or ignored them, MDR will raise query to the 
site in attempt to find appropriate answer. MDR will close the query after. On monthly basis all 
medical queries will be reviewed with the sponsor.. 


 
Corporate Medical Department 
 
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Previous Doc Number: 
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Version Number: 
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Sponsor: Menarini Pharmaceutical 
Study Code: MEIN/18/DEX-LBP/001 
Protocol Version 2 of 13/09/2021/  
 
 
 
  
 
CONFIDENTIAL                                                                                                                                               73 
 
11.13 Management of pregnancy exposure cases 
The Investigator is expected to record in the provided form any case of pregnancy exposure 
occurring in a female patient or in a male patient’s partner during the treatment and follow-up 
periods, sending it within 5 days after being made aware of the pregnancy, to the CRO by e-mail 
or fax, to be forwarded to the Sponsor within 24 hours. 
The Investigator is requested to follow each case of pregnancy exposure until the outcome. 
If the pregnancy results in an abnormal outcome, this will be recorded in the eCRF as a SAE and 
managed as above described. 
12. WITHDRAWAL CRITERIA 
The patient may withdraw from the study at any time without explanation, without losing the right 
to future medical care. The participation of the patient may, at any moment, be terminated by the 
Investigator, if considered appropriate. 
Study drug treatment must be terminated during the study for any of the following reasons: 
 
Any AE, including clinically significant abnormal laboratory value(s) which request treatment 
and study termination according to the Investigator’s judgment. 
 
Patient who will discover an abnormal renal function (creatinine clearance ≤ 60 mLl/min) 
and/or an abnormal hepatic function (Child-Pugh class A to C) after laboratory blood and 
urine analysis data available. 
 
Patient who will become pregnant during the study. 
 
Request of the patient (without giving any reason). 
 
Investigator deems it to be in the best interest of the patient to discontinue. 
 
Failure to comply adequately with the dosing, evaluations, or other requirements of the 
study. 
 
If the patients meets an exclusion criteria (newly developed or not previously recognized) 
that precludes further study partecipation. 
 
Use of a prohibited CM. 


 
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Previous Doc Number: 
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CONFIDENTIAL                                                                                                                                               74 
 
 
Patient does not achive adequate pain control by maximum allowed dose of rescue 
medication. 
 
Patient has overused rescue medication due to insufficient pain control. 
The reason for the withdrawal must be well documented in the eCRF. 
If a patient has been discontinued/withdrawn due to an SAE, the Investigator must immediately 
notify the relevant PhV contact (see Section 11.9). Any deviation from the protocol (to be classified 
as major or minor) will be accepted only in case of emergency and/or after a written agreement 
with the Sponsor. 
Furthermore, any patient who prematurely terminates participation after having received any dose 
of the IMP will be encouraged to undergo an end of study examination according to the procedures 
and the time-window required for the End of study visit (Visit 2). If patient withdraws the consent, 
but is willing to have an End of Study visit, the End of study visit according to the described 
procedures (Visit 2) can be performed at that time. 
If study participation is terminated due to an ADR, the patient has to be followed-up (with additional 
examinations, if necessary) according to the medical judgment of the Investigator, until the 
abnormal condition is resolved or the Investigator deems further observations or examinations as 
no longer medically indicated. Unless premature interruption occurs the End of study visit (Visit 2) 
will be the closure visit at clinical site. 
13. LOST TO FOLLOW-UP 
A patient will be considered lost to follow-up if he or she fails to return for scheduled visits and is 
unable to be contacted by the study site staff.  
 
Before a patient is deemed lost to follow-up, the Investigator or designee will make every effort to 
regain contact with the patient. These contact attempts should be documented in the patient’s medical 
record or study file. 
14. STATISTICS 
The primary objective of the study is to evaluate the analgesic efficacy of DKP.TRIS/TRAM.HCl versus 
placebo 8 hours after the first dose, using a two-sided significance level of 5%. The secondary efficacy 


 
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CONFIDENTIAL                                                                                                                                               75 
 
objective is to evaluate the analgesic efficacy of DKP.TRIS/TRAM.HCl versus TRAM.HCl 8 hours after 
the first dose and after multiple doses, using a one-sided significance level of 2.5%. 
 
The efficacy variables will be used to test both the superiority of DKP.TRIS/TRAM.HCl versus placebo 
(only for single-dose phase endpoints) and the non-inferiority with the possibility of switch to superiority 
of DKP.TRIS/TRAM.HCl versus TRAM.HCl. Data imputations will be considered for values collected 
after the RM intake and for intermediate missing data and missing data after early treatment 
discontinuation. 
Details for the statistical analysis including the procedures for accounting for missing or spurious data 
and the patient analysis sets, will be specified in the statistical analysis plan (SAP). The SAP will be 
developed and finalized prior to database lock and the unblinding of the database. 
14.1 
Statistical Methods (Blinding and Randomization) 
The study will be performed according to a randomized, double-blind, double-dummy, placebo and 
active-controlled, parallel group design, encompassing 2 study phases: a single dose-phase (first 
8 hours) and a multiple-dose phase starting after single-dose phase. 
 
Eligible patients, after successfully completing the screening phase for study eligibility assessment 
period on Day 1, will be randomized in a 4:4:1:1 ratio to 1 of the 4 possible treatment arms, as per 
treatment code delivered through IWRS in accordance with the randomization list, according to the 
following scheme: 
Arm 
Single-dose phase (t0-t8) 
Multiple-dose phase (t8-day5) 
1 
DKP.TRIS/TRAM.HCl 
DKP.TRIS/TRAM.HCl 
2 
TRAM.HCl 
TRAM.HCl 
3 
Placebo 
DKP.TRIS/TRAM.HCl 
4 
Placebo 
TRAM.HCl 
 
Double-blind conditions will be secured by using a double-dummy design.  
DKP.TRIS 25 mg/TRAM.HCl 75 mg as well as the placebo tablets will be provided as film-coated 
tablets with matching appearance and weight. 


 
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Study Code: MEIN/18/DEX-LBP/001 
Protocol Version 2 of 13/09/2021/  
 
 
 
  
 
CONFIDENTIAL                                                                                                                                               76 
 
The active comparator, TRAM.HCl 100 mg, will be provided as two capsules of a marketed drug 
Tramadol 50 mg and, for blinding, two capsules of placebo will be provided with matching appearance 
and weight.  
 
The CRO or its delegate will be responsible for generating the randomization list that assigns the 
treatment to each patient. In order to preserve the double-blind conditions of the study, people who 
are involved in the preparation or the handling of the randomization 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 randomization list will be prepared; one set will be provided for programming the IWRS 
and one set will be provided to the Clinical Trial Supply Department of A. Menarini Manufacturing 
Logistics and Services S.R,L., (MMLS), Via Sette Santi, 3  50131- Florence (Italy) for IMP/RM labelling 
operations. 
 
All patients will be centrally assigned to randomized study treatment using an IWRS. Before the study 
is initiated, the log in information and directions for the IWRS will be provided to each study center. 
The IWRS will be programmed with blind-breaking instructions. In case of an emergency, the 
Investigator has the sole responsibility for determining if unblinding of a patient’s treatment assignment 
is warranted. Patient safety must always be the first consideration in making such a determination. If 
the Investigator decides that unblinding is warranted, the Investigator should make every effort to 
contact the Sponsor prior to unblinding a patient’s treatment assignment unless this could delay 
emergency treatment of the patient. If a patient’s treatment assignment is unblinded, the Sponsor 
must be notified within 24 hours after breaking the blind. The date and reason that the blind was 
broken must be recorded in the source documentation and eCRF, as applicable. 
 
14.2 
Determination of Sample Size  
A sample size of 510 patients is required to detect the difference between DKP.TRIS/TRAM.HCl and 
placebo and to demonstrate the non-inferiority of DKP.TRIS/TRAM.HCl versus TRAM.HCl for the time 
to first achieve an NRS-PI score <4 or a pain intensity reduction of ≥30% from drug intake till 8 hours 
post-treatment.  


 
Corporate Medical Department 
 
Identification Number: 
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Previous Doc Number: 
CTWI10A 
Version Number: 
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Sponsor: Menarini Pharmaceutical 
Study Code: MEIN/18/DEX-LBP/001 
Protocol Version 2 of 13/09/2021/  
 
 
 
  
 
CONFIDENTIAL                                                                                                                                               77 
 
In detail, a total number of 204 patients (102 for each treatment arm) was considered appropriate for 
detecting the superiority of DKP.TRIS/TRAM.HCl versus Placebo, assuming a power of 80%, alpha 
of 0.05, and a hazard ratio of 1.5 with a relative Wald confidence interval of 1.17 to 1.97 and the 
probability of event of 0.961 and 0.835 in the treatment and placebo groups, respectively (based on 
previous studies).. 
 
Additionally, a total number of 408 patients (204 for each treatment arm) is sufficient for assessing the 
non-inferiority of DKP.TRIS/TRAM.HCl versus TRAM.HCl, assuming a hazard ratio of 1.06, a non-
inferiority margin of 0.8, a power of 80%, alpha of 0.025, and proportions of events of 96.1% and 
94.7%, respectively (based on previous studies). 
In order to keep a 4:4:1:1 ratio the following number of patients by treatment arms will be recruited: 
Arm 
N 
DKP.TRIS/TRAM.HCl+ DKP.TRIS/TRAM.HCl 
204 patients 
TRAM.HCl + TRAM.HCl 
204 patients 
Placebo + DKP.TRIS/TRAM.HCl 
51 patients 
Placebo + TRAM.HCl 
51 patients 
Assuming approximately 20% of screening failure rate, 612 patients are expected to be screened.  
 
14.3 
Analysis Populations 
The following analysis populations will be considered for statistical analysis: 
 
Safety population: All patients randomized who have received at least 1 dose of the study 
treatment. 
 
Intention-to-treat (ITT) population: all patients randomized. 
 
Per-protocol (PP) populations: All patients of the ITT population who have not experienced 
major protocol violations that could affect the analyses. Different PP populations will be 
defined accordingly to the different analyses and the relative timepoint in the SAP. The PP 
populations will be used to perform the confirmatory analyses and to assess non-inferiority. 
Efficacy analyses will be performed using the ITT population or PP population as defined in the SAP. 


 
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CONFIDENTIAL                                                                                                                                               78 
 
14.4 
Analysis Variables 
Efficacy Variables 
Primary Efficacy Variables:  
Time to first achieve an NRS-PI score <4 or a pain intensity reduction of ≥30% from drug intake till 
8 hours after the first dose. 
Secondary Efficacy Variables: 
The following derivations apply: 
 
Total Pain Relief (TOTPAR): 
TOTPAR is calculated as the time-weighted sum of the PAR-VRS scores. 
The general formula for calculating TOTPARx is as follows: 
TOTPAR8 =  ∑ [𝑻(𝒊) −𝑻(𝒊−𝟏)]  𝒙 𝑷𝑨𝑹(𝒊) for i = 15m, 30m, 1h, 1.5h, 2h, 4h, 6h, 8h 
TOTPAR24=  ∑ [𝑻(𝒊) −𝑻(𝒊−𝟏)]  𝒙 𝑷𝑨𝑹(𝒊) for i = from 10h to 32h  
TOTPAR48 = ∑ [𝑻(𝒊) −𝑻(𝒊−𝟏)]  𝒙 𝑷𝑨𝑹(𝒊) for i = from 10h to 56h 
TOTPAR72 = ∑ [𝑻(𝒊) −𝑻(𝒊−𝟏)]  𝒙 𝑷𝑨𝑹(𝒊) for i = from 10h to 80h 
TOTPAR96 = ∑ [𝑻(𝒊) −𝑻(𝒊−𝟏)]  𝒙 𝑷𝑨𝑹(𝒊) for i = from 10h to 104h 
TOTPAR104 =  ∑ [𝑻(𝒊) −𝑻(𝒊−𝟏)]  𝒙 𝑷𝑨𝑹(𝒊) for i = 15m, 30m, 1h, 1.5h, 2h, 4h, 6h, 8h, 10h, …, 104h 
where T(i) is the scheduled time, T(0) = 0, PAR(i) = PAR at time i. 
Please note that starting from multiple phase values are collected before and two hours after each 
intake and that for the evaluation of TOTPAR104 patients taking Placebo during the single phase will 
be excluded. 
 
Percent (%) max TOTPAR: 
The max TOTPAR is calculated as the theoretical maximum time-weighted sum of the PAR values 
for each patient. The maximum possible TOTPAR is the value of TOTPAR that would be obtained if 
the patient has a complete pain relief for that observation period (ie, PAR at each post-baseline time 
point evaluated was 4). 
The % max TOTPAR is the ratio between the TOTPAR of each patient and its theoretical maximum 
TOTPAR for a certain observation period. 
 
Summed Pain Intensity Difference (SPID): 


 
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CONFIDENTIAL                                                                                                                                               79 
 
SPID is calculated as the time-weighted sum of the pain intensity difference (PID) values, where PID 
is the difference in Pain Intensity calculated at each timepoint respect to the baseline value. The 
general formula for calculating SPIDx is as follows: 
SPID8 =  ∑ [𝑻(𝒊) −𝑻(𝒊−𝟏)]  𝒙 𝑷𝑰𝑫(𝒊) for i = 15m, 30m, 1h, 1.5h, 2h, 4h, 6h, 8h 
SPID24=  ∑ [𝑻(𝒊) −𝑻(𝒊−𝟏)]  𝒙 𝑷𝑰𝑫(𝒊) for i = from 10h to 32h 
SPID48 =  ∑ [𝑻(𝒊) −𝑻(𝒊−𝟏)]  𝒙 𝑷𝑰𝑫(𝒊) for i = from 10h to 56h 
SPID72 =  ∑ [𝑻(𝒊) −𝑻(𝒊−𝟏)]  𝒙 𝑷𝑰𝑫(𝒊) for i = from 10h to 80h 
SPID96 =  ∑ [𝑻(𝒊) −𝑻(𝒊−𝟏)]  𝒙 𝑷𝑰𝑫(𝒊) for i = from 10h to 104h 
SPID104 =  ∑ [𝑻(𝒊) −𝑻(𝒊−𝟏)]  𝒙 𝑷𝑰𝑫(𝒊) for i = 15m, 30m, 1h, 1.5h, 2h, 4h, 6h, 8h, 10h, …, 104h 
Please note that starting from multiple phase values are collected before and two hours after each 
intake and that for the evaluation of SPID104 patients taking Placebo during the single phase will be 
excluded. 
 
Percent (%) max SPID: 
The max SPID is calculated as the theoretical maximum time-weighted sum of the PID values for 
each patient. The maximum possible SPID is the value of SPID that would be obtained if the patient 
were pain free for that observation period (ie, PI at each post-baseline time point evaluated was 0). 
The % max SPID is the ratio between the SPID of each patient and its theoretical maximum SPID 
for a certain observation period. 
Single-dose phase: 
– 
Pain Relief (PAR) scores at each prespecified time point (t15m, t30m, t1h, t1.5h, t2h, t4h, t6h, 
t8h) over the 8 hours after the first dose 
– 
TOTPAR at 4, 6, and 8 hours (TOTPAR4, TOTPAR6, TOTPAR8) after the first dose 
– 
Percentage of maximum TOTPAR (% max TOTPAR) at 4, 6, and 8 hours after the first dose 
– 
Percentage of patients achieving at least 50% of maximum TOTPAR at 4, 6, and 8 hours after 
the first dose 
– 
Pain Intensity (PI) scores at each prespecified time point (t15m, t30m, t1h, t1.5h, t2h, t4h, t6h, 
t8h) over the 8 hours after the first dose 
– 
SPID at 4, 6, and 8 hours (SPID4, SPID6, SPID8) after the first dose 
– 
Percentage of maximum SPID (% max SPID) at 4, 6, and 8 hours after the first dose 


 
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CONFIDENTIAL                                                                                                                                               80 
 
– 
Percentage of patients achieving at least 30% of PI reduction versus baseline at 4, 6, and 
8 hours after the first dose 
– 
PGE of the study medication at 8 hours after the first dose 
– 
Time to RM: Time elapsed between treatment administration and the first dose of RM from 
baseline till 8 hours after the first dose 
– 
Percentage of patients who required RM within the first 4, 6, or 8 hours post-dose. 
Multiple-dose phase: 
– 
Pain Relief (PAR) scores at each prespecified time point  
– 
TOTPAR at 24, 48, 72, and 96 hours (TOTPAR24, TOTPAR48, TOTPAR72, TOTPAR96). 
– 
Percentage of maximum TOTPAR (% max TOTPAR) at 24, 48, 72, and 96 hours of the 
multiple-dose phase. 
– 
Percentage of patients achieving at least 50% of maximum TOTPAR at 24, 48, 72, and 
96 hours of the multiple-dose phase. 
– 
Pain Intensity (PI) scores at each prespecified time point over the multiple-dose phase. 
– 
SPID at 24, 48, 72, and 96 hours (SPID24, SPID48, SPID72, SPID96) of the multiple-dose 
phase. 
– 
Percentage of maximum SPID (% max SPID) at 24, 48, 72, and 96 hours of the multiple-dose 
phase. 
– 
Percentage of patients achieving at least 30% of PI reduction versus baseline at 24, 48, 72, 
and 96 hours of the multiple-dose phase. 
– 
PGE at 96 hours of the multiple-dose phase. 
– 
Percentage of patients who required RM within 24, 48, 72, and 96 hours of the multiple-dose 
phase. 
– 
Roland Morris Disability Questionnaire at 96 hours of the multiple-dose phase. 
– 
Treatment Satisfaction Questionnaire for Medication at 96 hours of the multiple-dose phase 
Complete treatment and assessment period (single and multiple-dose phase combined): 
– 
Time to first achieve an NRS score <4 or a pain intensity reduction ≥30% from the first drug 
intake till 5 days post-treatment, excluding patients assigned to placebo treatment arm during 
the single dose phase. 


 
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Study Code: MEIN/18/DEX-LBP/001 
Protocol Version 2 of 13/09/2021/  
 
 
 
  
 
CONFIDENTIAL                                                                                                                                               81 
 
– 
TOTPAR over 104 hours from the first drug intake till 5 days post-treatment (TOTPAR104), 
excluding patients assigned to placebo treatment arm during the single dose phase. 
– 
SPID over 104 hours from the first drug intake till 5 days post-treatment (SPID104), excluding 
patients assigned to placebo treatment arm during the single dose phase. 
– 
Time to RM: Time elapsed between the first drug intake till 5 days post-treatment, excluding 
patients assigned to placebo treatment arm during the single dose phase. 
Exploratory variable: 
Time to first achieve an NRS-PI score <4 AND a pain intensity reduction of ≥30% from drug intake till 
8 hours posttreatment (single-dose phase only) 
Safety Variables 
The safety variables included: 
– 
Adverse events (incidence, severity, seriousness, causality) 
– 
Clinically significant changes in physical examination, vital signs, and laboratory test results post-
dose versus baseline 
For physical examination, laboratory tests, and vital signs, values collected during the Screening will 
be used as baseline values. 
14.5 
STATISTICAL ANALYSIS  
.Descriptive statistics 
All study variables will be presented by treatment and overall (if appropriate), by using the appropriate 
descriptive statistics according to the variable nature, unless otherwise specified: 
 
Continuous variables: number of non-missing observations, mean, standard deviation, 
minimum, median, maximum. 
 
Categorical variables: number of non-missing observations and column percentages (N, %). 
 
Primary (efficacy) analysis  
The primary efficacy variable, time to first achieve an NRS-PI score <4 or a pain intensity reduction 
≥30% from drug intake till 8 hours after the first dose, will be analyzed for the superiority of 
DKP.TRIS/TRAM.HCl versus placebo on the ITT population using a Cox Proportional Hazard (CPH) 
model with treatment, baseline PI categories and baseline radiculopathy categories as covariates. A 
two-sided significance level of 5% will be used. In case of proportional hazard assumption is not 
satisfied additional analyses that permit relaxation of the assumption will be implemented. 


 
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CONFIDENTIAL                                                                                                                                               82 
 
Sensitivity analyses of the primary endpoint will also be done using the PP population. 
Missing data and data collected after the RM intake will be handled as described in Section 0. 
 
