Observational Study of Effectiveness and Safety of Add-on Milgamma® and Milgamma® Compositum Step-Therapy in Routine Practice of Management of Adult Patients With Acute Non-Specific Low Back Pain Receiving Modern NSAIDs
Conditions: Acute Non-specific Low Back Pain
Sponsor: Woerwag Pharma LLC

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OBSERVATIONAL STUDY OF EFFECTIVENESS AND 
SAFETY OF ADD-ON MILGAMMA® AND MILGAMMA® 
COMPOSITUM STEP-THERAPY IN ROUTINE PRACTICE 
OF MANAGEMENT OF ADULT PATIENTS WITH ACUTE 
NON-SPECIFIC LOW BACK PAIN RECEIVING MODERN 
NSAIDS 
 
Study ID: WP-RU-2018/1 
ClinicalTrials.gov ID (NCT number): NCT03892707 
 
Sponsor: 
Woerwag Pharma LLC  
 
 
STUDY TYPE: 
 
NIS 
DOCUMENT TYPE: 
VERSION: 
STUDY PROTOCOL (OBSERVATIONAL PLAN) 
1.0 
DATE: 
5 DECEMBER 2018 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Woerwag Pharma LLC 
 

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1 
 PROTOCOL APPROVAL AND SIGNATURES 
Study Protocol has been reviewed and approved by the company Woerwag Pharma LLC.  
I confirm that Protocol WP-RU-2018/1«Observational Study of Effectiveness and Safety of Add-on 
Milgamma® and  Milgamma® compositum Step-Therapy in Routine Practice of Management of Adult 
Patients With Acute Non-Specific Low Back Pain Receiving Modern NSAIDs» is created in accordance 
with the ethical principles that are consistent with the Declaration of Helsinki, in compliance with Good 
Pharmacoepidemiology Practices (GPP) and with other applicable legislation on Non-Interventional 
Studies and Russian regulatory requirements. 
 
 
Elena Troitskaya 
Medical manager (Woerwag Pharma LLC) 
 
 
 
 
   ____________________________ 
   Signature / Date 
 
 
 
Anna Shagako 
Clinical Trials Manager / Authorized Person of 
Pharmacovigilance (Woerwag Pharma LLC) 
 
 
 
   ____________________________ 
   Signature / Date 
 
 
 

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2 
 NATIONAL COORDINATOR SIGNATURE PAGE 
I have read and agree with this study protocol and will follow the described procedures. 
I agree to conduct the study according to the protocol in compliance with all applicable laws and 
regulations. 
 
 
 
Prof. V.A. Parfenov 
 
Head of Nervous Diseases and Neurosurgery 
Department of Medical Department of I.M. 
Sechenov 
First 
Moscow 
State 
Medical 
University 
 
 
 
 
   
_____________________________ 
   Signature / Date  
 

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3 
SCIENTIFIC CONSULTANT SIGNATURE PAGE 
I have read and agree with this study protocol and will follow the described procedures. 
I agree to conduct the study according to the protocol in compliance with all applicable laws and 
regulations. 
 
 
 
 
Prof. M.L.Kukushkin 
 
Head of the Laboratory of Fundamental and 
Applied Pain Studies, Scientific Research 
Institute 
of 
General 
Pathology 
and 
Pathophysiology 
 
 
 
 
   
_____________________________ 
   Signature / Date  
 
 

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4 
STUDY CONTACT LIST 
 
Sponsor:                             
Woerwag Pharma LLC 
Legal address:                     
Russia, 117587, Moscow, Varshavskoe shosse, 
125 ZH, bld.6. 
Mailing address:                   
Russia, 121170, Moscow, Poklonnaya str. 3, bld. 4, 
BC «Poklonka Place», 13th floor 
 
Office phone :                        
+7 (495) 382 85 56 
Office fax :                            
+7 (495) 382 28 01 
Internet : 
http ://www.woerwagpharma.ru 
 
Medical manager  
Elena Troitskaya 
Email: 
elena.Troitskaya@woerwagpharma.ru 
 
Clinical Trials Manager/ 
Authorized Person of 
Pharmacovigilance 
Anna Shagako 
Email : 
anna.Shagako@woerwagpharma.ru , adr@woerwagpharma.ru 
 
Contract Research Organization:   Almedis JSC 
Address: 
 
 
5, Malaya Pirogovskaya str., office 22 
119435, Moscow, Russia 
Office phone:  
            +7 495 937 43 18  
Office fax: 
 
            +7 495 937 43 19 
 
Project Manager: 
 
Elena Akimova  
Email:  
 
          
elena.akimova@almedis.ru 
 
Biostatistician:  
 
Kristina Bondareva  
Email:  
 
          
kristina.bondareva@almedis.ru 
 

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5 
TABLE OF CONTENTS 
1 
Protocol approval and signatures......................................................................................... 2 
2 
National Coordinator Signature page .................................................................................. 3 
3 
Scientific consultant signature page .................................................................................... 4 
4 
Study contact list ................................................................................................................. 5 
5 
Table of Contents ................................................................................................................ 6 
6 
List of abbreviations ............................................................................................................ 8 
7 
Synopsis ............................................................................................................................... 9 
8 
Introduction ....................................................................................................................... 14 
8.1 
Background ..................................................................................................... 14 
8.2 
Rationale ......................................................................................................... 17 
9 
Study Purpose and Objectives ........................................................................................... 17 
9.1 
Purpose ........................................................................................................... 17 
9.2 
Primary Objective ........................................................................................... 17 
9.3 
Secondary Objectives ..................................................................................... 17 
10 Investigational and Analysis Plan ..................................................................................... 18 
10.1 
Study Design and Plan .................................................................................... 18 
10.2 
Study Population ............................................................................................ 18 
10.2.1 
Inclusion criteria.................................................................................... 18 
10.2.2 
Exclusion criteria .................................................................................. 19 
10.2.3 
Site selection requirements ................................................................... 20 
10.3 
Study Duration ................................................................................................ 20 
10.4 
Study Conduct ................................................................................................ 20 
10.4.1 
Study procedures: .................................................................................. 22 
10.4.2 
Treatment .............................................................................................. 25 
10.5 
Study Assessments ......................................................................................... 26 
10.5.1 
Effectiveness ......................................................................................... 26 
10.5.2 
Patient treatment and satisfaction ......................................................... 27 
10.5.3 
Safety..................................................................................................... 27 
10.5.4 
Evaluation Criteria (Endpoints) ............................................................ 27 
10.5.4.1 Primary Endpoint: ................................................................................. 27 
10.5.4.2 Secondary Endpoints:............................................................................ 27 
11 Quality Management and Monitoring Procedures ............................................................ 28 
11.1 
Quality control ................................................................................................ 29 
11.1.1 
Monitoring ............................................................................................ 29 
11.1.2 
data quality control ................................................................................ 29 
11.2 
Quality Assurance .......................................................................................... 29 
11.2.1 
Audits .................................................................................................... 29 
11.2.2 
Training for Study staff ......................................................................... 30 

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12 Data Collection and Management ..................................................................................... 30 
13 Data Analysis Plans ........................................................................................................... 30 
13.1 
Definitions of Analysis Datasets .................................................................... 31 
13.2 
Effectiveness Analyses ................................................................................... 31 
13.3 
Safety .............................................................................................................. 32 
13.4 
Justification of Sample Size ........................................................................... 32 
13.5 
Other Analyses ............................................................................................... 33 
13.6 
Study limitations ............................................................................................. 33 
14 Collection and Reporting of Adverse Events/Adverse Drug Reactions and Quality 
Complaints ......................................................................................................................... 33 
14.1 
Definition of Adverse Drug Reaction and Other Safety Information ............ 34 
14.1.1 
Definition of Adverse Events (AE) ................................................................ 34 
14.1.2 
Adverse Drug Reaction (ADR) ...................................................................... 34 
14.1.3 
Serious Adverse Event (SAE) or Serious Adverse Drug Reaction (SADR) .. 34 
14.1.4 
Other Relevant Drug Safety Information ....................................................... 34 
14.2 
Collection of Adverse Drug Reactions during the Study ............................... 35 
14.3 
Reporting of ADRs, Other Safety Information and Quality Complaints ....... 35 
15 Adherence to Ethical, Regulatory, and Administrative Considerations ............................ 37 
15.1 
Regulatory and Ethical Compliance ............................................................... 37 
15.2 
Responsibilities of the Investigator and IEC .................................................. 37 
15.3 
Informed Consent ........................................................................................... 37 
15.4 
Publications and Other Rights ........................................................................ 38 
15.5 
Study Documents and Records Retention ...................................................... 38 
16 Investigators and Study Administrative Structure ............................................................. 38 
16.1 
Sponsor ........................................................................................................... 38 
16.2 
Investigators ................................................................................................... 38 
16.3 
Other Participants ........................................................................................... 39 
17 References ......................................................................................................................... 40 
Appendix 1 ............................................................................................................................... 44 
Appendix 2 ............................................................................................................................... 46 
Appendix 3 ............................................................................................................................... 47 

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6 
LIST OF ABBREVIATIONS 
 
Abbreviation or special term 
Explanation 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance 
COX 
Cyclooxygenase 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
GPP 
Good Pharmacoepidemiology Practices 
ICD-10 
International Classification of Diseases, 10th revision 
IEC 
Independent Ethics Committee 
INN 
International Nonproprietary Names  
LOCF 
Last Observation Carried Forward 
LBP 
Low back pain 
MedDRA             
Medical Dictionary for Regulatory Activities 
NIS 
Non-Interventional Study 
NRS 
Numerical Rating Scale 
NSAIDs 
Non-Steroidal Anti-Inflammatory Drugs 
NSLBP 
Non-specific low back pain 
RMQ 
Roland Morris questionnaire 
SADR 
Serious Adverse Drug Reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SmPC 
Summary of Product Characteristics 
VAS 
Visual Analogue Scale 
WhoDDE 
WHO Drug Dictionary Enhanced 

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7 
SYNOPSIS 
Study title 
Observational Study of Effectiveness and Safety of Add-on Milgamma® and Milgamma® compositum 
Step-Therapy in Routine Practice of Management of Adult Patients With Acute Non-Specific Low Back 
Pain Receiving Modern NSAIDs 
Sponsor 
Woerwag Pharma LLC 
National Coordinator  
Prof. V.A. Parfenov 
Deputy Investigator  
 
Study Site(s) 
Approx. 50 sites (neurologists in outpatient clinics, 1 medical 
physician = 1 site) 
Prior to the start of the study, neurologists (potential 
investigators) will be asked to fill out feasibility questionnaires 
to identify their individual routine practice regarding 
prescription or non-prescription of Milgamma® / Milgamma® 
compositum. Based on results of feasibility physicians will be 
divided to non-prescribers and prescribers of Milgamma® / 
Milgamma® compositum to the patients with acute non-
specific low back pain. In each medical institution, such non-
prescribers and prescribers will be proposed to participate in 
the study. Non-prescribers will be responsible for enrolling 
group (1) (NSAIDs alone), prescribers will be responsible for 
enrolling group (2) (NSAIDs + Milgamma® / Milgamma® 
compositum). 
Study Identification Code  
WP-RU-2018/1 
Study Phase 
Not applicable (NIS) 
Study Design 
Observational (non-interventional), multicentre, prospective 
Rationale 
There is still a lack of scientific and clinical data on 
neurotropic vitamins therapy in combination with modern 
NSAIDs (preferential/selective COX-2 inhibitors) in patients 
with non-specific back pain. Currently use of modern NSAIDs 
has been increased dramatically while traditional NSAIDs are 
decreasing. In previous clinical and observational studies on 
acute non-specific back pain only traditional NSAIDs were 
used. The current observational study will provide unique 
data on routine practices of management of adult patients 
with acute non-specific low back pain using modern NSAIDs 
in Russia and clinical use of Milgamma® and Milgamma® 
compositum step-therapy in Russian patients with acute low 
back pain receiving modern NSAIDs in a real life setting.  
This observational study will allow to clarify the effectiveness 
and safety of Milgamma® and Milgamma® compositum in 
Russian patients with acute low back pain. The study results 
can contribute to optimization of management and 
improvement of outcomes of this frequent disease by 
reducing use of NSAIDs that have many side effects. 
Indication/ Therapeutic Area 
Acute non-specific back pain / Neurology 
 
