Clinical trial NCT03469349
Conditions: Peripheral Arterial Diseases
Keywords: Drug Therapy
Sponsor: Takeda
Start date: 2018-05-01; Completion date: 2019-08-28
Enrollment: 366 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of the study is to evaluate the efficacy and safety of actovegin in participants with peripheral arterial disease (PAD) Fontaine Stage IIB.

Detailed description:
The study will enroll approximately 366 participants. Participants will be randomly assigned to one of the two treatment groups in 1:1 ratio:

1. Actovegin
2. Placebo (dummy inactive substance) - this is a tablet/intravenous infusion that looks like the study drug but has no active ingredient

All participants will be asked to take intravenous infusion for 2 weeks followed by oral tablets for 10 weeks.

This multi-center trial will be conducted Russia, Georgia, and Kazakhstan. The overall time to participate in this study is 25 to 26 weeks. Participants will make multiple visits to the clinic, and 12 weeks after last dose of study drug for a follow-up assessment.

Arms: arm 1: Actovegin 1200 milligram (mg), intravenously, once daily for up to 2 weeks followed by actovegin 200 mg, tablets, orally, thrice daily (TID) (1200 mg/day) for up to 10 weeks. arm 2: Actovegin placebo-matching, intravenously, once daily for up to 2 weeks and actovegin placebo-matching tablets, orally, TID for up to 10 weeks.
Interventions: intervention 1: Actovegin intervention 2: Placebo
Intervention descriptions: intervention 1: Actovegin intravenous infusion and tablets. intervention 2: Actovegin placebo-matching intravenous infusion and tablets.

Protocol documents:
Prot_000.pdf: 



Title: A Randomized, International, Multicenter, Parallel Group, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of Actovegin 12-Week Treatment Given 
First Intravenously and Subsequently Orally in Subjects With Peripheral Arterial Occlusive 
Disease Fontaine Stage IIB
NCT Number: NCT03469349
Protocol Approve Date: 19 February 2019
Certain information within this protocol has been redacted (ie, specific content is masked irreversibly from 
view with a black/blue bar) to protect either personally identifiable information (PPD) or company 
confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.
Other information as needed to protect confidentiality of Takeda or partners, personal information, or 
to otherwise protect the integrity of the clinical study.


TAKEDA PHARMACEUTICALS PROTOCOL
A Randomized, International, Multicenter, Parallel Group, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of Actovegin 12-Week Treatment 
Given First Intravenously and Subsequently Orally in Subjects With Peripheral Arterial 
Occlusive Disease Fontaine Stage IIB
Actovegin 12-Week Treatment Given First Intravenously and Subsequently Orally in 
Subjects With Peripheral Arterial Occlusive Disease Fontaine Stage IIB
Acronym Title: APOLLO
Phase 3
Sponsor:
Takeda Pharmaceuticals LLC,
2, bld.1, Usatchyova Str., 
Moscow 119048, 
Russian Federation
Study Number:
Actovegin-3001
IND Number:
Not Applicable
EudraCT Number:
2017-004741-24
Compound:
Actovegin
Date:
19 February 2019
Version/Amendment 
Number:
Amendment 04
Amendment History: 
Date
Amendment Number
Amendment Type (for regional 
Europe purposes only)
Region
19 December 2017
Initial version
Not applicable
Global
02 April 2018
1
Not applicable
Russia
25 May 2018
2
Not applicable
Global
26 July 2018
3
Not applicable
Global
19 February 2019
4
Not applicable
Global
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1.0
ADMINISTRATIVE INFORMATION
1.1
Contacts
A separate contact information list will be provided to each site.
Takeda sponsored investigators per individual country requirements will be provided with 
emergency medical contact information cards to be carried by each subject.
General advice on protocol procedures should be obtained through the monitor assigned to the 
study site. Information on service providers is given in Section 3.1 and relevant guidelines 
provided to the site.
Contact Type/Role
All Countries
Safety reporting
Medical Monitor
(medical advice on protocol 
and study drug)
Responsible Medical Officer 
(carries overall responsibility 
for the conduct of the study)
.
Property of Takeda: For non-commerci
er
he applicable Terms of Use
ith
ssigned 
signed
nt guide
t guid
he 
PPD


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1.2
APPROVAL
REPRESENTATIVES OF TAKEDA
This study will be conducted with the highest respect for the individual participants in 
accordance with the requirements of this study protocol and also in accordance with the 
following:
!
The ethical principles that have their origin in the Declaration of Helsinki.
!
International Conference on Harmonisation E6 Good Clinical Practice: Consolidated 
Guideline.
!
All applicable laws and regulations, including, without limitation, data privacy laws, clinical 
trial disclosure laws, and regulations.
SIGNATURES
The signature of the responsible Takeda medical officer (and other signatories, as applicable) can 
be found on the signature page.
Electronic Signatures are provided on the last page of this document.
Property of Ta
nd subject to the applicable Terms of Use
onso
nsolida
lid
data priv
ata pr
nd other 
d other
this do
this d
PPD


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1.3
Protocol Amendment 04 Summary of Changes 
This document describes the changes in reference to the Protocol incorporating Amendment 
No. 04. The primary reason for this amendment is to revise the number of participating sites and 
countries, clarify an inclusion criterion, clarify and correct specific study procedures and 
conditions, and include a list of adverse events of special interest (AESIs) in the protocol.
Minor grammatical, editorial, formatting, and administrative changes not affecting the conduct of 
the study are included for clarification and administrative purposes only. 
For specific descriptions of text changes and where the changes are located, see Appendix E.
Changes in Amendment 04
1. Revised number of participating sites and countries.
2. Clarified inclusion criterion #11.
3. Clarified early discontinuation procedures.
4. Clarified that subjects should continue companion medications for peripheral arterial disease 
(PAD) and prevention of cardiovascular events.
5. Specified minimum infusion duration.
6. Corrected timing of oral treatment period.
7. Deleted instruction to collect incorrect demographic information.
8. Specified timing of height and weight assessments.
9. Clarified that questionnaires should be provided to patients in a language in which they are 
fluent.
10. Clarified fasting conditions and revised maximum blood volume collected.
11. Specified details of white blood cell count.
12. Added requirement to document lost or damaged tablets and defined the nature of returned 
tablets.
13. Added AESIs.
14. Clarified method of signing the informed consent.
15. Removed specific assessments from the Schedule of Study Procedures.
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INVESTIGATOR AGREEMENT
I confirm that I have read and that I understand this protocol, the Investigator’s Brochure, 
package insert and any other product information provided by the sponsor. I agree to conduct this 
study in accordance with the requirements of this protocol and also to protect the rights, safety, 
privacy, and well-being of study subjects in accordance with the following:

The ethical principles that have their origin in the Declaration of Helsinki.

International Conference on Harmonisation, E6 Good Clinical Practice: Consolidated 
Guideline.

All applicable laws and regulations, including, without limitation, data privacy laws and 
regulations.

Regulatory requirements for reporting serious adverse events defined in Section 10.2 of this 
protocol.

Terms outlined in the study site agreement.

Responsibilities of the Investigator. (Appendix B)
I further authorize that my personal information may be processed and transferred in accordance 
with the uses contemplated in Appendix D of this protocol.
Signature of Investigator
Date
Investigator Name (print or type)
Investigator’s Title
Location of Facility (City, State/Provence)
Location of Facility (Country)
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TABLE OF CONTENTS
1.0
ADMINISTRATIVE INFORMATION ...........................................................................2
1.1
Contacts.....................................................................................................................2
1.2
APPROVAL..............................................................................................................3
1.3
Protocol Amendment 04 Summary of Changes ..........................................................4
2.0
STUDY SUMMARY ....................................................................................................11
3.0
STUDY REFERENCE INFORMATION ......................................................................14
3.1
Study-Related Responsibilities.................................................................................14
3.2
Coordinating Investigator.........................................................................................14
3.3
List of Abbreviations ...............................................................................................15
3.4
Corporate Identification...........................................................................................16
4.0
INTRODUCTION.........................................................................................................17
4.1
Background .............................................................................................................17
4.2
Rationale for the Proposed Study.............................................................................18
4.3
Benefit/Risk Profile .................................................................................................20
5.0
STUDY OBJECTIVES AND ENDPOINTS..................................................................21
5.1
Objectives................................................................................................................21
5.1.1
Primary Objective .........................................................................................21
5.1.2
Secondary Objectives ....................................................................................21
5.1.3
Safety Objective............................................................................................21
5.2
Endpoints.................................................................................................................21
5.2.1
Primary Endpoint ..........................................................................................21
5.2.2
Secondary Endpoints.....................................................................................21
5.2.3
Additional Endpoints: Safety.........................................................................21
6.0
STUDY DESIGN AND DESCRIPTION.......................................................................22
6.1
Study Design ...........................................................................................................22
6.2
Justification for Study Design, Dose, and Endpoints.................................................23
6.3
Premature Termination or Suspension of Study or Study Site...................................24
6.3.1
Criteria for Premature Termination or Suspension of the Study .....................24
6.3.2
Criteria for Premature Termination or Suspension of Study Sites...................24
6.3.3
Procedures for Premature Termination or Suspension of the Study or the
Participation of Study Site(s).........................................................................24
7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS..............25
7.1
Inclusion Criteria .....................................................................................................25
7.2
Exclusion Criteria ....................................................................................................26
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7.3
Excluded Medications and Treatments.....................................................................27
7.4
Diet, Fluid, Activity Control, Treatment Facilities, and General Recommendations 
and Restrictions ......................................................................................................27
7.5
Criteria for Discontinuation or Withdrawal of a Subject...........................................28
7.6
Procedures for Discontinuation or Withdrawal of a Subject......................................29
8.0
CLINICAL STUDY MATERIAL MANAGEMENT.....................................................30
8.1
Study Drug and Materials ........................................................................................30
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling ................................30
8.1.1.1
Investigational drug .................................................................................30
8.1.1.2
Companion Medication............................................................................31
8.1.1.3
Ancillary Materials..................................................................................32
8.1.1.4
Sponsor-Supplied Drug............................................................................32
8.1.2
Storage..........................................................................................................32
8.1.3
Dose and Regimen.........................................................................................32
8.1.3.1
IV Treatment Period (Week 0 to 2)..........................................................32
8.1.3.2
Oral Treatment Period (Week 3 to 12) .....................................................33
8.1.4
Overdose.......................................................................................................33
8.2
Study Drug Assignment and Dispensing Procedures ................................................34
8.3
Randomization Code Creation and Storage..............................................................34
8.4
Study Drug Blind Maintenance................................................................................34
8.5
Unblinding Procedure..............................................................................................35
8.6
Accountability and Destruction of Sponsor-Supplied Drugs.....................................35
9.0
STUDY PLAN ..............................................................................................................37
9.1
Study Procedures.....................................................................................................37
9.1.1
Informed Consent Procedure .........................................................................37
9.1.2
Demographics, Medical History, and Medication History Procedure .............37
9.1.3
Physical Examination Procedure....................................................................37
9.1.4
Weight and Height ........................................................................................37
9.1.5
Smoking Status and Physical Activity ...........................................................38
9.1.6
Vital Sign Procedure......................................................................................38
9.1.7
Efficacy Measurements .................................................................................38
9.1.7.1
Treadmill testing......................................................................................38
9.1.7.2
SF-36.......................................................................................................39
9.1.8
Documentation of Concomitant Procedures and Medications.........................40
9.1.9
Documentation of Concurrent Medical Conditions ........................................40
9.1.10
Ultrasound Color Duplex Imaging.................................................................40
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9.1.11
Procedures for Clinical Laboratory Samples ..................................................42
9.1.12
Contraception and Pregnancy Avoidance Procedure ......................................43
9.1.12.1
Male Subjects and Their Female Partners ................................................43
9.1.12.2
Female Subjects and Their Male Partners ................................................43
9.1.12.3
Definitions and Procedures for Contraception and Pregnancy 
Avoidance ...............................................................................................43
9.1.13
Pregnancy......................................................................................................45
9.1.14
ECG Procedure..............................................................................................46
9.1.15
Documentation of Screen Failure...................................................................46
9.1.16
Documentation of Randomization .................................................................46
9.2
Monitoring Subject Treatment Compliance..............................................................47
9.3
Schedule of Observations and Procedures................................................................48
9.3.1
Screening Period ...........................................................................................48
9.3.2
Randomization (Baseline), Day 1 Visit 1.......................................................49
9.3.3
Infusion (IV) Treatment Period......................................................................49
9.3.4
End-of-IV Treatment, Day 14, Visit 2............................................................50
9.3.5
Oral Treatment Period ...................................................................................50
9.3.6
End-of-Oral Treatment, Day 84, Visit 5 /Early Termination Visit..................51
9.3.7
Follow-up Period...........................................................................................51
9.3.8
Final Follow-up Visit/Early Termination Visit...............................................52
9.3.9
Post Study Care .............................................................................................52
10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS............................................53
10.1
Definitions...............................................................................................................53
10.1.1
PTEs .............................................................................................................53
10.1.2
AEs ...............................................................................................................53
10.1.3
Additional Points to Consider for PTEs and AEs ...........................................53
10.1.4
SAEs.............................................................................................................55
10.1.5
AESIs............................................................................................................56
10.1.6
Intensity of PTEs and AEs.............................................................................56
10.1.7
Causality of AEs ...........................................................................................57
10.1.8
Relationship to Study Procedures ..................................................................57
10.1.9
Start Date ......................................................................................................57
10.1.10
Stop Date ......................................................................................................57
10.1.11
Frequency......................................................................................................57
10.1.12
Action Concerning Study Drug......................................................................57
10.1.13
Outcome........................................................................................................58
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10.2
Procedures...............................................................................................................58
10.2.1
Collection and Reporting of AEs ...................................................................58
10.2.1.1
PTE and AE Collection Period.................................................................58
10.2.1.2
PTE and AE Reporting ............................................................................58
10.2.2
Collection and Reporting of SAEs.................................................................59
10.2.3
Reporting of Abnormal LFTs ........................................................................60
10.3
Follow-up of SAEs ..................................................................................................60
10.3.1
Safety Reporting to Investigators, Ethics Committees, and Regulatory 
Authorities ....................................................................................................60
11.0
STUDY-SPECIFIC COMMITTEES .............................................................................61
12.0
DATA HANDLING AND RECORDKEEPING............................................................62
12.1
eCRFs......................................................................................................................62
12.2
Record Retention .....................................................................................................62
13.0
STATISTICAL METHODS..........................................................................................64
13.1
Statistical and Analytical Plans ................................................................................64
13.1.1
Analysis Sets.................................................................................................64
13.1.2
Analysis of Demographics and Other Baseline Characteristics Analysis of 
Demographics and Other Baseline Characteristics...........................................64
13.1.3
Efficacy Analysis ..........................................................................................64
13.1.4
Safety Analysis..............................................................................................65
13.1.4.1
AEs .........................................................................................................65
13.1.4.2
Clinical Evaluations.................................................................................65
13.2
Interim Analysis and Criteria for Early Termination ................................................65
13.3
Determination of Sample Size..................................................................................65
14.0
QUALITY CONTROL AND QUALITY ASSURANCE...............................................67
14.1
Study-Site Monitoring Visits ...................................................................................67
14.2
Protocol Deviations..................................................................................................67
14.3
Quality Assurance Audits and Regulatory Agency Inspections ................................67
15.0
ETHICAL ASPECTS OF THE STUDY........................................................................68
15.1
Ethics Committee Approval.....................................................................................68
15.2
Subject Information, Informed Consent, and Subject Authorization .........................68
15.3
Subject Confidentiality ............................................................................................70
15.4
Publication, Disclosure, and Clinical Trial Registration Policy.................................70
15.4.1
Publication and Disclosure ............................................................................70
15.4.2
Clinical Trial Registration .............................................................................71
15.4.3
Clinical Trial Results Disclosure ...................................................................71
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15.5
Insurance and Compensation for Injury....................................................................71
16.0
REFERENCES..............................................................................................................72
LIST OF IN-TEXT TABLES
Table 8.a
Dose and Regimen .............................................................................................33
Table 9.a
Clinical Laboratory Tests...................................................................................42
Table 10.a
Takeda Medically Significant AE List................................................................56
Table 13.a
Sample Sizes Under Different Values of Power..................................................66
LIST OF IN-TEXT FIGURES
Figure 6.a
Schematic of Study Design ................................................................................23
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................75
Appendix B
Responsibilities of the Investigator.....................................................................77
Appendix C
Elements of the Subject Informed Consent .........................................................79
Appendix D
Investigator Consent to Use of Personal Information..........................................82
Appendix E
Detailed Description of Amendments to Text.....................................................83
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2.0
STUDY SUMMARY
Name of Sponsor:
Takeda Pharmaceutical LLC
Compound:
Actovegin
Title of Protocol: A Randomized, International,
Multicenter, Parallel Group, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of 
Actovegin 12-Week Treatment Given First Intravenously
and Subsequently Orally in Subjects With Peripheral 
Arterial Occlusive Disease Fontaine Stage IIB
IND No.: Not Applicable
EudraCT No.:
2017-004741-24
Study Number: Actovegin-3001
Phase: 3b
Study Design:
This is a randomized, multicenter, parallel group, double-blind, placebo-controlled phase 3b study to evaluate the
efficacy and safety of actovegin 12-week treatment given intravenously and subsequently orally in subjects with
peripheral arterial disease (PAD) Fontaine Stage IIB.
A total of 366 subjects with PAD Fontaine Stage IIB will be enrolled in approximately 17 to 25 sites in 3 countries
(Russia, Kazakhstan, and Georgia,).
The study will consist of a 1- to 2-week Screening Period, Randomization, 12-week Treatment Period, and 12-week
Follow-up Period. The overall study duration will be 25 to 26 weeks.
Subjects will enter a 1- to 2-week Screening Period during which, the stability of the subject’s condition will be
verified, a diagnosis of PAD will be confirmed, and subjects with high variability in the absolute claudication 
distance (ACD) will be detected and excluded. For this purpose, 2 treadmill tests will be performed within a time 
interval of ≥1 week (ie, 7 days). Subjects having a change of more than 25% in the ACD during the Screening Period
will be excluded.
Subjects with a confirmed history of stable intermittent claudication with symptoms that have been present 
continuously for at least 6 months at the time of Screening will be eligible for inclusion. A diagnosis of PAD (initial 
claudication distance [ICD] of <200 meters) will be confirmed by ultrasound color duplex imaging and treadmill 
test.
Eligible subjects will be randomized to receive either actovegin or placebo in a 1:1 ratio. The treatment period will
include 2 weeks of intravenous (IV) infusions of actovegin (deproteinized hemoderivate) at a dose of 1200 mg/day,
followed by 10 weeks of oral treatment in tablets at a dose of 1200 mg/day (two 200 mg tablets 3 times daily [TID]).
Matched placebo (solution for infusion 0.9% NaCl and placebo tablets) will be used throughout the treatment period to
maintain blinding. The overall treatment duration will be 12 weeks.
A 12-week follow-up period with no investigational medicinal product (IMP) treatment will follow the 12-week
treatment period to examine sustained efficacy after treatment as well as safety once actovegin treatment has stopped.
During the active treatment period and follow-up period, patients will be allowed to receive other specific therapy 
for PAD with the exception of prohibited medications.
Primary Objectives:
The primary objective is to investigate the efficacy of actovegin for the symptomatic treatment of PAD Fontaine
Stage IIB.
Secondary Objectives:

To investigate the effect of actovegin in sustained improvement in claudication distance of subjects with PAD
Fontaine Stage IIB.

To investigate the effect of actovegin on patients’ quality of life.

To evaluate the safety of actovegin compared to placebo.
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Subject Population: Male or female subjects with PAD Fontaine Stage IIB aged 40 to 75 years, inclusive.
Number of Subjects:
183 subjects per treatment group
Estimated total: Approximately 366 randomized subjects
Number of Sites:
Approximately 17 to 25 sites in 3 countries
(Russia, Kazakhstan, and Georgia)
Dose Level(s):
Actovegin ampoules 400 mg/10 mL Solution for infusion 0.9% 
NaCl 250 mL
280 mL /1200 mg /intravenously / day for 2 weeks
Actovegin placebo ampoules 0.9% NaCl /10 mL Solution for
infusion 0.9% NaCl 250 mL
280 mL / intravenously / day for 2 weeks
Actovegin tablets 200 mg
Oral treatment 2 tablets 200 mg TID (1200 mg/day) for 10 weeks
Actovegin placebo tablets
Oral treatment 2 tablets TID for 10 weeks
Route of Administration:
Actovegin IV infusions actovegin oral (tablets)
Placebo (0.9% NaCl) IV infusions Placebo oral 
(tablets)
Duration of Treatment:
12 weeks (2 weeks of IV treatment and 10 weeks of oral
treatment)
Period of Evaluation:
Screening Period: 1 to 2 weeks Treatment
Period: 12 weeks Follow-up Period: 12 weeks 
Overall study duration: 25 to 26 weeks
Main Criteria for Inclusion:

Male or female subjects 40 to75 years of age, inclusive.

The subject has a confirmed history of stable intermittent claudication with symptoms that have been present 
continuously for at least 6 months at the time of Screening.

The subject has a diagnosis of PAD (Code I70.2 according to the international classification of diseases-10th 
revision) Fontaine Stage IIB confirmed by ultrasound color duplex imaging.

The subject has a history of stable PAD therapy for at least 2 weeks before Screening and is not newly 
diagnosed with PAD.

The subject has a history of stable smoking habits for at least 3 months before Randomization (Day 1)

The subject has a resting Doppler ankle-brachial index of ≤0.9.

The subject has intermittent claudication with ICD <200 meters.
Main Criteria for Exclusion:

The subject has PAD Fontaine Stage III or IV (pain at rest, nonhealing ulceration, or gangrene).

The subject has evidence of nonatherosclerotic PAD.

The subject has >25% variability in ACD based on treadmill testing during the screening period.

The subject has lower extremity arterial reconstruction (surgical or endovascular) or sympathectomy within 
3 months before Screening.

The subject is eligible for surgical/interventional reconstruction.

The subject had a myocardial infarction or major cardiac surgery within 3 months before Screening.

The subject has congestive heart failure (New York Heart Association Class III/IV).

The subject has uncontrolled diabetes mellitus (glycosylated hemoglobin [HbA1c] >9%) or diabetic
polyneuropathy).
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
The subject has any other illness that significantly limits exercise capacity or other medical condition that limits
participation (in the judgement of the investigator).

The subject has received any prohibited medication (Section 7.3) within 14 days before Randomization (Day 1)

The subject is undergoing the supervised exercise training program by the time of Screening and is going to 
continue this program due to its effectiveness.
Criteria for Evaluation and Analyses:
The primary endpoint is the percent change in ICD from Baseline to 12 weeks. The secondary endpoints are:

The percent change in ICD from Baseline to 2 and 24 weeks.

The change in ACD from Baseline to 2, 12, and 24 weeks.

Proportion of patients having rest pain at 12 and 24 weeks.

Proportion of patients having revascularization procedures at 24 weeks.

Change in 36-item Short Form Survey (SF-36) at 12 and 24 weeks.
Statistical Considerations:
The primary and secondary endpoints will be analyzed in randomized patients who received at least 1 dose of study 
drug.
Percent change from Baseline in ICD and change from Baseline in SF-36 will be analyzed using a mixed model for 
repeated measurements (MMRM) analysis of covariance with treatment, center, sex, age group, visit, treatment-by-
visit interaction as fixed effects, Baseline as covariate, and subject as a random effect. Comparisons between 
actovegin and placebo will be performed on all assessment points. Based on a missing at random assumption, this 
analysis will be performed using observed case data only. The effect at each time point for each treatment is allowed 
to vary freely and an unstructured covariance matrix is assumed.
Proportion of subjects having rest pain and proportion of patients having revascularization procedures will be 
analyzed at all time points by logistic regression adjusting for treatment.
Sample Size Justification: Assuming a standard deviation of 85% for the percent change from Baseline in ICD and a
20% drop-out rate, a total of 366 subjects (183 per treatment group) is sufficient to achieve at least 80% power to
detect a 28% difference in percent change from Baseline in ICD between actovegin and placebo by a 2-sample t-test
with a 0.05 two-sided significance level.
The sample size justification is based on published data for the ICD for naftidrofuryl, for which the difference in 
percent change from Baseline in ICD between naftidrofuryl and placebo is approximately 28%, while the 
corresponding pooled standard deviation is approximately 85%.
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3.0
STUDY REFERENCE INFORMATION
3.1
Study-Related Responsibilities
The sponsor will perform all study-related activities with the exception of those identified in the
clinical study supplier list. The vendors identified for specific study-related activities will perform
these activities in full or in partnership with the sponsor.
3.2
Coordinating Investigator
Takeda will select a Signatory Coordinating Investigator(s) from the investigators who participate 
in the study. Selection criteria for this investigator will include significant knowledge of the
study protocol, the study drug, their expertise in the therapeutic area and the conduct of clinical
research as well as study participation. The Signatory Coordinating Investigator will be required 
to review and sign the clinical study report and by doing so agrees that it accurately describes 
the results of the study.
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3.3
List of Abbreviations
ABI
ankle brachial index
ACD
absolute claudication distance
ADR
adverse drug reaction
AE
adverse event
AESI
adverse event of special interest
ALT
alanine aminotransferase
AST
aspartate aminotransferase
BP
blood pressure
CPMP
Committee for Proprietary Medicinal Products
ECG
electrocardiogram
eCRF
electronic case report form
EMA
European Medicines Agency
FAS
full analysis set
FSH
follicle stimulating hormone
GCP
Good Clinical Practice
GGT
γ-glutamyl transferase
HbA1c
glycosylated hemoglobin
hCG
human chorionic gonadotropin
IC
intermittent claudication
ICD
initial claudication distance
ICH
International Conference on Harmonisation
IMP
investigational medicinal product
IP
investigational product
IRT
interactive response technology
IV
intravenous
LFT
liver function tests
LSU
lipasemic unit
MedDRA
Medical Dictionary for Regulatory Activities
Med ID
medication identification number
MMRM
mixed model for repeated measures
PAD
peripheral arterial disease
PSUR
Periodic Safety Update Report
PTE
pretreatment event
SAE
serious adverse event
SAP
statistical analysis plan
SF-36
36-item Short Form Survey
SUSAR
suspected unexpected serious adverse reaction
TID
3 times daily
ULN
upper limit of normal
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3.4
Corporate Identification
Takeda
TDC Japan, TDC Asia, TDC Europe, and/or TDC Americas, as applicable
TDC-Americas
Takeda Development Center Americas, Inc.
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4.0
INTRODUCTION
4.1
Background
Peripheral arterial disease (PAD), also known as peripheral arterial occlusive disease is a
manifestation of systemic atherosclerosis defined by progressive stenosis or occlusion within the
arteries of the lower extremities [1]. PAD affects approximately 202 million adults worldwide
[2]. The prevalence of PAD increases with age and the number of vascular risk factors 
(eg, diabetes, smoking, hypertension, hypercholesterolemia, age, sex, family history) [1,3].
More importantly, it is a marker of atherosclerotic disease burden, and is associated with increased
mortality from cardiovascular and cerebrovascular causes [1,3].
The decreased blood flow to the legs caused by PAD may be mild or severe, resulting in a broad
range of symptoms. Patients may not suffer recognizable limb symptoms, or they may experience
intermittent claudication (IC), or manifest symptoms of severe limb ischemia. IC, the most
common symptom of PAD, is defined as fatigue, cramping, or overt pain of the gluteal, thigh, or
calf muscles, that is consistently provoked by exercise and that is reproducibly relieved by rest.
Patients with IC are often limited in their daily activities owing to their walking impairment and 
in turn experience a diminished quality of life. With continued exposure to atherosclerotic risk
factors, PAD may progress to critical limb ischemia, which portends a severe diminution in quality
of life, and is associated with a high rate of amputation and a marked increase in short term
mortality. Thus, PAD is a common manifestation of atherosclerosis that is associated with a range
of symptoms, a variable impact on qualityof life, and a heightened risk of cardiovascular ischemic
events [1].
Actovegin is a deproteinized hemoderivate from calf blood that has been made free of pyrogens
and antigens through a stepwise ultrafiltration production process.
Actovegin contains physiological blood components, including vitamins, amino acids, lipids,
oligosaccharides and oligopeptides, nucleosides, intermediate products of carbohydrate and fatty
acid metabolism, as well as constituents of cellular membranes, such as glycosphingolipids. It
has pleiotropic metabolic, neuroprotective, and regenerative properties [4]. Experimental studies
have shown that actovegin improves oxygen utilization and uptake, as well as energy metabolism
and glucose uptake [5-7]. Actovegin has been shown to possess neuroprotective effects and to 
increase neuronal survival under ischemic conditions [8]. It also reduces amyloid beta-induced
apoptosis along with decreasing reactive oxygen species formation [9], modulates nuclear factor 
kappa B activity[10], and inhibits the nuclear enzyme poly(adenosine diphosphate ribose)
polymerase, which can also partially explain its neuroprotective properties [11]. Actovegin exerts 
positive effects on microcirculation and microvascular endothelium, increasing capillary blood
flow rate and reducing pericapillary zone and arteriolovenular shunting of blood flow [12].
Clinical efficacy data for actovegin provide evidence for the treatment of disturbances of the
cerebral circulation including dementia [13,14] and post stroke cognitive impairment [14]. Several
randomized controlled trials and many uncontrolled studies have been conducted for these
indications. Available clinical data also support the use of actovegin for the treatment of diabetic 
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polyneuropathy [15]. The efficacy of actovegin for these indications is further supported by
nonclinical pharmacodynamic research. The efficacy data are also supportive for peripheral
perfusion disorders with positive study outcomes for maximal and pain-free walking distance in
PAD and healing time in venous ulcer disease [16-20].
Actovegin received its first marketing authorization in the Federal Republic of Germany in 1976
and remains on the market in more than 20 countries (eg, in several countries in the
Commonwealth of Independent States and in a few countries in Europe and Asia region). It exists
in different formulations for oral, intravenous (IV), and intramuscular usage. Actovegin has been
approved for the following indications (which vary among countries):

Symptomatic treatment of cognitive impairment including post-stroke cognitive impairment
and dementia.

Symptomatic treatment of peripheral perfusion disorders and their sequelae.