Sensitivity analysis  
Sensitivity analyses will be conducted to the data imputation assumptions. Further details can be 
found in Section 0. 
Secondary (efficacy) analysis 
The secondary efficacy variable will be tested through an adhoc inferential analysis as below: 
– 
Secondary efficacy variables with quantitative outcome: 
o PI-NRS, SPIDs, %max SPIDs, TOTPARs, %max TOTPARs, and TSQM will be 
analyzed by an analysis of covariance (ANCOVA) with treatment and the baseline 
PI-NRS as covariates; 
o Roland Morris Disability Questionnaire will be analyzed using ANCOVA, with 
treatment and the baseline Roland Morris Disability Questionnaire score as 
covariates. Additionally, percent improvement from Baseline in the Roland Morris 
Disability Questionnaire score will also be presented by treatment. Patients 
assigned to placebo treatment arm during the single dose phase will be excluded. 
o PGE (8h after the first dose, and at 96 hours of the multiple dose-phase) and PAR-
VRS (at each time point separately) (ordinal variables) will be analyzed by 
Wilcoxon rank-sum test. 
– 
Secondary efficacy variables with binary outcome will be tested using a Chi-squared test. An 
additional analysis considering adjustment by covariates (baseline PI categories and baseline 
radiculopathy categories) may be considered. 
– 
Time to first use of RM will be assessed using a Log-rank test. An additional analysis 
considering adjustment by covariates (baseline PI categories and baseline radiculopathy 
categories) may be considered. 
– 
The amount of RM consumption and the number of patients using RM will be descriptively 
analyzed 
Non-inferiority of DKP.TRIS/TRAM.HCl versus TRAM.HCl will be tested with a one-sided significance 
level of 2.5%. Non-inferiority will be satisfied if the lower limit of the confidence interval is greater than 
a non-inferiority margin: 


 
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CONFIDENTIAL                                                                                                                                               83 
 
- 
For Time to "event" variables, the non-inferiority margin will be 0.80, based on Hazard Ratio. 
- 
For continuous variables the non-inferiority margin will be 20%, based on the LS Mean. 
- 
For binary variables the non-inferiority margin will be 0.80, based on the Odds Ratio. 
In case the non-inferiority is confirmed, the superiority of DKP.TRIS/TRAM.HCl versus TRAM.HCl will 
be also tested. All the secondary endpoints related to the single phase will be also analyzed for the 
superiority of DKP.TRIS/TRAM.HCl versus placebo.  
Non-inferiority will be tested on the PP population and in addition for the secondary endpoints of 
primary interest (TOPAR24, TOTPAR48) also on the ITT population. Superiority will only be tested on 
the ITT population, if non-inferiority is confirmed on the PP population. 
Missing PI and PAR data and PI and PAR assessments collected after the RM intake will be handled 
as described in Section 0. 
 
Exploratory (efficacy) analysis 
Time to first achieve an NRS-PI score <4 AND a pain intensity reduction ≥30% from drug intake till 
8 hours post-treatment (single dose phase only) will be analyzed analogously to the primary efficacy 
variable. 
 
Subgroup analysis 
There is no planned subgroup analysis; however, subgroup analysis may be conducted as post Hoc 
analysis. 
 
Safety analysis 
 
Adverse events will be coded using the MedDRA dictionary (latest version available at the time 
of the analysis). The incidence of each treatment emergent AEs (TEAEs - AE’s that occurred 
or worsened after the first administration of study treatment including the follow-up period 
[period between the last drug intake and the visit 2]) will be summarized by system organ class 
(SOC), preferred term (PT) and treatment. 
 
Reasons for early treatment termination will be summarized by treatment. 
 
Laboratory findings will be summarized as shift tables by treatment. 
 
Clinically significant abnormal findings in vital signs and physical examination will be listed by 
treatment. 
 
Safety analyses will be run on the safety population 


 
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CONFIDENTIAL                                                                                                                                               84 
 
 
Interim analysis and stopping rules 
No interim analysis is planned for this study. 
 
Data imputations 
Data imputations will be done for PI and PAR assessments under the following circumstances: 
 
First, for values collected after the RM intake 
 
Then, missing data. 
Once imputations are done, the efficacy variables based on PI and PAR assessments (SPID, 
TOTPAR, etc.) will be re-derived based on the PI and PAR imputed values. 
Different strategies will be used to handle data imputation. A summary is provided in the table below: 
 
Values collected after the RM intake 
Missing data 
Main Analysis 
Single dose phase: 
For all PI and PAR assessments at each timepoint after the 
first RM intake, PI will return to its baseline level and PAR to 
zero (Baseline Observation Carried Forward [BOCF]). 
Multiple-dose phase: 
PI and PAR assessments recorded during the 6 hours after 
the intake of RM (based on the effect of Paracetamol) will be 
replaced with the last observation carried forward (LOCF) 
(which should be the one done immediately before RM) or 
worst observation carried forward (WOCF) in case the 
assessment immediately before intake is missed. 
Single 
missing 
values 
between measurements will 
be linearly interpolated; if 
more consecutive data are 
missed LOCF method will be 
applied 
Sensitivity 
Analysis 1 
Treatment Policy Strategy: values collected are used 
regardless of whether or not the RM is taken without any 
imputation. 
No imputation, missing values 
will not be replaced. 
Sensitivity 
Analysis 2 
Hypothetical Strategy: a scenario is envisaged in which the 
intake of RM would not occur. Values collected for the 6 hours 
after the RM intake will be considered as missed and they will 
be imputed by using a multiple imputation approach. 
If a Missing At Random (MAR) 
pattern of missing data is 
detected, missing values will 
be 
replaced 
by 
using 
a 
multiple imputation approach. 
 
The SAP will provide additional details regarding methods for handling missing data and data collected 
after the RM intake for the main analysis and the sensitivity and exploratory analyses. 
14.6 
Protocol Deviations and Protocol Amendments 
No deviations from the Protocol should be initiated without prior approval by the EC/HA of a protocol 
amendment according to applicable Regulations, except in case of emergency or when the change 


 
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CONFIDENTIAL                                                                                                                                               85 
 
involves only logistical or administrative aspects of the study. Any deviation from the Protocol, SOPs, 
GCP and applicable Regulatory Requirements should be immediately reported to the Sponsor. 
 
Categories of protocol deviations will be defined before treatment unblinding and will be integrated in 
the statistical analysis. Details of major protocol violations, including those leading to exclusion from 
the PP population, will be documented in the SAP. For the final analysis, a blind data review meeting 
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 deviations. After this final meeting has taken place and the database is considered 
cleaned, the database will be locked and unblinded. 
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, ie, 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 ECs and the 
CAs in the participating countries have to approve these amendments before implementation, 
according to applicable regulatory requirements 
 
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 EC 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. 
14.7 
Statistical Analysis Plan 
The SAP will be finalized before the unblinding of the study. The SAP will describe in detail study 
endpoints and statistical analyses, including the analysis of the primary as well as additional 
endpoints. In case changes of the original primary endpoint or of the original primary analyses will 
occur during the study, these changes will be the patient of a substantial protocol amendment. 
All statistical analyses not prespecified and run after data unblinding will be considered 
additional/exploratory analyses.  


 
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CONFIDENTIAL                                                                                                                                               86 
 
15. STUDY DISCONTINUATION AND CLOSURE 
In case the study is temporarily suspended or prematurely terminated, written notification documenting 
the reason for study suspension or termination, will be provided by the suspending or terminating party 
to study patients, Investigators, ECs, Sponsor and Regulatory Authorities with the reason(s) for the 
termination or suspension. The study patients will be contacted, as applicable, and be informed of 
changes to study visit schedule. 
16. DIRECT ACCESS TO SOURCE DATA/DOCUMENTS 
The Investigator must permit study-related monitoring, audits, IEC review, and regulatory agency 
inspections and provide direct access to source data documents. The Investigator/institution should 
maintain adequate and accurate source documents and study records that include all pertinent 
observations on each of the study center’s patients. Source data should be attributable, legible, 
contemporaneous, original, accurate, and complete. Source documents are filed at the Investigator’s 
study center. 
The Sponsor or designee is responsible for the data management of this study including quality 
checking of the data. 
17. QUALITY CONTROL AND QUALITY ASSURANCE 
 
17.1 
Study Monitoring/Data Quality Control 
Site monitoring is conducted to ensure that the rights and well-being of study patients are protected, 
that the reported study data are accurate, complete, and verifiable, and that the conduct of the study 
is in compliance with the currently approved protocol/amendment(s), with International Council for 
Harmonisation-Good Clinical Practice (ICH-GCP), and with applicable regulatory requirement(s).  
 
The Investigator will be contacted by the study monitor on a regular basis. The monitor will have 
the responsibility of reviewing the ongoing study with the Investigator to verify adherence to the 
protocol and to deal with any problems.  
 


 
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CONFIDENTIAL                                                                                                                                               87 
 
The Investigator agrees to allow access to all study materials needed for the proper review of study 
conduct. The Investigator agrees to assist the monitor in resolving any problem that may be 
detected during the monitoring visit or data cleaning process. 
17.2 
Case Report Forms 
Data collected during the study will be recorded in the eCRF. Data reported on the eCRF must be 
consistent with the source documents. The Investigator must ensure the accuracy, the 
completeness and the consistency of the data entered in the eCRF. 
On the eCRF, patients will be identified by the patient number/code, assigned at the Screening 
Visit. The patient number/code will be a number composed of numeric values. 
During the conduct of the clinical part of the study, the eCRF must be available and up-to-date, so 
that it always reflects the latest observations on the respective patient. 
The Investigator or designee will be responsible for entering study data into the eCRF in 
accordance to the eCRF user guidelines. 
17.3 
Quality Assurance 
All clinical activities conducted under this protocol are subject to GCP regulations. This includes 
audits/inspections by the Sponsor, and/or by national/international HA representatives at any time. 
Principal Investigators must agree to the inspection of the study site, facilities, and of study related 
records by the HA representatives and/or by the Sponsor, and/or its delegates, which must be 
performed in accordance with national laws concerning personal data protection. 
18. ETHICS ASPECTS 
The study will be carried out in compliance with the study protocol, the recommendations on 
biomedical research on human patients of the Declaration of Helsinki, ICH-GCP Guidelines, 
EU-Directives and Regulations (where applicable) and national requirements of the participating 
countries. 
18.1 
Ethics Committees 
Before starting the study in a study site, Study Protocol and relevant documentation (Patient 
information leaflet, Informed Consent Form and the Investigator’s Brochure and other documents, 
according to National Regulations) must be submitted to and approved by the EC and the HAs of 
the participating countries. 


 
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Protocol Version 2 of 13/09/2021/  
 
 
 
  
 
CONFIDENTIAL                                                                                                                                               88 
 
In addition, all local national legal requirements for the conduct of a clinical study have to be 
followed. Any amendment to the protocol will be submitted to the ECs and HAs before 
implementation. 
Furthermore, the HAs and ECs of the participating countries will be informed about the study start, 
the end of the study, or the premature study termination as appropriate and within the requested 
time period. 
18.2 
Subject’s Insurance 
For patients participating in the study, Sponsor will issue an insurance policy in accordance with 
local regulatory requirements. 
Details on the insurance company, the insurance number and conditions will be made available to 
patients in the ICF and/or provided as a separate document, in accordance with national 
requirements. Insurance policy will be submitted for approval to the ECs along with the other study 
documents. 
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). 
The Investigator must notify to Sponsor immediately upon notice of any claims or lawsuits. 
19. DATA PROTECTION LAWS COMPLIANCE 
All clinical study information shall be recorded, processed, handled, and stored in such a way that 
it can be accurately reported, interpreted and verified; at the same time, the confidentiality of 
records and of the personal data of the patients shall remain protected in accordance with the 
applicable law on personal data protection such as the EU General Data Protection Regulation 
679/2016 and the EU Regulation on clinical trials on medicinal products for human use 536/2014. 
This section defines the appropriate technical and organizational measures that shall be 
implemented to protect information and personal data processed against unauthorized or unlawful 
access, disclosure, dissemination, alteration, or destruction or accidental loss as well as to assure 
the fulfilment of patients’ privacy rights. 
19.1 
Acknowledgment 
The Site, the Principal Investigator, the Centralized Laboratory, the CRO as well as their appointed 
staff and service providers acknowledge that: (a) the performance of the study will imply processing 


 
Corporate Medical Department 
 
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CONFIDENTIAL                                                                                                                                               89 
 
of sensitive personal data; (b) personal data processing is regulated by the applicable European 
(ie, the EU General Data Protection Regulation 679/2016 and the EU Regulation on clinical trials 
on medicinal products for human use 536/2014) and local laws (ie, the laws of the country where 
the study is conducted) as well as by the Sponsor’s national legislation. 
 
In particular, it is hereby acknowledged that being the Sponsor a company incorporated under 
Italian law, it has to mandatorily comply with Italian legal provisions on data protection: therefore, 
the Site, the Principal Investigator, the Centralized Laboratory, the CRO shall cooperate with the 
Sponsor to allow the fulfilment of such obligations; (c) strict compliance with the applicable data 
protection laws and this section of the protocol is deemed by the Sponsor as an essential condition 
of collaboration with the Site, the Principal Investigator, the Centralized Laboratory, the CRO. 
19.2 
Data Controllers and Data Processors  
The Sponsor, the Site, the Principal Investigator and the CRO acknowledge that according to the 
applicable privacy laws, Sponsor and Site will act as independent data controllers while CRO and 
the Principal Investigator will act as data processors respectively of the Sponsor and of Site. Before 
the beginning of the study, the Site will instruct in writing Principal Investigator as its data 
processor4. However, if specific local laws or regulations mandate a different definition of the 
privacy roles, the Sponsor, the Site, the Principal Investigator and the CRO will implement the 
relevant legal instruments (eg, if pursuant to the local laws the Site is a data processor of the 
Sponsor, a Data Processing Agreement will be finalized; if pursuant to the local laws Sponsor and 
Site are joined controllers, a Joint Controllership Agreement will be finalized). 
1 For clinical trials where the Principal Investigators are the owners of the Site, this provision may not apply. In such cases, the Principal 
Investigator might be considered as a Data Controller 
19.3 
Duties of the Parties involved in the performance of the study  
Collection and use of patients' data, including their biological samples, will be carried out in full 
respect of the provisions of the information notices submitted to patients, as well as the privacy 
rights, the fundamental freedoms, and the dignity of data patients. All the parties involved in this 
study undertake to adopt adequate measures to warrant that data will always be processed 
securely and in compliance with privacy laws. The Site, the Principal Investigator, the Sponsor, the 
CRO and the Centralized Laboratory as well as their appointed staff and service providers, each 
in its respective remit and within the limits of their specific role in the study, shall implement the 


 
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CONFIDENTIAL                                                                                                                                               90 
 
following safety measures (physical, logical, organizational, technical, electronic, I.T. etc) to ensure 
adequate protection of the personal data of the patients involved in the study. In particular: 
(i) DATA SAFETY. The Site and/or the Principal Investigator shall adopt all the necessary 
measures to prevent or minimize the risks of theft, fire, flooding, partial or total loss, accidental 
disclosure or illegal/unauthorized access to patient’s data or Sponsor’s proprietary confidential 
information; to this extent, before the beginning of the study, the Site and/or the Principal 
Investigator shall ensure that the actual measures they have implemented are fit-for purpose and 
law-compliant, and in particular:  
- in order to minimize the risk of unauthorized access and theft, the hardware on which patients’ 
personal data are stored shall be placed in a restricted-access area, accessible only to those 
individuals who need to retrieve the patients’ personal data included in the database for 
professional purposes; the same safeguards shall be put in place for non-electronic databases;  
- any electronic database containing the patients’ personal data shall be password-protected by 
means of a strong password. Systems shall be set so that passwords must be updated at least 
every three months and feature at least 8 characters, with upper-case and lower-case recognition, 
containing at least three "special" characters, such as upper-case letters [A-Z], lower case letters 
[a-z], numbers [0-9], symbols [!, #, $, etc] or other special characters [Á, ë, ö etc]. Passwords shall 
not include elements which may easily be associated with the assignee or information regarding 
him/her, such as name and year of birth (eg, “johnbrown80”) or easily predictable strings of 
characters (eg, “qwerty”, “12345”, “admin”, “user”, etc.); 
 - adequate cryptographic protection measures shall be put in place for data “at rest” and “in transit” 
(these include, for example, file system or database cryptography, or any other equivalent IT 
measure which renders data unintelligible to those who are not authorized to access them);  
-high level security measures shall be implemented also on the files or databases which contain 
the “key” to match the patients’ personal data (ie, name, surname, etc) with their respective “Patient 
IDs” (as defined at point (iv) below); 
- Backup processes and other measures that ensure rapid restoration of business-critical systems 
shall be implemented; 
- Updated Antivirus and firewall programs shall be installed on the IT devices. 


 
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CONFIDENTIAL                                                                                                                                               91 
 
- The patient diary must be handed in, in person by the patient. If this is not possible, it must be 
secured. A secure courier service should be used to collect the diary. 
The Site shall, regularly test and update the measures listed above. The Site shall, upon request 
from the Sponsor and/or the CRO, provide detailed written information about the measures listed 
above. The CRO shall ensure that the selected sites for the study have implemented the above 
listed measures. 
 
(ii) TRANSMISSION OF DATA. All the parties that transfer data through internet and/or to the 
centralized database(s) used to process study’s data or to generate statistical analyses shall 
implement secure protocols based on cryptographic standards which make data unintelligible to 
unauthorized individuals.  
 
(iii) SECURITY OF THE CENTRALIZED DATA BASE. The centralized database held by the 
Sponsor shall have the following safeguards in place: - appropriate authentication methods, which 
differentiate between different users according to their respective roles so as to ensure that access 
to a specific set of patients' data is permitted exclusively to those for whom access to such data is 
essential in the context of their work for the study; - appropriate measures to ensure that the 
authentication credentials are periodically updated (ie, password change);  
(iv) PSEUDONYMIZATION. All personal data that may allow identification of the patients involved 
in the study shall be adequately dissociated from the other data pertaining to the study (“pseudo-
anonymisation” process). The Principal Investigator shall adequately dissociate the identification 
data of patients from the data pertaining to the study by linking results to an alphanumerical code 
[“Patient ID”], whose format shall not make it possible to identify the patient directly or indirectly, so 
as to ensure that only anonymous data are transmitted to the Sponsor, the Centralized Laboratory 
and /or the CRO. Site/Principal Investigator shall securely store a separate list (eg, identification 
log) with the identification code, together with all signed informed consents, in accordance with the 
security measures as defined above. 
The patient code pairing list (ie, the list that where the Patient ID is linked to the patients’ 
identification data such as name and surname), shall be archived by the Principal Investigator.  