Investigational product  
 
 
Name of Investigational 
Product 
Milgamma® and Milgamma® compositum 
 
Active Ingredient(s) 
Millgamma®: Thiamin hydrochloride 100 mg, pyridoxine 
hydrochloride 100 mg, cyanocobalamin 1 mg, lidocaine 

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hydrochloride 20 mg  
Milgamma® compositum: benfotiamin 100 mg, pyridoxine 
hydrochloride 100 mg  
 
Dose and mode of 
administration 
5-10 Injections of Milgamma®, 2 mL injection solution, each. 
One injection per day, followed by oral administration of 
Milgamma® compositum, 1 tablet 3 times per day for 4 
weeks. Further continuation of treatment according to 
physician’s decision in accordance with the approved 
Instructions for Medicinal Use for Milgamma® and 
Milgamma® compositum. 
Milgamma® and Milgamma® compositum will be used in 
combination with modern NSAIDs (see comparator 
treatment), which will be prescribed in accordance with the 
instructions for medical use and the clinical practice of the 
physician.  
Comparator treatment (NIS)  
 
 
Name/ Descript. of reference 
Product (if applicable) 
Modern NSAIDs (preferential/selective COX-2 inhibitors): 
products with International Nonproprietary Names (INN) 
celecoxib, etoricoxib, meloxicam, nimesulide.  
 
Active Ingredient (if 
applicable) 
Please refer to the paragraph above. 
 
Dose and mode of 
administration 
NSAIDs will be prescribed in accordance with instruction for 
medical use and routine practice of the investigator. 
Duration of treatment 
Patients will be enrolled in one of the two groups depending 
on the prescribed therapy:  
(1) Modern NSAIDs (preferential/selective COX-2 inhibitors)  
(2) Modern NSAIDs (preferential/selective COX-2 inhibitors) + 
Milgamma® / Milgamma® compositum. 
Duration of treatment with NSAIDs will be defined in 
accordance with instructions for medical use and the clinical 
practice of the physician. 
For patients in treatment group (2) Milgamma® therapy will 
be lasted 5-10 days, Milgamma® compositum therapy 
approximately 4 weeks. 
Study period (clinical part) 
10 months 
Timing (Visits) 
Visit 1 (baseline), telephone/on-site visit 2 (after 5 days), visit 
3 (after 10 days) telephone/on-site visit 4 (after 24 days), 
telephone/on-site visit 5 (after 38 days), telephone/on-site 
visit 6 (after 52 days), telephone/on-site visit 7 (after 66 days), 
telephone/on-site visit 8 (after 80 days) and telephone/on-site 
visit 9 after 94 days 
Estimated Study Duration  
Q4 2018 to Q4 2019 
Study Population 
Adult out-patients with acute non-specific low back pain who 
have been prescribed (but have not started yet) therapy 
consisting of  
(1) modern NSAIDs 
(2) modern NSAIDs + Milgamma® / Milgamma® compositum  
 
 
Sample Size 
Approximately 500 patients within age group of 18-60 years 
(both inclusive). 
 
Inclusion Criteria 
1. Signed 
informed 
consent 
including 
data 
protection 
declaration according to the local legislation. 
2. Female and male outpatients aged 18-60 years (inclusive). 

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3. Acute non–specific low back pain less than 21 days (= 3 
weeks). 
4. Low back pain treatment with (1) modern NSAIDs 
(preferential/selective COX-2 inhibitors) or (2) modern 
NSAIDs 
(preferential/selective 
COX-2 
inhibitors) 
+ 
Milgamma®/ Milgamma® compositum prescribed (but not 
started yet) in frames of routine medical practice. 
5. Prescribed (but not started 
yet) step-therapy with 
Milgamma® to be followed by Milgamma® compositum in 
accordance with locally approved instruction for medical 
use (for the group planned to be treated with Milgamma®/ 
Milgamma® compositum step-therapy). 
6. Pain intensity according to Numerical Rating Scale (NRS) 
≥4 points ≤9 at the time of enrollment. 
7. In case of presence of previous episodes of acute non-
specific low back pain in medical history, the last one had 
resolved at least 30 days before the start of current 
episode. 
 
Exclusion Criteria 
 
1. Intolerance or hypersensitivity to the active ingredients or 
any excipient(s) of Milgamma®, Milgamma® compositum 
(for the group prescribed with Milgamma®/ Milgamma® 
compositum step-therapy) or other acute low back pain 
treatment received by patient. 
2. History or presence of any disease that, in the opinion of 
the investigator, might confound the results of the study, 
poses an additional risk to the subject during participation 
in the study or can change pain perception (examples of 
such possible conditions: any malignancy, stomach ulcer, 
duodenal ulcer, chronic heart failure, bronchial asthma, 
psychiatry disorders, epilepsy, Parkinson Disease etc). 
3. Spinal surgery/rehabilitation in the last 12 months. 
4. Acute back pain that is attributable to any known or 
suspected specific identifiable cause (e.g. discogenic 
radiculopathy, 
spondylolisthesis, 
osteomalacia, 
inflammatory arthritis, metabolic, neurological diseases or 
tumor). 
5. Severe scoliosis. 
6. Pregnancy, breast feeding.  
7. Severe conduction disturbances or acute decompensated 
cardiac insufficiency (for the group prescribed with 
Milgamma®/ Milgamma® compositum step-therapy). 
8. Use of anticoagulants with increased risk of bleeding 
and/or formation of hematoma after injection 
9. Use of NSAIDs or vitamins B within 2 months prior to 
enrollment into the study. 
10. Necessity to use myorelaxants or antidepressants for 
treatment of acute non-specific low back pain. 
11. Prior use of non-pharmacological treatment (physiotherapy, 
heat treatment (e.g. heat patch, hot water bottle) or 
topically applied medicinal products to the back area, 
procaine blocks) within the last 3 days before study entry. 
12. Participation in another clinical or observational study – 
currently or within 6 months prior to study entry. 
13. Legal incapacity and/or other circumstances rendering the 
patient unable to understand the nature, scope and 
possible impact of the study. 
14. Employees of the investigator or the institution who are 

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directly involved in the study or other studies under the 
direction of the investigator or his/her associates. 
Study Objectives  
 
 
Primary Objective 
Primary objective of the study is to assess the pain reduction 
in patients with acute non-specific low back pain receiving 
modern NSAIDs (preferential/selective COX-2 inhibitors) in 
combination with Milgamma®/ Milgamma® compositum step-
therapy in routine medical practice compared to patients 
receiving modern NSAIDs alone. 
 
Secondary Objective 
 
To assess pain related disability in patients with acute non-
specific low back pain in routine medical practice. 
 
To assess the safety of Milgamma®/ Milgamma® 
compositum step-therapy in patients with acute non-
specific low back pain in routine medical practice. 
 
To assess the patients’ prescribed and actual treatment 
with Milgamma®/ Milgamma® compositum step-therapy. 
 
To assess NSAIDs usage in patients receiving modern 
NSAIDs (preferential/selective COX-2 inhibitors) with and 
without Milgamma®/ Milgamma® compositum step-therapy 
in routine medical practice. 
 
To assess patients’ satisfaction with the treatment of acute 
non-specific low back pain in routine medical practice. 
 
To assess long-term effectiveness of Milgamma®/ 
Milgamma® compositum step-therapy 3 months after start 
of treatment in routine medical practice.  
Evaluation Criteria (Endpoints) 
All endpoints will be compared between therapeutic groups. 
 
Primary Endpoint 
Change of pain intensity measured on 0-10 points NRS scale 
from baseline to 10 days after the start of treatment.  
 
Secondary Endpoints 
Effectiveness endpoints: 
 
Change from baseline in pain intensity measured on 0-10 
points NRS scale at 5, 24 and 38 days after the start of 
treatment. 
 
Change from baseline in pain intensity measured on 0-10 
points NRS scale over time. 
 
Percentage of patients showing at least 30% relief with 
respect to pain intensity (as measured on 0-10 points NRS) 
at 5, 10, 24 and 38 days after the start of treatment. 
 
Change in pain-related disability, measured by Roland 
Morris disability questionnaire from baseline to 10 days 
after the start of treatment. 
 
Percentage of patients with at least one pain flare-up 
registered during 3 months after start of treatment. 
 
Percentage of patients with at least one pain flare-up 
resulting in consultancy with physician or professional 
management registered during 3 months after start of 
treatment. 
 
Percentage of patients with at least one pain flare-up 
resulting in disruption of daily activity registered during 3 
months after start of treatment. 
 
Percentage of patients with at least one pain flare-up 
resulting in NSAIDs intake registered during 3 months after 
start of treatment. 
 
Number of treatment days with NSAIDs 
 

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Patient treatment and patient satisfaction endpoints: 
 
Prescribed and actual number of Milgamma® injections (for 
the 
group 
treated 
with 
Milgamma®/ 
Milgamma® 
compositum step-therapy). 
 
Prescribed and actual number of treatment days with oral 
Milgamma® compositum (for the group treated with 
Milgamma®/ Milgamma® compositum step-therapy). 
 
Patient satisfaction with treatment using a 5-point verbal 
rating scale after 5, 10, 38 days and 3 months since the 
start of treatment. 
 
Number 
and 
percentage 
of 
patients 
prematurely 
discontinued 
prescribed 
therapy 
with 
Milgamma®/ 
Milgamma® compositum by reasons for discontinuation 
(for the group treated with Milgamma®/ Milgamma® 
compositum step-therapy). 
 
Reasons for early discontinuation of study participation.  
 
Safety endpoints 
 
Frequency and severity of ADRs during the study.  
 
Statistical Methods 
The between-group comparison on primary endpoint – 
change from baseline in pain intensity as measured on 0-10 
points NRS scale at 10 days after the start of treatment – as 
well as on changes from baseline in pain intensity at each 
individual time point and in pain-related disability at 10 days 
after the start of treatment (secondary endpoints) will be 
performed using analysis of covariance (ANCOVA) adjusting 
for baseline value of the corresponding parameter. Inclusion 
of center effect into the model will also be considered. The 
analysis of change in pain intensity over time will be 
performed, using linear mixed model repeated measures with 
a random effect for subject and fixed effect terms for 
treatment, visit, treatment-by-visit interaction and baseline 
pain intensity. The secondary endpoint – percentage of 
subjects showing at least 30% relief with respect to pain 
intensity – will be compared between groups using logistic 
regression with treatment group as fixed factor and baseline 
pain intensity as a covariate. Percentage of patients with at 
least one pain flare-up will be compared between groups 
using Fisher’s exact test. Number of days of treatment with 
NSAIDS will be compared between groups using Wilcoxon–
Mann–Whitney test.  
All comparisons will be conducted at the two-sided level of 
significance 5%. The results on the study endpoints will also 
be presented with two-sided 95% confidence intervals, where 
applicable. Descriptive summaries and listings will be 
provided for all collected data and derived parameters. 