Symptomatic treatment of diabetic polyneuropathy.
Actovegin has been used clinically for over 40 years. Due to its composition of biological
constituents present under normal physiological conditions and stringent production process, the
drug has an excellent safety profile, reflected by clinical experience equivalent to an exposure to
the drug of more than 1,200,000 patient years (Periodic Safety Update Report [PSUR] 2014
submitted to the Austrian Agency for Health and Food Safety). The profile of adverse drug
reactions (ADRs) has been consistent across PSURs without particular target organ toxicity.
4.2
Rationale for the Proposed Study
Actovegin has been used since the 1970s for the treatment of PAD of varying degrees of severity.
Several trials have evaluated the efficacy of actovegin (IV) in patients with mainly Fontaine Stage
II and III PAD.
A randomized, open-label, 8-week study has been conducted to investigate the effect of actovegin
on ischemic syndrome of the lower extremities in patients with type 1 and type 2 diabetes, in
comparison with sulodexide [16]. Patients were randomized to receive either IV infusions of
actovegin (2000 mg once daily; n=12) or sulodexide (1200 lipasemic units [LSU] per day; n=14)
for 2 weeks followed by oral administration of the 2 drugs for a further 6 weeks (1200 mg/day and
1000 LSU per day respectively). Both treatments increased maximum pain-free walking time after
8 weeks of treatment (p<0.05). However, actovegin treatment significantly increased maximum
pain-free walking time after 2 weeks of treatment versus Baseline (p<0.05), whereas treatment
with sulodexide did not. Additionally, the relative increment in pain-free walking time was greater
in the actovegin group compared with the sulodexide group (95.1% versus 38.1% respectively;
p<0.05).
A randomized, double-blind, placebo-controlled, parallel-group study including 60 patients with
Stage II PAD was conducted [17]. All patients took part in a regular physical training program for
12 weeks, at least 4 weeks before randomization. Patients then received daily IV infusions of
actovegin 20% (250 mL/day) or placebo (saline 250 mL/day) for a period of 4 weeks. The primary 
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endpoint, pain-free walking on a treadmill, increased by 27% (from 73 to 93 meters) in the
actovegin group and decreased in the placebo group by 12% (10 meters). The difference between
the 2 groups was statistically significant (p<0.001). A similar result was obtained with maximum
walking distances (+25% versus -10.4% for actovegin and placebo, respectively; p<0.01).
Horsch et al. conducted a randomized, double-blind, placebo-controlled study including 138
patients with Stage II PAD [18]. Actovegin 20% (250 mL) and matching placebo were
administered as daily IV infusions over a 3-week period. Efficacy was evaluated by means of a
responder analysis where response was defined as a 35% increase from Baseline in pain-free
walking distance measured on a treadmill. There were 57% responders in the actovegin group
compared with 33% in the placebo group (p=0.01).
In another double-blind study, Müller-Bühl et al. evaluated the efficacy and compatibility of
actovegin 20% infusion (250 mL) versus placebo (0.9% saline 250 mL) in patients with Stage II
PAD [19]. In this study, actovegin and placebo were administered intra-arterially into the femoral
arteryof the walking distance-limiting leg; patients were required to have a steady state in walking
distance before they were randomized to receive either actovegin (n=40) or placebo (n=40).
Infusions were administered daily, except for weekends, for a period of 4 weeks and training was
ceased with the commencement of the treatment phase. Actovegin therapy resulted in an increase
of pain-free walking distance from 112 to 162 meters (49%) and maximum walking distance from
171 to 266 meters (59%). In the placebo group, pain-free walking distance increased from 114 to
135 meters (23%), and maximum walking distance from 176 to 201 meters (17%). The differences
between the 2 groups were significant for both parameters (p<0.05). Following the discontinuation
of actovegin treatment and placebo, an 8-week follow-up showed that the walking distance fell
markedly in the placebo group, compared with patients previously treated with actovegin.
A randomized, single-blind study has also been performed to compare the efficacy of actovegin and
bencyclane in Stage III PAD [20]. Fifty-eight patients were randomized to receive either
actovegin 20% infusion (20 intra-arterial infusions) or 250 mg bencyclane in 250 mL saline 0.9%
over a period of 4 weeks. Endpoint analyses revealed that after 4 weeks, 23.1% of patients treated
with actovegin experienced pain at night compared with 61.5% of patients treated with
bencyclane (p<0.05). No patients treated with actovegin reported permanent pain after 4 weeks,
whereas 16% of patients treated with bencyclane did (p<0.05). Analgesic use at 4 weeks was also
lower in patients treated with actovegin compared with those treated with bencyclane (28.7%
versus 42.3% respectively; p<0.05). Finally, both treatments increased pain-free walking distances
(29.2±14.6 meters and 25.8±18.7 meters for the actovegin and bencyclane groups respectively)
but there was no statistically significant difference between the 2 groups.
In summary, IV treatment with actovegin has been shown to increase initial walking distance and 
relieve pain symptoms in patients with PAD in small, double-blind, controlled trials. To date, no 
large-scale randomized placebo-controlled trials have been undertaken to support this
observation. This will be the first large-scale study to provide data in support of the use of
actovegin (IV and oral) in the treatment of patients with PAD.
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4.3
Benefit/Risk Profile
This current study investigates the efficacy and safety of actovegin compared to placebo in
subjects with PAD. Several small randomized, controlled, clinical studies have evaluated the 
efficacy of actovegin in patients with PAD, mainly in Fontaine Stages II (mild (a), moderate,
severe (b) claudication) and III (ischemic pain at rest). Although some actovegin studies were
performed before implementation of current clinical investigation guidelines, such as the
European Committee for Proprietary Medicinal Products (CPMP)/ EWP/714/98 “Note for 
guidance on clinical investigation of medicinal products for treatment of peripheral arterial
occlusive disease,” most studies used the primary endpoints recommended in the European
guidelines (eg, walking distance for PAD Stage II).
As summarized in Section 4.2 results of these randomized, controlled trials showed short-term
benefit in initial walking distance and pain symptoms with actovegin solution for infusion in
populations with PAD.
The safety and tolerability of actovegin in clinical trials was broadly similar to that observed
following placebo administration.
The following undesirable effects are reflected in the Company Core Data Sheet for actovegin
(2016) in accordance with the classification of the frequency of an ADR based on the Council for
International Organizations of Medical Sciences guidelines:

Immune system disorders: allergic reactions (hypersensitivity, drug fever, shock symptoms).

Skin and subcutaneous tissue disorders: urticaria, flush.
The frequency of these ADRs has been classified as rare (≥1/10,000 to <1/1,000).
The safety profile for actovegin suggests that it is well tolerated in all approved indications and
the known risks can be mitigated by the appropriate use of the product, as directed by the label.
This includes the monitoring for hypersensitivity reactions and adherence to sterile practices on
handling and administrating the intravenous product.
Overall, a favorable benefit-risk profile has been established to support the clinical use of
actovegin.
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5.0
STUDY OBJECTIVES AND ENDPOINTS
5.1
Objectives
5.1.1
Primary Objective
The primary objective is to investigate the efficacy of actovegin for the symptomatic treatment of
PAD Fontaine Stage IIB.
5.1.2
Secondary Objectives

To investigate the effect of actovegin in sustained improvement in claudication distance of
subjects with PAD Fontaine Stage IIB.

To investigate the effect of actovegin on patients’ quality of life.
5.1.3
Safety Objective

To evaluate the safety of actovegin compared with placebo.
5.2
Endpoints
5.2.1
Primary Endpoint
The primary endpoint is the percent change in initial claudication distance (ICD) from Baseline to
12 weeks of study treatment.
5.2.2
Secondary Endpoints

The percent change in ICD from Baseline to 2 and 24 weeks after randomization.

The change in absolute claudication distance (ACD) from Baseline to 2, 12, and 24 weeks 
after randomization.

Proportion of patients having rest pain at 12 and 24 weeks after randomization.

Proportion of patients having revascularization procedures at 24 weeks after randomization.

Change in 36-item Short Form Survey (SF-36) at 12 and 24 weeks after randomization.
5.2.3
Additional Endpoints: Safety

Safety and tolerability of actovegin will be evaluated by assessment of adverse events (AEs), 
clinical safety laboratory tests, vital signs, weight, electrocardiogram (ECG), and physical 
examination.
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6.0
STUDY DESIGN AND DESCRIPTION
6.1
Study Design
This is a randomized, multi-center, parallel group, double-blind, placebo-controlled phase 3b
study to evaluate the efficacy and safety of actovegin 12-week treatment given intravenously and
subsequently orally in subjects with PAD Fontaine Stage IIB.
A total of 366 subjects with PAD Fontaine Stage IIB will be enrolled in approximately 17 to
25 sites in 3 countries (Russia, Kazakhstan, and Georgia).
The study will consist of a 1- to 2-week Screening Period, Randomization, 12-week Treatment
Period, and 12-week Follow-up Period. The overall study duration will be 25 to 26 weeks.
Subjects will enter a 1- to 2-week Screening Period during which, the stability of the subject’s
condition will be verified, a diagnosis of PAD will be confirmed, and subjects with high
variability in the claudication distance will be detected and excluded. For this purpose, 2 treadmill
tests will be performed within a time interval of ≥1 week (ie, 7 days). Subjects having a change of
more than 25% in the ACD during the Screening Period will be excluded.
Subjects with a history of stable intermittent claudication with symptoms that have been present 
continuously for at least 6 months at the time of Screening. A diagnosis of PAD (ICD of
<200 meters) will be confirmed by ultrasound color duplex imaging and treadmill test.
Eligible subjects will be randomized to receive either actovegin or placebo in a 1:1 ratio. The
treatment period will include 2 weeks of IV infusions of actovegin (deproteinized hemoderivate)
at a dose of 1200 mg/day, followed by 10 weeks of oral treatment in tablets at a dose of
1200 mg/day (two 200 mg tablets 3 times daily [TID]). Matched placebo (placebo ampoules and
placebo tablets) will be used throughout the treatment period to maintain blinding. The overall
treatment duration will be 12 weeks.
A 12-week follow-up period with no investigational medicinal product (IMP) treatment will
follow the 12-week treatment period to examine sustained efficacy after treatment as well as safety
once actovegin treatment has stopped.
A schematic of the study design is included as Figure 6.a. A schedule of assessments is listed in
Appendix A.
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Figure 6.a
Schematic of Study Design
V=visit.
6.2
Justification for Study Design, Dose, and Endpoints
The randomized parallel group, double-blind, placebo-controlled studydesign is consistent with
the recommendations in CPMP/EWP/714/98 “Note for guidance on clinical investigation of
medicinal products for treatment of peripheral arterial occlusive disease.”
The dosing regimen for this studyreflects the labelling except that the oral treatment will be for a
longer period than stipulated in the label. The recommended dose for actovegin is 800 to 2000 mg
(20-50 mL) intravenously for 4 weeks. The recommended dose for the tablet formulation is 1 to
2 tablets (each tablet containing 200 mg actovegin) TID with an average treatment duration of 4to
6 weeks. The oral dosing regimen in the current study is 2 tablets (200 mg) TID (1200 mg/day)
for 10 weeks.
The efficacy of actovegin 1000 mg IV was demonstrated in a comparative randomized study
in patients with PAD Fontaine Stage IIB. Maximum walking distance increased after 4
weeks of treatment by 100.7% in the actovegin group compared with 67% and 8.1% in the
naftidrofuryl and vitamin B groups, respectively [21]. In another open-label controlled study,
actovegin was administered at 1000 mg IV daily for 10 days and showed an increase of
pain-free walking distance comparable with pentoxifylline group. Analyses of
microcirculation in the skin using laser Doppler flowmetryshowed that actovegin had a
number of significant effects better pronounced when compared with pentoxifylline group
[22].
This prolonged oral treatment period has demonstrated safety and efficacy in previous actovegin
trials.
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The primary endpoint of change from Baseline in ICD was chosen as intermittent claudication as it
is a key symptom of Stage II PAD and is recommended in the European Medicines Agency 
(EMA) guideline “Note for guidance on clinical investigation of medicinal products for treatment
of peripheral arterial occlusive disease.”
6.3
Premature Termination or Suspension of Study or Study Site
6.3.1
Criteria for Premature Termination or Suspension of the Study
The study will be completed as planned unless 1 or more of the following criteria are satisfied that
require temporary suspension or early termination of the study.

New information or other evaluation regarding the safety or efficacy of the study drug that
indicates a change in the known risk/benefit profile for the actovegin, such that the risk is no
longer acceptable for subjects participating in the study.