 
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CONFIDENTIAL                                                                                                                                               92 
 
As outlined below, samples shall only be stored for as long as strictly necessary for the study’s 
performance and should be destroyed after the analysis. Biological samples and any other 
examination (eg, X-ray, ECG) shall bear Patient ID, and in no case will they bear other information 
that may lead to the direct or indirect identification of the patient, especially when, in accordance 
with this protocol, samples shall be forwarded and shared outside the clinical Site (eg, in case of 
centralized reading or local laboratory analysis). 
(v) TRAINING. The parties shall ensure that any personnel involved in the study have received 
proper training on data protection issues. All actions related to the implementation of the afore 
mentioned measures shall be provided by the Sponsor, the Center and/or the CRO to the 
competent authorities (including data protection authorities) and EC if and when requested. If such 
authorities or the Sponsor consider the implementation of the afore mentioned measures 
insufficient to guarantee an adequate level of protection of the patients’ personal data, The Site, 
the Principal Investigator, the CRO and the Centralized Laboratory undertake to adopt all the 
necessary activities to overcome such remarks to assure the full compliance with the data 
protection laws.  
19.4 
Data Breach  
Data Breach is an incident regarding personal data security and leading to the accidental or 
unlawful destruction, loss, alteration, unauthorized disclosure of, or access to, personal data 
transmitted, stored or otherwise processed. In particular: destruction of personal data is where the 
data no longer exists, or no longer exists in a form that is of any use to the Site, sponsor, CRO, 
Principal Investigator etc. data loss is when the data may still exist, but the Site, sponsor, CRO, 
Principal Investigator etc. has lost control or access to it, or no longer has it in its possession; 
damage is where personal data has been altered, corrupted, or is no longer complete; data 
unavailability is where, following a data incident (such as a network outage, a natural or manmade 
disaster, etc), personal data become temporarily inaccessible to the Site, sponsor, CRO, Principal 
Investigator etc. Anomalous Event is an event that is not part of the standard operational scope of 
an infrastructure, network or service and which affects, or is likely to affect, personal data; this may 
include theft or loss of IT devices and other physical events (eg, an unauthorized access to a locked 
storage room containing paper files with personal data), and/or electronic/IT anomalies (eg, cyber-
attacks, default or hacking of cloud services), which may in any way entail loss, unavailability, 


 
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CONFIDENTIAL                                                                                                                                               93 
 
alteration, theft, copy or dissemination of personal data. Whoever becomes aware in any way of 
an Anomalous Event and/or of a Data Breach (see definitions above) affecting the patients’ 
personal data and/or personal data collected in the context of the study shall, as appropriate, 
immediately (and in any case no later than 24 hours from the knowledge of an Anomalous Event 
and/or of a Data Breach) inform the Clinical Operations Director, the sponsor’s Data Protection 
Officer, the Site and the CRO (CRO responsible persons for data breach incidents management – 
Kim Gray [PrivacyOfficer@IQVIA.com]) and shall provide the following information: 
(i) 
Anomalous Event / Data Breach Type (eg, data loss, unauthorized access, loss of company 
 
device, etc.); 
(ii) 
Person or source that first reported the Anomalous Event/ Data Breach;  
(iii) 
Date and Time when the person who first reported the Anomalous Event / Data Breach 
 
became aware of it;  
(iv)  
Anomalous Event / Data Breach Date and Time (actual or presumed);  
(iv) 
Place (specify if actual or alleged) where the Anomalous Event / Data Breach occurred;  
(v) 
Anomalous Event / Data Breach Description;  
(vi) 
Indicate the source of the Anomalous Event / Data Breach (eg, I.P. source) - (if relevant);  
(viii)  
Indicate the affected infrastructure / system / application / cloud/ software / hardware 
database and their location;  
(ix)  
List or describe the processing/storage systems affected by the Anomalous Event/Data 
Breach (if relevant);  
(x)  
Number of data patients involved (if known);  
(xi)  
Amount of allegedly breached data  
(xii) 
Other relevant information. 
Once all the above information has been provided, the Sponsor and/or the Site should have a 
reasonable degree of certainty that a security incident has occurred that has led to personal data 
being compromised.  
Then, as appropriate, Sponsor and Site, each one in its respective remit, shall manage the Data 
Breach in accordance with the applicable data protection regulations.  


 
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CONFIDENTIAL                                                                                                                                               94 
 
For Data Breach affecting personal data of patients enrolled within the European Union, Sponsor 
and Site autonomously or jointly depending on the circumstances and their privacy responsibilities 
as defined by the Regulation 679/2016- shall: 
1. Collect the necessary evidence and information; 
2. Categorize the breach; 
3. Determine the risk probability and level to the rights and freedom of the concerned patients; 
4. Identify and put in place appropriate remedies to minimize the impact of the Data Breach; 
5. Determine the notification and communication duties vis à vis the competent supervisory 
authority and/or the concerned patients.  
19.5 
Information Notice on Personal Data Protection and Pseudo-
anonymization  
Prior to patients’ enrolment in the study, the Principal Investigator and/or the Site (including their 
personnel) shall provide each patient with adequate, law-compliant “information notices and 
consent forms to process personal data” as included in the ICF (or, as the case may be, through a 
separate, specific form) provided by the Sponsor or delegated CRO and shall collect his/her written 
consent to the processing of personal data according to the actual performance conditions in which 
the study is carried out. The Principal Investigator is responsible to archive the signed ICF in 
accordance with the security measures described above. Among other things, the ICF (or the 
separate form) shall inform patients about:  
(i) the applicable data protection legislation  
(ii) what kind of data shall be collected during the study listing them in detail or by category;  
(iii) the purpose of data processing (eg, performance of the study, pharmacovigilance) and the legal 
basis; 
(iv) whether granting the consent(s) to process personal data is a necessary or an optional condition 
to take part in the study; 
(v) the use of data for future scientific researches / secondary use of data (if any). In such a case 
the future scientific purposes / secondary use shall include the future / further scientific processing 
activities/purposes; 
(vi) the pseudonymization procedure and scope; 
(vii) who can access patients’ data and under what circumstances;  


 
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CONFIDENTIAL                                                                                                                                               95 
 
(viii) the period of data retention/storage as defined in Paragraph 19, including the storage of the 
biological sample;  
(ix) to which entities/countries outside the EU patients’ data will be transmitted (if applicable), as 
per Paragraph 18.7. 
(x) patients’ data protection rights as defined by the EU General Data Protection Regulation 
679/2016. 
(xi) Data Controllers / Data Processors and the relevant contact details  
(xii) Sponsor’s Data Protection Officer contacts (DPO)  
(xiii) in case of genetic data processing the possible findings, also with regard to unexpected 
findings that might be disclosed on account of the processing of the genetic data. 
19.6 
Genetic Data 
Genetic data will not be collected for this study. 
19.7 
Transfer of subjects’ data outside the European Union 
The study performance entails transferring patients ‘personal data (coded data) outside the EU. To 
this extent, the Sponsor, the Site, the Principal Investigator, the Centralized Laboratory, the CRO, 
undertake to export such data in compliance with adequate safeguards/legal basis as required by 
the Regulation 679/2016 including the Commission Decisions, the Standard Contract Clauses, the 
Privacy Shield, patients’ specific consent. 
19.8 
Exercise of subjects’ data privacy rights  
Each study patient has the right to contact the Sponsor, the Site, the Principal Investigator, the 
Centralized Laboratory, the CRO to exercise the rights afforded to the patient by the law, including 
the afforded ones under articles 15 to 22 of Regulation (EU) 2016/679, namely: knowing whether 
or not any data referring to his/her is being processed in the context of the study; access his/her 
data; verify the data’s content, origin, exactness, location (including, where applicable, the non-EU 
countries where the data might be); obtain a copy of the data including their transmission to another 
entity indicated by the patient; ask that the data are supplemented, updated, amended; in the 
circumstances set forth by the law, ask that the processing of data is restricted, that data are 
anonymized or frozen; oppose to the processing of his/her data for legitimate reasons. Each patient 
has the right to lodge a complaint with his/her local supervisory authority and/or to notify to the Data 
Protection Officer any use of his/her personal data the patient regards as inappropriate. Each study 
patient is free to withdraw at any time from the study. In such case, each study patient may ask the 


 
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CONFIDENTIAL                                                                                                                                               96 
 
Sponsor, the Site, the Principal Investigator, the Centralized Laboratory, the CRO to destroy/delete 
his/her personal data (IF APPLICABLE: including his/her biological samples, unless they have 
been permanently anonymized), thus preventing any further processing or analysis of his/her data. 
However, data and results of tests that may have been used to determine the results of the study 
shall not be deleted, to avoid altering or impairing altogether the results of the study. Specific rights 
in relation to the processing of genetic data applies. Please Refer To Paragraph 18.6. If the Site, 
the Principal Investigator, the Centralized Laboratory, the CRO receive a request for data privacy 
rights exercise, the concerned recipient shall immediately inform the Sponsor DPO by e-mail at 
dpo@menarini.com. The request shall be fulfilled within the term set forth by the applicable privacy 
laws (normally 30 days). The Sponsor, the Site, the Principal Investigator, the Centralized 
Laboratory, the CRO shall implement adequate organizational measures to reply to patients within 
the above-mentioned deadline. 
19.9 
Future research  
With patients’ optional and additional consent, the Sponsor and/or the Center may use the data 
collected during the course of the study for further medical and scientific research purposes. These 
may include, for example: retrospective clinical studies; clinical studies pertaining to the patients’ 
pathology/medical condition(s)or similar conditions; studies which compare the data of this Study 
with those from other sources to identify the factors involved in a disease; registration of new drugs. 
 
In the context of these additional research activities, patients’ data will be processed, 
pseudonymized and transferred abroad and may be shared with future research partners. In the 
context of these additional research activities, patients’ data will be processed, anonymized and 
transferred abroad, and may be shared with future research partners - in most cases this will 
prevent patient’s identification; however, in the unlikely event patient’s full identity really needs to 
be disclosed, the same precautions and safeguards as those described in this protocol will be 
implemented. 
20. DATA HANDLING AND RECORDS KEEPING 
Unless other laws require archiving for a longer period, the Center and the Principal Investigator 
shall archive the content of the clinical study file, including the relevant patients’ personal data, for 


 
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CONFIDENTIAL                                                                                                                                               97 
 
at least 25 years after the end of the clinical study. However, medical records shall be archived in 
accordance with the national laws of the country where the study is performed. 
 
The Investigator should keep all study-related documents, as specified in ICH E6 (GCP) Section 8 
and by the applicable regulatory requirement(s), in the Investigator's File. The media used to 
archive the content of the clinical study file shall be such that the content remains complete and 
legible throughout the period referred to in the first paragraph. Any modification to the content of 
the clinical trial master file shall be traceable. 
 
The content of the Investigator’s File shall be archived in a way that ensures that it is readily 
available and accessible, upon request, to the competent authorities. If the responsible Investigator 
retires, relocates, or for other reasons withdraws from the responsibility of keeping the study 
records, custody must be transferred to a person who will accept the responsibility.  
The Sponsor must be notified in writing of the name and address of the new custodian. 
21. PUBLICATION POLICY AND RESULTS 
By signing the study protocol, the Investigator (and his/her appointed staff) ensures that any 
information and all the study documents provided by the Sponsor will be maintained strictly 
confidential. None of this material may be disclosed to any party not directly involved in the study 
without written permission from Sponsor. All information concerning the study, the drug as well as 
data and results of the study are confidential and property of the Sponsor. 
 
The Sponsor will prepare the final report, including the statistical and clinical evaluations, and study 
results will be posted and made public, according to applicable Regulatory Regulations. The 
Investigator’s agreement and signature will be obtained, and a copy will be provided to the 
Investigator. Sponsor reserves the exclusive right to publish and present data and results of the 
present study at scientific meetings, or to submit these clinical study data to national and 
international Regulatory Authorities. The Investigator may not use the results of this study for 
publication or presentation without written authorization from Sponsor. 


 
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CONFIDENTIAL                                                                                                                                               98 
 
22. REFERENCES 
1. NICE clinical guideline 88 www.nice.org.uk/cg88 2009. 
2. Oliveira CB, Maher CG, Pinto RZ, Traeger AC, Lin CC, Chenot JF, et al. Clinical practice 
guidelines for the management of non-specific low back pain in primary care: an updated overview. 
Eur Spine J, Nov 2018;27(11):2791-2803. 
3. Babej DR, Freytag S, Eckmeyer J, Zerle G, Schinzel S, Schmeider G, et al. Parenteral dipyrone 
versus diclofenac and placebo in patients with acute lumbago or sciatic pain: randomized observer 
blind multicenter study. Int J Clin Pharmacol Ther 1994 Apr;32(4):204-9. 
4. Amlie E, Weber H, Holme I. Treatment of acute low-back pain with piroxicam: results of a double-
blind placebo-controlled trial. Spine (Phila Pa 1976). 1987 Jun;12(5):473-6. 
5. Williams CM, Maher CG, Latimer J, McLachlan AJ, Hancock MJ, Day RO, et al. Efficacy of 
paracetamol for acute low-back pain: a double-blind, randomised controlled trial. Lancet. 2014 
Nov 1;384(9954):1586-96. 
6. Friedman BW, Dym AA, Davitt M, Holden L, Solorzano C, Esses D et al. Naproxen with 
Cyclobenzaprine, Oxycodone/Acetaminophen, or Placebo for Treating Acute Low Back Pain: A 
Randomized Clinical Trial. JAMA. 2015 Oct 20;314(15):1572-80. 
7. Lasko B, Levitt RJ, Rainsford KD, Bouchard S, Rozova A, Robertson S. Extended-release 
tramadol/paracetamol in moderate-to-severe pain: a randomized, placebo-controlled study in 
patients with acute low back pain. Curr Med Res Opin. 2012 May;28(5):847-57. 
8. Curatolo M, Sveticic G. Drug combinations in pain treatment: to review of the published evidence 
and to method for finding the optimal combination. Best Pract. Animal Clin. Anaesthesiol. 2002 
Dec;16 (4): 507-19. 
9. Hartrick C.G. Multimodal postoperative pain management. Am. J. Health-Syst. Pharm. 2004 Apr; 
61, Suppl.1:S4-S10. 
10. Kehlet H., Wilmore D.W. Multimodal strategies to improve surgical outcome. Am. J. Surg. 2002 
Jun;183(6):630-641. 
11. Committee 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. 
12. Cadwell J, Hutt AJ, Fournel-Gigleux S. The metabolic chiral inversion and dispositional 
enantioselectivity of the 2-arylpropionic acids and their biological consequences. Biochem 
Pharmacol 1988; 37:105-14. 
13. Hayball PJ, Nation RL, Bochner F. Enantioselective pharmacodynamics of the nonsteroidal anti-
inflammatory drug ketoprofen: in vitro inhibition of human platelet cyclooxygenase activity. Chirality 
1992;4: 484-7. 
14. Gay-Escoda C, Planas E, Donado M, Martinez JM, Artigas R, Torres F, Mauleón D, Carganico G. 
Analgesic effect of low doses of dexketoprofen in the dental pain model: a randomised, double-
blind, placebo-controlled study. Clin Drug Invest 1996; 11: 320-30. 
15. Ezcurdia M, Cortejoso FJ, Lanzón R, Ugalde FJ, Herruzo A, Artigas R, Fernández MF, Torres F, 
Mauleón D. Comparison of the efficacy and tolerability of DKP.TRIS and ketoprofen in the 
treatment of primary dismenorrhea. J Clin Pharmacol 1998; 38 (12 Suppl): 65S-73S. 
16. Beltran J, Martin-Mola E, Figueroa M, Granados J, Sanmarti R, Artigas R, Torres F, Forns M, 


 
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CONFIDENTIAL                                                                                                                                               99 
 
Mauleón D. Comparison of dexketoprofen trometamol and ketoprofen in the treatment of 
osteoartritis of the knee. J. Clin. Pharmacol. 1998; 38: 33S-40S. 
17. Bagán JV, López Arranz S, Valencia E, Santamaría J, Eguidazu I, Horas M, Forns M, Zapata A, 
Artigas R, Mauleón D. Clinical comparison of dexketoprofen trometamol, and dipyrone in 
postoperative dental pain. J Clin Pharmacol. 1998;38 (12 Suppl): 55S-64S. 
18. Iohom G, Walsh M, Higgins G, Shorten G. Effect of perioperative administration of dexketoprofen 
on opioid requirements and inflammatory response following elective hip arthroplasty. Br J 
Anaesth. 2002;88: 520-526. 
19. Rodríguez MJ, Contreras D, Gálvez R, Castro A, Camba MA, Busquets C, Herrera J. Doubleblind 
evaluation of short-term analgesic efficacy of orally administered dexketoprofen trometamol and 
ketorolac in bone cancer pain. Pain. 2003;104 (1-2): 103-110. 
20. McEwen J, De Luca M, Casini A et al. The effect of food and an antacid in the bioavailability of 
dexketoprofen trometamol. J Clin Pharmacol. 1998; 38: 41S-45S 
21. Barbanoj JM, Gich I., Artigas R. Tost D., Moros C., Antonijoan R.M., Garcia M.L., Mauleón D. 
Pharmacokinetics of dexketoprofen trometamol in healthy volunteers after single and repeated 
oral doses. J. Clin Pharmacol. 1998; 38:33S-40S. 
22. Dexketoprofen Trometamol (12.5 mg and 25 mg film-coated tablets) EU Common Summary of 
Product Characteristics. 
23. Dexketoprofen Trometamol (50 mg/2 ml; solution for injection or concentrate for solution for 
infusion) EU Common Summary of Product Characteristics. 
24. Grond S, Sablotzki A. Clinical pharmacology of tramadol. Clin. Pharmacokinet. 2004;43: 879- 923. 
25. Tramadol Hydrochloride (Zydol® 50 mg capsules, UK) Summary of Product Characteristics. 
26. Gay-Escoda C, Hanna M, Montero A, Dietrich T, Milleri S, Giergiel E et al. Tramadol/dexketoprofen 
(TRAM/DKP) compared with tramadol/paracetamol in moderate to severe acute pain: results of a 
randomised, double-blind, placebo and active-controlled, parallel group trial in the impacted third 
molar extraction pain model (DAVID study). BMJ Open 2019;9:e023715. 
 
27. Moore RA, McQuay HJ, Tomaszewski J, Raba G, Tutunaru D, Lietuviete N, et al. 
Dexketoprofen/tramadol 25 mg/75 mg: randomised double-blind trial in moderate-to-severe 
acute pain after abdominal hysterectomy. BMC Anaesthesiol. 2016 Jan;16:9. 
28. McQuay HJ, Moore RA, Berta A, Gainutdinovs O, Fülesdi B, Porvaneckas N, et al. Randomized 
clinical trial of dexketoprofen/tramadol 25 mg/75 mg in moderate-to-severe pain after total hip 
arthroplasty. Br J Anaesthesia.2016 Feb;116(2):269-276. 
29. Guideline 
on 
Clinical 
Development 
of 
Fixed 
Combination 
Medicinal 
Products 
(CPMP/EWP/240/95) https://www.ema.europa.eu/en/clinical-development-fixed-combination-
medicinal-products. 
30. Guidance on Clinical Investigation of Medicinal Products for Treatment of Nociceptive Pain 
(CPMP/EWP/612/00) 
https://www.ema.europa.eu/en/documents/scientific-guideline/note-
guidance-clinical-investigation-medicinal-products-treatment-nociceptive-pain_en.pdf  
31. Guideline on Clinical Medicinal Products Intended for the Treatment of Neuropathic Pain 
(CPMP/EWP/252/03) https://www.ema.europa.eu/en/documents/scientific-guideline/guideline-
clinical-medicinal-products-intended-treatment-neuropathic-pain_en.pdf  


 
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CONFIDENTIAL                                                                                                                                               100 
 
32. Paracetamol (500 mg tablets BP) EU Common Summary of Product Characteristics 
https://www.medicines.org.uk/emc/product/5916/smpc. 
33. Stochkendahl MJ, Kjaer P, Hartvigsen J et al (2017) National clinical guidelines for non-surgical 
treatment of patients with recent onset low back pain or lumbar radiculopathy. Eur Spine J 
27(1):60–75. 
34. Canada TOP (2015) Evidence-informed primary care management of low back pain. Edmonton 
(AB): toward optimized practice https://www.guidelinecentral.com/summaries/guideline-for-the-
evidence-informed-primary-care-management-of-low-back-pain/#section-society 
35. Spitzer WO, Skovron ML, Salmi LR, Cassidy JD, Duranceau J, Suissa S, et al. Scientific 
monograph of the Quebec Task Force on Whiplash-Associated Disorders: redefining ‘‘whiplash’’ 
and its management. Spine (Phila Pa 1976) 1995;20(8 Suppl):1S-73S 
 
 


 
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CONFIDENTIAL                                                                                                                                               101 
 
23. Protocol Approval Page 
Study Title: A randomized, double-blind, placebo-controlled, parallel arm group study to evaluate 
the analgesic efficacy and safety of Dexketoprofen trometAmol aNd tramadol hydrochloride oral 
fixEd dose combination on moderate to severe acute pain in patients with acute low back pain - 
DANTE study 
Code: MEIN/18/DEX-LBP/001 
EUDRA-CT number: 2019-003656-37 
 
The signers confirm that they have read and approved the protocol 
 
 
Study Medical Expert: Deniz Coskunsever 
 
Signature & Date: ________________________________                             29 / 09 /2021 
 
 
Corporate Medical Director: Lorenzo Melani 
 
Signature & Date:                                                                                              29 / 09 /2021 
 
 
Coordinating Investigator: Prof. Giustino Varrassi  
 
Signature & Date:                                                                                              29 / 09 / 2021                                            
 
 
Statistician Giorgio Reggiardo 
 
29 / 09 / 2021 
Signature& Date:  
 
 


 
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CONFIDENTIAL                                                                                                                                               102 
 
24. Investigator’s approval Page  
INVESTIGATOR’S APPROVAL PAGE 
(original to be kept in the Trial Center File) 
 
I understand that all information concerning the product Menarini Pharmaceutical supplied in 
connection with this study protocol are confidential information. This information includes: Protocol, 
Investigator’s Brochure, Case Report Form, Other documents _________________. 
 