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8 
INTRODUCTION 
8.1 
BACKGROUND 
Low back pain (LBP) is a pain in the lumbar or lumbosacral area. It takes the first place among all non-
infectious diseases according to the indicator reflecting the number of years of life lost due to persistent 
deterioration of health [1-3].  
Low back pain is defined as a pain localized between the twelfth pair of ribs and gluteal folds. Acute 
low back pain includes all episodes of pain with duration up to 4 weeks. If the pain persists from 4 to 12 
weeks, it is considered as subacute, and pain lasting 12 weeks and more - as chronic. [1, 4, 53] Relapse is 
defined for scenario when the pain occurs after at least 6 months of pain-free period. If the pain has 
resumed after a shorter period, its appearance is considered as an exacerbation of chronic back pain [1, 4, 
5]. 
LBP is one of the most common reasons for visiting the physician, about 6-9% of adults are consulted 
about this complaint during the year [6]. According to Global Burden of Disease 2010 Study LBP is the 
leading cause of activity limitation and work absence throughout much of the world, and disability-adjusted 
life years increased from 58.2 million in 1990 to 83.0 million in 2010 [17]. LBP occurs in the majority (more 
than 70%) of people during their life, the peak frequency of pain is observed for the age of 35-55 years [10]. 
According to epidemiological data, 18.3% of the population participated in the survey noted that back pain 
worries them currently, 30.8% reported that they experienced back pain within the last month, 38.9% – 
during the last year [11]. According to the survey conducted in Moscow outpatient settings in 2006, 24.9% 
of 1300 patients turned to the physician because of LBP, while more than half of the respondents (52.9%) 
were concerned about LBP during previous year [12]. In the UK, about 30% of visits to a general practitioner 
are related to the pain in back and limbs, and LBP is a reason for visiting a physician in about 7 million cases 
per year [13].  
In most patients, LBP regresses within 1-3 months, however, 60-80% of patients with acute pain 
periodically experience pain or discomfort during the next year, and among those who experienced 
disability due to pain, 40% notice repeated episodes of pain with disability [14]. Repeated exacerbations are 
developed in 24-80% of cases, the peak incidence hits in average age, the frequency of cases remains 
increased up to 60-65 years, then gradually decreases [11]. Observation of 973 patients with acute LBP 
showed that almost a third of them (28%) experienced repeated exacerbations during the next year [15]. In 
general, after an episode of acute LBP, it is continued or reoccurred during the year in one third of patients 
[1, 4, 5, 16].   
Low back pain is associated with enormous social and economic losses due to patients’ temporary 
disability [17-19]. In study published in 2016 pharmacoeconomic analysis revealed that total mean annual 
cost was found to be $6137.41 for NSAIDs per patient [9]. LBP is one of the most frequent causes of 
disability, it accounts for 10% of all cases of disability caused by various diseases [19].  
In most cases, the cause of acute LBP is a non-life-threatening disease (non-specific low back pain), 
but it is necessary to exclude serious underlying condition, such as infection, tumor, osteoporosis, 
ankylosing spondylitis etc. Despite of favorable prognosis of non-specific low back pain inadequate 
treatment of this disease worsens the prognosis, contributes to its chronicity and significantly reduces the 
patient's quality of life [1, 4, 20]. The recommendations of experts provide significant input in the 
management of patients with low back pain. One of the first was the Canadian recommendations proposed 
30 years ago and based on the results of 109 randomized trials [21]. Currently, several national and 
international guidelines for the management of patients with LBP have been developed, based on the 

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results of a large number of randomized trials (958 by April 2009) to assess the effectiveness of various 
methods of treatment of low back pain [22-37].  
The principles of medical care for patients with LBP vary depending on which specialist conducts the 
treatment. Patients often refer not only to general practitioners, but also to chiropractors, osteopaths, 
specialists in acupuncture etc. Some patients come to see neurologists, rheumatologists, orthopedists and 
neurosurgeons. According to a US study published in 2013, 40% of patients with low back pain refer to 
physical therapists (chiropractors), 34% to general practitioners, 8% to orthopedists and sports physicians, 
3% to neurologists, and 4% to emergency physicians [38]. Common treatment targets of acute non-specific 
LBP are reduction of pain, improvement of functional ability and prophylaxis of recurrence and chronicity. 
Important role in the management of patients with acute LBP belongs to non-drug methods. Active lifestyle 
and, if possible, keeping of routine daily activities is recommended for patients with acute nonspecific back 
pain. Long-term inactivity and disability worsen the prognosis for such patients. A meta-analysis of several 
studies has shown that active lifestyle in acute nonspecific back pain improves the course of the disease. [1, 
2, 22, 37]. It is also very important to inform the patients about the nature of the disease, its favorable 
prognosis and necessity to maintain physical activity. The educational programs for patients are considered 
as a component of patient management program despite the fact that it increases the cost of treatment it 
increases the cost of treatment [1, 4, 22]. 
In clinical practice non-steroidal anti-inflammatory drugs (NSAIDs) and myorelaxants are the most 
common method of pharmacotherapy in acute back pain, [1, 22, 32, 39].Non-steroidal anti-inflammatory 
drugs (NSAIDs) are a class of medicines used to treat inflammation, mild to moderate pain, and fever; they 
are among the most frequently prescribed drugs in modern medicine. Majority of NSAIDs work by inhibiting 
the activity of cyclooxygenase enzymes (COX-1 and/or COX-2), thus reducing the biosynthesis of 
prostaglandins, mediators of pain and inflammation. COX-1 is a constitutively expressed enzyme with a 
"house-keeping" role in regulating many normal physiological processes. One of these is in the stomach 
lining, where prostaglandins serve a protective role, preventing the stomach mucosa from being eroded by 
its own acid. COX-2 is expressed mostly in inflammation and inhibition of COX-2 produces the desirable 
effects of NSAIDs [40, 41]. Most NSAIDs act as nonselective inhibitors of the enzyme cyclooxygenase, 
inhibiting both the COX-1 and COX-2 isoenzymes. When nonselective COX-1/COX-2 inhibitors (such as 
aspirin, ibuprofen, and naproxen) lower stomach prostaglandin levels, ulcers of the stomach or duodenum 
internal bleeding can result. Most of modern NSAID (such as celecoxib, etoricoxib, meloxicam and 
nimesulide) are preferential or selective COX-2 inhibitors that do not cause gastrointestinal side effects 
characteristic of older NSAIDs. There is also concern about the cardiovascular safety of COX-2 inhibitors, 
while serious gastrointestinal adverse reactions are more closely linked to nonselective NSAIDs, although all 
NSAIDs have been associated with cardiovascular and gastrointestinal risks including stomach ulcers, 
constipation, diarrhea, nausea, liver and kidney lab. abnormalities, arterial hypertension, headaches, 
dizziness, leg swelling allergic reactions etc [40].   
Additionally, for many years vitamin B complex is used for the relief of acute local pain syndromes. B 
vitamins belong to the hydrosoluble group of vitamins, among their major representatives to manage pain 
there are vitamins B1 (thiamine), B6 (pyridoxine) and B12 (cyanocobalamin), which have high metabolic 
activity in the cells of both the central and peripheral nervous system [42]. Possible analgesic and anti-
neuralgic effects of vitamin B complex (especially vitamins B1 and B12) was shown in experimental animal 
studies: animal models demonstrated that B-vitamins have antinociceptive and anti-inflammatory 
properties in the rat tail pressure test, and are able to significantly decrease the responses evoked in spinal 
dorsal horn nociceptive neurons in the cat [42, 43].  
From a clinical standpoint, several studies have reported that thiamine, pyridoxine and 
cyanocobalamin have an important role for the adequate function of the myelin cover and other cell 
structures; it is essential for nutrition, axonal transport, neural excitability and neurotransmitter synthesis, 

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and combined with NSAIDs they present a synergic action in ostheomuscular diseases and pain 
management [42-44]. The results of clinical research applications of group B vitamins confirm, that vitamins 
B1, B6, B12 and containing them complex drugs have pronounced antinociceptive effect [42-46]. For example, 
the efficacy and safety of parenteral Vitamin B12 in alleviating low back pain and related disability and in 
decreasing the consumption of paracetamol was confirmed in patients with no signs of nutritional 
deficiency in a double-blind randomised, placebo-controlled study with participation of 60 patients aged 
between 18 and 65 years with lumbago or sciatic neuritis of mechanical origin [45]. Another clinical 
randomized, double-blind study included 187 patients that received diclofenac and vitamin B complex 
(thiamine, pyridoxine and cyanocobalamin twice a day and 185 patients that received diclofenac twice a 
day. It was demonstrated that combination of diclofenac/vitB complex was superior to diclofenac 
monotherapy for lower back pain relief after 3 days of treatment [46]. 
Milgamma® and Milgamma® compositum are vitamin B complexes available in a number of countries 
worldwide. Milgamma® is a solution for intramuscular injections, which allows to combine in one 
composition and stabilize vitamins B1, B6 and B12, which under normal conditions are mutually destructive. 
In addition, the composition includes a local anesthetic component, which makes the drug administration 
less painful and more convenient to use. One 2 ml ampule of Milgamma® contains the active ingredients 
which are the thiamin hydrochloride (vitamin B1) 100 mg, pyridoxine hydrochloride (vitamin B6) 100 mg, 
cyanocobalamin (vitamin B12) 1 mg and lidocaine hydrochloride 20 mg [47].  
 Milgamma® compositum is a tablet form of vitamin B complex. When used orally, not all of vitamins 
B, in particular thiamine (vitamins B1), have sufficient bioavailability, especially in the presence of 
concomitant gastrointestinal disorders [50, 53, 54]. This problem can be solved by using fat-soluble forms of 
medications. Milgamma® compositum contains two active substances: benfotiamin and pyridoxine. 
Benfotiamine is a lipophilic substance with a thiamine-like activity with a much higher bioavailability than 
genuine thiamine and it is well absorbed when administered orally [48, 53]. Pyridoxine (vitamins B6) 
participates in metabolism of proteins and fats. Both components of medicines potentiate effects of each 
other. One tablet of Milgamma® compositum contains pyridoxine hydrochloride (vitamin B6) 100 mg and 
benfotiamin 100 mg. [48].  
The numerous studies performed have shown the positive effect of Milgamma® and Milgamma® 
compositum on subjective and objective clinical parameters in patients with various nervous system lesions: 
alcoholic and diabetic polyneuropathy, trigeminal neuralgia, discogenic lumbosacral radiculopathy, etc. [50, 
52, 53, 54]. In particular, Milgamma® and Milgamma® compositum have an additional analgesic effect 
during standard analgesic therapy with various non-steroidal anti-inflammatory drugs. So the open 
controlled clinical study performed by prof. O. Levin evaluated the short-term and long-term effectiveness 
of a complex of B vitamins in 38 patients with vertebrogenic lumbosacral radiculopathy suffered from 
moderate or severe pain during 1 month or longer [49]. One group of patients was treated with diclofenac, 
and the other group with a combination of diclofenac and vitamin B complex (10 injections followed by oral 
administration for 2 weeks). A significant and moderate effect after 24 days of treatment with Milgamma® 
was observed in 66 % of patients, in the control group - in 34 % (р < 0,05). After 3 months of therapy pain 
was absent or minimal in 63% of patients of the main group and in 50% of patients of the control group (p < 
0.05). Another randomized open comparative study of efficacy of Milgamma®, diclofenac and their 
combinations for acute pain in the lower back was conducted by prof. A. Danilov: 90 patients with acute 
back pain were divided into 3 groups: the first group included 40 patients who received 2.0 ml of Milgamma 
injections for up to 10 days , the second group – 30 patients who took 75 mg diclofenac intramuscularly at 
per day for up to 10 days, the third group – 20 patients who received daily injections of Milgamma (2.0 ml) 
and diclofenac (75 mg). [51,52]. The effect of Milgamma® was comparable to diclofenac, which indicates 
that the combination of vitamin B complex in Milgamma® has an analgesic effect. Combination of diclofenac 
with Milgamma® was significantly more effective than monotherapy with diclofenac or a complex of 