Significant violation of Good Clinical Practice (GCP) that compromises the ability to achieve
the primary study objectives or compromises subject safety.
6.3.2
Criteria for Premature Termination or Suspension of Study Sites
A study site may be terminated prematurely or suspended if the site (including the investigator) is
found in significant violation of GCP, protocol, or contractual agreement, is unable to ensure
adequate performance of the study, or as otherwise permitted by the contractual agreement.
6.3.3
Procedures for Premature Termination or Suspension of the Study or the
Participation of Study Site(s)
In the event that the sponsor, an ethics committee or regulatory authority elects to terminate or
suspend the study or the participation of a study site, a study-specific procedure for early
termination or suspension will be provided by the sponsor; the procedure will be followed by
applicable study sites during the course of termination or study suspension.
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7.0
SELECTION AND DISCONTINUATION/WITHDRAWAL OF SUBJECTS
All entry criteria, including test results, need to be confirmed before randomization or first dose.
7.1
Inclusion Criteria
Subject eligibility is determined according to the following criteria before entry into the study:
1. The subject is male or female and aged 40 to 75 years, inclusive.
2. The subject has a confirmed history of stable intermittent claudication with symptoms that 
/have been present continuously for at least 6 months at the time of Screening.
3. The subject has a diagnosis of PAD (Code I70.2 according to the international classification
of diseases-10th revision) Fontaine Stage IIB confirmed by ultrasound color duplex imaging.
4. The subject has a history of stable smoking habits for at least 3 months before 
Randomization (Day 1).
5. The subject has a resting Doppler ankle-brachial index of ≤0.9.
6. The subject has intermittent claudication with ICD <200 meters.
7. In the opinion of the investigator, the subject is capable of understanding and complying with
protocol requirements.
8. The subject or, when applicable, the subject’s legally acceptable representative signs and dates
a written, informed consent form and any required privacy authorization before the initiation
of any study procedures.
9. A male subject who is nonsterilized and sexually active with a female partner of childbearing
potential agrees to use barrier method of contraception (eg, condom with or without
spermicide) from signing of informed consent throughout the duration of the study or for
30 days after the last dose in case of premature termination. The female partner of a male
subject should also be advised to use a highly effective/effective method of contraception 
throughout the duration of the study or for 30 days after the last dose in case of premature 
termination.
10. A female subject of childbearing potential who is sexually active with a nonsterilized male 
partner agrees to use an effective or a highly effective method of contraception from signing of 
informed consent throughout the duration of the study or for 30 days after the last dose in case 
of premature termination. Definitions of effective/highly effective methods of contraception are 
defined in Section 9.1.12 and reporting responsibilities are defined in Section 9.1.13.
11. The subject has a history of stable PAD therapy for at least 2 weeks before Screening and is 
not newly diagnosed with PAD.
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7.2
Exclusion Criteria
Any subject who meets any of the following criteria after the screening period will not qualify for
entry into the study:
1. The subject has PAD Fontaine Stage III or IV (pain at rest, non-healing ulceration, or
gangrene).
2. The subject has evidence of nonatherosclerotic PAD.
3. The subject has >25% variability in ACD based on treadmill testing during the screening 
period.
4. The subject has lower extremity arterial reconstruction (surgical or endovascular) or
sympathectomy within 3 months before Screening.
5. The subject is eligible for surgical/interventional reconstruction.
6. The subject had a myocardial infarction or major cardiac surgery within 3 months before
Screening.
7. The subject has congestive heart failure (New York Heart Association Class III/IV).
8. The subject has uncontrolled diabetes mellitus (glycosylated hemoglobin [HbA1c >9%]) or
diabetic polyneuropathy.
9. The subject has any other illness that significantly limits exercise capacity or other medical
condition, including any psychiatric disorder that limits participation (in the judgement of the
investigator).
10. The subject has received any prohibited medication (Section 7.3) within 14 days before 
Randomization (Day 1).
11. The subject has received any investigational compound within 30 days before Screening.
12. The subject has received actovegin as a therapeutic agent within 30 days prior Screening.
13. The subject is an immediate family member, study site employee, in a dependent
relationship with a study site employee who is involved in the conduct of this study (eg, 
spouse, parent, child, sibling), or may consent under duress.
14. The subject has, in the judgment of the investigator, clinically significant abnormal
hematological parameters of hemoglobin, hematocrit, or erythrocytes at Screening.
15. The subject has a history of hypersensitivity or allergies to actovegin or similar preparations
or the excipients.
16. The subject has a history of drug abuse (defined as any illicit drug use) or a history of alcohol
abuse within 6 months before Screening.
17. If female, the subject is pregnant or lactating or intending to become pregnant before
participating in this study and during the study, or intending to donate ova during such time 
period.
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18. The subject has participated in another clinical study within 30 days before Screening.
19. The subject is undergoing the supervised exercise training program by the time of Screening 
and is going to continue this program due to its effectiveness.
7.3
Excluded Medications and Treatments
Concomitant and prior medication should be checked carefully and documented in the electronic 
case report form (eCRF).
Medications that are prohibited during the course of the study are listed as follows:
Alprostadil and other prostaglandins
Angiogenic growth factors
Chronic use of nonsteroidal anti-inflammatory agents
Cilostazol
Ginkgo bilobae foliorum extract
L-carnitine
L-lysine aescinat
Naftidrofuryl
Nicotinic acid
Pentoxifylline
Sulodexide
Vincamine
Solcoseryl (nontopical forms)
L-arginine based compounds
A supervised exercise training program, hyperbaric oxygenation and any type of physiotherapy
that can potentially influence peripheral circulation will not be allowed during the study.
Concomitant medication for any other acute or chronic medical condition can be started or 
continued according to prescription by a healthcare professional. Subjects should be instructed 
not to take any medications, including over-the-counter products, without first consulting with 
the investigator. Additional information on concomitant PAD therapy is provided in 
Section 8.1.1.2.
7.4
Diet, Fluid, Activity Control, Treatment Facilities, and General Recommendations 
and Restrictions
It is expected that advice on lifestyle changes to minimize vascular risk factors (eg, smoking
cessation and regular physical exercise) has been given to all subjects before entering the 
study.
It is expected that the supervised exercise training program is tried for subjects before they are 
considered for entering the trial unless otherwise justified (supervised exercise training 
program was performed with no effect, or was recommended, but was not done due to subject 
related reasons). Proper documentation is required.
Smoking habits should be stable for at least 3 months at the time of Randomization (Day 1) and 
throughout the study. Smoking status and comedications will be assessed and documented. These 
therapies should be maintained at a stable level throughout the study.
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In addition, the treatment and status of glycemic control in diabetic patients and the occasional 
use of nonsteroidal anti-inflammatory agents may also affect PAD. These medications should be 
reviewed and documented in the eCRF. 
During the IV Treatment Period, either hospitalization or day hospital is required to provide this
treatment procedure.
7.5
Criteria for Discontinuation or Withdrawal of a Subject
The primary reason for discontinuation or withdrawal of the subject from the study or study drug
should be recorded in the eCRF using the following categories listed below. For screen failure 
subjects, refer to Section 9.1.15.
1. Pretreatment event (PTE) or AE. The subject has experienced a PTE or AE that requires early
termination because continued participation imposes an unacceptable risk to the subject’s 
health or the subject is unwilling to continue because of the PTE or AE.

Liver Function Test (LFT) Abnormalities
Study drug should be discontinued immediately with appropriate clinical follow-up
(including repeat laboratory tests, until a subject’s laboratory profile has returned to
normal/baseline status, see Section 9.1.10), if the following circumstances occur at any
time during study drug treatment:
–
alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >8 × the upper 
limit of normal (ULN), or
–
ALT or AST >5 × ULN and persists for more than 2 weeks, or
–
ALT or AST >3 × ULN in conjunction with elevated total bilirubin >2 × ULN, or
–
ALT or AST >3 × ULN with appearance of at least 1 of the next symptoms: fatigue,
nausea, vomiting, right upper quadrant pain or tenderness, fever, rash and/or 
eosinophilia (>5%).
2. Significant protocol deviation. The discovery post-randomization that the subject failed to
meet protocol entry criteria or did not adhere to protocol requirements, and continued
participation poses an unacceptable risk to the subject’s health.
3. Lost to follow-up. The subject did not return to the clinic and attempts to contact the subject
were unsuccessful. Attempts to contact the subject must be documented in the subject’s source
documents.
4. Voluntary withdrawal. The subject (or subject’s legally acceptable representative) wishes to
withdraw from the study. The reason for withdrawal, if provided, should be recorded in the
eCRF.
Note: All attempts should be made to determine the underlying reason for the withdrawal 
and, where possible, the primary underlying reason should be recorded (ie, withdrawal due 
to an AE should not be recorded in the “voluntary withdrawal” category. Similarly, lack of 
efficacy should not be recorded in the “voluntary withdrawal” category).
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5. Study termination. The sponsor, ethics committee, or regulatory agency terminates the study.
6. Pregnancy. The subject is found to be pregnant.
Note: If the subject is found to be pregnant, the subject must be withdrawn immediately. 
The procedure is described in Section 9.1.13.
7. Disease progression. There are clinical signs of critical limb ischemia (pain at rest, ulcer
formation, and gangrene) supported by instrumental methods which require revascularization
procedure.
8. Other.
Note: The specific reasons should be recorded in the “specify” field of the eCRF.
7.6
Procedures for Discontinuation or Withdrawal of a Subject
The investigator may discontinue a subject’s study participation at any time during the study when
the subject meets the study termination criteria described in Section 7.5. In addition, a subject may
discontinue his or her participation without giving a reason at any time during the study. Should a
subject’s participation be discontinued, the primary criterion for termination must be recorded by
the investigator. In addition, efforts should be made to perform all procedures scheduled for the
Early Termination Visit at the earliest possible date. The Early Termination Visit for subjects 
who discontinue the study before completing the Oral Treatment Period will be identical to 
Visit 5. The Early Termination Visit for subjects who discontinue the study after completing the 
Oral Treatment Period will be identical to the Final Follow-up visit. The Follow-up Period is not 
required for subjects who discontinue the study early. Discontinued or withdrawn subjects will 
not be replaced.
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8.0
CLINICAL STUDY MATERIAL MANAGEMENT
This section contains information regarding all medications and materials provided directly by the
sponsor, and/or sourced by other means, that are required by the study protocol, including
important sections describing the management of study material.
8.1
Study Drug and Materials
8.1.1
Dosage Form, Manufacturing, Packaging, and Labeling
In this protocol, the term study drug refers to actovegin (400 mg/10 mL and 200 mg) active and
matching placebo as described below. Study medication will be packed in a blinded fashion.
8.1.1.1
Investigational drug
Actovegin ampoules (400 mg/10 mL) and tablets (200 mg)
The study drug (actovegin) will be supplied as ampoules (400 mg/10 mL) and tablets (200 mg).
Actovegin (deproteinized hemoderivate) is commercially available both as ampoules and tablets.
The commercially available actovegin ampoules and tablets will be packed and labeled in a
blinded fashion by the contract manufacturing organization (
and therefore both products are considered investigational medicinal product.
Takeda GmbH, Austria is the original manufacturer of the 400 mg/10 mL actovegin ampoules.
One ampoule contains actovegin 400 mg in 10 mL water for injection. The solution is clear,
yellowish, and almost free from particles. The color can change to a stronger yellow color over the
course of the shelf life. Taking into account the color of the actovegin solution and the different 
design of the ampoules, an unblinded pharmacist will be included in the site study team and will 
be responsible for preparation of the investigational product (IP) during the IV treatment period.
The ampoules will be packed into 7-day (21 ampoules for 1 week plus 3 ampoules for 1 day) In-
Patient kits. Dosing consists of 3 ampoules daily.
Each ampoule will bear a multilingual booklet label or a single language label, including pertinent
study information. Each kit of 400 mg/10 mL actovegin will bear a multilingual booklet label or a
single language label that includes pertinent study information along with caution statement.
Takeda GmbH, Germany is the primary manufacturer of the 200 mg actovegin tablets. The tablets
are round, biconvex, bright greenish-yellow, film-coated, shiny, and bear no print.
The tablets will be packed into child-resistant bottles, containing a total of 50 tablets each. Dosing
consists of 6 tablets daily.
Each bottle of 200 mg actovegin will bear a multilingual booklet label or a single language label
that includes pertinent study information along with caution statement. Each bottle kit will also
bear a multilingual booklet label or a single language label that includes pertinent study
information along with caution statement.
Labels will be in the appropriate language where the study medication is dispensed.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
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Placebo ampoules and tablets
The placebo ampoules to match 400 mg actovegin ampoules will be commercially available
ampoules containing 10 mL 0.9% NaCl solution for infusion.
 is the original manufacturer of the placebo ampoules. The ampoules will 
be sourced, packed, and labeled at 
.
The placebo ampoules will be packed into 7-day (21 ampoules for 1 week plus 3 ampoules for 1
day) In-Patient kits. Dosing consists of 3 ampoules daily.
Each ampoule will bear a multilingual booklet label or a single language label, including pertinent
study information. Each kit of placebo ampoules will bear a multilingual booklet label or a single
language label that includes pertinent study information along with caution statement.
The placebo tablets to match 200 mg actovegin tablets will be manufactured by
and then packed and labeled
at 
.
The tablets will be packed into child-resistant bottles, containing a total of 50 tablets each. Dosing
consists of 6 tablets daily.
Each bottle of placebo tablets will bear a multilingual booklet label or a single language label that
includes pertinent study information along with caution statement. Each bottle kit will also bear a
multilingual booklet label or a single language label that includes pertinent study information
along with caution statement.
Labels will be in the appropriate language where the study medication is dispensed.
8.1.1.2
Companion Medication
Concomitant PAD Therapy 
Subjects should continue their current treatment for PAD and for prevention of cardiovascular 
events. These therapies should be optimized and stable for at least 2 weeks before Screening and 
throughout the study. 
Therapy for the treatment of PAD and for prevention of cardiovascular events includes:
–
Antiplatelet drugs and anticoagulants (except medications listed in Section 7.3).
–
Lipid-lowering agents.
–
Antihypertensive drugs.
In addition to the listed medications for PAD, the treatment and status of glycemic control in 
diabetic patients and the occasional use of nonsteroidal anti-inflammatory agents may also affect 
PAD. These medications should be reviewed and documented in the eCRF. 
Property of Takeda: For non-commercial use only and sub
 to the applicable Terms of Use
es will
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8.1.1.3
Ancillary Materials
The sponsor will further supply the sites with bags of 250 mL 0.9% NaCl solution for infusion, 
opaque infusion sets, cover bags for the infusion bags, and ancillary labels to affix to the cover 
bags at the sites.
 is the original manufacturer of 0.9% NaCl solution for infusion bags, 
250 mL.
8.1.1.4
Sponsor-Supplied Drug
Actovegin ampoules (400 mg/10 mL), tablets (200 mg), placebo ampoules, and placebo tablets will
be supplied by the sponsor. In addition, infusion bags containing 250 mL 0.9% NaCl solution for
infusion will be supplied by the sponsor. Opaque infusion sets, cover bags and ancillary labels for
the infusion bags will be supplied by the sponsor.
8.1.2
Storage
Study drug ie, actovegin ampoules (400 mg/10 mL), actovegin tablets (200 mg), placebo
ampoules, placebo tablets, and ancillary materials ie, 0.9% NaCl solution for infusion bags,
opaque infusion sets, cover bags, and ancillary labels must be kept in an appropriate, limited-
access, secure place until it is used or returned to the sponsor or designee for destruction. Study
drug, and ancillary materials must be stored under the conditions specified on the label (below 
25ºC [77ºF]; do not freeze), protected from light and remain in the original container until
dispensed. Please consult the Pharmacy Manual for further information. A daily temperature log 
of the drug storage area must be maintained every working day.
8.1.3
Dose and Regimen
8.1.3.1
IV Treatment Period (Week 0 to 2)
Each subject who satisfies the eligibility criteria will be randomly assigned to receive either
actovegin or placebo via interactive web response system. 
After Randomization (Visit 1, Day 1), subjects will receive 3 ampoules of either 
actovegin 400 mg/10 mL or placebo/10 mL in 250 mL 0.9% NaCl (total infusion volume will be 
280 mL) as a single infusion. The infusion rate will be about 2 mL per minute (40 to
50 drops/minute). Total infusion duration should not be less than 112 minutes. Subjects will 
receive 1 infusion per day for 14 days. Starting on Day 2, the start time of infusion should be the 
same as the start time of infusion on Day 1 ±2 hours. The investigator or designee must ensure
that the sponsor-supplied drug is prepared and administered according to the Pharmacy Manual.
IP infusions must be performed at the investigational site under medical supervision. During the 
first 15 minutes of the first infusion, the supervision should be carried out by the investigator (or 
designated physician) in order to detect possible allergic reactions and ensure urgent measures to 
prevent or treat them.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
on bags,
bags
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8.1.3.2
Oral Treatment Period (Week 3 to 12)
When the IV Treatment Period is over (Visit 2), subjects will be dispensed a box with 4 bottles
containing a total 200 tablets of actovegin 200 mg or placebo. Subjects will be instructed to take
2 tablets of actovegin 200 mg or placebo TID, in total 6 tablets per day starting the day after the 
end of the IV treatment period. Subjects will receive study drug for 4 weeks of treatment and the
subject will be reminded to bring the study medication bottle (including any unused study
medication) to the following study visit.
A further box with 4 bottles containing a total of 200 tablets of actovegin 200 mg or placebo will
be dispensed to the subjects at the third visit (Visit 3) so that the subjects will receive study drug
for another 4 weeks of treatment. Subjects will be instructed to take 2 tablets of actovegin 200 mg
or placebo TID, in total 6 tablets per day. The subject will also be reminded to bring the study
medication bottle (including any unused study medication) to the following study visit.
At the fourth visit (Visit 4), subjects will be dispensed a last box containing 2 bottles containing a
total of 100 tablets of actovegin 200 mg or placebo, so that they receive study drug for 2 weeks
treatment. Subjects will be instructed to take 2 tablets of actovegin 200 mg or placebo TID, in
total 6 tablets per day. The subject will also be reminded to bring the study medication bottle
(including any unused study medication) to the following study visit (Visit 5).
Thereafter, subjects will move into the follow-up phase where they will not receive any further
study drug.
Table 8.a describes the dose and ampoule/tablet count that will be provided to each group.
Table 8.a
Dose and Regimen
Treatment Group
Treatment Phase
Treatment Description
Treatment Dose
A
IV Treatment
Actovegin 400 mg/10 mL
3 ampoules in 0.9% NaCl 250 mL 
(1200 mg/280 mL IV infusion) per day
B
IV Treatment
Placebo/10 mL
3 ampoules in 0.9% NaCl 250 mL 
(280 mL IV infusion) per day 
A
Oral treatment
Actovegin 200 mg/tablet
6 tablets per day from bottle
B
Oral treatment
Placebo/tablet
6 tablets per day from bottle
8.1.4
Overdose
An overdose is defined as a known deliberate or accidental administration of study drug, to or by a
study subject, at a dose above that which is assigned to that individual subject according to the 
study protocol.
All cases of overdose (with or without associated AEs) will be documented on an overdose page
of the eCRF, in order to capture this important safety information consistently in the database.
Cases of overdose without manifested signs or symptoms are not considered AEs. AEs
associated with an overdose will be documented on AE eCRF(s) according to Section 10.0.
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Serious adverse events (SAEs) associated with overdose should be reported according to the
procedure outlined in Section 10.2.2.
There has been no experience of overdose with actovegin. According to nonclinical study data, 
actovegin does not show toxic effects with doses of up to 30 to 40 times higher than the dose 
recommended for human use.
No compound-specific instructions of overdose treatment exist. On the basis of its pharmacology, 
no undesirable effects would be anticipated. 
8.2
Study Drug Assignment and Dispensing Procedures
The investigator or the investigator’s designee will access the interactive response technology
(IRT) system at Screening to obtain the study-specific subject identification number (subject
number).
The investigator or the investigator’s designee will use the IRT system to randomize the subject
into the study. During this contact, the investigator or the investigator’s designee will provide the
necessary subject-identifying information, including the subject number assigned at Screening.
At drug-dispensing visits, the investigator or the investigator’s designee will again contact the IRT
system to register the visits. At Visits 1, 2, 3, and 4 for all subjects in both treatment groups, a
medication identification number (Med ID) will be assigned by the IRT system and provided to the
unblinded site pharmacist/nurse via email notification.
If sponsor-supplied drug is lost or damaged, the unblinded site pharmacist/nurse can request a
replacement from the IRT system.
8.3
Randomization Code Creation and Storage
Takeda randomization personnel or designee will generate the randomization schedule for the
study; an IRT system will be used in a centralized fashion for subject randomization and study
medication assignments.
All randomization information will be stored in a secured area, accessible only by authorized
personnel.
8.4
Study Drug Blind Maintenance
The study medication blind will be maintained using the IRT system. The principal investigator at
each study site will receive instructions on obtaining the medication assignment through the IRT
system.
Investigators, clinical site team staff involved in subject care or clinical examinations, statistical
team, data-management team, sponsor and CRO study teams, and subjects will be blinded 
regarding the type of therapy until the database lock, except an unblinded study monitor from the 
sponsor or a designee. Staff at the pharmacy (study nurse, pharmacist) will not be blinded. All 
bags and infusion system for infusions will be closed and sealed material does not allow the 
unauthorized opening, in order to maintain blinding.
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The site-designated study personnel will maintain the investigational drug blind information.
During regularly scheduled monitoring visits, an unblinded study monitor from the sponsor or a
designee will perform an inventory of investigational drug unassigned and assigned treatment
box/bottles. All assigned and unassigned treatment packages will be reconciled and returned to the
sponsor or a designee before study closure.
8.5
Unblinding Procedure
The study medication blind shall not be broken by the investigator unless information concerning
the study medication is necessary for the medical treatment of the subject. If possible, the
sponsor/designee should be notified before the study medication blind is broken. 
For unblinding a subject, the study medication blind can be obtained by accessing the IRT system. 
In case of IRT system unavailability, the investigator should follow the instructions for the backup 
unblinding system (provided as a separate document). The sponsor/designee must be notified 
immediately if the study medication blind is broken. The date, time, and reason the blind was 
broken must be recorded in the source documents and on the appropriate eCRF.
If any site personnel become unblinded, study medication must be stopped immediately and the
subject must be withdrawn from the study. The reason for withdrawal should be recorded as
“Significant Protocol Deviation.”
8.6
Accountability and Destruction of Sponsor-Supplied Drugs
Drug supplies will be counted and reconciled at the site before being returned to the sponsor or 
designee.
The investigator or designee must ensure that the sponsor-supplied drug (actovegin
ampoules/placebo, actovegin tablets/placebo) and ancillary material (0.9% NaCl solution for
infusion, opaque infusion sets, cover bags, and ancillary labels) is used in accordance with the 
protocol and is dispensed only to subjects enrolled in the study. To document appropriate use of 
sponsor-supplied drug, the investigator or designee must maintain records of all sponsor-supplied 
drug delivery to the site, site inventory, dispensation and use by each subject, and return to the 
sponsor or designee.
Upon receipt of sponsor-supplied drug, the investigator or designee must verify the contents of the
shipments against the packing list. The verifier should ensure that the quantity is correct, and the
medication is in good condition. If quantityand conditions are acceptable, investigator or designee
should acknowledge the receipt of the shipment by signing bottom half of the packing list and
sending by e-mail/fax per instructions provided on the form/by recording in the IRT system. If
there are any discrepancies between the packing list versus the actual product received, Takeda or
designee must be contacted to resolve the issue. The packing list should be filed in the
investigator’s essential document file.
The investigator or designee must maintain 100% accountability for all sponsor-supplied drugs
received and dispensed during his or her entire participation in the study. Proper drug
accountability includes, but is not limited to:
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
Continuously monitoring expiration dates (monitored via the IRT system).