I understand that any change in this study protocol must be approved in writing by Menarini 
Pharmaceutical and the Co-ordinating Investigator, submitted to the Ethics Committee and Health 
Authorities before implementation, except where necessary to eliminate apparent immediate hazard 
to patients. 
 
I confirm that I will conduct the study according to this protocol, the Good Clinical Practice (GCP), the 
Declaration of Helsinki and laws and regulations in the Country where the study is to be conducted. 
 
I confirm that I will record and report all adverse events occurring during the study, according to this 
protocol. 
 
I confirm that I am informed about the need of data records retention, according to current regulations 
and that no data can be destroyed without the written consent of Menarini Pharmaceutical. 
 
I confirm that I will transfer adequate ownership of my responsibilities for the trial and will inform the 
Sponsor in case I retire from my PI role. 
 
I confirm that in case the Trial Center File is stolen or anyhow damaged, I will promptly inform the 
Sponsor and declare it to the Competent Authorities. 
 
Principal Investigator: ____________________________________________________ 
 
Signature & Date: _________________________________________________________    
 
 


 
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CONFIDENTIAL                                                                                                                                               103 
 
25. APPENDICES 
25.1 
Appendix 1: Declaration of Helsinki  
 

SAP_001.pdf: 
Menarini Pharmaceutical 
PROTOCOL MEIN/18/DEX-LBP/001 
 
Statistical Analysis Plan 
Page 1 of 61 
 
Document: 
\\ieedc-vnasc01\BIOSdata\Menarini\Dexketoprofen\YYA36087\Biostatistics\Documentation\SAP 
Author: 
Aswin Nair 
Version Number: 
Final V1.0 
 
Version Date:  
[04Jul2022] 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
 
 
 
 
 
 
STATISTICAL ANALYSIS PLAN 
MEIN/18/DEX-LBP/001 
 
 
 
A randomized, double-blind, placebo-controlled, parallel arm group study to evaluate the analgesic 
efficacy and safety of Dexketoprofen trometAmol aNd Tramadol hydrochloride oral fixEd dose 
combination on moderate to severe acute pain in patients with acute low back pain - DANTE 
 
 
 
AUTHOR: ASWIN NAIR 
VERSION NUMBER AND DATE: V1.0, 04JUL2022 
 
 
 


Menarini Pharmaceutical 
PROTOCOL MEIN/18/DEX-LBP/001 
 
Statistical Analysis Plan 
Page 2 of 61 
 
Document: 
\\ieedc-vnasc01\BIOSdata\Menarini\Dexketoprofen\YYA36087\Biostatistics\Documentation\SAP 
Author: 
Aswin Nair 
Version Number: 
Final V1.0 
 
Version Date:  
[04Jul2022] 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
STATISTICAL ANALYSIS PLAN SIGNATURE PAGE 
Statistical Analysis Plan V1.0(Dated 04Jul2022) for Protocol MEIN/18/DEX-LBP/001 
 
 
Name 
Signature 
Date (DDMMYYYY) 
Author: 
Aswin Nair 
Refer to eSignature 
 
Position: 
Biostatistician 2 
Company: 
IQVIA 
 
Upon review of this document, the undersigned approves this version of the Statistical Analysis Plan, 
authorizing that the content is acceptable for the reporting of this study. 
 
Name 
Signature 
Date (DDMMYYYY) 
Approved By: 
Jisho Jose 
 
 
Position: 
Assoc Dir, Biostatistics 
Company: 
IQVIA 
 
Approved By: 
Irma Litton 
 
 
 
Position: 
Sr Clin Project Mgr 
 
Company: 
IQVIA 
 
Approved By: 
Dr. Giorgio Reggiardo 
 
 
 
Position: 
Biostatistician 
 
Company: 
Menarini International Operations- external consultant. 
 
Approved By: 
Paolo Fabrizzi 
 
 
 
Position: 
Clinical Operations Director 
 
Company: 
Menarini International Operations 
 
 
luglio 7, 2022


Menarini Pharmaceutical 
PROTOCOL MEIN/18/DEX-LBP/001 
 
Statistical Analysis Plan 
Page 3 of 61 
 
Document: 
\\ieedc-vnasc01\BIOSdata\Menarini\Dexketoprofen\YYA36087\Biostatistics\Documentation\SAP 
Author: 
Aswin Nair 
Version Number: 
Final V1.0 
 
Version Date:  
[04Jul2022] 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
MODIFICATION HISTORY 
 
Unique 
Identifier for 
this Version 
Date of the 
Document 
Version 
Author 
Significant 
Changes 
from  
Previous Authorized Version 
Reviewed by 
Version 1.0 
04Jul2022 
Aswin Nair 
Not Applicable – Draft Version 
 
 
 


Menarini Pharmaceutical 
PROTOCOL MEIN/18/DEX-LBP/001 
 
Statistical Analysis Plan 
Page 4 of 61 
 
Document: 
\\ieedc-vnasc01\BIOSdata\Menarini\Dexketoprofen\YYA36087\Biostatistics\Documentation\SAP 
Author: 
Aswin Nair 
Version Number: 
Final V1.0 
 
Version Date:  
[04Jul2022] 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
TABLE OF CONTENTS 
1. 
INTRODUCTION .................................................................................................................................. 9 
2. 
STUDY OBJECTIVES AND ESTIMANDS ........................................................................................ 9 
2.1. 
Primary Objective.................................................................................................................................................................... 9 
2.2. 
Secondary Objectives ............................................................................................................................................................. 9 
2.3. 
Estimands................................................................................................................................................................................... 9 
3. 
STUDY DESIGN .................................................................................................................................. 19 
3.1. 
General Description ............................................................................................................................................................. 19 
3.2. 
Study Scheme ......................................................................................................................................................................... 20 
3.3. 
Schedule of Events ............................................................................................................................................................... 21 
3.4. 
Changes to Analysis from Protocol ................................................................................................................................. 21 
4. 
PLANNED ANALYSES ...................................................................................................................... 21 
4.1. 
Final Analysis ......................................................................................................................................................................... 22 
5. 
ANALYSIS POPULATION ................................................................................................................ 22 
5.1. 
Intent-to-Treat [ITT] Population .................................................................................................................................... 22 
5.2. 
Modified Intent-to-Treat [mITT] Population .............................................................................................................. 22 
5.3. 
Safety [SAF] Population ...................................................................................................................................................... 22 
5.4. 
Per Protocol [PP] Population ........................................................................................................................................... 23 
6. 
GENERAL CONSIDERATIONS........................................................................................................ 23 
6.1. 
Reference Start Date and Study Time ............................................................................................................................ 23 
6.2. 
Baseline .................................................................................................................................................................................... 24 


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6.3. 
Retests, Unscheduled Visits and Early Termination Data ...................................................................................... 24 
6.4. 
Windowing Conventions and Timepoint Derivation for Questionnaire Data ................................................. 24 
6.5. 
Statistical Tests ..................................................................................................................................................................... 27 
6.6. 
Common Calculations ......................................................................................................................................................... 27 
6.7. 
Software Version .................................................................................................................................................................. 27 
7. 
STATISTICAL CONSIDERATIONS................................................................................................. 28 
7.1. 
Adjustments for Covariates and Factors to be Included in Analyses.................................................................. 28 
7.2. 
Multicenter Studies .............................................................................................................................................................. 28 
7.3. 
Missing data ........................................................................................................................................................................... 28 
7.4. 
Multiple Comparisons/ Multiplicity ............................................................................................................................... 30 
7.5. 
Examination of Subgroups ................................................................................................................................................ 30 
8. 
OUTPUT PRESENTATIONS ............................................................................................................ 30 
9. 
DISPOSITION AND WITHDRAWALS ........................................................................................... 30 
9.1. 
Disposition .............................................................................................................................................................................. 30 
9.2. 
Protocol Deviations ............................................................................................................................................................. 31 
10. 
DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS ............................................ 32 
10.1. 
Derivations ......................................................................................................................................................................... 32 
11. 
MEDICAL AND SURGICAL PROCEDURE HISTORY ................................................................. 32 
12. 
CONCOMITANT ILLNESSES ........................................................................................................... 32 
13. 
PRIOR, CONCOMITANT AND POST TREATMENT MEDICATIONS/ NON-DRUG 
TREATMENT 33 
13.1. 
Rescue Medication ........................................................................................................................................................... 34 


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14. 
STUDY MEDICATION EXPOSURE ................................................................................................ 34 
14.1. 
Derivations ......................................................................................................................................................................... 34 
15. 
STUDY MEDICATION COMPLIANCE ........................................................................................... 35 
15.1. 
Derivations ......................................................................................................................................................................... 35 
16. 
EFFICACY OUTCOMES ..................................................................................................................... 36 
16.1. 
Primary Efficacy ............................................................................................................................................................... 36 
16.1.1. 
Primary Efficacy Variable(s) & Derivation(s) ......................................................................................................... 36 
16.1.2. 
Missing Data Methods for Primary Efficacy Variable(s) ..................................................................................... 36 
16.1.3. 
Primary Analysis of Primary Efficacy Variable(s) ................................................................................................. 36 
16.1.4. 
Sensitivity Analysis of Primary Efficacy Variable(s) ............................................................................................ 38 
16.1.4.1. 
Intent-to-Treat Analysis ........................................................................................................................................... 38 
16.1.4.2. 
Per protocol Analysis ................................................................................................................................................ 38 
16.1.4.3. 
No Data Imputation .................................................................................................................................................... 38 
16.1.4.4. 
Multiple Imputation ................................................................................................................................................... 39 
16.1.4.5. 
Inclusion of strata variables collected in the CRF instead of IRT strata variables ......................... 39 
16.1.4.6. 
Removal of patients with incorrect stratification on randomization .................................................. 40 
16.2. 
Secondary Efficacy .......................................................................................................................................................... 40 
16.2.1. 
Secondary Efficacy Variables & Derivations ............................................................................................................. 42 
16.2.1.1. 
Total Pain Relief (TOTPAR) .................................................................................................................................... 42 
16.2.1.2. 
Percent (%) max TOTPAR ...................................................................................................................................... 42 
16.2.1.3. 
% max TOTPAR104 = TOTPAR104/ max TOTPAR104Summed Pain Intensity Difference 
(SPID) 
43 
16.2.1.4. 
Percent (%) max SPID .............................................................................................................................................. 44 
16.2.2. 
Missing Data Methods for Secondary Efficacy Variable(s) ................................................................................ 45 
16.2.3. 
Analysis of Secondary Efficacy Variables ................................................................................................................... 45 
16.2.3.1. 
PI-NRS, SPIDs, %max SPIDs, TOTPARs, %max TOTPARs and Roland Morris Disability 
Questionnaire (RMQ) ........................................................................................................................................................................ 45 
16.2.3.2. 
PGE and PAR-VRS ....................................................................................................................................................... 46 
16.2.3.3. 
Time to first use of RM .............................................................................................................................................. 46 
16.2.3.4. 
Other Analysis .............................................................................................................................................................. 47 
16.3. 
Exploratory Efficacy ........................................................................................................................................................ 48 
16.3.1. 
Exploratory Efficacy Variables & Derivations .......................................................................................................... 48 
16.3.2. 
Missing Data Methods for Exploratory Efficacy Variable(s) ............................................................................. 48 
16.3.3. 
Analysis of Exploratory Efficacy Variables ................................................................................................................ 48 
17. 
QUALITY OF LIFE ANALYSIS ......................................................................................................... 48 


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18. 
SAFETY OUTCOMES ......................................................................................................................... 49 
18.1. 
Adverse Events ................................................................................................................................................................. 49 
18.1.1. 
All TEAEs .................................................................................................................................................................................. 49 
18.1.1.1. 
Severity ............................................................................................................................................................................ 49 
18.1.1.2. 
Relationship to Study Medication ........................................................................................................................ 50 
18.1.2. 
TEAEs Leading to Discontinuation of Study Medication ..................................................................................... 50 
18.1.3. 
Serious Adverse Events ...................................................................................................................................................... 50 
18.1.4. 
Adverse Events Leading to Death .................................................................................................................................. 50 
18.2. 
Laboratory Evaluations ................................................................................................................................................. 50 
18.2.1. 
Laboratory Reference Ranges ......................................................................................................................................... 51 
18.3. 
Vital Signs ........................................................................................................................................................................... 51 
18.4. 
Physical Examination ..................................................................................................................................................... 51 
19. 
DATA NOT SUMMARIZED OR PRESENTED .............................................................................. 52 
20. 
REFERENCES ..................................................................................................................................... 53 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS .................................................... 54 
IQVIA Output Conventions .............................................................................................................................................................. 54 
Dates & Times ...................................................................................................................................................................................... 54 
Spelling Format ................................................................................................................................................................................... 54 
Presentation of Treatment Groups............................................................................................................................................... 54 
Presentation of Visits ........................................................................................................................................................................ 54 
Listings ................................................................................................................................................................................................... 55 
Text Case ............................................................................................................................................................................................... 55 
APPENDIX 2. PARTIAL DATE CONVENTIONS ................................................................................... 59 
Algorithm for Treatment Emergence of Adverse Events: .................................................................................................... 59 
Algorithm for Prior / Concomitant Medications: .................................................................................................................... 60 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
AE 
 
 
Adverse event 
ANCOVA  
 
Analysis of covariance 
BOCF   
 
Baseline observation carried forward 
CMH  
 
Cochran–Mantel–Haenszel 
DKP.TRIS  
 
Dexketoprofen trometamol 
eCRF   
 
Electronic case report forms 
ITT  
 
 
Intention-to-treat 
LBP  
 
 
Low back pain 
LOCF   
 
Last observation carried forward 
MedDRA  
 
Medical Dictionary for Regulatory Activities 
NRS   
 
Numerical Rating Scale 
PAR   
 
Pain relief 
PGE  
 
 
Patient Global Evaluation 
PI  
 
 
Pain intensity 
PP  
 
 
Per-protocol 
RM  
 
 
Rescue medication 
RMQ   
 
Roland Morris Disability Questionnaire 
SAE  
 
 
Serious adverse event 
SAP  
 
 
Statistical analysis plan 
SOP  
 
 
Standard operating procedures 
SPID   
 
Summed Pain Intensity Difference 
TEAE   
 
Treatment emergent adverse event 
TOTPAR  
 
Total pain relief 
TRAM.HCl  
 
Tramadol hydrochloride 
TSQM   
 
Treatment Satisfaction Questionnaire for Medication 
VAS  
 
 
Visual Analogue Scale 
VRS  
 
 
Verbal rating scale 
 
 


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1. INTRODUCTION  
This document describes the rules and conventions to be used in the presentation and analysis of 
efficacy and safety data for Protocol MEIN/18/DEX-LBP/001. It describes the data to be summarized 
and analyzed, including specifics of the statistical analyses to be performed. This statistical analysis 
plan (SAP) is based on protocol version 2.0 (Amendment 1), dated 13 September 2021. 
2. STUDY OBJECTIVES AND ESTIMANDS 
2.1. PRIMARY OBJECTIVE 
The primary objective is to evaluate the analgesic efficacy of DKP.TRIS/TRAM.HCl fixed combination 
versus placebo in moderate to severe acute low back pain after the first dose (first 8 hours). 
2.2. SECONDARY OBJECTIVES 
The secondary objectives are, 
• 
To evaluate the analgesic efficacy of DKP.TRIS/TRAM.HCl fixed combination versus 
TRAM.HCL 100 mg in moderate to severe acute low back pain after the first dose (first 8 
hours). 
• 
To evaluate the analgesic efficacy of DKP.TRIS/TRAM.HCl fixed combination in moderate to 
severe acute low back pain versus TRAM.HCl 100 mg after multiple doses (from t8h until day 
5). 
• 
To assess the safety and tolerability of DKP.TRIS/TRAM.HCl fixed combination after single 
and multiple doses. 
2.3. ESTIMANDS 
The primary, and secondary estimands to support regulatory decisions are described in the following 
table: 
 
 


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Table A: 
List of Estimands 
Estimand 
Definition 
Attributes 
Population 
Variable/Endpoin
t 
Intercurrent 
event 
handling 
strategy 
Population
-level 
summary 
measure 
Single 
Dose 
Phase 
 
 
 
 
 
Primary 
Estimand 
 
Efficacy 
of 
DKP.TRIS/ 
TRAM.HCl 
fixed 
combinatio
n 
versus 
placebo 
in 
moderate to 
severe acute 
low 
back 
pain 
after 
the 
first 
dose (first 8 
hours). 
mITT 
Population 
(All 
patients 
randomized 
and 
satisfies 
the 
randomizatio
n 
ratio 
4:4:1:1)  
Time 
to 
first 
achieve an NRS-PI 
score <4 or a pain 
intensity 
reduction 
of 
≥30% from drug 
intake till 8 hours 
after the first dose 
 
 
Composite 
Strategy. 
Initiation 
of 
rescue 
medication (RM). 
Scores after RM 
return to baseline 
level. 
This 
assumes that the 
treatment has no 
impact 
on 
the 
primary 
endpoint.  The 
patients 
are 
censored at the 
point 
of 
first 
intake of rescue 
medication 
(i.e. 
considered as no 
longer at risk of 
an event).  
 
Hazard 
Ratio 
Primary 
Estimand 
Sensitivit
y 1  
 
mITT 
Population 
(All 
patients 
randomized 
and 
satisfies 
Time 
to 
first 
achieve an NRS-PI 
score <4 or a pain 
intensity 
reduction 
of 
Treatment Policy 
Strategy 
Initiation 
of 
rescue 
medication. 
Hazard 
Ratio 


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the 
randomizatio
n 
ratio 
4:4:1:1) 
≥30% from drug 
intake till 8 hours 
after the first dose 
 
 
Values collected 
are 
used 
regardless 
of 
whether the RM 
is taken without 
imputation.  This 
reflects 
the 
assumption that 
rescue mediation 
does 
not 
influence 
the 
primary endpoint 
Primary 
Estimand 
Sensitivit
y 2 
 
mITT 
Population 
(All 
patients 
randomized 
and 
satisfies 
the 
randomizatio
n 
ratio 
4:4:1:1) 
Time 
to 
first 
achieve an NRS-PI 
score <4 or a pain 
intensity 
reduction 
of 
≥30% from drug 
intake till 8 hours 
after the first dose 
 
Hypothetical 
Strategy Scenario 
envisaged 
in 
which the intake 
of 
rescue 
medication 
would not occur.  
Values collected 
for the six hours 
after 
the 
RM 
intake 
will 
be 
considered 
as 
missed 
and 
imputed by using 
a 
multiple 
imputation 
approach.  If a 
missing 
at 
random 
(MAR) 
pattern 
of 
missing data is 
detected, missing 
values 
will 
be 
replaced using a 
Hazard 
Ratio 


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multiple 
imputation 
approach.  
Primary 
Estimand 
Sensitivit
y 3 
 
ITT 
Population 
(All 
patients 
randomized) 
Time 
to 
first 
achieve an NRS-PI 
score <4 or a pain 
intensity 
reduction 
of 
≥30% from drug 
intake till 8 hours 
after the first dose 
 
Composite 
Strategy. 
Initiation 
of 
rescue 
medication (RM). 
Scores after RM 
return to baseline 
level. 
This 
assumes that the 
treatment has no 
impact 
on 
the 
primary 
endpoint.  The 
patients 
are 
censored at the 
point 
of 
first 
intake of rescue 
medication 
(i.e. 
considered as no 
longer at risk of 
an event).  
 