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vitamins. More rapid and pronounced reduction of pain was shown in the first days of therapy, thus, the 
study confirms the effectiveness of the clinical application of Milgamma® in the treatment of acute back 
pain. Since therapy with NSAIDs in combination with B vitamins is more effective and rapid, Milgamma® and 
Milgamma® compositum step-therapy could be possibly reduce side effects of NSAIDs. 
8.2 
RATIONALE 
There is still a lack of scientific and clinical data on neurotropic vitamins therapy in combination with 
modern NSAIDs (preferential/selective COX-2 inhibitors) in patients with non-specific back pain. Currently 
use of modern NSAIDs has been increased while traditional NSAIDs are decreasing. In previous clinical and 
observational studies on acute non-specific back pain only traditional NSAIDs were used. The current 
observational study will provide unique data on routine practices of management of adult patients with 
acute non-specific low back pain using modern NSAIDs in Russia and clinical use of Milgamma® and 
Milgamma® compositum step-therapy in Russian patients with acute low back pain receiving modern 
NSAIDs in a real life setting.  
This observational study will allow to clarify the effectiveness and safety of Milgamma® and 
Milgamma® compositum in Russian patients with acute low back pain. The study results can contribute to 
optimization of management and improvement of outcomes of this frequent disease by achievement of 
maximal pain relief with reducing use of NSAIDs that have many side effects. 
9 
STUDY PURPOSE AND OBJECTIVES 
9.1 
PURPOSE 
The purpose of this observational study is to assess the effectiveness and safety of add-on 
Milgamma®/ Milgamma® compositum step-therapy in patients with acute non-specific low back pain 
receiving modern NSAIDs in routine medical practice.  
9.2 
PRIMARY OBJECTIVE 
Primary objective of the study is to assess the pain reduction in patients with acute non-specific low 
back pain receiving modern NSAIDs (preferential/selective COX-2 inhibitors) in combination with 
Milgamma®/ Milgamma® compositum step-therapy in routine medical practice compared to patients 
receiving modern NSAIDs alone. 
9.3 
SECONDARY OBJECTIVES 
 To assess pain related disability in patients with acute non-specific low back pain in routine medical 
practice. 
  To assess the safety of Milgamma®/ Milgamma® compositum step-therapy in patients with acute 
non-specific low back pain in routine medical practice. 
 To assess the patients’ prescribed and actual treatment with Milgamma®/ Milgamma® compositum 
step-therapy. 
 To assess NSAIDs usage in patients receiving modern NSAIDs (preferential/selective COX-2 
inhibitors) with and without Milgamma®/ Milgamma® compositum step-therapy in routine 
medical practice. 
 To assess patients’ satisfaction with the treatment of acute non-specific low back pain in routine 
medical practice. 

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 To assess long-term effectiveness of Milgamma®/ Milgamma® compositum step-therapy 3 months 
after start of treatment in routine medical practice. 
10 
INVESTIGATIONAL AND ANALYSIS PLAN 
10.1 
STUDY DESIGN AND PLAN 
This is a multi-centre observational (non-interventional) prospective study that is planned to be 
conducted to assess the effectiveness of neurotropic vitamins therapy with Milgamma®/ Milgamma® 
compositum in combination with modern NSAIDs (preferential/selective COX-2 inhibitors) in patients with 
non-specific back pain. Planned study duration is approximately 10 months (clinical part).  
Adult out-patients with acute non-specific low back pain who have been prescribed (but have not 
started yet) therapy consisting of (1) modern NSAIDs (preferential/selective COX-2 inhibitors) or (2) modern 
NSAIDs (preferential/selective COX-2 inhibitors) + Milgamma® / Milgamma® compositum will be enrolled in 
the study. Decision concerning prescribing certain treatment should be made by the treating physician prior 
to proposal to participate in the study and prior to informed consent signing.  
After enrollment in the study each patient will be observed over a period of approximately 94 days. 9 
visits/phone contacts are planned to be conducted during this period. Information about patient’s 
condition, pain intensity, pain flare-ups, satisfaction with the treatment, patient’s disability, therapy used 
for acute back pain treatment, data on safety will be collected during these visits. 
Patients will undergo clinical assessment and receive the standard medical care as usual determined 
by the treating physician based on clinical judgment and national recommendations. Patients will not 
receive experimental treatment as a consequence of their participation in the observational study. 
10.2 
STUDY POPULATION 
It is planned to enroll approximately 500 patients within age group of 18-60 years. 
Only patients, who provide written consent to participate in the study and have been informed by a 
physician on objectives and methods of this project, will be enrolled in the study. 
Each patient should meet all inclusion criteria and none of the exclusion criteria for this study. 
10.2.1 
INCLUSION CRITERIA 
1. Signed informed consent including data protection declaration according to the local 
legislation. 
2. Female and male outpatients aged 18-60 years (inclusive). 
3. Acute non–specific low back pain less than 21 days (= 3 weeks). 
4. Low back pain treatment with (1) modern NSAIDs (preferential/selective COX-2 inhibitors) or 
(2) modern NSAIDs (preferential/selective COX-2 inhibitors) + Milgamma®/ Milgamma® 
compositum prescribed (but not started yet) in frames of routine medical practice. 
5. Prescribed (but not started yet) step-therapy with Milgamma® to be followed by Milgamma® 
compositum in accordance with locally approved instruction for medical use (for the group 
planned to be treated with Milgamma®/ Milgamma® compositum step-therapy). 
6. Pain intensity according to Numerical Rating Scale (NRS) ≥4 points ≤9 at the time of 
enrollment. 

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7. In case of presence of previous episodes of acute non-specific low back pain in medical 
history, the last one had resolved at least 30 days before the start of current episode. 
 
10.2.2 
EXCLUSION CRITERIA 
1. Intolerance or hypersensitivity to the active ingredients or any excipient(s) of Milgamma®, 
Milgamma® compositum (for the group prescribed with Milgamma®/ Milgamma® 
compositum step-therapy) or other acute low back pain treatment received by patient. 
2. History or presence of any disease that, in the opinion of the investigator, might confound the 
results of the study, poses an additional risk to the subject during participation in the study or 
can change pain perception (examples of such possible conditions:  any malignancy, stomach 
ulcer, duodenal ulcer, chronic heart failure, bronchial asthma, psychiatry disorders, epilepsy, 
Parkinson Disease etc). 
3. Spinal surgery/rehabilitation in the last 12 months. 
4. Acute back pain that is attributable to any known or suspected specific identifiable cause (e.g. 
discogenic radiculopathy, spondylolisthesis, osteomalacia, inflammatory arthritis, metabolic, 
neurological diseases or tumor). 
5. Severe scoliosis. 
6. Pregnancy, breast feeding.  
7. Severe conduction disturbances or acute decompensated cardiac insufficiency (for the group 
prescribed with Milgamma®/ Milgamma® compositum step-therapy). 
8. Use of anticoagulants with increased risk of bleeding and/or formation of hematoma after 
injection. 
9. Use of NSAIDs or vitamins B within 2 months prior to enrollment into the study. 
10. Necessity to use myorelaxants or antidepressants for treatment of acute non-specific low 
back pain. 
11. Prior use of non-pharmacological treatment (physiotherapy, heat treatment (e.g. heat patch, 
hot water bottle) or topically applied medicinal products to the back area, procaine blocks 
within the last 3 days before study entry. 
12. Participation in another clinical or observational study – currently or within 6 months prior to 
study entry. 
13. Legal incapacity and/or other circumstances rendering the patient unable to understand the 
nature, scope and possible impact of the study. 
14. Employees of the investigator or the institution who are directly involved in the study or other 
studies under the direction of the investigator or his/her associates. 
Investigator(s) should keep the subject screening log of patients who entered screening. 
The Investigator(s) will obtain signed informed consent from the patient eligible for the current study 
before any study specific procedures are performed. The patient will be assigned a unique enrolment 
number. If the patient withdraws from participation in the study, then his/her enrolment number cannot be 
reused. 

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Patients who fail to meet the eligibility criteria should not, under any circumstances, be enrolled. 
10.2.3 
SITE SELECTION REQUIREMENTS 
Prior to the start of the study, neurologists (potential investigators) will be asked to fill out feasibility 
questionnaires to identify their individual routine practice regarding prescription or non-prescription of 
Milgamma® / Milgamma® compositum. Based on results of feasibility physicians will be divided to non-
prescribers and prescribers of Milgamma® / Milgamma® compositum to the patients with acute non-specific 
low back pain. In each medical institution, such non-prescribers and prescribers will be proposed to 
participate in the study. Non-prescribers will be responsible for enrolling group (1) (NSAIDs alone), 
prescribers will be responsible for enrolling group (2) (NSAIDs + Milgamma® / Milgamma® compositum). 
10.3 
STUDY DURATION 
Anticipated study duration is from Q4 2018 till Q4 2019. Period of clinical part of the study is planned 
to be approximately 10 months. 
10.4 
STUDY CONDUCT 
Flow chart of the study is shown in the Table 1. 
 

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TABLE 1 STUDY FLOW CHART 
Visits 
Visit 1 
Visit 2 (Phone 
call or on-site 
visit) 
Visit 3  
Visit 4 (Phone 
call or on-site 
visit) 
Visit 5 (Phone 
call or on-site 
visit) 
Visit 6 (Phone 
call or on-site 
visit) 
Visit 7 (Phone 
call or on-site 
visit) 
Visit 8 (Phone 
call or on-site 
visit) 
Visit 9 (Phone 
call or on-site 
visit) 
Days since the start of 
therapy  
Day 0 (Therapy is 
prescribed, but 
not started yet) 
Day 5 since 
the start of 
therapy 
Day 10 since 
the start of 
therapy 
Day 24 since 
the start of 
therapy 
Day 38 since 
the start of 
therapy 
Day 52 since 
the start of 
therapy 
Day 66 since 
the start of 
therapy 
Day 80 since 
the start of 
therapy 
Day 94 since 
the start of 
therapy 
Informed consent 
X 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
X 
 
 
 
 
 
 
 
 
Demographics 
and 
baseline characteristics 
X 
 
 
 
 
 
 
 
 
Medical History  
X 
 
 
 
 
 
 
 
 
Pain intensity – NRS 
(Numerical 
Rating 
Scale) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Pain-related 
disability 
(Roland Morris disability 
questionnaire) 
X 
 
X 
 
 
 
 
 
 
Presence of days with 
pain 
 
X 
X 
X 
X 
X 
X 
X 
X 
Pain flare-up1  
 
 
 
 
X 
X 
X 
X 
X 
Patient satisfaction with 
treatment (5-point verbal 
rating scale) 
 
X 
X 
X 
X 
 
 
 
X 
Details 
on 
LBP 
treatment 
with 
Milgamma®/ 
Milgamma® compositum 
(if applicable) 
Х 
X 
X 
X 
X 
X 
X 
X 
X 
Assessment 
of 
medication/ treatment of 
LBP including NSAIDs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
ADR assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
1 Pain flare-ups: reappearance of pain after pain-free period lasting approximately 4 weeks, including those resulting in consultancy with physician or professional management, 
resulting in disruption of daily activity and resulting in NSAIDs intake.