Frequently verifying that actual inventory matches documented inventory.

Verifying that the log is completed for the Medication ID/other used to prepare each dose.

Verifying that all containers used are documented accurately on the log.

Verifying that required fields are completed accurately and legibly.

Unblinded site representative or unblinded monitor will review the randomization schedule
and subject dosing log to ensure all subjects received the correct dose of study drug.
If any dispensing errors or discrepancies are discovered, the sponsor must be notified immediately.
The IRT system will include all required information as a separate entry for each subject to whom
sponsor-supplied drug is dispensed.
The investigator or designee must record the current inventory of all sponsor-supplied drugs on a
sponsor-approved drug accountability log. The following information will be recorded at a
minimum: protocol number and title, name of investigator, site identifier and number, description
of sponsor-supplied drugs, expiry date and amount dispensed including initials, seal, or signature
of the person dispensing the drug, and the date and amount returned to the site by the subject, 
including the initials, seal, or signature of the person receiving the sponsor-supplied drug. The log 
should include all required information as a separate entry for each subject (by subject identifier)
to whom sponsor-supplied drug is dispensed.
The investigator or its designated site staff administering the study medication (actovegin/placebo
infusion) must complete an individual subject accountability log to document if infusion was
complete or if incomplete and study medication was returned to the pharmacy, including the date
and amount returned to the pharmacy, including initials, seal, or signature of the person
administering the infusion.
All study drug not returned to the site by a subject must be investigated by the site and
appropriately documented on the drug accountability log.
Before site closure or at appropriate intervals, a representative from the sponsor or its designee
will perform sponsor-supplied drug accountability and reconciliation before sponsor-supplied
drugs are returned to the sponsor or its designee for destruction. The investigator or designee will
retain a copy of the documentation regarding sponsor-supplied drug accountability, return, and/or
destruction, and originals will be sent to the sponsor or designee.
The investigator will be notified of any expiry date of sponsor-supplied drug during the study
conduct. On expiry date notification from the sponsor or designee, the site must complete all
instructions outlined in the notification, including segregation of expired sponsor-supplied drug
for return to the sponsor or its designee for destruction.
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9.0
STUDY PLAN
9.1
Study Procedures
The following sections describe the study procedures and data to be collected. For each procedure,
subjects are to be assessed by the same investigator or site personnel whenever possible. The
Schedule of Study Procedures is located in Appendix A.
9.1.1
Informed Consent Procedure
The requirements of the informed consent are described in Section 15.2.
Informed consent must be obtained before the subject entering into the study, and before any
protocol-directed procedures are performed.
A unique subject identification number (subject number) will be assigned to each subject at the
time that informed consent is obtained; this subject number will be used throughout the study.
9.1.2
Demographics, Medical History, and Medication History Procedure
Demographic information to be obtained will include date of birth, sex, and race as described by
the subject at Screening.
Medical history to be obtained will include determining whether the subject has any significant
conditions or diseases relevant to the disease under study that resolved at, or before, signing of
informed consent, including psychiatric history (any psychiatric disorders is exclusion criteria).
Ongoing conditions are considered concurrent medical conditions (Section 9.1.9).
Medication history information to be obtained includes any medication relevant to eligibility
criteria (Sections 7.1, 7.2, 7.3) stopped at 14 days before Randomization (Day 1).
9.1.3
Physical Examination Procedure
A baseline physical examination (defined as the assessment before the first dose of study drug) 
will consist of the following body systems: (1) eyes; (2) ears, nose, throat; (3) cardiovascular 
system; (4) respiratory system; (5) gastrointestinal system; (6) dermatologic system; 
(7) extremities; (8) musculoskeletal system; (9) nervous system; (10) lymph nodes; and 
(11) other. All subsequent physical examinations should assess clinically significant changes
from the assessment before the first dose examination.
9.1.4
Weight and Height
Weight and height of subjects should be measured while wearing indoor clothing and no shoes. 
Values are to be reported to 1 decimal place. Height will be measured at V1. Weight will be 
measured at V1, V5, and V8.
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9.1.5
Smoking Status and Physical Activity
Smoking status will be classified as follows: 
1. Never smoked.
2. Current smoker (information about years of smoking and current number of cigarettes per 
day will be collected).
3. Former smoker (information about years of smoking, approximate number of cigarettes 
smoked per day previously, and date of cessation will be collected).
For the purposes of the study, e-cigarette use should not be considered in determination of 
smoking history. One gram of tobacco = 1 cigarette.
Smoking status will be checked every study visit. 
Physical activity will be evaluated using the Physical Activity Questionnaire developed by FSI 
“National Medical Research Center for Preventative Medicine” of the Ministry of Healthcare of 
the Russian Federation as part of national clinical guidelines “Medical assistance for optimizing 
physical activity in adults.” 
Patients should be provided with the Physical Activity Questionnaire in a language in which they 
are fluent. The questionnaire contains 8 statements describing current level of patient’s physical 
activity, each statement is assigned to score from 1 (the lowest activity) to 8 (the highest 
activity). Patients should complete the Physical Activity Questionnaire by circling the statement 
that best describes their current physical activity. The investigator must check that the 
questionnaire is completed appropriately.
Physical activity level will be checked at every study visit.
9.1.6
Vital Sign Procedure
Vital signs will include blood pressure (systolic and diastolic) and pulse (beats/minute) after 
resting not less than 5 minutes in a sitting position. When vital signs are scheduled at the same 
time as blood draws, the blood draw will take priority and vital signs will be obtained within 
0.5 hours before or after the scheduled blood draw.
9.1.7
Efficacy Measurements
9.1.7.1
Treadmill testing
A treadmill is a device used for walking or running while staying in place. In this study, this
method will be used to define claudication distances. Claudication distance will be measured by 
using the constant workload protocol (constant speed 3.0 km/h and 10% grade on treadmill).
From signing of the informed consent during the screening period through the Randomization 
visit, the treadmill test will be conducted twice. The first test is to be performed during the 
Screening period. The screening period length should be a maximum of 2 weeks. The second
treadmill test should be repeated within a time interval of ≥1 week (ie, 7 days) from the first 
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treadmill test. It is acceptable for the second treadmill test to be completed on the day of 
Randomization (Day 1).
Subjects with high variability in ACD [>25% for the maximum claudication distance] will be
excluded. 
Variability of ACD will be calculated by the investigator using the formula:
ACD % of variation = [ACD Test 2 − ACD Test 1] / Test 1 × 100%
If a subject is randomized for the study therapy, the Day 1 testing will be used as Baseline.
The following steps should be followed for the treadmill test:

The test should be performed on a treadmill with changeable incline and speed.

The subject should take off their shoes and outerwear.

The subject should not have a meal within 3 hours before the test, and should avoid physical 
exercises and stress within 12 hours before the test. 

When the test starts, the subject will be placed on a treadmill and asked to prepare for 
walking. The investigator or designee should turn the treadmill on and set the incline and 
speed required by the protocol.

The subject is not allowed to hold onto the railings in order to avoid measurement bias.

The subject will be instructed, when beginning to experience pain or discomfort, to inform 
the investigator by saying a short word (eg, “pain” or “hurts”), and the investigator will 
record the distance from walking start to the pain appearance (initial claudication distance). 

The subject will then continue walking and then inform the investigator by saying a short 
word (eg, “done”) when he can no longer continue walking and needs rest. The investigator 
will record the distance from walking start to the point where the subject is unable to walk 
anymore (absolute claudication distance). 

The signal words should be agreed with the subject and investigator in advance of the test to 
avoid wasting time during the test. 

The distance walked by patient during incline and speed set up might be neglected.

As much as possible, the same assessor should be responsible for treadmill test results 
assessment at a given site.