Hazard 
Ratio 
Primary 
Estimand 
Sensitivit
y 4 
 
ITT 
Population 
(All 
patients 
randomized) 
Time 
to 
first 
achieve an NRS-PI 
score <4 or a pain 
intensity 
reduction 
of 
≥30% from drug 
intake till 8 hours 
after the first dose 
 
Treatment Policy 
Strategy 
Initiation 
of 
rescue 
medication. 
Values collected 
are 
used 
regardless 
of 
whether the RM 
is taken without 
imputation.  This 
Hazard 
Ratio 


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reflects 
the 
assumption that 
rescue mediation 
does 
not 
influence 
the 
primary endpoint 
Primary 
Estimand 
Sensitivit
y 5 
 
ITT 
Population 
(All 
patients 
randomized) 
Time 
to 
first 
achieve an NRS-PI 
score <4 or a pain 
intensity 
reduction 
of 
≥30% from drug 
intake till 8 hours 
after the first dose 
 
Hypothetical 
Strategy Scenario 
envisaged 
in 
which the intake 
of 
rescue 
medication 
would not occur.  
Values collected 
for the six hours 
after 
the 
RM 
intake 
will 
be 
considered 
as 
missed 
and 
imputed by using 
a 
multiple 
imputation 
approach.  If a 
missing 
at 
random 
(MAR) 
pattern 
of 
missing data is 
detected, missing 
values 
will 
be 
replaced using a 
multiple 
imputation 
approach.  
Hazard 
Ratio 
Primary 
Estimand 
Sensitivit
 
PP Population 
(All 
patients 
randomized 
Time 
to 
first 
achieve an NRS-PI 
score <4 or a pain 
Composite 
Strategy. 
Initiation 
of 
Hazard 
Ratio 


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y 6 
without 
any 
major PDs that 
affect primary 
efficacy 
analysis) 
intensity 
reduction 
of 
≥30% from drug 
intake till 8 hours 
after the first dose 
 
rescue 
medication (RM). 
Scores after RM 
return to baseline 
level. 
This 
assumes that the 
treatment has no 
impact 
on 
the 
primary 
endpoint.  The 
patients 
are 
censored at the 
point 
of 
first 
intake of rescue 
medication 
(i.e. 
considered as no 
longer at risk of 
an event).  
 
Primary 
Estimand 
Sensitivit
y 7 
 
PP Population 
(All 
patients 
randomized 
without 
any 
major PDs that 
affect primary 
efficacy 
analysis) 
Time 
to 
first 
achieve an NRS-PI 
score <4 or a pain 
intensity 
reduction 
of 
≥30% from drug 
intake till 8 hours 
after the first dose 
 
Treatment Policy 
Strategy 
Initiation 
of 
rescue 
medication. 
Values collected 
are 
used 
regardless 
of 
whether the RM 
is taken without 
imputation.  This 
reflects 
the 
assumption that 
rescue mediation 
does 
not 
influence 
the 
primary endpoint 
Hazard 
Ratio 


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Primary 
Estimand 
Sensitivit
y 8 
 
PP Population 
(All 
patients 
randomized 
without 
any 
major PDs that 
affect primary 
efficacy 
analysis) 
Time 
to 
first 
achieve an NRS-PI 
score <4 or a pain 
intensity 
reduction 
of 
≥30% from drug 
intake till 8 hours 
after the first dose 
 
Hypothetical 
Strategy Scenario 
envisaged 
in 
which the intake 
of 
rescue 
medication 
would not occur.  
Values collected 
for the six hours 
after 
the 
RM 
intake 
will 
be 
considered 
as 
missed 
and 
imputed by using 
a 
multiple 
imputation 
approach.  If a 
missing 
at 
random 
(MAR) 
pattern 
of 
missing data is 
detected, missing 
values 
will 
be 
replaced using a 
multiple 
imputation 
approach.  
Hazard 
Ratio 
Primary 
Estimand 
Sensitivit
y 9 
 
Efficacy 
of 
DKP.TRIS/ 
TRAM.HCl 
fixed 
combinatio
n 
versus 
placebo 
in 
moderate to 
severe acute 
mITT 
Population 
(All 
patients 
randomized 
and 
satisfies 
the 
randomizatio
n 
ratio 
4:4:1:1)  
Time 
to 
first 
achieve an NRS-PI 
score <4 or a pain 
intensity 
reduction 
of 
≥30% from drug 
intake till 8 hours 
after the first dose 
 
Composite 
Strategy. 
Initiation 
of 
rescue 
medication (RM). 
Scores after RM 
return to baseline 
level. 
This 
assumes that the 
Hazard 
Ratio 


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low 
back 
pain 
after 
the 
first 
dose (first 8 
hours). 
 
treatment has no 
impact 
on 
the 
primary 
endpoint.  The 
patients 
are 
censored at the 
point 
of 
first 
intake of rescue 
medication 
(i.e. 
considered as no 
longer at risk of 
an event).  
The IRT collected 
strata 
will 
be 
replaced by CRF 
collected/derive
d strata 
 
Primary 
Estimand 
Sensitivit
y 10 
 
Efficacy 
of 
DKP.TRIS/ 
TRAM.HCl 
fixed 
combinatio
n 
versus 
placebo 
in 
moderate to 
severe acute 
low 
back 
pain 
after 
the 
first 
dose (first 8 
hours). 
ITT 
Population 
(All 
patients 
randomized)  
Time 
to 
first 
achieve an NRS-PI 
score <4 or a pain 
intensity 
reduction 
of 
≥30% from drug 
intake till 8 hours 
after the first dose 
 
 
Composite 
Strategy. 
Initiation 
of 
rescue 
medication (RM). 
Scores after RM 
return to baseline 
level. 
This 
assumes that the 
treatment has no 
impact 
on 
the 
primary 
endpoint.  The 
patients 
are 
censored at the 
point 
of 
first 
intake of rescue 
medication 
(i.e. 
Hazard 
Ratio 


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Version Date:  
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considered as no 
longer at risk of 
an event).  
The IRT collected 
strata 
will 
be 
replaced by CRF 
collected/derive
d strata 
 
Primary 
Estimand 
Sensitivit
y 11 
 
Efficacy 
of 
DKP.TRIS/ 
TRAM.HCl 
fixed 
combinatio
n 
versus 
placebo 
in 
moderate to 
severe acute 
low 
back 
pain 
after 
the 
first 
dose (first 8 
hours). 
PP Population 
(All 
patients 
randomized 
without 
any 
major PDs that 
affect primary 
efficacy 
analysis) 
Time 
to 
first 
achieve an NRS-PI 
score <4 or a pain 
intensity 
reduction 
of 
≥30% from drug 
intake till 8 hours 
after the first dose 
 
 
Composite 
Strategy. 
Initiation 
of 
rescue 
medication (RM). 
Scores after RM 
return to baseline 
level. 
This 
assumes that the 
treatment has no 
impact 
on 
the 
primary 
endpoint.  The 
patients 
are 
censored at the 
point 
of 
first 
intake of rescue 
medication 
(i.e. 
considered as no 
longer at risk of 
an event).  
The IRT collected 
strata 
will 
be 
replaced by CRF 
collected/derive
d strata 
 
Hazard 
Ratio 


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Primary 
Estimand 
Sensitivit
y 12 
 
Efficacy 
of 
DKP.TRIS/ 
TRAM.HCl 
fixed 
combinatio
n 
versus 
placebo 
in 
moderate to 
severe acute 
low 
back 
pain 
after 
the 
first 
dose (first 8 
hours). 
mITT 
Population 
(All 
patients 
randomized 
and 
satisfies 
the 
randomizatio
n 
ratio 
4:4:1:1) 
and 
having 
same 
strata 
collected 
in 
both CRF and 
IRT 
Time 
to 
first 
achieve an NRS-PI 
score <4 or a pain 
intensity 
reduction 
of 
≥30% from drug 
intake till 8 hours 
after the first dose 
 
 
Composite 
Strategy. 
Initiation 
of 
rescue 
medication (RM). 
Scores after RM 
return to baseline 
level. 
This 
assumes that the 
treatment has no 
impact 
on 
the 
primary 
endpoint.  The 
patients 
are 
censored at the 
point 
of 
first 
intake of rescue 
medication 
(i.e. 
considered as no 
longer at risk of 
an event).  
Hazard 
Ratio 
Primary 
Estimand 
Sensitivit
y 13 
 
Efficacy 
of 
DKP.TRIS/ 
TRAM.HCl 
fixed 
combinatio
n 
versus 
placebo 
in 
moderate to 
severe acute 
low 
back 
pain 
after 
the 
first 
dose (first 8 
hours). 
ITT 
Population 
(All 
patients 
randomized)  
and 
having 
same 
strata 
collected 
in 
both CRF and 
IRT 
Time 
to 
first 
achieve an NRS-PI 
score <4 or a pain 
intensity 
reduction 
of 
≥30% from drug 
intake till 8 hours 
after the first dose 
 
 
Composite 
Strategy. 
Initiation 
of 
rescue 
medication (RM). 
Scores after RM 
return to baseline 
level. 
This 
assumes that the 
treatment has no 
impact 
on 
the 
primary 
endpoint.  The 
patients 
are 
censored at the 
Hazard 
Ratio 


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Version Date:  
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point 
of 
first 
intake of rescue 
medication 
(i.e. 
considered as no 
longer at risk of 
an event).  
Primary 
Estimand 
Sensitivit
y 14 
 
Efficacy 
of 
DKP.TRIS/ 
TRAM.HCl 
fixed 
combinatio
n 
versus 
placebo 
in 
moderate to 
severe acute 
low 
back 
pain 
after 
the 
first 
dose (first 8 
hours). 
PP Population 
(All 
patients 
randomized 
without 
any 
major PDs that 
affect primary 
efficacy 
analysis) and 
having 
same 
strata 
collected 
in 
both CRF and 
IRT 
Time 
to 
first 
achieve an NRS-PI 
score <4 or a pain 
intensity 
reduction 
of 
≥30% from drug 
intake till 8 hours 
after the first dose 
 
 
Composite 
Strategy. 
Initiation 
of 
rescue 
medication (RM). 
Scores after RM 
return to baseline 
level. 
This 
assumes that the 
treatment has no 
impact 
on 
the 
primary 
endpoint.  The 
patients 
are 
censored at the 
point 
of 
first 
intake of rescue 
medication 
(i.e. 
considered as no 
longer at risk of 
an event).  
Hazard 
Ratio 
3. STUDY DESIGN 
3.1. GENERAL DESCRIPTION 
This is a Phase IV, multicenter, randomized, double-blind, double-dummy parallel group, placebo-
controlled study encompassing 2 study phases: a single-dose phase (first 8 hours) and a multiple-
dose phase starting after the single-dose phase (from 8th hour until Day 5) aimed to investigate the 
efficacy of DKP.TRIS/TRAM.HCl fixed combination in moderate to severe acute lower back pain 


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(LBP). 
 In the single-dose phase the patients will receive a single dose treatment, consisting of 1 film-coated 
tablet and 2 capsules which must be orally administered together at the same time (Day 1) and 
according to Investigator’s instructions. The multiple-dose phase will begin 8 hours after the first 
dose. The patients assigned to DKP.TRIS/TRAM.HCl fixed combination or TRAM.HCL 100 mg during 
the single-dose phase will continue to receive the same treatment during the multiple-dose phase; 
however, the patients assigned to receive placebo during the single-dose phase will either receive 
DKP.TRIS/TRAM.HCl fixed combination or TRAM.HCL 100 mg during the multiple-dose phase. The 
study is considered completed when the last patient’s last study visit has occurred. 510 eligible 
patients will be randomized in a 4:4:1:1 ratio to 1 of the 4 possible treatment arms.  Data are collected 
through a combination of e-Diary and data entered through the eCRF at site. All efficacy related, 
Rescue medication and study medication data are collected through e-diary. 
3.2. STUDY SCHEME 
  
Figure 1: Overview of Trial Design 


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3.3. SCHEDULE OF EVENTS 
Schedule of events can be found in Section 4.1 of the protocol. 
3.4. CHANGES TO ANALYSIS FROM PROTOCOL 
• 
As per protocol, the definition of Per Protocol Population is “All patients of the ITT population 
who have not experienced major protocol violations that could affect the analyses”. In SAP, 
this has been updated to,  
“The per-protocol (PP) population will contain all patients in the ITT who have not 
experienced major protocol violations that could affect the primary efficacy analysis”. 
• 
Randomization eliminates a systematic difference between subjects in treatment groups 
inducing approximate balance with respect to covariates, both observed and 
unobserved.  The correct proportion of patients among treatment groups represents a 
fundamental element to increase the efficiency of the study.  Not respecting the study 
protocol randomization scheme can have consequences for statistical power that is directly 
related to statistical efficiencies.  In this study  a 4:4:1:1 ratio produces a justified post-
randomization belief regarding allocation to the investigational treatments versus placebo. 
However, one of the four treatment arms randomized more patients than initially designed 
in the protocol, leading to an unbalanced proportion among the four arms of the study.  So, 
an additional analysis population, modified Intent-to-Treat (mITT) is added in the study 
which maintains the 4:4:1:1 ratio of patients across the treatment groups. The definition of 
mITT population is, 
• 
“The modified intent-to-treat population will contain the first cohort of 510 patients 
randomized to the four treatment groups((204 patients in the DKP.TRIS/TRAM.HCl + 
DKP.TRIS/TRAM.HCl arm,  204 patients in the TRAM.HCl + TRAM.HCl arm, 51 patients in the 
placebo + DKP.TRIS/TRAM.HCl arm and finally 51 patients in the placebo + TRAM.HCl arm).“ 
Efficacy analyses will be performed using the mITT population (primary efficacy dataset), 
ITT population and PP population. 
4. PLANNED ANALYSES 
A final Analysis after database lock (DBL) is planned for this study. 


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4.1. FINAL ANALYSIS 
All final, planned analyses identified in this SAP will be performed by IQVIA Biostatistics following 
Sponsor Authorization of this Statistical Analysis Plan, Database Lock, Sponsor Authorization of 
Analysis Sets and Unblinding of Treatment.  
5. ANALYSIS POPULATION 
Agreement and authorization of patients included/excluded from each analysis set will be conducted 
prior to database lock and the unblinding of the study.  
5.1. INTENT-TO-TREAT [ITT] POPULATION 
The intent-to-treat (ITT) population will contain all patients randomized to any of the treatment 
groups. For analyses and displays based on ITT, patients will be classified according to randomized 
treatment. 
5.2. MODIFIED INTENT-TO-TREAT [MITT] POPULATION 
The modified intent-to-treat population will contain the first cohort of 510 patients randomized to 
the four treatment groups ((204 patients in the DKP.TRIS/TRAM.HCl + DKP.TRIS/TRAM.HCl 
arm, 204 patients in the TRAM.HCl + TRAM.HCl arm, 51 patients in the placebo + 
DKP.TRIS/TRAM.HCl arm and finally 51 patients in the placebo + TRAM.HCl arm). In this cohort of 
patients, the randomization scheme 4:4:1:1 was completely respected.  For analyses and displays 
based on mITT, patients will be classified according to randomized treatment.  
The patients will be included in the mITT based on the randomization order. i.e., the first 204 patients 
randomized to active arm and the first 51 patients randomized to Placebo arm will be considered in 
the mITT set. 
5.3. SAFETY [SAF] POPULATION 
The safety (SAF) population will contain all patients in the ITT who have received at least 1 dose of 
the study treatment. 
If there is any doubt whether a patient was treated or not, they will be assumed treated for the 
purposes of analysis. Patients will be assigned to the treatment received, for each category in case 


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the treatment received differs from that randomized. 
5.4. PER PROTOCOL [PP] POPULATION 
The per-protocol (PP) population will contain all patients in the ITT who have not experienced major 
protocol violations that could affect the primary efficacy analysis. Protocol violations which have a 
major distorting influence on the primary endpoints will result in patients being excluded from the 
PP. PDs identified during the clinical conduct of the study, as authorized in the final PD log, will also 
be taken into consideration in the final assignment of patients to the analysis sets. 
Patients will be assigned to the treatment received, for each category in case the treatment received 
differs from that randomized. 
 
Reasons for exclusion can be, but not limited to: 
- 
Non-compliance with the inclusion or exclusion criteria. 
- 
Insufficient essential efficacy data for the primary analysis. 
- 
Intake of prohibited medication. 
- 
Non-compliance with the study treatment. 
- 
Non-compliance with time window for the primary efficacy data. 
- 
Non-compliance with randomization criteria. 
6. GENERAL CONSIDERATIONS 
6.1. REFERENCE START DATE AND STUDY TIME 
Study Day and Time will be calculated from the reference start date/time and will be used to show 
start/stop day / time of assessments and events as applicable.  
 
Reference start date/time is defined as the day/time of the first dose of study medication, (Day 1 is 
the day of the first dose of study medication) and will appear in every listing where an assessment 
date/time or event date appears.  
• 
If the date and time of the event is on or after the reference date and time, then:  
• 
Study Day and Time = (date and time of event – reference date and time+1). 
• 
If the date of the event is prior to the reference date, then:  
• 
Study Day = (date of event – reference date). 
In the situation where the event date is partial or missing, Study Day, and any corresponding 


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durations will appear partial or missing in the listings. 
 
Multiple dose phase start date/time will be assessed based on the date/time of second dose 
administration. If a patient skipped the second dose at 8th hour and took dose at 16th hour, then the 
multiple dose phase start date/time for that patient will be 16th hour. 
6.2. BASELINE 
Unless otherwise specified, baseline is defined as the last non-missing measurement taken prior to 
reference start date/time (including unscheduled assessments). In the case where the last non-
missing measurement and the reference start date coincide, that measurement will be considered 
baseline, but Adverse Events (AEs) and medications commencing on the reference start date/time 
will be considered post-baseline, unless the start time of the AE/medications is known to be prior to 
the first dosing of the investigational product. 
6.3. RETESTS, UNSCHEDULED VISITS AND EARLY TERMINATION DATA 
In general, for by-visit summaries, data recorded at the nominal visit will be presented. Unscheduled 
measurements will not be included in by-visit summaries. Listings will include scheduled, 
unscheduled, retest and early discontinuation data. 
6.4. WINDOWING CONVENTIONS AND TIMEPOINT DERIVATION FOR QUESTIONNAIRE DATA 
 
Timepoint  
Questionnaire 
Window 
0h 
Study Medication Use 
Rescue Medication Use 
Open until completed 
15min* 
NRS-PI 
VRS-PAR 
+/- 7 mins 
30min* 
NRS-PI 
VRS-PAR 
+/- 7 mins 
1h* 
NRS-PI 
VRS-PAR 
+/- 15 mins 
1.5h* 
NRS-PI 
VRS-PAR 
+/- 15 mins 
2h* 
NRS-PI 
+/- 15 mins 


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VRS-PAR 
4h* 
NRS-PI 
VRS-PAR 
+/- 15 mins 
6h* 
NRS-PI 
VRS-PAR 
+/- 15 mins 
8h* 
PGE  
NRS-PI 
VRS-PAR 
Study Medication Use 
+/- 35 min 
10h 
NRS-PI 
VRS-PAR 
+/- 30 min 
16h 
NRS-PI 
VRS-PAR 
Study Medication Use 
+/- 30 min 
18h 
NRS-PI 
VRS-PAR 
+/- 30 min 
24h 
NRS-PI 
VRS-PAR 
Study Medication Use 
+/- 30 min 
26h 
NRS-PI 
VRS-PAR 
+/- 30 min 
32h 
NRS-PI 
VRS-PAR 
Study Medication Use 
+/- 30 min 
34h 
NRS-PI 
VRS-PAR 
+/- 30 min 
40h 
NRS-PI 
VRS-PAR 
Study Medication Use 
+/- 30 min 
42h 
NRS-PI 
VRS-PAR 
+/- 30 min 
48h 
NRS-PI 
VRS-PAR 
Study Medication Use 
+/- 30 min 
50h 
NRS-PI 
VRS-PAR 
+/- 30 min 
56h 
NRS-PI 
VRS-PAR 
+/- 30 min 


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Study Medication Use 
58h 
NRS-PI 
VRS-PAR 
+/- 30 min 
64h 
NRS-PI 
VRS-PAR 
Study Medication Use 
+/- 30 min 
66h 
NRS-PI 
VRS-PAR 
+/- 30 min 
72h 
NRS-PI 
VRS-PAR 
Study Medication Use 
+/- 30 min 
74h 
NRS-PI 
VRS-PAR 
+/- 30 min 
80h 
NRS-PI 
VRS-PAR 
Study Medication Use 
+/- 30 min 
82h 
NRS-PI 
VRS-PAR 
+/- 30 min 
88h 
NRS-PI 
VRS-PAR 
Study Medication Use 
+/- 30 min 
90h 
NRS-PI 
VRS-PAR 
+/- 30 min 
96h 
NRS-PI 
VRS-PAR 
Study Medication Use 
+/- 30 min 
98h 
NRS-PI 
VRS-PAR 
+/- 30 min 
104h 
NRS-PI 
VRS-PAR 
RMDQ 
TSQM 
PGE 
+/- 30 min 
 
*  The window period specified in the ERT project design specification document (version 3.0) for 
the timepoints within the first 8 hours (single dose phase) is very narrow. There are chances to have 
records for the questionnaire responses a few minutes outside the window period for each of the 
timepoints since the data is collected through e-diary. So, in order to include the maximum number 


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of data points in the analysis, without clinically meaningful impact, the window period for the 
timepoints were extended as follows:   
• 
Timepoints 15min and 30min          : Window period extended from +/- 5 min to +/- 
7 min 
• 
Timepoints 1h till 6h                          : Window period extended from +/- 10 min to 
+/- 15 min 
• 
Timepoint 8h                                       : Window period extended from +/- 30 min to +/- 
35 min 
 
The timepoint of each questionnaire will be derived based on the difference between the first 
treatment administration date/time and the assessment date/time, considering the above-
mentioned window period. Any assessment falling out of the window will be considered as 
unscheduled and will not be considered for the summary or statistical analysis but will be displayed 
in the listings. 
If a patient is having multiple entries with respect to a particular timepoint, then the assessment 
which is closer to the scheduled date/time of that particular timepoint will be considered. In case if 
a patient has multiple records at a timepoint which is equidistant from the scheduled time, then the 
latest record will be considered for the analysis. 
6.5. STATISTICAL TESTS 
The default significant level will be (5%); confidence intervals will be 95% and all tests will be two-
sided, unless otherwise specified in the description of the analyses. 
6.6. COMMON CALCULATIONS 
For quantitative measurements, change from baseline (absolute and percentage) will be calculated 
as: 
 
• 
Test Value at Visit X – Baseline Value 
• 
 (Test Value at Visit X – Baseline Value)/ Baseline Value*100 
6.7. SOFTWARE VERSION 
All analyses will be conducted using SAS Enterprise Guide 8.2. 