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10.4.1 
STUDY PROCEDURES: 
 
All procedures will be conducted in accordance with routine practice. 9 visits are planned to be 
conducted during the study. First and third visits will be conducted on-site (Visit 1 and Visit 3) and the rest 
can be performed as either phone calls or on-site visits. 
VISIT 1 
At Visit 1 the patient will sign informed consent form. After that the investigator can conduct all 
study-related activities. At the moment of Visit 1 treatment with NSAIDs or with NSAIDs + Milgamma® / 
Milgamma® compositum should have been prescribed, but not started yet. Following data will be collected 
at Visit 1: 
 Subject Information 
 ICF procedure 
 Check of inclusion/ exclusion criteria 
 Demographics and baseline characteristics (date of birth, sex, height, weight, body mass index). 
 Medical History: 
o Description of diagnosis of low back pain 
o Start date of current episode of acute non-specific low back pain. 
o Other existing clinically relevant conditions. 
 Prescribed therapy for back pain management: 
o Type of NSAIDs, other medicines (if applicable), doses, duration.  
o For patients prescribed with Milgamma® / Milgamma® compositum number of 
Milgamma® injections and number of treatment days with oral Milgamma® 
compositum should be indicated. 
o Further therapies prescribed/ received in the context of low back pain (e.g. cryo 
therapy, acupuncture, manual therapy etc.) 
 
Concomitant medication 
 Pain intensity using NRS. 
 Pain-related disability with Roland Morris disability questionnaire. 
 
VISIT 2 
Visit 2 can be conducted as either phone call or on-site visit at day 5 of therapy. Following data will be 
collected at Visit 2: 
 Pain intensity using NRS. 
 Presence of day(s) with pain since previous contact. 
 Patient’s satisfaction with the treatment using 5-point verbal rating scale (1= very dissatisfied, 2= 
dissatisfied, 3= neutral, 4= satisfied, 5= very satisfied). 

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 Therapy for back pain management: 
o Current treatment with NSAIDs, other medications (if applicable), doses, duration.  
o For patients prescribed with Milgamma® / Milgamma® compositum - current 
treatment with these products. 
o Concomitant non-drug treatment for low back pain management 
 Adverse drug reactions occurred since start of therapy. 
 
VISIT 3 
Visit 3 should be conducted at Day 10 from the start of therapy. Following data will be collected at 
Visit 3: 
 Pain intensity using NRS. 
 Presence of day(s) with pain since previous contact. 
 Pain-related disability with Roland Morris disability questionnaire. 
 Patient’s satisfaction with the treatment using 5-point verbal rating scale (1= very dissatisfied, 2= 
dissatisfied, 3= neutral, 4= satisfied, 5= very satisfied). 
 Therapy for back pain management: 
o Current treatment with NSAIDs, other medications (if applicable), doses, duration.  
o For patients prescribed with Milgamma® / Milgamma® compositum - current 
treatment with these products. 
o Concomitant non-drug treatment for low back pain management 
 Adverse drug reactions occurred since previous visit. 
 
VISIT 4 
The visit 4 will be conducted as either phone call or on-site visit at day 24 after start of therapy. 
Following information will be collected: 
 Pain intensity using NRS. 
 Presence of day(s) with pain since previous contact. 
 Patient’s satisfaction with the treatment using 5-point verbal rating scale (1= very dissatisfied, 2= 
dissatisfied, 3= neutral, 4= satisfied, 5= very satisfied). 
 Therapy for back pain management: 
o Current treatment with NSAIDs, other medications (if applicable), doses, duration.  
o For patients prescribed with Milgamma® / Milgamma® compositum - current 
treatment with these products.  
o Concomitant non-drug treatment for low back pain management 
 Adverse drug reactions occurred since previous visit. 

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VISIT 5 
Visit 5 should be conducted at day 38 after start of therapy as either phone call or on-site visit. It is 
anticipated that step-therapy with Milgamma®/ Milgamma® compositum will be completed by this time. 
Following data will be collected at Visit 5: 
 Pain intensity using NRS. 
 Presence of days with pain since previous contact. 
 Presence of new pain flare-up. 
o In case of presence of pain flare-up, assessment of: 
 
Whether pain flair-up resulted in consultancy with physician or professional 
management.  
 
Whether pain flair-up resulted in disruption of daily activity.  
 
Whether pain flair-up resulted in NSAIDs intake.  
 Patient’s satisfaction with the treatment using 5-point verbal rating scale (1= very dissatisfied, 2= 
dissatisfied, 3= neutral, 4= satisfied, 5= very satisfied). 
 Therapy for back pain management: 
o Current treatment with NSAIDs, other medications (if applicable), doses, duration.  
o For patients prescribed with Milgamma® / Milgamma® compositum - current 
treatment with these products. 
o Concomitant non-drug treatment for low back pain management 
 Adverse drug reactions occurred since previous visit. 
VISITS 6, 7, 8 
These visits will be conducted at day 52, 66 and 80 after start of therapy as either phone calls or on-
site visits. Following information will be collected on these visits: 
 Pain intensity using NRS. 
 Presence of days with pain since previous contact. 
 Presence of new pain flare-up. 
o In case of presence of pain flare-up, assessment of: 
 
Whether pain flair-up resulted in consultancy with physician or professional 
management. 
 
Whether pain flair-up resulted in disruption of daily activity. 
 
Whether pain flair-up resulted in NSAIDs intake.  
 Therapy for back pain management: 
o Current treatment with NSAIDs, other medications (if applicable), doses, duration.  
o For patients prescribed with Milgamma® / Milgamma® compositum - current 
treatment with these products. 

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o Concomitant non-drug treatment for low back pain management 
 Adverse drug reactions occurred since previous visit. 
VISIT 9/ EARLY DISCONTINUATION VISIT 
Visit 9/ early discontinuation can be conducted as either phone call or on-site visit after 3 months (day 
94) from start of therapy or in case of patient’s early discontinuation from the study. Following data will be 
collected: 
 Pain intensity using NRS. 
 Presence of days with pain since previous contact. 
 Presence of at least 1 pain-free period with approximately 4 weeks duration during the study. 
 Presence of new pain flare-up. 
o In case of presence of pain flare-up, assessment of: 
 
Whether pain flair-up resulted in consultancy with physician or professional 
management. 
 
Whether pain flair-up resulted in disruption of daily activity. 
 
Whether pain flair-up resulted in NSAIDs intake.  
 Patient’s satisfaction with the treatment using 5-point verbal rating scale (1= very dissatisfied, 2= 
dissatisfied, 3= neutral, 4= satisfied, 5= very satisfied). 
 Therapy for back pain management (if it is continued): 
o Current treatment with NSAIDs, other medicines (if applicable), doses, duration.  
o For patients prescribed with Milgamma® / Milgamma® compositum - current 
treatment with these products. 
o Concomitant non-drug treatment for low back pain management 
 Adverse drug reactions occurred since previous visit. 
 Study completion status and reason for early discontinuation, if applicable (patient lost to follow-
up, patient withdrew consent, administrative reasons, pain resolution, adverse event, death, 
other). 
 
10.4.2 
TREATMENT 
The responsibility for the treatment of each patient lies solely by the attending physician.  
Patients will be enrolled in one of the two groups depending on the prescribed therapy: 
1) 
Modern NSAIDs (preferential/selective COX-2 inhibitors); 
2)  
Modern NSAIDs (preferential/selective COX-2 inhibitors) + Milgamma® / Milgamma® 
compositum. 
Modern NSAIDs (preferential/selective COX-2 inhibitors): products with INN celecoxib, etoricoxib, 
meloxicam, nimesulide. NSAIDs will be prescribed in accordance with instruction for medical use and 
routine practice of the investigator. Dose and route of administration will be according to instruction for 
medical use. 

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Millgamma®: 2 mL injection solution containing thiamin hydrochloride 100 mg, pyridoxine 
hydrochloride 100 mg, cyanocobalamin 1 mg, lidocaine hydrochloride 20 mg. 
 Milgamma® compositum: 1 tablet containing benfotiamin 100 mg, pyridoxine hydrochloride 100 mg. 
Following doses and modes are used for Milgamma® / Milgamma® compositum in accordance with 
instruction for medical use: 
5-10 Injections of Milgamma®, 2 mL injection solution, each; 1 injection per day, followed by oral 
administration of Milgamma® compositum; 1 tablet 3 times per day for 4 weeks. Further continuation of 
treatment according to physician’s decision in accordance with the approved Instructions for Medicinal Use 
for Milgamma® and Milgamma® compositum. 
 
10.5 
STUDY ASSESSMENTS 
10.5.1 
EFFECTIVENESS 
Effectiveness assessments will be performed at visits 1-9 based on patient-reported outcome 
instrument for pain intensity, as measured on 0-10 point NRS (numeric rating scale). 
Numeric Rating scale is 11-step scale for assessment of pain intensity at the moment of patient’s 
examination, where 0=No pain and 10= Worst pain imaginable. The scale will be used in verbal 
communication, via the phone as well. The Investigator should ask the patient to assess pain intensity at the 
moment of examination by rating from 0 to 10, where 0 is “No pain” and 10 is “Worst pain imaginable”. The 
answer of patient should be fixed at source documents and in CRF [57]. 
Patients’ disability will be assessed at visits 1 and 3 on the basis of patient-reported outcome 
instrument Roland Morris disability questionnaire. This instrument has been translated into Russian and 
validated [55] (Appendix 1). Roland Morris questionnaire (RMQ) is a commonly used patient-reported 
outcome measure that assesses pain-related functional status; its measurement properties are consistent 
with or better than those of competing measures. The RMQ is a 24-item self-administered disability 
measure in which greater levels of disability are reflected by higher numbers on a 24-point scale. Items are 
scored 0 if left blank or 1 if endorsed, for a total RMQ score ranging from 0 to 24; higher scores represent 
higher levels of pain-related disability. The RMQ has been shown to yield reliable measurements, which are 
valid for inferring the level of disability, and to be sensitive to change over time for groups of patients with 
low back pain. The patient is instructed to put a mark next to each appropriate statement. Add up the total 
number of marked statements to get a patient’s score. [57, 58] 
Assessment of long-term efficacy will be conducted based on collection of episodes of pain flare-ups. 
Episode of pain flare-up will be defined as presence of at least 1 day with pain following a period without 
pain lasting at least 4 weeks. Description of pain flare-up is adapted from widely used definition of 
recurrence of pain episode according to which it should be preceded by at least 1 month of pain-free period 
[64,65,66]. Presence of pain flare-up will be determined by the investigator during conversation with the 
patient. Assessment of pain flare-ups will be started from visit 5 (day 38 of treatment) and will be conducted 
regularly in accordance with visit schedule. To judge whether pain flare-up occurred the investigator should 
1) consider data on patient’s assessment of pain intensity with NRS at current and previous visits, as well as 
information regarding presence of days with pain between visits, 2) determine as precisely as possible when 
was the last time the patient experienced pain and when the pain returned to decide whether the pain-free 
period was long enough to consider that a flare-up occurred. For collection of data on presence of day(s) 
with pain since previous contact, the investigator will ask the patient whether there was at least 1 day since 
previous contact when patient experienced pain (see Figure 1 below).  