As much as possible, assessor change throughout the study should be avoided.
9.1.7.2
SF-36
The SF-36 is a 36-item, patient-reported measure of health-related quality of life. The SF-36 has 
been extensively evaluated and tested with a variety of populations and is able to distinguish
between groups of varying health quality-of-life status in clinical trials [22,23]. The SF-36
consists of 8 sections (vitality, physical functioning, bodily pain, general health perceptions,
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physical role functioning, emotional role functioning, social role functioning, and mental health) 
that are the weighted sums of the questions in each health domain. Each scale is directly
transformed to a 0 to 100 scale on the assumption that each question carries equal weight. The
lower the score, the more disability, and the higher the score, the less disability, ie, a score of 
zero is equivalent to maximum disability and a score of 100 is equivalent to no disability.
A validated language-specific version of the SF-36 will be available for each participating 
country; patients should be provided with an SF-36 in a language in which they are fluent. 
Patients should complete the SF-36 at Visits 1, 5 and 8 (or End-of-Treatment) before any study-
related procedures are performed. The investigator must check that all questions are answered. 
9.1.8
Documentation of Concomitant Procedures and Medications
Concomitant medication is any drug given in addition to the study drug. These may be prescribed
by a physician or obtained by the subject over-the-counter. Concomitant medication is not provided
by the sponsor. At each study visit, subjects will be asked whether they have taken any medication
other than the study drug (used from signing of informed consent through the end of the study),
and all medication including vitamin supplements, over-the-counter medications, and oral herbal
preparations must be recorded in the eCRF. In addition, concomitant procedures will be collected 
and recorded in the eCRF.
9.1.9
Documentation of Concurrent Medical Conditions 
Concurrent medical conditions are those significant ongoing conditions or diseases that are present
at signing of informed consent. This includes clinically significant laboratory, ECG, or physical 
examination abnormalities noted at the screening examination, according the judgment of the 
investigator.
9.1.10 Ultrasound Color Duplex Imaging
Ultrasound color duplex imaging will be used at Screening for verification of the PAD diagnosis
and exclusion of other pathology that may lead to peripheral artery occlusion. The location of
arterial narrowing and occlusion will also be identified, and an aortoiliac or femoropopliteal 
lesion will be documented in the patient’s medical chart and case report form. The examination 
will be carried out on certified equipment by a qualified specialist of ultrasonic diagnostics in 
accordance with the generally accepted methodology. The examination will be performed 
according to local routine practice. Results (at a minimum, paper conclusion) should be stored 
together with other source documents. 
Ultrasound duplex imaging of the lower limb vessels is to be performed by the standard method.
Special preconditioning of the subject is not required. The subject will remove clothing from the 
lower limbs and then will be placed on the bed in the supine position. The subject should be 
advised to wear an underwear which opens inguinal folds, which is where the duplex imaging 
begins.
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After placing the subject on the bed and preparing him/her for the examination, the investigator
will apply ultrasound gel on the probe and run the probe along the main vessels of the leg. Both 
legs will be examined individually. If necessary, the subject may be asked to stand up to continue 
examination in the upright position.
Besides the standard parameters, the level (segment) of the vessel lesion (aortoiliac or 
femoropopliteal) and the lesion type (occlusion or stenosis) will be recorded.
The ankle brachial index (ABI) assessment will be performed by measuring the systolic blood 
pressure (BP) from both brachial arteries, posterior tibial arteries, and both dorsalis pedis 
arteries. 
Smoking and alcoholic or soft drinks are not allowed for patients during at least 2 hours before 
the procedure. The subject should be physically and emotionally relaxed for at least 30 minutes 
before the procedure. The measurement is to be performed in the supine position after the rest in 
this position for 10 minutes.
The blood pressure cuff should be placed as follows: right arm, left arm, then both lower limbs in 
any order.
The lower edge of the cuff should be at 3 to 5 cm superior to the elbow bend or 3 to 5 cm 
superior to the ankle-joint. The cuff should be inflated to stop the blood flow in the brachial 
artery or in the tibia, respectively. The cuff should then be slowly deflated and the pressure 
recorded when the first pulse wave appears. The systolic blood pressure of the artery at the 
appearance of the first pulse will then used for calculations. 
The systolic blood pressure from upper and lower limbs should be measured by a hand-held 
Doppler probe on 5-10 MHz. 
ABI should be calculated using the following formula:
ABI = ankle sBP/ brachial sBP
Ankle sBP is defined as the higher of two systolic BPs from a lower limb. Systolic BP of the 
postural tibial artery should be compared to systolic BP of the dorsalis pedis artery of the same 
leg, the highest value should be used for calculations. This will be repeated to determine the 
value for the opposite leg.
As a result, 2 ankle systolic BPs will be provided for ABI calculations.
Brachial sBP is defined as the higher of systolic BPs from both upper limbs. As a result, one 
brachial systolic BP will be provided for ABI calculations.
Blood pressure should be measured on both arms because of possible lesions of clavicular or 
axillary arteries in patients with PAD.
ABI calculations should yield in 2 values rounded to 2 decimal places. The worst (the lowest) 
ABI should be chosen for further investigations.
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9.1.11 Procedures for Clinical Laboratory Samples
All samples will be collected under fasting conditions (at least 8 hours after the last meal) and in
accordance with acceptable local laboratory procedures. The maximum volume of blood
collected at any single visit will be approximately 15 mL, with an approximate total volume of
blood collection over the course of the study of 45 mL.
Timing of collection for clinical laboratory testing is provided in Table 9.a and Appendix A.
Table 9.a
Clinical Laboratory Tests
Hematology
Serum Chemistry
Urinalysis
Hemoglobin
Glucose
HbA1c (for Screening only) (a)
Creatinine
Glucose
Hematocrit
Total bilirubin (b)
Nitrites
Erythrocytes
Alkaline phosphatase
Erythrocytes
Thrombocytes
Albumin
Leucocytes
Leukocytes
AST
Protein
White blood cell count (d)
ALT
γ-glutamyl transferase (GGT)
Creatine kinase
Sodium
Potassium
Cholesterol (total, high-density 
lipoprotein, and low-density
lipoprotein)
Triglycerides
Diagnostic Screening:
Serum
Urine
Human chorionic gonadotropin (hCG), female subjects (c)
hCG (female subjects)
(a) HbA1c at Screening for eligibility assessment.
(b) If values are above the normal range, then direct and indirect bilirubin will be determined.
(c) At Screening. 
(d) Must include numbers of segmented neutrophils and band cells.
The local laboratory will perform laboratory tests for hematology, serum chemistries, and 
urinalysis. The results of laboratory tests will be returned to the investigator, who is responsible 
for reviewing and filing these results.
If subjects experience ALT or AST >3 ×ULN, follow-up laboratory tests (at a minimum, serum
alkaline phosphatase, ALT, AST, total bilirubin, and GGT should be performed within a
maximum of 7 days and preferably within 48 to 72 hours after the abnormality was noted. (Refer to 
Section 7.5 and Section 10.2.3 for the appropriate guidance on reporting abnormal liver function
tests.)
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If ALT or AST remains elevated >3 ×ULN on these 2 consecutive occasions the investigator must
contact the Medical Monitor for consideration of additional testing, close monitoring, possible
discontinuation of study drug, discussion of the relevant subject details and possible alternative
etiologies. The abnormality should be recorded as an AE (please refer to Section 10.2.3).
The investigator will maintain a copy of the laboratory accreditation and the reference ranges for
the laboratory used.
9.1.12 Contraception and Pregnancy Avoidance Procedure
9.1.12.1 Male Subjects and Their Female Partners
From the signing of the informed consent, throughout the duration of the study or for 30 days 
after the last dose of study drug (in case of early study termination), nonsterilized male subjects 
who are sexually active with a female partner of childbearing potential must use barrier 
contraception (eg, condom with or without spermicidal cream or jelly). In addition, they must be
advised not to donate sperm during this period. Females of childbearing potential who are 
partners of male subjects are also advised to use additional contraception as shown in the list of 
highly effective/effective contraception (Section 9.1.12.3).
9.1.12.2 Female Subjects and Their Male Partners
From the signing of the informed consent, throughout the duration of the study or for 30 days 
after the last dose of study drug (in case of early study termination), female subjects of 
childbearing potential who are sexually active with a nonsterilized male partner must use a highly
effective/effective method of contraception (Section 9.1.12.3).
In addition, they must be advised not to donate ova during this period.
9.1.12.3 Definitions and Procedures for Contraception and Pregnancy Avoidance
The following definitions apply for contraception and pregnancy avoidance procedures.
A postmenopausal state is defined as no menses for 12 months without an alternative medical 
cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range (FSH 
>40 IU/L) may be used to confirm a post-menopausal state in younger women (eg, those 
<45 year old) or women who are not using hormonal contraception or hormonal replacement 
therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is 
insufficient.
Sterilized males should be at least 1 year post-bilateral vasectomy and have confirmed that 
they have obtained documentation of the absence of sperm in the ejaculate or have had bilateral
orchidectomy.
The following procedures apply for contraception and pregnancy avoidance.
1. Highly effective methods of contraception are defined as those, alone or in combination, that
result in a low failure rate (ie, less than 1% failure rate per year when used consistently and
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correctly). In this study, where medications and devices containing hormones are included, the
acceptable methods of highly effective contraception are:

Nonhormonal methods:
–
Intrauterine device.
–
Bilateral tubal occlusion.
–
Vasectomized partner (provided that partner is the sole sexual partner of the study
participant and that the vasectomized partner has received medical assessment of the
surgical success).

Hormonal methods:
–
Combined (estrogen and progestogen) hormonal contraception associated with
inhibition of ovulation initiated at least 3 months before the first dose of study drug 
OR combined with a barrier method (male condom, female condom or diaphragm) if
for shorter duration until she has been on contraceptive for 3 months:

Oral.

Intravaginal (eg, ring).

Transdermal.
–
Progestogen-only hormonal contraception associated with inhibition of ovulation
initiated at least 3 months before the first dose of study drug OR combined with a
barrier method (male condom, female condom or diaphragm) if shorter till she has
been on contraceptive for 3 months:

Oral.

Injectable.

Implantable.
2. Effective methods of contraception are defined as those that result in a low failure rate that may
be higher than a 1% failure rate. In this study, where medications and devices containing
hormones are included, the acceptable effective methods of contraception are:

Double-barrier method (contraceptive sponge, diaphragm or cervical cap with
spermicidal jellies or creams PLUS male condom).

Progestogen only hormonal contraception, where inhibition of ovulation is not the
primary mode of action PLUS condom with or without spermicide.
3. Unacceptable methods of contraception are:

Periodic abstinence (eg, calendar, ovulation, symptothermal, post-ovulation methods).

Spermicides only.

Withdrawal.
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
No method at all.

Use of female and male condoms together.

Cap/diaphragm/sponge without spermicide and without condom.

Sexual abstinence is NOT an acceptable method of contraception.
4. Subjects will be provided with information on highly effective and effective methods of
contraception as part of the subject informed consent process and will be asked to sign a
consent form stating that they understand the requirements for avoidance of pregnancy, 
donation of ova, and sperm donation during the course of the study.
5. During the course of the study, regular urine hCG pregnancy tests will be performed only for
women of childbearing potential and all subjects (male and female) will receive continued
guidance with respect to the avoidance of pregnancy and sperm donation as part of the study
procedures. Such guidance should include a reminder of the following:
a) Contraceptive requirements of the study.
b) Assessment of subject compliance through questions such as:
i.
Have you used the contraception consistently and correctly since the last visit?
ii.
Have you forgotten to use contraception since the last visit?
iii.
Are your menses late (even in women with irregular or infrequent menstrual cycles a 
pregnancy test must be performed if the answer is “yes”)
iv.
Is there a chance you could be pregnant?
6. In addition to a negative serum hCG pregnancy test at Screening, female subjects of
childbearing potential must also have confirmed menses in the month before first dosing (no
delayed menses), and a negative urine hCG pregnancy test at the Randomization (Baseline)
Visit before receiving any dose of the study drug.
9.1.13 Pregnancy
If any subject is found to be pregnant during the study, she should be withdrawn and any
sponsor-supplied drug should be immediately discontinued. In addition, any pregnancies in the 
partner of a male subject during the study or for 30 days after the last dose (in case of early study 
termination) should also be recorded following authorization from the subject’s partner.
If the pregnancy occurs during administration of the study drug, eg, after Visit 1 or within
30 days of the last dose of the study drug, the pregnancy should be reported immediately, using a 
pregnancy notification form, to the contact listed in Section 1.1.
Should the pregnancy occur during or after administration of blinded drug, the investigator must
inform the subject of their right to receive treatment information. If the subject chooses to receive
unblinded treatment information, the individual blind should be broken by the investigator.
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If the female subject and/or female partner of a male subject agrees to the primary care physician
being informed, the investigator should notify the primary care physician that the female subject or
female partner of the male subject was participating in a clinical study at the time she became
pregnant and provide details of the study drug the subject received (blinded or unblinded, as
applicable).
All pregnancies, including female partners of male subjects, in subjects on active study drug will
be followed up to final outcome, using the pregnancy form. Pregnancies will remain blinded to the
study team. The outcome, including any premature termination, must be reported to the sponsor.
An evaluation after the birth of the child will also be conducted.
9.1.14 ECG Procedure
A standard 12-lead ECG will be recorded. The investigator (or a qualified observer at the study
site) will interpret the ECG using 1 of the following categories: within normal limits, abnormal
but not clinically significant, or abnormal and clinically significant. A copyof the ECG trace
should be kept with the subject’s study source documentation.
9.1.15 Documentation of Screen Failure
Investigators must account for all subjects who sign informed consent. If the subject is withdrawn
at the Screening Visit, the investigator should complete the eCRF.
The data to be collected in eCRF for Screen Failures as a minimum: subject number and initials,
date of informed consent, demographic data, inclusion/exclusion criteria, PTEs/SAEs, date of
screen failure.
The primary reason for screen failure is recorded in the eCRF using the following categories:

PTE/AE.

Did not meet inclusion criteria or did meet exclusion criteria <specify reason>.

Significant protocol deviation.

Lost to follow-up.

Voluntary withdrawal <specify reason>.

Study termination.

Other <specify reason>.
Subject identification numbers assigned to subjects who fail Screening should not be reused.
9.1.16 Documentation of Randomization
Only subjects who meet all of the inclusion criteria and none of the exclusion criteria are eligible
for randomization into the treatment phase.
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If the subject is found to be not eligible for randomization, the investigator should record the
primary reason for failure on the applicable eCRF.
9.2
Monitoring Subject Treatment Compliance
During the IV Treatment Period, the daily IV infusions will be recorded on an infusion log. The
following data will be recorded:

Kit details.

Infusion date.

Start time.

Stop time.

Initials of person administering IMP.

Infusion successfully completed; yes or no.

Comments.
During the OralTreatment Period, the investigator must check subject compliance by counting the
number of returned tablets at time points specified in the clinical study overview. Subjects will be
required to bring the dispensed study medication bottles to each site visit. All cases of lost or 
damaged tablets must be documented.
Treatment compliance will be calculated by the investigator at Visits 3, 4, and 5 using the formula:
Compliance in % = 
100 × (number of tablets dispensed – number of tablets returned*) / (expected number of tablets 
to be taken)
Whereby expected number of tablets to be taken = 
6 × (date of last dose – date of first dose + 1) - 2 × (3 - time of last dose) - 2 × (time of first 
dose - 1)
Where time of first/last dose of medication equal to

1 for Morning dose

2 for Daytime dose

3 for Evening dose
* Returned tablets include lost/damaged tablets, those that were expected to be returned.
These data will subsequently be recorded in the eCRF by site personnel.
Subjects will be considered to be non-compliance with study medication if they miss > 20% of 
doses required for the visit period, or to take more than 120% of the doses for the treatment period 
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since last visit. If these criteria for noncompliance are met protocol deviation is to be reported. 
Any detected overdose (Section 8.1.4) must be reported on an Overdose page of the eCRF.
In case of a compliance deviation, all subjects should be reinstructed about the dosing 
requirements during study contacts. The authorized study personnel conducting the re-education 
must document the process in the source records.
If a subject is persistently noncompliant with the study drug (eg, compliance for 2 subsequent 
visits is outside of 80% to 120%), it should be reported as a significant protocol deviation and 
may be appropriate (based on investigator’s judgment) to withdraw the subject from the study.
9.3
Schedule of Observations and Procedures
The schedule for all study-related procedures for all evaluations is shown in Appendix A. 
Assessments should be completed at the designated visit/time point(s).
9.3.1
Screening Period
Screening is considered to be started from the moment of informed consent form signed. Subjects 
will be screened 1 to 2 weeks before Randomization. Subjects will be screened in accordance 
with predefined inclusion and exclusion criteria as described in Section 7.0. See Section 9.1.15
for procedures for documenting screening failures.
The following will be recorded or conducted at Screening (Visit 0):

Informed consent.