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7. STATISTICAL CONSIDERATIONS 
7.1. ADJUSTMENTS FOR COVARIATES AND FACTORS TO BE INCLUDED IN ANALYSES 
The following covariates/factors will be used in the analyses.  
 
• 
Treatment 
• 
Baseline PI categories based on NRS scale 
- 
≥ 5 to ≤7 (moderate pain) 
- 
˃7 (severe pain) 
• 
Baseline radiculopathy categories based on Quebec Task Force classification35 
- 
LBP without radiation 
- 
LBP+ radiation to extremity, proximally 
- 
LBP+ radiation to extremity, distally 
• 
Baseline Roland Morris Disability Questionnaire score 
 
For further details on statistical models based on the above factors, please refer to section 16. 
7.2. MULTICENTER STUDIES 
This study will be conducted by multiple investigators at multiple centers internationally. 
7.3. MISSING DATA 
Missing safety data will not be imputed. Missing efficacy data will be handled as follows.  
 
Data imputations will be done for Pain intensity (PI) and Pain relief (PAR) assessment under the 
following circumstances: 
• 
First, for values collected after the rescue medication (RM) intake 
• 
Then, missing data. 
For all PI assessments at each timepoint after the first RM intake, PI will return to its baseline level. 
Single missing values between measurements will be linearly interpolated using the formula; 
Y = (( X - X1 )( Y2 - Y1) / ( X2 - X1)) + Y1 
Where, (X1, Y1) = First co-ordinates, (X2, Y2) = Second co-ordinates, X = Target X co-ordinate, Y = 
Interpolated Y co-ordinate. 


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If more than one consecutive data are missed, Last Observation Carry Forward (LOCF) method will 
be applied. 
Once imputations are done, the efficacy variables based on PI and PAR assessments (SPID, TOTPAR, 
etc.) will be re-derived based on the PI and PAR imputed values. Different strategies will be used to 
handle data imputation. A summary is provided in the table below: 
 
 
Values collected after the RM intake  
Missing data 
Main 
Analysis 
Single dose phase: 
For all PI and PAR assessments at each 
timepoint after the first RM intake, PI will 
return to its baseline level and PAR to zero 
(Baseline Observation Carried Forward 
[BOCF]). 
Multiple-dose phase: 
PI and PAR assessments recorded during the 6 
hours after the intake of RM (based on the 
effect of Paracetamol) will be replaced with the 
last observation carried forward (LOCF) 
(which should be the one done immediately 
before RM) or worst observation carried 
forward (WOCF) in case the assessment 
immediately before intake is missed. 
Single missing values 
between measurements will be 
linearly interpolated, if more 
consecutive data are missed LOCF 
method will be applied 
Sensitivity 
Analysis 1 
Treatment Policy Strategy: values collected are 
used regardless of whether the RM is taken 
without any imputation. 
No imputation, missing values will 
not be replaced. 
Sensitivity 
Analysis 2 
Hypothetical Strategy: a scenario is envisaged in 
which the intake of RM would not occur. Values 
collected for the 6 hours after the RM intake will 
be considered as missed and they will be 
imputed by using a multiple imputation 
approach. 
Missing values will be replaced by 
using 
a 
multiple 
imputation 
approach.  
 
The intake of RM can be identified from the diary data (Rescue Medication Use). 
For duration of disease and birth date, the missing date will not be imputed. Calculation for the partial 
date is described in Appendix 2 


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7.4. MULTIPLE COMPARISONS/ MULTIPLICITY 
There is one primary endpoint comparison for superiority (as detailed in Section 16.1.3) 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. 
7.5. EXAMINATION OF SUBGROUPS 
No subgroup analyses will be performed for this study. however, subgroup analysis may be 
conducted as post Hoc analysis. 
8. OUTPUT PRESENTATIONS 
Appendix 1 shows conventions for presentation of data in outputs.  
The templates provided with this SAP describe the presentations for this study and therefore the 
format and content of the summary tables, figures, and listings to be provided by IQVIA Biostatistics. 
Few tables will contain two set of population counts (N1 and N2) for DKP.TRIS/TRAM.HCl and 
TRAM.HCl each, since placebo subjects will receive either DKP.TRIS/TRAM.HCl or TRAM.HCl after 
the single dose phase. Thus, N1 and N2 will represent the number of patients under 
DKP.TRIS/TRAM.HCl and TRAM.HCl arm at the single dose phase and multiple dose phase 
respectively. 
9. DISPOSITION AND WITHDRAWALS 
All patients who provide informed consent will be accounted for in this study.  
9.1. DISPOSITION 
Patient disposition including count and percentage of patients screened, screen failures, randomized, 
completed the treatment, discontinued the study, reason for discontinuation of treatment, completed 
the study, discontinued the study, and reason for discontinuation of study will be tabulated by 
treatment group and overall. 
Completion and discontinuation of study treatment can be identified from the filed “Date of 
Treatment discontinuation” of eCRF page “End of study”. If the date is missing then the patient 


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completed the treatment, and if the date is not missing then patient discontinued the treatment. 
Completion and discontinuation of study can be identified based on the treatment discontinuation 
date and study completion or discontinuation date.  
- 
If both the dates are same, then the patient discontinued the study. 
- 
If the dates are different and the difference between the study completion/ 
discontinuation date and the screening date is at least 6, then the patient is completed 
the study else discontinued. 
 
Number and percentage of patients in each population and exclusion patients from each population 
will also be summarized. Percentages for population exclusion will be based on ITT population. 
 
Patients who are excluded from safety, ITT, mITT and PP population and reason for exclusion from 
PP population will be listed. 
9.2. PROTOCOL DEVIATIONS 
All PDs will be recorded and classified in Clinical Trial Management System (CTMS). 
 
All protocol deviations (PD) will be discussed and reviewed on a case-by-case basis before the DBL.  
Additional evaluation regarding the COVID-19 related PDs will be implemented and discussed before 
the DBL. In acknowledgement of multiple regulatory guidance (FDA Guidance on Conduct of Clinical 
Trials of Medical Products during COVID-19 Pandemic, FDA, 2020; Guidance on the Management of 
Clinical Trials during the COVID-19 Pandemic, EMA, 2020; Points to consider on implications of 
Coronavirus disease on methodological aspects of ongoing clinical trials, EMA, 2020) protocol 
deviations due to COVID-19 pandemic will be summarized and will be indicated in the listing of 
protocol deviation. 
All PDs authorized by Sponsor will be documented. 
 
Individual PDs will be presented in a data listing. The number and percentage of patients with 
major/critical PDs as well as the number and percentage of patients with major/critical PDs that 
could affect the primary efficacy analysis will be summarized by deviation on ITT population. 
Additional Major and Minor PDs may be identified during data review and will be reflected in the 
Table and Listing as appropriate. 
All PDs will be recorded and classified in Clinical Trial Management System (CTMS). 


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10. DEMOGRAPHIC AND OTHER BASELINE CHARACTERISTICS 
Demographic data and other baseline characteristics will be presented for the ITT and mITT. 
No statistical testing will be carried out for demographic or other baseline characteristics. 
The following demographic and other baseline characteristics will be reported for this study. 
• 
Age (years)  
• 
Sex 
• 
Childbearing potential for female subjects 
• 
Race  
• 
Weight (kg) 
• 
Height (cm) 
• 
BMI (kg/m2) 
• 
Baseline radiculopathy categories 
• 
NRS-PI score at baseline 
• 
Baseline PI categories 
• 
Roland Morris Disability Questionnaire Score 
10.1. 
DERIVATIONS 
• 
BMI (kg/ m2) = weight (kg)/ height (m)2 
11. MEDICAL AND SURGICAL PROCEDURE HISTORY 
Medical and Surgical Procedure History information will be presented for the ITT and mITT.  
• 
Medical History data captured on eCRF will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA, Version 24.1 or latest) dictionary 
o Medical History conditions are defined as those conditions which stop prior to or at 
Screening.  
o Presented by SOC and PT.  
 
A listing will be provided for both medical and surgical procedure history. 
12. CONCOMITANT ILLNESSES 
Concomitant Illnesses will be presented for the SAF. 


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• 
Concomitant Illnesses will be coded using Medical Dictionary for Regulatory Activities (MedDRA, 
Version 24.1 or latest available) dictionary 
o Concomitant Illnesses are conditions started prior to or at Screening and are ongoing 
at the date of Screening.  
o Presented by SOC and PT.  
o Concomitant illness conditions are defined as those conditions recorded in the eCRF 
form “Medical History”. 
13. PRIOR, CONCOMITANT AND POST TREATMENT MEDICATIONS/ NON-
DRUG TREATMENT 
Medications will be presented for the SAF and coded using WHO Drug dictionary Version 01SEP2021 
or latest available. See Appendix 2 for handling of partial dates for medications, in the case where it 
is not possible to define a medication as prior or concomitant, the medication will be classified by the 
worst case, i.e. concomitant.  
Frequency tabulations will be presented for prior and concomitant medications by preferred name. 
• 
‘Prior’ medications are medications which started and stopped prior to the first dose of study 
medication.  
• 
‘Concomitant’ medications are medications which:  
o started prior to, on or after the first dose of study medication,  
o AND ended on or after the date of first dose of study medication or were ongoing at 
the end of the study. 
Concomitant medications will be summarized separately for single dose and multiple dose phases. 
Concomitant medications which are stopped prior to first multiple dose start date will be 
summarized for single dose phase. Concomitant medications that are failed to include in single dose 
phase will be summarized for multiple dose phase.  
Concomitant medications ending on the multiple dose phase start date/time will be considered for 
the multiple dose phase summary, unless the end time of the medication is known to be prior to the 
multiple dose phase. 
• 
“Post Treatment” medications are medications which are started after the multiple dose end date. 
 
A listing of concomitant non-drug treatment will be provided for SAF. 
 


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13.1. RESCUE MEDICATION 
Summary of rescue medication will be presented for ITT and mITT separately for single dose phase 
and multiple dose phase. The summary will include the number of subjects took rescue medication, 
the frequency of rescue medication (1 time, 2 times, 3 times, and more than 3 times), summary of 
NRS PI score before taking rescue medication, frequency of NRS PI score before rescue medication, 
frequency of VRS-PAR score before taking rescue medication. 
 
A listing of RM t will be provided for ITT. 
14. STUDY MEDICATION EXPOSURE 
Exposure to study medication in hours will be presented for the SAF. 
The extent of exposure will be calculated for DKP.TRIS/TRAM.HCl and TRAM.HCl. Exposure to 
placebo will not be summarized since it is administered only at one time and interruptions, dose 
change, and noncompliance are not applicable for placebo as per the study design. 
  
Exposure will be calculated separately for patients received DKP.TRIS/TRAM.HCl or TRAM.HCl at t0 
and patients switched to DKP.TRIS/TRAM.HCl or TRAM.HCl in the multiple dose phase. 
The date and time of first study medication administration will be taken from the eCRF “Study drug 
administration at t0h” form. The date and time of first study medication for the multiple dose phase 
(t8) will be taken from the e-diary data. The date of last study medication will be taken from the eCRF 
“End of Study” form. In the case of missing data on the eCRF, the e-diary data will be used in order to 
determine the first and last date of study medication. 
Interruptions, compliance, and dose changes are not considered for duration of exposure.  
14.1. 
DERIVATIONS 
Duration of exposure of study medication (minutes), 
- 
For patients received DKP.TRIS/TRAM.HCl or TRAM.HCl at t0 = (Date/Time of last 
study medication administration – Date/Time of first study medication 
administration (t0))/60.  
- 
For patients switched to DKP.TRIS/TRAM.HCl or TRAM.HCl in the multiple phase = 
(Date/Time of last study medication administration – Date/Time of first study 
medication administration on multiple phase (t8))/60. 


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15. STUDY MEDICATION COMPLIANCE  
Compliance to study drug will be presented for the SAF population. 
 
A table consisting of summary statistics for percent compliance along with the number and percent 
of patients with compliance in each of the following groups: <80%, =>80% - <=120% and >120% 
as well as the overall number and percentage of patients compliant for each treatment group and 
overall will be produced by phases and across the whole study on SAF population. 
 
A listing of drug accountability will be presented on SAF population to account for all drug distributed 
to each patient, including the box number, total number capsules dispensed, returned, consumed, 
lost (if any). percentage compliance and compliant (yes/no) will also be displayed for study drug. 
15.1. 
DERIVATIONS 
Compliance with study drug based on the drug accountability data will be calculated as the number 
of capsules/tablets taken x 100 / expected number of tablets/capsules which should have been taken 
expressed as a percentage, see calculations below.  
 
Compliance(%) = 
units of tablets/capsules actually taken 
Total units of tablets / capsules expected to be taken × 100 
 
The actual number of tablets/capsules taken can be identified from the drug accountability data 
collected in the eCRF. The “Amount Consumed” field in the “Drug Return and Accountability” page of 
eCRF will provide the number of tablets/capsules consumed by each patient. The expected number 
of total tablets/capsules taken for each patient will be 39 based on 13 (thirteen) administrations with 
1 tablet and 2 capsules per administration. For patients who permanently stop the study medication, 
the expected number of tablets/capsules will be calculated up-to the date of study withdrawal. 


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16. EFFICACY OUTCOMES  
16.1. 
PRIMARY EFFICACY 
16.1.1. 
PRIMARY EFFICACY VARIABLE(S) & DERIVATION(S) 
The primary efficacy variable is time to first achieve an NRS-PI score <4 or a pain intensity reduction 
of ≥30% from drug intake till 8 hours after the first dose. 
The time to achieve an NRS-PI score <4 or a pain intensity reduction of ≥30% will be the minimum 
of the following 2 values, 
1) The time (till 8 hours after the first dose) where a patient achieves an NRS-PI score <4. 
2) The time (till 8 hours after the first dose) where a patient is achieving a percentage change 
in PI score from baseline ≤ -30%.  
16.1.2. 
MISSING DATA METHODS FOR PRIMARY EFFICACY VARIABLE(S) 
Handling of missing data need to follow as per section 7.3 
16.1.3. 
PRIMARY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
The primary objective of this study is to evaluate the analgesic efficacy of DKP.TRIS/TRAM.HCl versus 
placebo by the time to first achieve an NRS-PI score <4 or a pain intensity reduction of ≥30% from 
drug intake till 8 hours after the first dose. 
 
The primary efficacy analysis will be performed for the mITT population, where the randomization 
scheme 4:4:1:1 is properly respected.  The ITT population (total cohort of patients randomized) will 
be used to assess the robustness of the results obtained using the mITT population.  The results of 
mITT and ITT analyses will be compared, and the two analyses will be concordant if both reach the 
same conclusions. 
 
The analysis will be performed for the superiority of DKP.TRIS/TRAM.HCl versus placebo using a Cox 
Proportional Hazard (CPH) model with treatment, baseline PI categories and baseline radiculopathy 
categories as covariates/ factors. 
Hazard ratio ((DKP.TRIS/TRAM.HCl)/ Placebo) will be presented together with two-sided 95% CI 
and p-value for the test for significance of the difference at 5% significance level. 


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Figure 2: Hypotheses for Superiority Test 
 
 
 
The Hypothesis to be tested is; 
H0: HR = 1 
Vs 
H1: HR ≠ 1 
Where HR is hazard ratio comparing DKP.TRIS/TRAM.HCl to Placebo. 
If the lower confidence interval for the Hazard Ratio is greater than 1, the superiority is achieved. 
 
In case of proportional hazard assumption is not satisfied, covariates with nonproportional effects 
may be incorporated into the model as stratification factors rather than predictors. Assumption of 
Proportionality will be examined based on supremum test using PROC PHREG SAS procedure. 
 
Table 1 
Situation 
Censoring/Event Rule 
NRS-PI score <4 or a pain intensity reduction of 
≥30% at timepoint ti without prior Rescue 
Medication 
Event at ti 
Completed study without achieving NRS-PI 
score <4 or a pain intensity reduction of ≥30% 
Censor at timepoint of 8 hours 
 
The NRS-PI Score is obtained from Diary Data (NRS-PI). 
The NRS-PI Score will be summarized categorically based on the following categories: 0, 1, 2, 3, and 
>=4.  


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If the NRS PI at 8th hour is captured after 15 minutes from the second dose, then those PI values will 
not be included in the analysis, since the maximum plasma concentration (Cmax) is reaching at 30 
minutes (ranging from 15 to 60 minutes) when DKP.TRIS is orally administered in humans. Also, the 
analgesic effect of DKP starts after 15 minutes. 
16.1.4. 
SENSITIVITY ANALYSIS OF PRIMARY EFFICACY VARIABLE(S) 
16.1.4.1. 
Intent-to-Treat Analysis 
Primary efficacy endpoints will be analyzed using the ITT population. 
16.1.4.2. 
Per protocol Analysis 
Primary efficacy endpoints will be analyzed using the PP population. 
16.1.4.3. 
No Data Imputation 
Analysis will be carried out on primary endpoint without any imputation on missing values 
regardless of whether or not the rescue medication is taken on mITT, ITT, and PP population. Only 
observed values will be used for the analysis. 
 
Table 2 
Situation 
Censoring/Event Rule 
NRS-PI score <4 or a pain intensity reduction of 
≥30% at timepoint ti without prior Rescue 
Medication 
Event at ti 
Completed study without achieving NRS-PI 
score <4 or a pain intensity reduction of ≥30% 
Censor at timepoint of 8 hours 
Early Discontinuation 
Censor at Time of Last Assessment 
Early Discontinuation and later known to have 
a death 
Censor at Time of Last Assessment 
Intake of Rescue Medication before 
event/without event 
Censor at Time of Rescue Medication 


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16.1.4.4. 
Multiple Imputation 
An analysis based on the envisage in which the intake of RM would not occur. This will be analyzed 
using MI based on the missing data assumption Missing at Random (MAR) on mITT, ITT, and PP 
population. This process will follow five steps: 
 
1) Consider the values collected for the 6 hours after the RM intake as missing. 
2) Partially impute the data for a monotone missing pattern with 100 as a number of 
imputations and “1234” as seed number. Employ the Markov Chain Monte Carlo (MCMC) 
method with treatment, baseline PI categories, baseline radiculopathy, and Baseline Roland 
Morris Disability Questionnaire score 
3) Impute the monotone data using a regression imputation model. Apply by imputation using 
seed number “1234” with treatment, baseline PI categories, baseline radiculopathy, and 
Baseline Roland Morris Disability Questionnaire score 
4) Each multiple imputed dataset in Step 3 will be analyzed separately, as described in Section 
16.1.3 of the SAP.  
5) The estimates (LS means, CI, etc.) from the model analysis in Step 4 will be combined using 
Rubin’s combination rules for statistical inference 
 
Refer Table 1 for censoring/event rules. 
 