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If a flare-up is identified the investigator will ask whether patient had consultancy with physician, at 
least 1 day unable to carry out usual daily activities (including work absence), or received NSAIDs (at least 1 
dose) because of low back pain since previous contact.  
 
A pain-free period of approximately 4 weeks or longer is considered sufficiently long for the assessment of pain flare-up 
FIGURE 1 PAIN FLARE-UP 
 
Number of treatment days with NSAIDs will be evaluated based on information on NSAIDs intake by 
the patient during the whole observational period. 
10.5.2 
PATIENT TREATMENT AND SATISFACTION 
Prescribed and actual number of Milgamma® injections and prescribed and actual number of 
treatment days with oral Milgamma® compositum will be assessed. Data on treatment with NSAIDs will be 
collected including trade name, formulation, dose, route of administration and duration.  
Patient satisfaction with the treatment will be estimated at Visits 2, 3, 5 and 9 using 5-point verbal 
rating scale (1= very dissatisfied, 2= dissatisfied, 3= neutral, 4= satisfied, 5= very satisfied). 
 
10.5.3 
SAFETY 
Safety assessment will be based on frequency and severity of ADRs recorded during the study.  
 
10.5.4 
EVALUATION CRITERIA (ENDPOINTS) 
All effectiveness endpoints will be compared between treatment groups.  
10.5.4.1 
PRIMARY ENDPOINT: 
 Change of pain intensity measured on 0-10 points NRS scale from baseline to 10 days after the start 
of treatment.  
10.5.4.2 
SECONDARY ENDPOINTS: 
EFFECTIVENESS ENDPOINTS 
 Change from baseline in pain intensity measured on 0-10 points NRS scale at 5, 24 and 38 days after 
the start of treatment. 

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 Change from baseline in pain intensity measured on 0-10 points NRS scale over time. 
 Percentage of patients showing at least 30% relief with respect to pain intensity (as measured on 0-
10 points NRS) at 5, 10, 24 and 38 days after the start of treatment. 
 Change in pain-related disability, measured by Roland Morris disability questionnaire from baseline 
to 10 days after the start of treatment. 
 Percentage of patients with at least one pain flare-up registered during 3 months after start of 
treatment. 
 Percentage of patients with at least one pain flare-up resulting in consultancy with physician or 
professional management registered during 3 months after start of treatment.  
 Percentage of patients with at least one pain flare-up resulting in disruption of daily activity 
registered during 3 months after start of treatment. 
 Percentage of patients with at least one pain flare-up resulting in NSAIDs intake registered during 3 
months after start of treatment. 
 Number of treatment days with NSAIDs 
 
PATIENT TREATMENT AND PATIENT SATISFACTION ENDPOINTS: 
 Prescribed and actual number of Milgamma® injections (for the group treated with Milgamma®/ 
Milgamma® compositum step-therapy). 
 Prescribed and actual number of treatment days with oral Milgamma® compositum (for the group 
treated with Milgamma®/ Milgamma® compositum step-therapy). 
 Patient satisfaction with treatment using a 5-point verbal rating scale after 5, 10, 38 days and 3 
months since the start of treatment. 
 Number and percentage of patients prematurely discontinued prescribed therapy with Milgamma®/ 
Milgamma® compositum by reasons for discontinuation (for the group treated with Milgamma®/ 
Milgamma® compositum step-therapy). 
 Reasons for early discontinuation of study participation. 
 
SAFETY ENDPOINTS 
 Frequency and severity of ADRs during the study. 
 
11 
QUALITY MANAGEMENT AND MONITORING PROCEDURES 
The sponsor should ensure that the study is conducted in accordance with the protocol and all 
applicable regulations (mentioned in relevant sections below).  

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11.1 
QUALITY CONTROL 
11.1.1 
MONITORING 
Frequency of monitoring visits, responsibilities and methods for monitoring will be described in detail 
a Monitoring Plan, which has to be finalized previously to study start. 
Before the study initiation, the assigned monitor will establish the adequacy of the facilities and the 
investigator’s capability to select the patients appropriately.  
“Green light” for study sites initiation will be given at the time point when all activities prior to study 
execution are complete and documented (including approval of Monitoring Plan, signing the contracts with 
sites and investigators, preparation of Trial Specific Trial Master File and Investigator File, accomplishment 
of all start-up project-related tasks).  
At the initiation visit, monitor will discuss with the investigators study protocol and CRF, as well their 
responsibilities with regards to protocol compliance. During the study clinical sites will be visited by the 
monitor on a sample basis to check the progress of enrolment, completeness and correctness of ICFs, the 
completeness of patient’ source documents, the accuracy of entries in the CRFs and the adherence to the 
protocol and all applicable regulatory requirements. Investigators and other study personnel must be 
available to assist a monitor during these visits.   
The investigator must maintain source documents, including all demographic and medical 
information, as well as the results of all assessments for each patient in the study. The investigator also has 
to keep signed copy of informed consent for each patient.  
The investigator agrees for conduction of regular visits to the site by authorized employees of the CRO 
and the Sponsor. The investigator must have sufficient time for the visit. The investigator must give a 
monitor, auditors, authorized employees from Woerwag Pharma, IECs and regulatory authorities (if 
required) access to all relevant source documents to confirm their consistency with the CRF data. Checks of 
the consistency of the source data with the CRFs will be performed according to the study-specific 
monitoring plan. No information in source documents about the identity of the patients will be disclosed.  
11.1.2 
DATA QUALITY CONTROL 
Collected data from the CRFs will be entered into specially designed study database using double data 
entry method and undergo electronic verification. The Data Management staff will check entered data for 
completeness and accuracy. The authorized Data Management personnel will enter detected errors or 
omissions on Data Query Forms, which will be returned to the participating physician for resolution. The 
signed and dated resolved Data Query Forms are sent to the company authorized by Woerwag Pharma for 
data correction and the copies kept by the participating physician. 
Detailed information on data management procedures and data quality check will be described in 
Data Management Plan.  
11.2 
QUALITY ASSURANCE 
11.2.1 
AUDITS 
Audits can be conducted during the study, as well as after its completion. Audits can be conducted in 
the clinical site or CRO. The investigator must give to auditors access to the Study-related documents and 
information. The Sponsor and any persons authorized to act on the Sponsor’s behalf for the purpose of 
audit will be given unhindered access to CRO premises and its Study-related documents and information.  

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Such documents and information shall include (without limitation) relevant materials and data, related to 
the Study, and documents describing personnel’s professional training and experience. 
11.2.2 
TRAINING FOR STUDY STAFF  
Training for investigators on study procedures will be conducted during Investigators meeting, on Site 
Initiation Visits and during the study if necessary. 
12 
DATA COLLECTION AND MANAGEMENT 
Each enrolled patient will be assigned with unique identification number (the last available from the 
pre-designed sequence). The individual Case Report Form (CRF), specially designed for this study, will be 
completed for each patient enrolled. 
The collection of data from out-patient medical records, as well as collection of data received by a 
physician during the routine patient examination will be performed. Any special data collection procedures 
are not stipulated within the framework of this study. All information received during the study period 
should be documented in out-patient medical records. The information necessary for CRF should be entered 
based on the patient source documents. Source documents are kept by physician. 
Data collection, data entry and management will be performed by the company authorized by 
Woerwag Pharma. 
The originals of completed CRFs will be sent on a regular basis, after approval by the monitor by the 
participating physicians to the company authorized by Woerwag Pharma. Copies of CRFs, as well as the 
original signed Informed Consents forms will be kept by the physician during the study and after the study 
completion during 5 years. 
Relevant drug therapy and concomitant therapy entered into the database will be coded based on 
WhoDDE current version. Medical history/current medical conditions and adverse dug reactions, as well as 
non-pharmacological therapy will be coded using current version of the Medical Dictionary for Regulatory 
Activities (MedDRA). Database will have to be completed, and then passed appropriate quality check, 
considered to be full and accurate, and then will be locked. Any changes after the database lock will be 
possible only with written permission of sponsor, project manager, statistician and data manager. Collected 
data will be analyzed. 
Essential study documents must be retained by the participating physician for 5 years. No source 
documents, containing patients’ personal data, should be taken away from the physician. 
Data Management processes will be defined in Data Management Plan. 
13 
DATA ANALYSIS PLANS 
A Statistical Analysis Plan (SAP) will be prepared as a separate document and will include a more 
technical and detailed description of the planned statistical analyses. 
All comparisons will be conducted at the two-sided level of significance 5%. Between-group 
comparisons of change from baseline in pain and disability will be performed using analysis of covariance in 
order to estimate treatment effect adjusted for baseline pain/disability. Inclusion of center effect into the 
model will also be considered. 

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Baseline value will be defined as measurement obtained at the initial visit (before start of therapy). 
Changes from baseline at each individual visit will be calculated as (post-baseline-baseline value).  
Baseline data as well as all data obtained during the observation period will be presented 
descriptively by group as follows: the number of observations, mean and standard deviation, median, first 
and third quartiles, minimum and maximum, lower 95% CI of mean and upper 95% CI of mean will be 
calculated for continuous variables, and the absolute frequencies and percentage of patients presenting the 
given feature will be calculated for qualitative variables. Baseline characteristics among groups will be 
compared using the Fisher’s exact test for binary variables and the Wilcoxon–Mann–Whitney test for 
continuous variables. 
The results on the study endpoints (by treatment group as well as difference between groups) will 
also be presented with two-sided 95% confidence intervals, where applicable. The results on effectiveness 
variables will be presented graphically. 
 For the primary analysis missing values of the primary variable will be imputed using the Last 
observation carried forward (LOCF) approach: if available, post-baseline observations obtained at Visit 2 
conducted at day 5 since the start of treatment will be used to impute missing values at Visit 3, day 10.  
Similar approach will be used for the primary analysis of change from baseline in pain intensity at day 
38 since the start of treatment. Supportive analysis will be conducted using complete case approach. 
13.1 
DEFINITIONS OF ANALYSIS DATASETS 
All Enrolled Set as all patients who signed informed consent for entry into the study. 
Full Analysis Set (FAS) will be defined as all patients who signed informed consent for entry into the 
study, started the study treatment, and provided baseline and at least one post-baseline assessment of at 
least one effectiveness parameter. FAS will be the primary population for the analysis of effectiveness. 
Valid Case Analysis Set will be defined as all FAS patients who are eligible (had no inclusion/exclusion 
criteria violations) and for whom the assessment of the primary efficacy variable is available. VCAS will be 
used for sensitivity analysis of the primary endpoint. 
Safety Population will be defined as all patients who signed informed consent for entry into the study 
and started the study treatment. Safety population will be used for the analysis of ADRs. 
13.2 
EFFECTIVENESS ANALYSES  
The between-group comparison on primary endpoint – change from baseline in pain intensity as 
measured on 0-10 points NRS scale at 10 days after the start of treatment – will be performed using analysis 
of covariance (ANCOVA). The difference between pain intensity at 10 days after the start of treatment and 
baseline (V3-V1) as response variable, treatment group as fixed factor and baseline pain intensity as a 
covariate will be included into the model. Similar ANCOVA models will be fitted for change from baseline in 
pain intensity at each individual time point (secondary endpoints). Mean change from baseline along with 
95% confidence interval estimated using the appropriate model will be presented by treatment group. 
Change from baseline in pain-related disability as measured by Roland Morris disability questionnaire 
at 10 days after the start of treatment will be compared between groups using analysis of covariance 
(ANCOVA) model with treatment group as fixed factor and baseline value on disability scale as a covariate. 
A mixed model repeated measures will be used to analyse change from baseline in pain intensity over 
time. The model will include a random effect for subject and fixed effect terms for treatment, visit, 
treatment-by-visit interaction, baseline pain intensity. An unstructured covariance structure will be used to 
model the within-subject errors. If this model fails to converge, other covariance structures will be tested. 