Demographics.

Medical history and concurrent medical conditions.

Medication history.

Concomitant medications.

PTEs.

Physical examination.

Vital signs.

Smoking status and physical activity.

12-lead ECG procedure.

Clinical laboratory tests.

Serum hCG pregnancy test (for female subjects of childbearing potential only) and oral 
confirmation of menses in the month before first dosing (no delayed menses).

Ultrasound color duplex imaging.
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
Treadmill testing (up to 2 tests are to be done during the screening period. The second 
treadmill test should be repeated in ≥1 week (ie, 7 days) after the first treadmill test. It is 
acceptable for the second treadmill test to be completed on the day of randomization).

Inclusion/exclusion criteria.
9.3.2
Randomization (Baseline), Day 1 Visit 1
Randomization will take place on Day 1.
The following will be recorded or conducted at Randomization (Visit 1):

Inclusion/exclusion criteria.

SF-36 (before any procedure).

PTEs.

Smoking status and physical activity.

Treadmill testing (this may be the second test within screening period to verify that results of 
both tests are within 25%) (Sections 7.2 and 9.1.7.1; Appendix A).

Urine pregnancy test (for female subjects of childbearing potential only). 

Assessment of subject compliance with contraception requirements. 

Physical examination.

Vital signs.

Weight and height.

Concomitant medications.

Medication history.
If the subject has satisfied all of the inclusion criteria and none of the exclusion criteria for
randomization, the subject should be randomized using the IRT system, as described in 
Section 8.2.
9.3.3
Infusion (IV) Treatment Period
Following Randomization, subjects will enter the IV Treatment Period (Day 1 Visit 1 until Day 14
Visit 2), during which they receive daily infusions of actovegin or placebo (up to a maximum of
14 infusions).
IP Infusions must be performed in the investigational site under medical supervision. During the 
first 15 min of the first infusion such supervision should be carried out by Investigator (or 
designated physician) in order to find out promptly possible allergic reactions and to be able to 
take urgent measures to prevent or treat them.
The following will be recorded during the IV Treatment Period from Day 1 to Day 13:
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
AEs (at Day 1 after the first infusion). Starting on Day 2, AEs should be checked before 
(since previous infusion) and after the infusion.
9.3.4
End-of-IV Treatment, Day 14, Visit 2
The End-of-IV treatment is defined as the day of the last infusion (Day 14) and before the
initiation of oral treatment. The assessments required at this visit should take place following the
final infusion. For subjects who terminate the study before completing the IV treatment period, 
the Early Termination Visit will be Visit 5.
The End-of-IV visit and subsequent switch to oral treatment may either be performed while the
subject is still hospitalized or upon discharge in accordance with the subject’s needs.
The following will be recorded or conducted at the End-of-IV treatment visit (Visit 2):

AEs (before infusion [since last visit] and after the infusion).

Concomitant medications.

Smoking status and physical activity.

Treadmill testing.

Urine pregnancy test (for female subjects of childbearing potential only).

Assessment of subject compliance with contraception requirements.

Study drug dispensation for oral treatment.
9.3.5
Oral Treatment Period
The Oral Treatment Period is defined as the period from the day after the last infusion until 12
weeks after Randomization (Days 15 to 84). During the Oral Treatment Period, the subject will
visit the site on Day 42 (±2 days) Visit 3 and Day 70 (±2 days) Visit 4.
The following will be recorded or conducted during the Oral Treatment Period (Visits 3 and 4):

AEs (since last visit).

Concomitant medications.

Smoking status and physical activity.

Urine pregnancy test (for female subjects of childbearing potential only).

Assessment of subject compliance with contraception requirements.

Study drug dispensation for oral treatment.

Return study drug for oral treatment.

Study drug compliance check.
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9.3.6
End-of-Oral Treatment, Day 84, Visit 5 /Early Termination Visit
The End-of-Oral Treatment Visit will occur on the last day of oral dosing at Week 12 (Day 84
±2 days). This will also be the Early Termination Visit for subjects who terminate the study
before completing the Oral Treatment Period.
The following will be recorded or conducted at the End-of-Oral Treatment Visit (Visit 5):

AEs (since last visit).

Physical examination.

Vital signs.

Weight.

Concomitant medications.

Smoking status and physical activity.

SF-36 (before any procedure).

Clinical laboratory tests.

Urine pregnancy test (for female subjects of childbearing potential only).

Assessment of subject compliance with contraception requirements.

Treadmill testing.

Return study drug for oral treatment.

Study drug compliance check.
9.3.7
Follow-up Period
A 12-week Follow-up Period will begin the first day after the End-of-Oral Treatment Visit
(Visit 5), during which, subjects will visit the site every 4 weeks at Day 112 (±5 days) Visit 6 and
Day 140 (±5 days) Visit 7.
The following will be recorded during each Follow-Up visit (Visits 6 and 7):

AEs (since last visit).

Concomitant medications.

Smoking status and physical activity.

Urine pregnancy test (for female subjects of childbearing potential only).

Assessment of subject compliance with contraception requirements.
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9.3.8
Final Follow-up Visit/Early Termination Visit
The Final Follow-up Visit will occur on the last day of the Follow-up Period (Day 168 ±2 days).
This will also be the Early Termination Visit for subjects who terminate the study during the
Follow-up Period.
The following will be recorded or conducted at the Final Follow-up Visit (Visit 8):

AEs (since last visit).

Physical examination.

Vital signs.

Weight.

Concomitant medications.

Smoking status and physical activity.

Clinical laboratory tests.

Urine pregnancy test (for female subjects of childbearing potential only).

Assessment of subject compliance with contraception requirements.

Treadmill testing.

SF-36 (before any procedure).
For all subjects receiving study drug, the investigator must complete the End of Study eCRF page.
9.3.9
Post Study Care
Study drug will not be available upon completion of the subject’s participation in the study. The
subject should be returned to the care of a physician and standard therapies as required.
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10.0
PRETREATMENT EVENTS AND ADVERSE EVENTS
10.1
Definitions
10.1.1 PTEs
A PTE is defined as any untoward medical occurrence in a clinical investigation subject who has
signed informed consent to participate in a study but before the administration of any study drug;
it does not necessarily have to have a causal relationship with study participation.
10.1.2 AEs
An AE is defined as any untoward medical occurrence in a clinical investigation subject
administered a drug; it does not necessarily have to have a causal relationship with this treatment.
An AE can therefore be any unfavorable and unintended sign (eg, an abnormal laboratory value),
symptom, or disease temporally associated with the use of a drug whether or not it is considered 
related to the drug.
10.1.3 Additional Points to Consider for PTEs and AEs
An untoward finding generally may:

Indicate a new diagnosis or unexpected worsening of a pre-existing condition. (Intermittent
events for pre-existing conditions or underlying disease should not be considered PTEs or
AEs.)

Necessitate therapeutic intervention.

Require an invasive diagnostic procedure.

Require discontinuation or a change in dose of study drug or a concomitant medication.

Be considered unfavorable by the investigator for any reason.
PTEs/AEs caused by a study procedure (eg, a bruise after blood draw) should be recorded as a
PTE/AE.
Diagnoses vs signs and symptoms:

Each event should be recorded to represent a single diagnosis. Accompanying signs (including
abnormal laboratory values or ECG findings) or symptoms should NOT be recorded as
additional AEs. If a diagnosis is unknown, sign(s) or symptom(s) should be recorded
appropriately as a PTE(s) or as an AE(s).
Laboratory values and ECG findings:

Changes in laboratory values or ECG findings are only considered to be PTEs or AEs if they
are judged to be clinically significant (ie, if some action or intervention is required or if the
investigator judges the change to be beyond the range of normal physiologic fluctuation). A 
laboratory or ECG retest and/or continued monitoring of an abnormal value or finding is not
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considered an intervention. In addition, repeated or additional noninvasive testing for
verification, evaluation or monitoring of an abnormality is not considered an intervention.

If abnormal laboratory values or ECG findings are the result of pathology for which there is
an overall diagnosis (eg, increased creatinine in renal failure), the diagnosis only should be
reported appropriately as a PTE or as an AE.
Pre-existing conditions:

Pre-existing conditions (present at the time of signing of informed consent) are considered
concurrent medical conditions and should NOT be recorded as PTEs or AEs. Baseline
evaluations (eg, laboratory tests, ECG, X-rays etc.) should NOT be recorded as PTEs unless
related to study procedures. However, if the subject experiences a worsening or complication
of such a concurrent medical condition, the worsening or complication should be recorded
appropriately as a PTE (worsening or complication occurs before start of study drug) or an AE
(worsening or complication occurs after start of study drug). Investigators should ensure that
the event term recorded captures the change in the condition (eg, “worsening of…”).

If a subject has a pre-existing episodic concurrent medical condition (eg, asthma, epilepsy),
any occurrence of an episode should only be captured as a PTE/AE if the condition becomes
more frequent, serious, or severe in nature. Investigators should ensure that the AE term 
recorded captures the change in the condition from Baseline (eg “worsening of…”).

If a subject has a degenerative concurrent medical condition (eg, cataracts, rheumatoid
arthritis), worsening of the condition should only be recorded as a PTE/AE if occurring to a
greater extent to that which would be expected. Investigators should ensure that the AE term
recorded captures the change in the condition (eg, “worsening of…”).
Worsening of PTEs or AEs:

If the subject experiences a worsening or complication of a PTE after the start of study drug, 
the worsening or complication should be recorded as an AE. Investigators should ensure that
the AE term recorded captures the change in the PTE (eg, “worsening of…”).

If the subject experiences a worsening or complication of an AE after any change in study
drug, the worsening or complication should be recorded as a new AE. Investigators should
ensure that the AE term recorded captures the change in the condition (eg, “worsening
of…”).
Changes in intensity of AEs /serious PTEs:

If the subject experiences changes in intensity of an AE/serious PTE, the event should be
captured once with the maximum intensity recorded.
Preplanned procedures (surgeries or interventions):

Preplanned procedures (surgeries or therapies) that were scheduled before the signing of
informed consent are not considered PTEs or AEs. However, if a preplanned procedure is
performed early (eg, as an emergency) due to a worsening of the pre-existing condition, the 
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worsening of the condition should be recorded as a PTE or an AE. Complications resulting
from any planned surgery should be reported as AEs.
Elective surgeries or procedures:

Elective procedures performed where there is no change in the subject’s medical condition
should not be recorded as PTEs or AEs, but should be documented in the subject’s source
documents. Complications resulting from an elective surgery should be reported as AEs.
Insufficient clinical response (lack of efficacy):

Insufficient clinical response, efficacy, or pharmacologic action, should NOT be recorded as
an AE. The investigator must make the distinction between exacerbation of pre-existing illness
and lack of therapeutic efficacy.
Overdose:

Cases of overdose with any medication without manifested side effects are NOT considered
PTEs or AEs, but instead will be documented on an Overdose page of the eCRF. Any
manifested side effects will be considered PTEs or AEs and will be recorded on the AE page of
the eCRF.
10.1.4 SAEs
An SAE is defined as any untoward medical occurrence that at any dose:
1. Results in DEATH.
2. Is LIFE THREATENING.

The term “life threatening” refers to an event in which the subject was at risk of death at the
time of the event; it does not refer to an event that hypothetically might have caused 
death if it were more severe.
3. Requires inpatient HOSPITALIZATION or prolongation of existing hospitalization.
4. Results in persistent or significant DISABILITY/INCAPACITY.
5. Leads to a CONGENITAL ANOMALY/BIRTH DEFECT.
6. Is an IMPORTANT MEDICAL EVENT that satisfies any of the following:

May require intervention to prevent items 1 through 5 above.

May expose the subject to danger, even though the event is not immediately life 
threatening or fatal or does not result in hospitalization.

Includes any event or synonym described in the Takeda Medically Significant AE List
(Table 10.a).
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Table 10.a
Takeda Medically Significant AE List
Term
Acute respiratory failure/acute respiratory distress
syndrome
Hepatic necrosis
Torsade de pointes/ventricular fibrillation/ventricular 
tachycardia
Acute liver failure
Anaphylactic shock
Malignant hypertension 
Acute renal failure
Convulsive seizure
Pulmonary hypertension
Agranulocytosis
Pulmonary fibrosis
Aplastic anemia
Confirmed or suspected endotoxin shock
Toxic epidermal necrolysis/Stevens-Johnson syndrome 
Confirmed or suspected transmission of infectious agent
bya medicinal product 
Neuroleptic malignant syndrome / malignant 
hyperthermia
Spontaneous abortion / stillbirth and fetal death
Note: Terms identified on the Medically Significant AE List represent the broad medical concepts to be considered as
“Important Medical Events” satisfying SAE reporting requirements.
PTEs that fulfill 1 or more of the serious criteria above are also to be considered SAEs and should
be reported and followed up in the same manner (see Sections 10.2.2 and 10.3).
10.1.5 AESIs
AESIs in this study include the following.

Hypersensitivity:
Hypersensitivity or AEs relating to hypersensitivity.

Transmission of bovine infective agents:
Prion-associated disorders, iatrogenic infections, suspected transmission or transmission 
of an infectious agent via product, and encephalopathy.

Transmission of infectious agents – lack of sterility:
All AEs of infections.

Off-label use as an athletic performance enhancer:
Intentional product misuse.
10.1.6 Intensity of PTEs and AEs
The different categories of intensity (severity) are characterized as follows:
Mild:
The event is transient and easily tolerated by the subject.
Moderate:
The event causes the subject discomfort and interrupts the subject’s usual activities.
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Severe:
The event causes considerable interference with the subject’s usual activities.
10.1.7 Causality of AEs
The relationship of each AE to study drug(s) will be assessed using the following categories:
Related:
An AE that follows a reasonable temporal sequence from administration of a drug (including 
the course after withdrawal of the drug), or for which possible involvement of the drug cannot 
be ruled out, although factors other than the drug, such as underlying diseases, complications, 
concomitant medications and concurrent treatments, may also be responsible.
Not Related:
An AE that does not follow a reasonable temporal sequence from administration of a drug 
and/or that can reasonably be explained by other factors, such as underlying diseases, 
complications, concomitant medications, and concurrent treatments.
10.1.8 Relationship to Study Procedures
Relationship (causality) to study procedures should be determined for all PTEs and AEs.
The relationship should be assessed as Related if the investigator considers that there is reasonable
possibility that an event is due to a study procedure. Otherwise, the relationship should be assessed
as Not Related.
10.1.9 Start Date
The start date of the AE/PTE is the date that the first signs/symptoms were noted by the subject
and/or investigator.
10.1.10 Stop Date
The stop date of the AE/PTE is the date at which the subject recovered, the event resolved but with
sequelae or the subject died.
10.1.11 Frequency
Episodic AEs/PTE (eg, vomiting) or those which occur repeatedly over a period of consecutive
days are intermittent. All other events are continuous.
10.1.12 Action Concerning Study Drug

Drug withdrawn – a study drug is stopped due to the particular AE.

Dose not changed – the particular AE did not require stopping a study drug.

Unknown – only to be used if it has not been possible to determine what action has been taken.