Refer Appendix 1 for more details. 
16.1.4.5. 
Inclusion of strata variables collected in the CRF instead of IRT strata variables 
Primary efficacy endpoints will be analyzed on mITT, ITT, and PP population by replacing the strata 
variables (baseline NRS PI categories and baseline radiculopathy categories) collected in the IRT by 
the strata variables derived/collected based on the CRF data. 
Screening NRS PI will be classified into two groups based on the score collected at screening as 
follows. 
- 
Moderate pain: if the Screening NRS PI is between 5 and 7 (both inclusive) 
- 
Severe pain: if the screening NRS PI is >7 
 
Baseline radiculopathy categories are collected in the “Quebec Task force classification” page in the 
CRF at screening visit. The categories to be considered are, 
- 
LBP without radiation  
- 
LBP+ radiation to extremity, proximally  


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- 
LBP+ radiation to extremity, distally  
 
If the sensitivity analysis will show that the mITT, ITT, and PP primary endpoint result and 
conclusions are not affected by the incorrect stratification on randomization, the ITT and PP results 
can be regarded as certainty. If sensitivity analyses will identify that the incorrect stratification on 
randomization influences the ITT and PP primary endpoint results, additional subgroups analysis 
will be performed to try to resolve these inconsistencies. If this cannot be achieved, the impact of 
the incorrect stratification on the primary endpoint results will be interpreted and justified in the 
Clinical Study Report. 
16.1.4.6. 
Removal of patients with incorrect stratification on randomization 
Primary efficacy endpoints will be analyzed on mITT, ITT, and PP population by removing the 
patients  with incorrect stratification at screening. i.e., the patients who are having difference in 
stratification categories (baseline NRS PI categories and baseline radiculopathy categories) between 
CRF and IRT will be omitted from the analysis. 
16.2. 
SECONDARY EFFICACY 
The secondary efficacy analyses will be performed for the PP population, mITT population, and ITT 
population. 
These includes: 
 
Single-dose phase 
• 
Pain Relief (PAR) scores at each prespecified time point (t15m, t30m, t1h, t1.5h, t2h, t4h, t6h, 
t8h) over the 8 hours after the first dose 
• 
TOTPAR at 4, 6, and 8 hours (TOTPAR4, TOTPAR6, TOTPAR8) after the first dose 
• 
Percentage of maximum TOTPAR (% max TOTPAR) at 4, 6, and 8 hours after the first dose 
• 
Percentage of patients achieving at least 50% of maximum TOTPAR at 4, 6, and 8 hours after 
the first dose 
• 
Pain Intensity (PI) scores at each prespecified time point (t15m, t30m, t1h, t1.5h, t2h, t4h, 
t6h, t8h) over the 8 hours after the first dose 
• 
SPID at 4, 6, and 8 hours (SPID4, SPID6, SPID8) after the first dose 
• 
Percentage of maximum SPID (% max SPID) at 4, 6, and 8 hours after the first dose 
• 
Percentage of patients achieving at least 30% of PI reduction versus baseline at 4, 6, and 8 
hours after the first dose 
• 
PGE of the study medication at 8 hours after the first dose 


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Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
• 
Time to RM (Minutes): Time elapsed between treatment administration and the first dose of 
RM from baseline till 8 hours after the first dose 
• 
Percentage of patients who required RM within the first 4, 6, or 8 hours post-dose. 
 
Multiple-dose phase 
• 
Pain Relief (PAR) scores at each prespecified time point 
• 
TOTPAR at 24, 48, 72, and 96 hours (TOTPAR24, TOTPAR48, TOTPAR72, TOTPAR96). 
• 
Percentage of maximum TOTPAR (% max TOTPAR) at 24, 48, 72, and 96 hours of the 
multiple-dose phase. 
• 
Percentage of patients achieving at least 50% of maximum TOTPAR at 24, 48, 72, and 96 
hours of the multiple-dose phase. 
• 
Pain Intensity (PI) scores at each prespecified time point over the multiple-dose phase. 
• 
SPID at 24, 48, 72, and 96 hours (SPID24, SPID48, SPID72, SPID96) of the multiple-dose 
phase. 
• 
Percentage of maximum SPID (% max SPID) at 24, 48, 72, and 96 hours of the multiple-dose 
phase. 
• 
Percentage of patients achieving at least 30% of PI reduction versus baseline at 24, 48, 72, 
and 96 hours of the multiple-dose phase. 
• 
PGE at 96 hours of the multiple-dose phase. 
• 
Percentage of patients who required RM within 24, 48, 72, and 96 hours of the multiple-dose 
phase. 
• 
Roland Morris Disability Questionnaire at 96 hours of the multiple-dose phase. 
• 
Treatment Satisfaction Questionnaire for Medication at 96 hours of the multiple-dose phase 
 
Complete treatment and assessment period (single and multiple-dose phase combined) 
• 
Time to first achieve an NRS score <4 or a pain intensity reduction ≥30% from the first drug 
intake till 5 days post-treatment, excluding patients assigned to placebo treatment arm 
during the single dose phase. 
• 
TOTPAR over 104 hours from the first drug intake till 5 days post-treatment (TOTPAR104), 
excluding patients assigned to placebo treatment arm during the single dose phase. 
• 
SPID over 104 hours from the first drug intake till 5 days post-treatment (SPID104), 
excluding patients assigned to placebo treatment arm during the single dose phase. 
• 
Time to RM: Time elapsed between the first drug intake till 5 days post-treatment, excluding 
patients assigned to placebo treatment arm during the single dose phase. 
 
The assessments performed after 15 minutes from the second dose at 8th hour will not be considered 


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Version Date:  
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for the single dose phase analysis, but for multiple dose phase. 
Multiple dose phase analysis will include only those assessments which are collected after the date 
and time of second dose of study medication. i.e., if a subject skipped the second dose at 8th hour and 
took the dose at 16th hour, then those assessments performed after the 16th hour will be considered 
for the analysis. In this case, assessments performed at t10h and t16h (if the assessment at t16h is 
before the time of second medication + 15 minutes) will be omitted. 
16.2.1. 
SECONDARY EFFICACY VARIABLES & DERIVATIONS 
16.2.1.1. 
Total Pain Relief (TOTPAR) 
TOTPAR is calculated as the time-weighted sum of the PAR-VRS scores.  
The general formula for calculating TOTPARx is as follows:  
TOTPAR4 
= ∑ [T(i) – T(i-1)] x PAR(i) for i = 15m, 30m, 1h, 1.5h, 2h, 4h 
TOTPAR6 
= ∑ [T(i) – T(i-1)] x PAR(i) for i = 15m, 30m, 1h, 1.5h, 2h, 4h, 6h 
TOTPAR8 
= ∑ [T(i) – T(i-1)] x PAR(i) for i = 15m, 30m, 1h, 1.5h, 2h, 4h, 6h, 8h  
TOTPAR24 
= ∑ [T(i) – T(i-1)] x PAR(i) for i = from 10h to 32h   
TOTPAR48 
= ∑ [T(i) – T(i-1)] x PAR(i) for i = from 10h to 56h  
TOTPAR72  
= ∑ [T(i) – T(i-1)] x PAR(i) for i = from 10h to 80h  
TOTPAR96  
= ∑ [T(i) – T(i-1)] x PAR(i) for i = from 10h to 104h  
TOTPAR104  = ∑ [T(i) – T(i-1)] x PAR(i) for i = 15m, 30m, 1h, 1.5h, 2h, 4h, 6h, 8h, 10h, …, 104h  
where T(i) is the scheduled time, T(0) = 0, PAR(i) = PAR at time i.  
 
Please note that starting from multiple phase values are collected before and two hours after each  
intake and that for the evaluation of TOTPAR104 patients taking Placebo during the single phase will 
be excluded. 
16.2.1.2. 
Percent (%) max TOTPAR 
The max TOTPAR is calculated as the theoretical maximum time-weighted sum of the PAR values  
for each patient. The maximum possible TOTPAR is the value of TOTPAR that would be obtained if  
the patient has a complete pain relief for that observation period (i.e., PAR at each post-baseline  
time point evaluated was 4).  
The general formula for calculating max TOTPARx is as follows:  
max TOTPAR4  
= 
∑ [T(i) – T(i-1)] x 4 for i = 15m, 30m, 1h, 1.5h, 2h, 4h  
max TOTPAR6  
= 
∑ [T(i) – T(i-1)] x 4 for i = 15m, 30m, 1h, 1.5h, 2h, 4h, 6h 


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Version Date:  
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
max TOTPAR8  
= 
∑ [T(i) – T(i-1)] x 4 for i = 15m, 30m, 1h, 1.5h, 2h, 4h, 6h, 8h  
max TOTPAR24 
= 
∑ [T(i) – T(i-1)] x 4 for i = from 10h to 32h 
max TOTPAR48 
= 
∑ [T(i) – T(i-1)] x 4 for i = from 10h to 56h 
max TOTPAR72 
= 
∑ [T(i) – T(i-1)] x 4 for i = from 10h to 80h 
max TOTPAR96 
= 
∑ [T(i) – T(i-1)] x 4 for i = from 10h to 104h  
max TOTPAR 104 
= 
∑ [T(i) – T(i-1)] x 4 for i = 15m, 30m, 1h, 1.5h, 2h, 4h, 6h, 8h, 10h, …, 
104h 
where T(i) is the scheduled time and T(0) = 0. 
 
The % max TOTPAR is the ratio between the TOTPAR of each patient and its theoretical maximum  
TOTPAR for a certain observation period. 
The general formula for calculating % max TOTPARx is as follows: 
% max TOTPAR4 
= 
TOTPAR4/ max TOTPAR4 
% max TOTPAR6 
= 
TOTPAR6/ max TOTPAR6 
% max TOTPAR8 
= 
TOTPAR8/ max TOTPAR8 
% max TOTPAR24 
= 
TOTPAR24/ max TOTPAR24 
% max TOTPAR48 
= 
TOTPAR48/ max TOTPAR48 
% max TOTPAR72 
= 
TOTPAR72/ max TOTPAR72 
% max TOTPAR96 
= 
TOTPAR96/ max TOTPAR96 
16.2.1.3. 
% max TOTPAR104 
= 
TOTPAR104/ max TOTPAR104Summed Pain 
Intensity Difference (SPID) 
SPID is calculated as the time-weighted sum of the pain intensity difference (PID) values, where  
PID is the difference in Pain Intensity calculated at each timepoint respect to the baseline value.  
The general formula for calculating SPIDx is as follows:  
SPID4   
= ∑ [T(i) – T(i-1)] x PID(i) for i = 15m, 30m, 1h, 1.5h, 2h, 4h 
SPID6   
= ∑ [T(i) – T(i-1)] x PID(i) for i = 15m, 30m, 1h, 1.5h, 2h, 4h, 6h 
SPID8   
= ∑ [T(i) – T(i-1)] x PID(i) for i = 15m, 30m, 1h, 1.5h, 2h, 4h, 6h, 8h  
SPID24  
= ∑ [T(i) – T(i-1)] x PID(i)   for i = from 10h to 32h  
SPID48  
= ∑ [T(i) – T(i-1)] x PID(i) for i = from 10h to 56h  
SPID72  
= ∑ [T(i) – T(i-1)] x PID(i) for i = from 10h to 80h  
SPID96  
= ∑ [T(i) – T(i-1)] x PID(i) for i = from 10h to 104h  
SPID104  
= ∑ [T(i) – T(i-1)] x PID(i) for i = 15m, 30m, 1h, 1.5h, 2h, 4h, 6h, 8h, 10h, …, 104h  
where T(i) is the scheduled time, T(0) = 0, PID(i) = PID at time i = PI (0) – PI (i).  
 


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Version Number: 
Final V1.0 
 
Version Date:  
[04Jul2022] 
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Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
Please note that starting from multiple phase values are collected before and two hours after each  
intake and that for the evaluation of SPID104 patients taking Placebo during the single phase will be 
excluded. 
16.2.1.4. 
Percent (%) max SPID 
The max SPID is calculated as the theoretical maximum time-weighted sum of the PID values for  
each patient. The maximum possible SPID is the value of SPID that would be obtained if the patient  
were pain free for that observation period (i.e., PI at each post-baseline time point evaluated was 0).  
 
The general formula for calculating max SPIDx is as follows: 
max SPID4 
= 
∑ [T(i) – T(i-1)] x PI(0) for i = 15m, 30m, 1h, 1.5h, 2h, 4h  
max SPID6 
= 
∑ [T(i) – T(i-1)] x PI(0) for i = 15m, 30m, 1h, 1.5h, 2h, 4h, 6h  
max SPID8 
= 
∑ [T(i) – T(i-1)] x PI(0) for i = 15m, 30m, 1h, 1.5h, 2h, 4h, 6h, 8h  
max SPID24 
= 
∑ [T(i) – T(i-1)] x PI(0) for i = from 10h to 32h 
max SPID48 
= 
∑ [T(i) – T(i-1)] x PI(0) for i = from 10h to 56h 
max SPID72 
= 
∑ [T(i) – T(i-1)] x PI(0) for i = from 10h to 80h 
max SPID96 
= 
∑ [T(i) – T(i-1)] x PI(0) for i = from 10h to 104h 
max SPID104 = 
∑ [T(i) – T(i-1)] x PI(0) for i = 15m, 30m, 1h, 1.5h, 2h, 4h, 6h, 8h, 10h, …, 104h 
where T(i) is the scheduled time, T(0) = 0.  
 
The % max SPID is the ratio between the SPID of each patient and its theoretical maximum SPID  
for a certain observation period. 
The general formula for calculating % max SPIDx is as follows: 
% max SPID4  
= 
SPID4/ max SPID4 
% max SPID6  
= 
SPID6/ max SPID6 
% max SPID8  
= 
SPID8/ max SPID8 
% max SPID24  
= 
SPID24/ max SPID24 
% max SPID48  
= 
SPID48/ max SPID48 
% max SPID72  
= 
SPID72/ maxSPID72 
% max SPID96  
= 
SPID96/ max SPID96 
% max SPID104 
= 
SPID104/ max SPID104 
 
All the parameters that use the data captured till 8 hours from the dosing start will be considered in 
the single dose phase. The assessment results that are collected within 8 hours but after 15 minutes 
from the second dose will not be used to derive the single dose phase parameters. For example, if a 
patient has pain relief (PAR) score at 8 hour after 15 minutes of second dose, then the PAR at t8 will 


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not be used to derive TOTPAR8. In such cases TOTPAR6 and TOTPAR8 will be same for that patient. 
16.2.2. 
MISSING DATA METHODS FOR SECONDARY EFFICACY VARIABLE(S) 
Handling of missing data need to follow as per section 7.3 
16.2.3. 
ANALYSIS OF SECONDARY EFFICACY VARIABLES 
16.2.3.1. 
PI-NRS, SPIDs, %max SPIDs, TOTPARs, %max TOTPARs and Roland Morris 
Disability Questionnaire (RMQ) 
A descriptive statistical summary will be provided for each of the endpoints. Additionally, these 
endpoints will be analysed using Analysis of Covariance (ANCOVA). For all the endpoints except RMQ 
will be analysed considering treatment and the baseline PI-NRS as covariates. 
RMQ will be analysed with Treatment and baseline RMQ score as covariates.  
 
LS means will be presented for each of the treatment groups. In addition, estimates of the treatment 
effect will be presented together with a one sided 95% CI for the difference and p-value for the test 
for significance of difference at 5% significance level. 
 
Additionally, percent improvement from Baseline in the Roland Morris Disability Questionnaire 
score will also be presented by treatment. Patients assigned to placebo treatment arm during the 
single dose phase will be excluded. Roland Morris Disability Questionnaire score is calculated from 
each fully completed questionnaire using proportional recalculation method. For example, if 17 
questions had been answered “Yes,” a raw sum score of 17 would be a proportional recalculated 
score of 71% if all 24 questions were answered (17/24 × 100). However, the raw sum score of 17 
would be proportionally recalculated to a score of 81% if 3 questions had not been answered (17/ 
(24–3) × 100).  
 
The below given endpoints with binary outcomes will be analysed using chi-square test at 5% 
significance level. Odds ratio will be presented together with a two-sided 95% CI for the difference 
and p-value for the test for significance of difference. An additional Cochran–Mantel–Haenszel (CMH) 
test will be performed by adjusting the covariates baseline PI categories and baseline radiculopathy 
categories. Odds ratio will be presented with two-sided 95% CI and p-value. 
- 
Percentage of patients achieving at least 50% of maximum TOTPAR at 4, 6, and 8 hours after 
the first dose 


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Version Number: 
Final V1.0 
 
Version Date:  
[04Jul2022] 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
- 
Percentage of patients achieving at least 30% of PI reduction versus baseline at 4, 6, and 8 
hours after the first dose 
- 
Percentage of patients achieving at least 50% of maximum TOTPAR at 24, 48, 72, and 96 
hours of the multiple-dose phase 
- 
Percentage of patients achieving at least 30% of PI reduction versus baseline at 24, 48, 72, 
and 96 hours of the multiple-dose phase 
- 
Percentage of patients who required RM within the first 4, 6, or 8 hours post-dose 
- 
Percentage of patients who required RM within 24, 48, 72, and 96 hours of the multiple-dose 
phase. 
16.2.3.2. 
PGE and PAR-VRS 
PGE (8h after the first dose, and at 96 hours of the multiple dose-phase) and PAR-VRS (at each time 
point separately) (ordinal variables) will be analysed by Wilcoxon rank-sum 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 probabilities 
are different.  
In an easy way the set of hypotheses can be summarized saying that under H0 the distributions of 
both treatment populations are equal against the alternative hypothesis that they are not. 
16.2.3.3. 
Time to first use of RM  
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 (Minutes) = trm – t0,  
trm is the time (hours and minutes) of RM intake 
 
 
 
t0 is the time (hours and minutes) of study drug intake 
 
In the case of no rescue medication intake, time to RM will be calculated as the time that occurred 
between t0 and the end of the time period of interest (8 hours after t0) and the relative patient will 
be considered as censored. 
 
Time to first use of RM will be assessed using Log-rank test. 
An additional CPH model will be performed with treatment, baseline PI categories and baseline 
radiculopathy categories as covariates/factors. 


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Hazard ratio ((DKP.TRIS/TRAM.HCl)/ TRAM.HCl) will be presented together with two-sided 95% CI 
and p-value for the test for significance of the difference at 5% significance level. 
 
Situation 
Censoring/Event Rule 
RM Intake at ti 
Event at ti 
Completed study without RM Intake 
Censor at timepoint of 8 hours 
16.2.3.4. 
Other Analysis 
A descriptive summary will be provided for the following endpoints, 
 
- 
Treatment Satisfaction Questionnaire for Medication at 96 hours of the multiple-dose phase 
- 
Time to first achieve an NRS score <4 or a pain intensity reduction ≥30% from the first drug 
intake till 5 days post-treatment, excluding patients assigned to placebo treatment arm 
during the single dose phase. 
- 
TOTPAR over 104 hours from the first drug intake till 5 days post-treatment (TOTPAR104), 
excluding patients assigned to placebo treatment arm during the single dose phase. 
- 
SPID over 104 hours from the first drug intake till 5 days post-treatment (SPID104), 
excluding patients assigned to placebo treatment arm during the single dose phase. 
- 
Time to RM (Minutes): Time elapsed between the first drug intake till 5 days post-treatment, 
excluding patients assigned to placebo treatment arm during the single dose phase. 
Censoring/Event rule is as follows: 
 
Situation 
Censoring/Event Rule 
RM Intake at ti 
Event at ti 
Completed study without RM Intake 
Censor at timepoint of 5 Days Post-Treatment 
Death 
Censor at Time of Death 
Early Discontinuation without taking RM 
Censor at Time of Discontinuation 
Early Discontinuation and later known to 
have a death 
Censor at Time of Discontinuation 
 
Non-inferiority of DKP.TRIS/TRAM.HCl versus TRAM.HCl will be tested with a one-sided significance 
level of 2.5%. Non-inferiority will be satisfied if the lower limit of the confidence interval is greater 
than a non-inferiority margin: 
- 
For Time to "event" variables, the non-inferiority margin will be 0.80, based on Hazard Ratio. 
- 
For continuous variables the non-inferiority margin will be 20% (0.20), based on the LS Mean 


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of treatment difference. 
- 
For binary variables the non-inferiority margin will be 0.80, based on the Odds Ratio. 
 