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The secondary endpoint – percentage of subjects showing at least 30% relief with respect to pain 
intensity – will be compared between groups using logistic regression with treatment group as fixed factor 
and baseline pain intensity as a covariate. Treatment effect will be tested using the corresponding p-value 
and odds ratios will be presented with 95% confidence intervals.  
Percentage of patients with at least one pain flare-up and at least one pain flare-up resulting in 
consultancy with physician, resulting in disruption of daily activity, resulting in NSAIDs intake among 
patients who had a sufficiently long pain-free period allowing for such assessment will be compared 
between groups using Fisher’s exact test. 
Number of days of treatment with NSAIDS will be compared between groups using Wilcoxon–Mann–
Whitney test.  
 
13.3 
SAFETY 
Safety assessment will be based on the analysis of adverse drug reactions (ADRs) frequency and 
severity. Adverse drug reactions will be coded with the current version of Medical Dictionary for Regulatory 
Activities. ADRs will be presented by the total number (percent) of patients with ADRs by treatment group, 
by each system organ class and by each preferred term within a system organ class. ADRs will also be 
presented by maximum severity grade. Safety analyses will be performed on the Safety Population. 
 
13.4 
JUSTIFICATION OF SAMPLE SIZE 
Since the superiority of one treatment over the other is investigated and taking into consideration 
that smaller negative values of the primary variable correspond to the greater reduction of pain in 
comparison to baseline, the statistical hypotheses for this study are formulated as follows:  
Null hypothesis (H0):  
H0: μ2 – μ1 ≥ 0 
Alternative hypothesis (HA):  
HA: μ2 – μ1 < 0, where μ1 и μ2 are the true mean changes from baseline in pain intensity for (1) modern 
NSAIDs (preferential/selective COX-2 inhibitors) therapy and for (2) modern NSAIDs (preferential/selective 
COX-2 inhibitors) + Milgamma® / Milgamma® compositum therapy, correspondingly. 
A between-group difference of 10 points (on a 0–100 scale) for pain is generally considered as the 
smallest clinically important effect (compared with placebo) [40,56]. However, it is well known that therapy 
of low back pain with NSAIDs rarely reaches this threshold. The recent meta-analyses [40] estimated the 
effect of NSAIDs relative to placebo in treatment of acute non-specific low back pain in the immediate (<2 
weeks) term as −6.4 points mean difference, 95% CI −10.3 to −2.5, on 100 mm VAS scale. Therefore, 0.5 
points difference is chosen to be detected in the current study as half of the 1 point difference 
conventionally considered as clinically significant in placebo-controlled studies. It is considered attainable in 
the current study based on results of DOLOR clinical trial [46] which showed 3.8 difference (24,5 ± 18,0 vs. 
20,7 ± 18,0) on 100 mm VAS scale between combined treatment with NSAIDs and vitamins B and NSAIDs 
alone after 3 days of treatment. It is expected that the difference after 10 days of treatment will be at least 
0.5 points on 0-10 NRS scale. Such assumptions are also sustained by the results of randomized open-label 
comparative study of efficacy of Milgamma, diclofenac and their combination for acute lower back pain 

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[51,52] in which the difference between groups was 0.38 after 3 days of treatment and reached 1.17 points 
after 10 days of treatment. 
The sample size of 227 patients per group will provide at least 80% power to detect 0.5 points 
difference between groups on 0-10 points NRS scale as statistically significant, assuming a standard 
deviation (SD) of 1.9. The SD for change from baseline at day 10 is conservatively estimated based on the 
results of the study of efficacy of Milgamma, diclofenac and their combination for acute lower back pain 
[51,52] as common standard deviation for pain intensity values at day 10 in the two groups of interest (1.36) 
multiplied by 
2 [63]. This is also in line with the DOLOR study [46] in which the SD of changes from 
baseline was 18 points on 100 mm VAS scale in both groups. 
In order to account for drop-out rate of approximately 10%, it is planned to include 250 patients in 
each treatment group. 
13.5 
OTHER ANALYSES  
Patient satisfaction with treatment will be presented descriptively by treatment group as percentage 
of patients in each category and, additionally, as a continuous variable measured on a Likert-like scale. The 
comparisons between groups will be performed by means of Wilcoxon–Mann–Whitney test for continuous 
variable. 
Data on prescribed and actual number of Milgamma® injections and number of treatment days with 
oral Milgamma® compositum will be summarized descriptively. 
 
13.6 
STUDY LIMITATIONS 
Like any other non-interventional study, this study has some limitations. One of the most important 
limitations is the lack of randomization which might lead to selection bias. The comparability between 
groups at baseline with respect to the most important demographic and anamnestic characteristics will be 
assessed and will be discussed in the final report. The second limitation is related to variety of back pain 
management approaches by different physicians due to lack of national clinical guidelines on this condition. 
Another limitation is that in routine practice therapy with Milgamma® / Milgamma® compositum is usually 
prescribed to patients with a more pronounced neuropathic component of pain syndrome compared to 
patients prescribed NSAIDs monotherapy. Next limitation is different duration of therapy for each patient. 
All assessments will be done at fixed time points from the start of therapy and will be interpreted 
accordingly. To reduce the risk of patients’ drop-out during the study, all visits except Visits 1 and 3 can be 
conducted as phone calls.  
14 
COLLECTION AND REPORTING OF ADVERSE EVENTS/ADVERSE DRUG 
REACTIONS AND QUALITY COMPLAINTS 
To allow continuous monitoring of product safety, all ADRs and other safety information as defined 
below have to be documented by the investigator and reported to the sponsor. 

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14.1 
DEFINITION OF ADVERSE DRUG REACTION AND OTHER SAFETY INFORMATION 
14.1.1 
DEFINITION OF ADVERSE EVENTS (AE) 
An Adverse Event (AE) is any untoward medical occurrence in a patient or clinical study subject 
administered a medicinal product and which does not necessarily have a causal relationship with this 
treatment. An adverse event can therefore be any unfavorable and unintended sign (e.g. an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal product, 
whether or not considered related to the medicinal product. 
14.1.2 
ADVERSE DRUG REACTION (ADR) 
An Adverse Drug Reaction (ADR) is an Adverse Event suspected to be causally related to the medicinal 
product. 
An ADR is a response to a medicinal product which is noxious and unintended. Adverse reactions may 
arise from use of the product within or outside the terms of the marketing authorization or from 
occupational exposure. Conditions of use outside the marketing authorisation include off-label use, 
overdose, misuse, abuse, and medication errors. 
14.1.3 
SERIOUS ADVERSE EVENT (SAE) OR SERIOUS ADVERSE DRUG 
REACTION (SADR) 
An AE or ADR that fulfils at least one of the following criteria: 
 
Results in death 
 
Is life-threatening (this implies that the patient was at risk of death at the time of the event; it 
does not refer to a reaction that hypothetically might have caused death if more severe) 
 
Requires in-patient hospitalisation or prolongation of existing in-patient hospitalisation 
 
Results in persistent or significant disability/incapacity 
 
Is a congenital anomaly/birth defect 
 
Is a medically important event that may jeopardise the subject or may require intervention to 
prevent one of the outcomes listed above (e.g. suspected transmission via a medicinal product 
of an infectious agent, thromboembolic events, or other reactions that should be reported in an 
expedited manner although they did not immediately result in one of the above seriousness 
criteria, e.g., intensive treatment in an emergency room or at home for allergic bronchospasm, 
blood dyscrasias or convulsions that do not result in hospitalisation or development of 
dependency or abuse). Medical and scientific judgement should be exercised in deciding 
whether other situations should be considered. 
14.1.4 
OTHER RELEVANT DRUG SAFETY INFORMATION 
Any safety information relating to: 
 
Pregnancies/breastfeeding. 
 
Drug abuse (persistent, sporadic or intentional excessive use of a medicinal product inconsistent 
with the SmPC or acceptable medical practice which is accompanied by harmful physical or 
psychological effects). 

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 
Misuse (situations where the medicinal product is intentionally and inappropriately used not in 
accordance with the authorised product information) 
 
Overdose (administration of a quantity of a medicinal product given per administration or 
cumulatively which is above the maximum recommended dose according to the authorised 
product information. Clinical judgment should always be applied) 
 
Medication errors (an unintended failure in the drug treatment process that leads to, or has the 
potential to lead to, harm to the patient). 
 
Interactions with other medicinal products or devices. 
 
Occupational exposure (an exposure to a medicinal product as a result of one’s professional or 
non-professional occupation). 
 
Off-label use (situations where a medicinal product is intentionally used for a medical purpose 
not in accordance with the authorized product information). 
 
Lack of effectiveness. 
 
that is associated with Milgamma® or Milgamma® compositum, even if no ADRs occurred.  
14.2 
COLLECTION OF ADVERSE DRUG REACTIONS DURING THE STUDY 
Every patient must be examined by the investigator regarding appearance of adverse drug reactions, 
which should be classified in accordance with their connection with the medicinal product(s) used for LBP 
treatment. During the Study ADRs (both non-serious and serious) are actively collected if an Investigator 
suspects that they can be causally related to the medicinal product used for LBP treatment under study. For 
each ADR the following variables will be collected; 
 Description of ADR  
 ADR start date and end date (if applicable) 
 ADR severity (mild, moderate, severe) (see details in Appendix 3) 
 ADR seriousness (whether an ADR is serious or not) 
 Medicinal product which is suspected to have casual relationship with an ADR, including start and 
stop dates of medicinal product administration.  
 Action taken with regard to a suspected medicinal product 
 Outcome of ADR 
All ADRs will be recorded by the Investigator in CRF. Each month safety information collected in 
database will be provided to the Sponsor by Data Manager of CRO ALMEDIS. 
 