In case the non-inferiority is confirmed on PP population, the superiority of DKP.TRIS/TRAM.HCl 
versus TRAM.HCl will be also tested on mITT and ITT for all secondary endpoints. All the secondary 
endpoints related to the single phase will be also analysed for the superiority of DKP.TRIS/TRAM.HCl 
versus placebo. Non-inferiority will be tested on the PP population and in addition for the secondary 
endpoints of primary interest (TOPAR24, TOTPAR48) also on the mITT and ITT population. 
Superiority will only be tested on the mITT and ITT population, if non-inferiority is confirmed on the 
PP population. For continuous variables, superiority is achieved if the lower confidence interval for 
the LS Mean of treatment difference is greater than 0. For binary variables, if the lower confidence 
interval for the Odds ratio/Hazard ratio is greater than 1, then the superiority is achieved. 
16.3. 
EXPLORATORY EFFICACY  
16.3.1. 
EXPLORATORY EFFICACY VARIABLES & DERIVATIONS 
The exploratory efficacy variable is the Time to first achieve an NRS-PI score <4 and a pain intensity 
reduction ≥30% from drug intake till 8 hours post-treatment (single dose phase only) 
 
16.3.2. 
MISSING DATA METHODS FOR EXPLORATORY EFFICACY VARIABLE(S) 
No imputation will be performed for exploratory analysis 
16.3.3. 
ANALYSIS OF EXPLORATORY EFFICACY VARIABLES 
Follow the analysis of primary efficacy variable, section 16.1.3. Exploratory analysis will be 
performed on mITT, ITT, and PP population. 
17. QUALITY OF LIFE ANALYSIS  
Not Applicable 


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18. SAFETY OUTCOMES 
All outputs for safety outcomes will be based on the Safety Analysis Set.  
There will be no statistical comparisons between the treatment groups for safety data, unless 
otherwise specified with the relevant section.  
18.1. 
ADVERSE EVENTS 
Adverse Events (AEs) will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
central coding dictionary, Version 24.1 or latest. 
Treatment emergent adverse events (TEAEs) are defined as AEs that occurred or worsened in 
severity after the first administration of study treatment including follow-up [period between the 
last drug intake and the visit 2]. 
 
See Appendix 2 for handling of partial dates for AEs.  In the case where it is not possible to define an 
AE as treatment emergent or not, the AE will be classified by the worst case, i.e. treatment emergent.  
 
An overall summary of number of patients within each of the categories described in the sub-section 
below, will be provided as specified in the templates.  
Treatment emergent AEs will be summarized separately for single dose and multiple dose phases. 
All TEAEs which are started before the multiple dose phase will be summarized for single dose phase 
and those TEAEs started on or after the multiple dose phase will be summarized for multiple dose 
phase. 
TEAEs commencing on the multiple dose phase start date/time will be considered for the multiple 
dose phase summary, unless the start time of the TEAE is known to be prior to the multiple dose 
phase. 
Listings will include TEAEs and Non-TEAEs. 
18.1.1. 
ALL TEAES 
Incidence of TEAEs will be presented by System Organ Class (SOC) and Preferred Term (PT) and 
broken down further by maximum severity and relationship to study medication. 
18.1.1.1. 
Severity 
Severity is classed as mild/ moderate/ severe (increasing severity). TEAEs starting after the first 


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dose of study medication with a missing severity will be classified as severe. If a patient reports a 
TEAE more than once within that SOC/ PT, the AE with the worst-case severity will be used in the 
corresponding severity summaries. 
18.1.1.2. 
Relationship to Study Medication 
Relationship, as indicated by the Investigator, is classed as “Unrelated”, “Related” (increasing severity 
of relationship). A “Related” TEAE is defined as a TEAE with a relationship to study medication as 
“Certainly Related”, ”Probable Related”, ”Possibly Related” or “Un-assessable” to study medication. 
TEAEs with a missing relationship to study medication will be regarded as “Probably Related” to 
study medication. If a patient reports the same AE more than once within that SOC/ PT, the AE with 
the worst-case relationship to study medication will be used in the corresponding relationship 
summaries.  
18.1.2. 
TEAES LEADING TO DISCONTINUATION OF STUDY MEDICATION 
Treatment-emergent Adverse Events leading to discontinuation of study medication are those events 
recorded as ‘Drug Withdrawal’  for the ‘Actions taken with study drug treatment’ filed on the AE page 
of the eCRF. 
For TEAEs leading to discontinuation of study medication, summaries of incidence rates (frequencies 
and percentages) by SOC and PT will be prepared. 
18.1.3. 
SERIOUS ADVERSE EVENTS 
Serious adverse events (SAEs) are those events recorded as “Serious” on the Adverse Events page of 
the (e)CRF. A summary of serious TEAEs by SOC and PT will be prepared. 
18.1.4. 
ADVERSE EVENTS LEADING TO DEATH 
TEAEs leading to Death are those events which are recorded as “Fatal” on the Adverse Events page 
of the (e)CRF. A summary of TEAEs leading to death by SOC and PT will be prepared. 
18.2. 
LABORATORY EVALUATIONS 
Results from the central laboratory will be included in the reporting of this study for Hematology, 
Serum Chemistry, Coagulation test (only at Screening), Pregnancy test and Urinalysis. A list of 


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Version Date:  
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Effective Date: 02Dec2019 
 
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
laboratory assessments to be included in the outputs is included in the protocol, Section 10.2.  
 
The following summaries will be provided for chemistry, hematology, and Urinalysis data: 
• 
Actual and change from baseline by visit (for quantitative measurements) 
• 
Incidence of clinically significant abnormalities by visit 
• 
Shift from baseline according to normal range criteria (for quantitative 
measurements and categorical measurements) 
 
A by-patient listing of all laboratory data and pregnancy test data will be presented. 
18.2.1. 
LABORATORY REFERENCE RANGES  
Quantitative laboratory measurements will be compared with the relevant laboratory reference 
ranges in SI units and categorized as: 
• 
Low: Below the lower limit of the laboratory reference range.  
• 
Normal: Within the laboratory reference range (upper and lower limit included). 
• 
High: Above the upper limit of the laboratory reference range. 
18.3. 
VITAL SIGNS 
The following Vital Signs measurements will be reported for this study: 
• 
Systolic Blood Pressure (mmHg) 
• 
Diastolic Blood Pressure (mmHg) 
• 
Heart Rate (bpm) 
• 
Height (at Screening only) 
• 
Weight (at Screening only) 
 
Summary statistics for the absolute and change from baseline will be provided. Clinically significant 
abnormal findings in vital signs will be listed by treatment.  
18.4. 
PHYSICAL EXAMINATION  
The following Physical Examination measurements will be reported for this study as collected on the 
Physical Examination (PE) eCRF unless otherwise specified below: 
• 
General Appearance 


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Version Number: 
Final V1.0 
 
Version Date:  
[04Jul2022] 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
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proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
• 
Head eyes ears and nose 
• 
Mouth teeth and throat 
• 
Neck and thyroid 
• 
Chest 
• 
Heart 
• 
Abdomen 
• 
Dermatologic 
• 
Musculoskeletal 
• 
Circulatory 
• 
Neurologic 
• 
Lymphatic 
• 
Other system examined 
 
The listing of patients with clinically significant abnormal findings will be provided for physical 
examination data. 
19. DATA NOT SUMMARIZED OR PRESENTED 
The other variables and/or domains not summarized or presented are: 
• 
Comments 
These domains and/or variables will not be summarized or presented, but will be available in the 
clinical study database, SDTM and/or ADaM datasets. 


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Document: 
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Author: 
Aswin Nair 
Version Number: 
Final V1.0 
 
Version Date:  
[04Jul2022] 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
20. REFERENCES  
Dobson, A. J. (2002). An introduction to generalized linear models, 2nd ed. Chapman & Hall/CRC. 
EMA. (n.d.). Guideline on Missing Data in Confirmatory Clinical Trials. Retrieved December 15, 2011, from 
European Medicines Agency: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2010/09/WC500096793.pd
f 
Little, R., & Yau, L. (1996). Intent-to-Treat Analysis for Longitudinal Studies with Drop-Outs. Biometrics , vol 
52, 1324-1333. 
 
 
 
 
 
 


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Document: 
\\ieedc-vnasc01\BIOSdata\Menarini\Dexketoprofen\YYA36087\Biostatistics\Documentation\SAP 
Author: 
Aswin Nair 
Version Number: 
Final V1.0 
 
Version Date:  
[04Jul2022] 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
APPENDIX 1. PROGRAMMING CONVENTIONS FOR OUTPUTS 
IQVIA OUTPUT CONVENTIONS 
Outputs will be presented according to the following Global Bios > Processes > GBIOS Processes - 
Implementation Guidelines and Templates > General Guidelines and Templates > Output 
Conventions.   
DATES & TIMES 
Depending on data available, dates and times will take the form yyyy-mm-ddThh:mm:ss. 
 
SPELLING FORMAT 
English US.  
PRESENTATION OF TREATMENT GROUPS 
For outputs, treatment groups will be represented as follows and in the given order: 
Treatment Group 
For Tables, Listings and Graphs 
DKP.TRIS 25mg/TRAM. HCl 75 mg 
DKP.TRIS/TRAM.HCl 
TRAM.HCl 100 mg 
TRAM.HCl 
Placebo 
Placebo 
Or 
Placebo-DKP.TRIS/TRAM.HCl 
Or 
Placebo-TRAM.HCl 
PRESENTATION OF VISITS 
For outputs, visits will be represented as follows and in that order: 
Long Name (default) 
Short Name  
 Time 0 
t0 


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Author: 
Aswin Nair 
Version Number: 
Final V1.0 
 
Version Date:  
[04Jul2022] 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
Long Name (default) 
Short Name  
 Time 15 minutes 
t15m 
Time 30 minutes 
t30m 
Time 1 hour 
t1h 
… 
 
Time 8 hours 
t8h 
Time 16 hours 
t16h 
… 
… 
End of Study Visit  
EOS 
LISTINGS 
All listings will be ordered by the following (unless otherwise indicated in the template): 
• 
Randomized treatment group (or treatment received if it’s a safety output), first by active dose 
[by ascending dose group] and then control/ placebo  
• 
Center-patient ID,  
• 
Date (where applicable), 
• 
For listings where non-randomized patients are included, these will appear in a category after 
the randomized treatment groups labeled ‘Not Randomized’. 
 
TEXT CASE 
• 
For titles and column labels, capitalize important words, i.e. nouns, pronouns, verbs, adverbs and 
adjectives, but not articles, conjunctions or prepositions. 
• 
All Footnotes will be in sentence case format. 
• 
All symbols used in body of outputs will be footnoted. 
• 
For Continuous Variables the following statistics will be presented on the original scale: 
· 
Number (“n”) 
· 
Mean 
· 
Standard Deviation (“SD”) 
· 
Median 
· 
Minimum (“min”) 
· 
Maximum (“max”) 
• 
For Categorical Variables, for each category, the following statistics will be shown in a summary 
presentation: 


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Author: 
Aswin Nair 
Version Number: 
Final V1.0 
 
Version Date:  
[04Jul2022] 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
· 
Number (“n”)  
· 
Percentage (%)  
The percentage of patients in each category relative to the total number of patients in the relevant 
analysis population will be the default. Percentages relative to the total number of patients in the 
relevant analysis population with a non‐missing assessment will be specified in a programming note 
on the shell, if required.  
• 
Derived parameters (e.g. BMI) has to keep the result values with 1 decimal. 
• 
Where percentages are presented, a footnote is added to explain what the denominator of the 
percentage is, in the form “Percentages are calculated relative to the total number of patients in 
the safety population” as the first footnote. 
• 
All computed percentages are presented with one decimal place but 100% value, where no 
decimal places are presented. 
• 
Mean and median: 1 more than the number of decimal places allotted in the raw data received 
from data management. 
• 
SD: 2 more than the number of decimal places allotted in the raw data. 
• 
Minimum and maximum: equal to the number of decimal places allotted in the raw data. 
• 
95% CI: As for the mean percentages: will be reported to 1 decimal place. 
• 
Percentage is not presented for zero counts. 
• 
Statistical estimates (i.e. LS mean, Hazard ratio) will be reported in 2 decimal 
• 
P values will be reported in 3 decimal places. If p value is less than 0.001, display as “<0.001” 
 
 


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Document: 
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Author: 
Aswin Nair 
Version Number: 
Final V1.0 
 
Version Date:  
[04Jul2022] 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
• 
REFERENCE CODE 
▪ 
Primary Analysis of Primary Efficacy Variable(s) 
 
Ods output ParameterEstimates=est; 
proc phreg data=dataset_name;  
class treatment; 
model AVAL * CENSOR (1) = treatment baseline_PI_categories 
baseline_radiculopathy_categories/ rl=wald alpha=0.05 ties=exact; 
hazardratio trt; 
run; 
 
▪ 
Missing Data Methods for Primary Analysis of the Primary Efficacy Variable Using 
Multiple Imputation – Sensitivity Analysis 2 
 
a. Creation of monotone missing data structure: 
Intermediate (non-monotone) missing data (since some patients may have missing records in an 
intermediate timepoint; but then have data for subsequent assessment) will be multiply imputed 
using Markov chain Monte Carlo (MCMC) method and assuming MAR and multivariate normality. 
 
      The SAS procedure PROC MI with the MCMC option will be used. 
 
      proc mi data=xxx out=yyy nimpute=200 seed=1234 ; 
       
var treatment timepoints; 
       
mcmc chain=single nbiter=200 niter=100 impute=monotone; 
      run; 
 
b. Further Imputations: 
The dataset with monotone missing data will be imputed using regression model by 
considering the stratification factors and respective timepoints. 
 
       proc mi data=yy out=zz nimpute=1 seed=1234 ; 
var treatment timepoints baseline_PI_categories baseline_radiculopathy_categories 
baseline_Roland_Morris_disability_questionnaire; 
class treatment timepoints baseline_PI_categories baseline_radiculopathy_categories 
baseline_Roland_Morris_disability_questionnaire; 
        
monotone regression; 
       run; 
 
c. Once imputation is done, 
   Ods output ParameterEstimates=est; 
   Proc phreg data=zz;  


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Document: 
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Author: 
Aswin Nair 
Version Number: 
Final V1.0 
 
Version Date:  
[04Jul2022] 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
   
class _imputation_ treatment; 
   
model AVAL * CENSOR (1) = treatment baseline_PI_categories  
baseline_radiculopathy_categories baseline_Roland_Morris_disability_questionnaire/ 
rl=wald alpha=0.05 ties=exact; 
   
hazardratio trt; 
   run; 
 
d. The following SAS code will be used to combine the results: 
 
    proc mianalyze data=est; 
     
modeleffects ESTIMATE; 
   
stderr SE; 
    run; 
 
 
 


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Document: 
\\ieedc-vnasc01\BIOSdata\Menarini\Dexketoprofen\YYA36087\Biostatistics\Documentation\SAP 
Author: 
Aswin Nair 
Version Number: 
Final V1.0 
 
Version Date:  
[04Jul2022] 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
APPENDIX 2. PARTIAL DATE CONVENTIONS 
Imputed dates will NOT be presented in the listings. 
ALGORITHM FOR TREATMENT EMERGENCE OF ADVERSE EVENTS: 
START DATE 
STOP DATE 
ACTION 
Known 
Known/Partial/ 
Missing 
If start date < study med start date, then not TEAE 
If start date >= study med start date, then TEAE 
 
 
 
Partial, 
but 
known 
components show that it 
cannot be on or after 
study med start date 
Known/Partial/ 
Missing 
Not TEAE 
 
 
 
Partial, could be on or 
after study med start date 
OR Missing 
Known 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Partial 
Impute stop date as latest possible date (i.e. last day 
of month if day unknown or 31st December if day 
and month are unknown), then: 
If stop date < study med start date, then not TEAE 
If stop date >= study med start date, then TEAE 
 
Missing 
Assumed TEAE 
 
 
 
 
Note: Medical history and concomitant illness will follow the same derivations   


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Document: 
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Author: 
Aswin Nair 
Version Number: 
Final V1.0 
 
Version Date:  
[04Jul2022] 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
ALGORITHM FOR PRIOR / CONCOMITANT MEDICATIONS:  
START DATE 
STOP DATE 
ACTION 
Known 
Known 
If stop date < study med start date, assign as prior  
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant  
If stop date >= study med start date and start date > end of 
treatment, assign as post study  
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if 
day unknown or 31st December if day and month are unknown), 
then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant 
If stop date >= study med start date and start date > end of 
treatment, assign as post treatment 
 
Missing 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Partial 
Known 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown), then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant 
If stop date >= study med start date and start date > end of 
treatment, assign as post treatment 


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Document: 
\\ieedc-vnasc01\BIOSdata\Menarini\Dexketoprofen\YYA36087\Biostatistics\Documentation\SAP 
Author: 
Aswin Nair 
Version Number: 
Final V1.0 
 
Version Date:  
[04Jul2022] 
Template No.:  CS_TP_BS016 Revision 6 
Reference:  CS_WI_BS005 
Effective Date: 02Dec2019 
 
Copyright © 2009, 2010, 2012, 2016, 2018, 2019 IQVIA. All rights reserved. The contents of this document are confidential and 
proprietary to IQVIA Holdings Inc. and its subsidiaries. Unauthorized use, disclosure or reproduction is strictly prohibited. 
START DATE 
STOP DATE 
ACTION 
 
Partial 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown) and 
impute stop date as latest possible date (i.e. last day of month if 
day unknown or 31st December if day and month are unknown), 
then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date and start date <= end of 
treatment, assign as concomitant 
If stop date >= study med start date and start date > end of 
treatment, assign as post treatment 
 
Missing 
Impute start date as earliest possible date (i.e. first day of month if 
day unknown or 1st January if day and month are unknown), then: 
If stop date is missing could never be assumed a prior medication 
If start date <= end of treatment, assign as concomitant 
If start date > end of treatment, assign as post treatment 
 
 
 
Missing 
Known 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Partial 
Impute stop date as latest possible date (i.e. last day of month if 
day unknown or 31st December if day and month are unknown), 
then: 
If stop date < study med start date, assign as prior 
If stop date >= study med start date, assign as concomitant 
Cannot be assigned as ‘post treatment’ 
 
Missing 
Assign as concomitant 
 


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Browsers: 
  Internet Explorer (Windows Only) 8.0 or above – compatibility mode is 
supported only for 9.0 and above.  
  Windows Edge Current Version  
  Mozilla Firefox Current Version  
  Safari (Mac OS only) 6.2 or above  
  Google Chrome Current Version  
PDF Reader: 
Acrobat® or similar software may be required to view and print PDF files 
Screen Resolution: 
1024 x 768 Recommended  
Enabled Security 
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Allow per session cookies 
Mobile Signing: 
  Apple iOS 7.0 or above  
  Android 4.0 or above  
** These minimum requirements are subject to change. If these requirements change, we will 
provide you with an e-mail message at the e-mail address we have on file for you at the time the 
hardware and software requirements are revised.  
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Statistical Analysis Plan - 
SAP_Menarini_MEIN_18_DEX_LBP_001_Final_V01_04Jul2022 - 12-Jul-2022
Electronic Signature Manifestation 
This page is a manifestation of the electronic signature(s) used in compliance with the organization's 
electronic signature policies and procedures.
Page 67 - Object 1000551A00000000652AED50
Signer Full 
Name
Meaning of Signature
Date and Time
Aswin Nair
Document Approval (I certify that I have the 
education, training and experience to perform this 
task)
08 Jul 2022 
05:33:48 UTC
Jisho Jose
Document Approval (I certify that I have the 
education, training and experience to perform this 
task)
08 Jul 2022 
05:51:07 UTC
Irma Litton
Document Approval (I certify that I have the 
education, training and experience to perform this 
task)
08 Jul 2022 
07:45:52 UTC
Paolo 
Fabrizzi
Document Approval (I certify that I have the 
education, training and experience to perform this 
task)
12 Jul 2022 
09:24:40 UTC