14.3 
REPORTING OF ADRS, OTHER SAFETY INFORMATION AND QUALITY COMPLAINTS 
All suspected ADRs, other safety information and quality complaints associated with the 
administration of Milgamma® or Milgamma® compositum (or any other Woerwag Pharma product, if 
applicable) have to be reported to Woerwag Pharma LLC: 

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Contacts: 
Anna Shagako, Clinical Trials Manager / Authorized Person of Pharmacovigilance 
Phone:  
+7 495 269 69 20 ext. 116 
Cell:  
 
+7 985 233 32 46 
 
Denis Zhivotov, Head of Regulatory Department / Deputy Authorized Person of Pharmacovigilance 
Phone:  
+7 495 269 69 20 ext. 117 
Cell:  
 
+7 985 179 20 04 
E-mail: adr@woerwagpharma.ru 
 
SADRs including safety information as in Section 13.1.4 associated with SADR have to be reported by 
an 
Investigator 
using 
special 
form 
provided 
by 
the 
Sponsor 
immediately 
by 
email 
(adr@woerwagpharma.ru, within 24 hours). Non-serious ADRs and other safety information should be 
reported to the sponsor via completion of corresponding CRF form, which will be periodically collected by a 
CRO or Woerwag Pharma representatives. Each month safety information collected in database will be 
provided to the Sponsor by Data Manager of CRO ALMEDIS. 
Patients should be asked to immediately inform an Investigator of any AEs or other relevant safety 
information. An Investigator has to report ADRs and other relevant drug safety information to the sponsor. 
For more information about possible ADRs and other safety information, please refer to the local 
SmPC (see Appendix 2 to the Study Protocol). 
Safety events which are suspected to be related to other medicinal products used for LBP treatment 
should be reported by the investigator to the responsible marketing authorization holder in frames of 
spontaneous reporting as required by Guidelines for Good Pharmacovigilance Practices of Eurasian 
Economic Commission and order of the Federal Service for pharmacovigilance dated February 15, 2017 No. 
1071 [61, 62]. 
The local Woerwag Pharma pharmacovigilance team is responsible to inform the Global Woerwag 
Pharma Pharmacovigilance Department (dso@woerwagpharma.com) within the below defined timelines: 
SADRs including safety information as in 13.1.4 associated with SADR as soon as possible, but no later than 
5 (five) calendar days. If there is a potential fatal or life threatening ADR Global Woerwag Pharma 
Pharmacovigilance Department must be informed within 24 hours. 
The local Woerwag Pharma pharmacovigilance team is also responsible to inform the Russian Health 
Authorities on SADRs in accordance with Guidelines for Good Pharmacovigilance Practices of Eurasian 
Economic Commission and order of the Federal Service for pharmacovigilance dated February 15, 2017 No. 
1071 [61, 62]:  
 
Within 15 calendar days - for SADRs including cases of transmission of infectious disease, cases of 
drug abuse, cases of deliberate overdose,  
 
Within 3 days - for fatal and life-threatening SADRs.  

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15 
ADHERENCE TO ETHICAL, REGULATORY, AND ADMINISTRATIVE 
CONSIDERATIONS 
15.1 
REGULATORY AND ETHICAL COMPLIANCE 
This study is a non-interventional study where the medicinal product(s) is (are) prescribed in the usual 
manner in accordance with the terms of the marketing authorisation. The assignment of the patient to a 
particular therapeutic strategy is not decided in advance by a study protocol but falls within current practice 
and the prescription of the medicine is clearly separated from the decision to include the patient in the 
study. No additional diagnostic or monitoring procedures shall be applied to the patients and 
epidemiological methods shall be used for the analysis of collected data [59]. This observational study was 
designed and will be performed in accordance with ethical principles that are consistent with the 
Declaration of Helsinki, in compliance with Good Pharmacoepidemiology Practices (GPP) and with other 
applicable legislation on Non-Interventional Studies. The study also will be carried out in keeping with 
applicable Russian regulatory requirements [60, 61, 62].  
Before implementing this study, the main documents of the study (including Protocol and Subject 
Informed Consent Form) must be reviewed and approved by a properly constituted Independent Ethics 
Committee (IEC). The Ethics Committee must also approve any amendment to the protocol and all 
advertising used to recruit subjects for the study, according to local regulations. 
15.2 
RESPONSIBILITIES OF THE INVESTIGATOR AND IEC 
The Investigator will perform the observational study in accordance with the regulations and 
guidelines governing medical practice and ethics in the country of the observational study and in 
accordance with currently acceptable techniques and know-how. 
The planned ethical review of the study will be aimed, primarily, to ethical assessment of the 
possibility of patient data using for CRF completion and possibility of third party access to the source 
documentation of patients. The investigator must keep all information provided by the company-sponsor in 
strict confidence and request similar confidentiality from his/her staff and the Independent Ethics 
Committee. Study documents provided by the company-sponsor or its representative will be safeguarded 
appropriately to ensure their confidentiality. The information provided by the company-sponsor to the 
investigator may not be disclosed to others parties without direct written authorization from the company-
sponsor, except to the extent necessary to obtain informed consent from patients who wish to participate 
in the study. 
15.3 
INFORMED CONSENT 
The Investigator at each site will ensure that the patient is given full and adequate oral and written 
information about the nature, purpose, possible risk and benefit of this observational study. Patients must 
also be notified that they are free to discontinue from the study at any time. The patients should be given 
the opportunity to ask questions and allowed time to consider the information provided. 
The Patient Informed Consent Form will incorporate wording that complies with relevant data 
protection and privacy legislation. Pursuant to this wording, subjects will authorize the collection, use and 
disclosure of their personal data by the Investigator and by those persons who need that information for 
the purposes of the study. 
The Patient Informed Consent Form will explain that study data will be stored in a computer database, 
maintaining confidentiality in accordance with the local law for Data Protection. 

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The signed and dated patient informed consent must be obtained before any specific procedure for 
the study is performed. 
The Investigator must store the original, signed patient informed consent form for 5 years. A copy of 
the signed patient informed consent form must be given to the patient. 
 
15.4 
PUBLICATIONS AND OTHER RIGHTS 
The sponsor has sole ownership of all data, results, reports, and any other information collected and 
full rights of publication based on data from this study and will maintain full access to the database. 
Upon the study completion and finalization of the clinical study report the results of this study will be 
submitted for publications. Publications will be based on data from all centers, analyzed as stipulated in the 
protocol. The investigator agrees not to publish or publicly present any interim results of the study or data 
gathered from one center or a small group of centers before the global publication without the prior written 
consent of the sponsor. The investigator further agrees to provide to the sponsor prior to submission for 
publication or presentation, review copies of abstracts or manuscripts for publication that report any results 
of the study. The sponsor shall have the right to review and comment with respect to publications, 
abstracts, slides, and manuscripts with regard to the following concerns: 
 
Proprietary information that is protected by the provisions contained in; 
 
The accuracy of the information contained in the publication;  
 
To ensure that the presentation is fairly balanced and in compliance with applicable 
regulations; 
 
Others. 
15.5 
STUDY DOCUMENTS AND RECORDS RETENTION 
The investigator must complete the CRF as required by the protocol. All information on CRF must be 
traceable to the source documents in the patient's medical file. Data on patients collected on CRF during the 
study will be anonymous to ensure patient confidentiality. Patients will be identified in the CRF and the 
database only by the patient’s number. No source documents, containing patients’ personal data, should be 
taken away from the clinical site. All study documents shall be made available if required by the company-
sponsor or its designee, auditors or relevant health authorities. 
During the study and after the study termination the investigator must maintain copies of all 
documents and records relating to the conduct of the study. Essential study documents must be retained by 
the investigator during 5 years. 
16 
INVESTIGATORS AND STUDY ADMINISTRATIVE STRUCTURE 
16.1 
SPONSOR 
The sponsor of this study is the company «Woerwag Pharma LLC». 
16.2 
INVESTIGATORS 
Investigators should have qualification and experience for management of patients with acute non-
specific low back pain. The sponsor will contact and select all investigators, who, in turn, will select their 
staff. 

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16.3 
OTHER PARTICIPANTS 
CRO ALMEDIS will be responsible for essential documents preparation, study conduction and 
management, data management, biostatistics and study report writing. 

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17 
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36. Airaksinen O., Brox J.I., Cedraschi C. et al. European guidelines for the management of chronic 
nonspecific low back pain // Eur. Spine J. – 2006. – Vol. 15 (Suppl. 2). – P . 192–300 
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55. Roland Morris disability questionnaire http://www.rmdq.org/Download.htm 

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56. Ferreira ML, Herbert RD, Ferreira PH, et al. The smallest worthwhile effect of nonsteroidal anti-
inflammatory drugs and physiotherapy for chronic low back pain: a benefit-harm trade-off study. J 
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pain recurrence terminology. Eur Spine J. 2011 May;20(5):744-52. 
 
 

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APPENDIX 1 
The Roland-Morris Disability Questionnaire 
 
When your back hurts, you may find it difficult to do some of the things you normally do. 
This list contains sentences that people have used to describe themselves when they have back 
pain.  When you read them, you may find that some stand out because they describe you today.   
As you read the list, think of yourself today.  When you read a sentence that describes you today, 
put a tick against it.  If the sentence does not describe you, then leave the space blank and go on to 
the next one.  Remember, only tick the sentence if you are sure it describes you today. 
 
1. 
I stay at home most of the time because of my back. 
 
 
 
 
 
2. 
I change position frequently to try and get my back comfortable.  
 
 
3. 
I walk more slowly than usual because of my back. 
4. 
Because of my back I am not doing any of the jobs that I usually do around the house. 
5. 
Because of my back, I use a handrail to get upstairs. 
6. 
Because of my back, I lie down to rest more often. 
7. 
Because of my back, I have to hold on to something to get out of an easy chair. 
8. 
Because of my back, I try to get other people to do things for me. 
9. 
I get dressed more slowly then usual because of my back. 
10. 
I only stand for short periods of time because of my back. 
11. 
Because of my back, I try not to bend or kneel down. 
12. 
I find it difficult to get out of a chair because of my back. 
13. 
My back is painful almost all the time. 
14. 
I find it difficult to turn over in bed because of my back. 
15. 
My appetite is not very good because of my back pain. 
16. 
I have trouble putting on my socks (or stockings) because of the pain in my back. 
17. 
I only walk short distances because of my back. 
18. 
I sleep less well because of my back. 
19. 
Because of my back pain, I get dressed with help from someone else. 
20. 
I sit down for most of the day because of my back. 
21. 
I avoid heavy jobs around the house because of my back. 
22. 
Because of my back pain, I am more irritable and bad tempered with people than usual. 
23. 
Because of my back, I go upstairs more slowly than usual. 
24. 
I stay in bed most of the time because of my back. 
 

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Note to users: 
This questionnaire is taken from: Roland MO, Morris RW. A study of the natural history of back 
pain.  Part 1: Development of a reliable and sensitive measure of disability in low back pain. Spine 
1983; 8: 141-144  
The score of the RDQ is the total number of items checked – i.e. from a minimum of 0 to a 
maximum of 24. 
It is acceptable to add boxes to indicate where patients should tick each item. 
The questionnaire may be adapted for use on-line or by telephone. 
 

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APPENDIX 2 
Local Summary of Product Characteristics for Milgamma® and Milgamma® compositum will be 
attached as separate documents. 

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APPENDIX 3 
Following definitions should be used for assessment of ADR severity: 
Mild 
An experience that is usually transient and requires no special treatment or intervention. The 
experience does not generally interfere with usual daily activities. Includes as well transient 
laboratory test alterations 
Moderate 
An experience that is alleviated with simple therapeutic treatments. The experience impacts 
usual daily activities. Includes as well laboratory test alterations indicating injury, but without 
long-term risk. 
Severe 
An experience that requires therapeutic intervention. The experience interrupts usual daily 
activities.