Not applicable – a study drug was stopped for a reason other than the particular AE eg, the
study has been terminated, the subject died, dosing with study drug was already stopped before
the onset of the AE.
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10.1.13 Outcome

Recovered/resolved – Subject returned to first assessment status with respect to the AE/PTE.

Recovering/resolving – the intensity is lowered by 1 or more stages: the diagnosis or
signs/symptoms has almost disappeared; the abnormal laboratory value improved, but has not
returned to the normal range or to Baseline; the subject died from a cause other than the
particular AE/PTE with the condition remaining “recovering/resolving.”

Not recovered/not resolved – there is no change in the diagnosis, signs or symptoms; the
intensity of the diagnosis, signs/ symptoms or laboratory value on the last day of the observed
study period has got worse than when it started; is an irreversible congenital anomaly; the
subject died from another cause with the particular AE/PTE state remaining “Not
recovered/not resolved”.

Resolved with sequelae – the subject recovered from an acute AE/PTE but was left with
permanent/significant impairment (eg, recovered from a cardiovascular accident but with
some persisting paresis.

Fatal – the AEs/PTEs which are considered as the cause of death.

Unknown – the course of the AE/PTE cannot be followed up due to hospital change or
residence change at the end of the subject’s participation in the study.
10.2
Procedures
10.2.1 Collection and Reporting of AEs
10.2.1.1 PTE and AE Collection Period
Collection of PTEs will commence from the time the subject signs the informed consent to
participate in the study and continue until the subject is first administered study drug (Study
Visit 1) or until screen failure. For subjects who discontinue before study drug administration,
PTEs are collected until the subject discontinues study participation.
Collection of AEs will commence from the time that the subject is first administered study drug
(Study Visit 1). Routine collection of AEs will continue until Study Visit 8.
10.2.1.2 PTE and AE Reporting
At each study visit, the investigator will assess whether any subjective AEs have occurred. A
neutral question, such as “How have you been feeling since your last visit?” may be asked.
Subjects may report AEs occurring at any other time during the study. Subjects experiencing a
serious PTE must be monitored until the symptoms subside and any clinically relevant changes in
laboratory values have returned to Baseline or there is a satisfactory explanation for the change.
Nonserious PTEs, related or unrelated to the study procedure, need not to be followed-up for the
purposes of the protocol.
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All subjects experiencing AEs, whether considered associated with the use of the study drug or
not, must be monitored until the symptoms subside and any clinically relevant changes in
laboratory values have returned to Baseline or until there is a satisfactory explanation for the
changes observed. All PTEs and AEs will be documented in the PTE/AE page of the eCRF,
whether or not the investigator concludes that the event is related to the drug treatment. The
following information will be documented for each event:
1. Event term.
2. Start and stop date.
3. Frequency.
4. Intensity.
5. Investigator’s opinion of the causal relationship between the event and administration of study
drug(s) (related or not related) (not completed for PTEs).
6. Investigator’s opinion of the causal relationship to study procedure(s), including the details of
the suspected procedure.
7. Action concerning study drug (not applicable for PTEs).
8. Outcome of event.
9. Seriousness.
10.2.2 Collection and Reporting of SAEs
When an SAE occurs through the AE collection period it should be reported according to the 
following procedure:
A Takeda SAE form must be completed, in English and signed by the investigator immediately or
within 24 hours of first onset or notification of the event. The information should be completed as
fully as possible but contain, at a minimum:
A short description of the event and the reason why the event is categorized as serious.

Subject identification number.

Investigator’s name.

Name of the study drug(s)

Causality assessment.
The SAE form should be transmitted within 24 hours to the attention of the contact listed in
Section 1.1.
Any SAE spontaneously reported to the investigator following the AE collection period should be
reported to the sponsor if considered related to study participation.
Reporting of Serious PTEs will follow the procedure described for SAEs.
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10.2.3 Reporting of Abnormal LFTs
If a subject is noted to have ALT or AST elevated >3 ×ULN on 2 consecutive occasions, the
abnormality should be recorded as an AE. In addition, an LFT Increases eCRF must be completed
providing additional information on relevant recent history, risk factors, clinical signs and
symptoms and results of any additional diagnostic tests performed.
If a subject is noted to have ALT or AST >3 ×ULN and total bilirubin >2 ×ULN for which an
alternative etiology has not been identified, the event should be recorded as an SAE and reported
as per Section 10.2.2. The investigator must contact the Medical Monitor for discussion of the
relevant subject details and possible alternative etiologies, such as acute viral hepatitis A or B or
other acute liver disease or medical history/concurrent medical conditions. Follow-up laboratory
tests as described in Section 9.1.10 must also be performed. In addition, an LFT Increases eCRF
must be completed and transmitted with the Takeda SAE form (as per Section 10.2.2).
10.3
Follow-up of SAEs
If information not available at the time of the first report becomes available at a later date, the
investigator should complete a follow-up SAE form or provide other written documentation and
fax or e-mail it immediately within 24 hours of receipt. Copies of any relevant data from the 
hospital notes (eg, ECGs, laboratory tests, discharge summary, postmortem results) should be 
sent to the addressee, if requested.
All SAEs should be followed up until resolution or permanent outcome of the event. The timelines
and procedure for follow-up reports are the same as those for the initial report.
10.3.1 Safety Reporting to Investigators, Ethics Committees, and Regulatory Authorities
The sponsor will be responsible for reporting all suspected unexpected serious adverse reactions
(SUSARs) and any other applicable SAEs to regulatory authorities, including the EMA,
investigators, and ethics committee, as applicable, in accordance with national regulations in the
countries where the study is conducted. Relative to the first awareness of the event by/or further
provision to the sponsor or sponsor’s designee, SUSARs will be submitted to the regulatory
authorities as expedited report within 7 days for fatal and life-threatening events and 15 days for
other serious events, unless otherwise required by national regulations. The sponsor will also
prepare an expedited report for other safety issues where these might materially alter the current
benefit-risk assessment of a study drug/sponsor supplied drug or that would be sufficient to
consider changes in the study drug/sponsor supplied drug administration or in the overall conduct
of the study. The study site also will forward a copy of all expedited reports to his or her ethics
committee in accordance with local regulations.
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11.0
STUDY-SPECIFIC COMMITTEES
No steering committee, data safety monitoring committee, or clinical endpoint committee will be
used in this study.
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12.0
DATA HANDLING AND RECORDKEEPING
The full details of procedures for data handling will be documented in the Data Management Plan.
AEs, medical history, and concomitant procedures will be coded using the Medical Dictionary for
Regulatory Activities (MedDRA). Drugs will be coded using the World Health Organization
Drug Dictionary.
12.1
eCRFs
Completed eCRFs are required for each subject who signs an informed consent.
The sponsor or its designee will supply investigative sites with access to eCRFs. The sponsor will
make arrangements to train appropriate site staff in the use of the eCRF. These forms are used to 
transmit the information collected in the performance of this study to the sponsor and regulatory
authorities. All eCRFs must be completed in English. Data are transcribed directly onto eCRFs.
After completion of the entry process, computer logic checks will be run to identify items, such as
inconsistent dates, missing data, and questionable values. Queries may be issued by Takeda
personnel (or designees) and will be answered by the site.
Corrections to eCRFs are recorded in an audit trail that captures the old information, the new
information, identification of the person making the correction, the date the correction was made,
and the reason for change. Reasons for significant corrections should additionally be included.
The principal investigator must review the eCRFs for completeness and accuracy and must sign
and date the appropriate eCRFs as indicated. Furthermore, the investigator must retain full
responsibility for the accuracy and authenticity of all data entered on the eCRFs.
The eCRFs will be reviewed for completeness and acceptability at the study site during periodic
visits by study the sponsor or its designee. The sponsor or its designee will be permitted to review
the subject’s medical and hospital records pertinent to the study to ensure accuracy of the eCRFs.
The completed eCRFs are the sole property of the sponsor and should not be made available in any
form to third parties, except for authorized representatives of appropriate governmental health or
regulatory authorities, without written permission of the sponsor.
12.2
Record Retention
The investigator agrees to keep the records stipulated in Section 12.1 and those documents that
include (but are not limited to) the study-specific documents, the identification log of all
participating subjects, medical records, temporary media such as thermal sensitive paper, source
worksheets, all original signed and dated informed consent forms, subject authorization forms
regarding the use of personal health information (if separate from the informed consent forms),
electronic copy of eCRFs, including the audit trail, and detailed records of drug disposition to
enable evaluations or audits from regulatory authorities, the sponsor or its designees. Any source
documentation printed on degradable thermal sensitive paper should be photocopied by the site
and filed with the original in the subject’s chart to ensure long term legibility. Furthermore,
International Conference on Harmonisation (ICH) E6 Section 4.9.5 requires the investigator to 
retain essential documents specified in ICH E6 (Section 8) until at least 2 years after the last 
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approval of a marketing application for a specified drug indication being investigated or, if an
application is not approved, until at least 2 years after the investigation is discontinued and
regulatory authorities are notified. In addition, ICH E6 Section 4.9.5 states that the study records
should be retained until an amount of time specified by applicable regulatory requirements or for a
time specified in the Clinical Study Site Agreement between the investigator and sponsor.
Refer to the Clinical Study Site Agreement for the sponsor’s requirements on record retention. The
investigator should contact and receive written approval from the sponsor before disposing of any
such documents.
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13.0
STATISTICAL METHODS
13.1
Statistical and Analytical Plans
A statistical analysis plan (SAP) will be prepared and finalized before the unblinding of subject’s
treatment assignment. This document will provide further details regarding the definition of
analysis variables and analysis methodology to address all study objectives.
A blinded data review will be conducted before the unblinding of subject’s treatment assignment. 
This review will assess the accuracy and completeness of the study database, subject evaluability,
and appropriateness of the planned statistical methods.
13.1.1 Analysis Sets
The full analysis set (FAS) will include all subjects who were randomized, received at least 1 dose
of study drug, and have at least 1 valid post-baseline value for assessment of primary endpoint. In
FAS efficacy summaries and analyses, subjects will be analyzed by the treatment to which they
were randomized.
The Safety Set will include all subjects who were randomized and received at least 1 dose of
double-blind study medication. In safety summaries, subjects will be analyzed according to the
treatment they received. In the event that a subject receives more than 1 treatment, the actual
treatment will be defined as the one that is used most frequently. If the 2 most common treatments
are used with equal frequency, then the randomized treatment will be used as the actual treatment.
13.1.2 Analysis of Demographics and Other Baseline Characteristics Analysis of 
Demographics and Other Baseline Characteristics
Baseline characteristics will be listed and summarized for demographics (sex, age, and race),
physical examination, and medical history including psychiatric history, smoking history, diabetic 
status, and concomitant medications.
Baseline values for efficacy and safety parameters will be in the standard tables summarizing data
per visit; however, baseline efficacy data will also be presented separately based on the all subjects
randomized.
For continuous variables, comparability of treatment groups will be assessed using an analysis of
variance with treatment and center as factors. For discrete variables, comparability will be
assessed using the Cochran-Mantel-Haenszel general association test, stratified by center. The p-
values will be displayed as descriptive statistics of comparability.
13.1.3 Efficacy Analysis
The primary and secondary endpoints will be analyzed in randomized patients who received at
least one dose of study drug.
Percent change from Baseline in ICD and change from Baseline in SF-36 will be analyzed using 
a mixed model for repeated measurements (MMRM) analysis of covariance with treatment, 
center, sex, age group, visit, treatment-by-visit interaction as fixed effects, Baseline as covariate, 
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and subject as a random effect. Comparisons between actovegin and placebo will be performed 
on all assessment points. Based on a missing at random assumption, this analysis will be 
performed using observed case data only. The effect at each time point for each treatment is 
allowed to vary freely and an unstructured covariance matrix is assumed.
Proportion of subjects having rest pain and proportion of patients having revascularization
procedures will be analyzed at all time points by logistic regression adjusting for treatment.
13.1.4 Safety Analysis
13.1.4.1 AEs
AEs will be reported throughout the study.
The definition of treatment-emergent AEs will be provided in the SAP. AEs will be coded using
MedDRA and will be summarized by system organ class and preferred term in the core treatment
period and entire study.
AEs that were reported more than once by a subject during the same period will be counted only
once for that subject and period at the maximum severity.
13.1.4.2 Clinical Evaluations
Absolute values and changes from Screening/Baseline in clinical safety laboratory tests, vital
signs, and weight will be summarized for each treatment group using descriptive techniques.
Values outside normal ranges and potentially clinically significant values will be flagged and
tabulated. Physical examination findings will also be summarized for each treatment group.
13.2
Interim Analysis and Criteria for Early Termination
No interim analysis is planned.
13.3
Determination of Sample Size
The primary endpoint of change from Baseline in ICD (initial claudication distance) is the most 
clinically important parameter for evaluation of effectiveness of Fontaine Stage II PAD 
treatment; this endpoint is recommended in the EMA guideline “Note for guidance on clinical 
investigation of medicinal products for treatment of peripheral arterial occlusive disease.” 
Although several trials about actovegin have been done [16-19], [24], none of them have the 
same primary endpoint as the proposed study. Additionally, the study design, study duration, 
primary endpoint, treadmill test setting and/or target patients is also different in the proposed 
study.
The sample size justification is based on published data for Naftidrofuryl study [25]. This study 
is a randomized, double-blind, placebo-controlled, parallel-group study, including 154 patients 
with Stage II intermittent claudication. The 90-day examination data of Naftidrofuryl study is 
close to our 12-week treatment duration. The study design, measurement time, targeted patients 
and treadmill test setting for [25] are similar to the proposed study. For the Naftidrofuryl study, 
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the primary endpoint change from Baseline in ICD is similar to our primary endpoint (percent 
change from Baseline in ICD), the difference in percent change from Baseline in ICD between 
Naftidrofuryl and placebo is approximately 28%, while the corresponding pooled standard 
deviation is approximately 85%.
Two-sample t test with a 0.05 two-sided significance level is used for sample size calculation. 
Since the allocation ratio is 1:1, the sample size per each arm is calculated by the formula below 
[26,27]:
 =  =
(	
	
)(



)
∆
,
where  is the sample size without drop-out for group i (i=1,2), δ is the assumed standard 
deviation for group i (i=1,2), α is the two-sided significance level, 1-β is the power, ∆ is the 
difference in population means, and / and  are the z-values. 
Assuming δ = δ =85% and ∆=28% for the percent change from Baseline in ICD, a total of 292 
subjects (146 per each arm) is sufficient to achieve at least 80% power. Considering 20% drop-
out rate, a total of 366 patients (183 per each arm) should be randomized in the study.
Table 13.a shows the sensitivity test for sample sizes (with and without drop-out) required for 
different values of power (from 70% to 95%) while 85% SD, 28% mean difference, 0.05 
significance level and 20% drop-out rate are assumed. 
Table 13.a
Sample Sizes Under Different Values of Power
Power (1-β)
70%
75%
80%
85%
90%
95%
Significant level (α)
0.05
0.05
0.05
0.05
0.05
0.05
Mean difference (∆=m1-m2)
28%
28%
28%
28%
28%
28%
Standard deviation (δ)
85%
85%
85%
85%
85%
85%
 (without drop-out)
115
129
146
167
195
241
Drop-out rate
20%
20%
20%
20%
20%
20%
 (considering drop-out)
144
162
183
209
244
302
N (total sample size)
288
324
366
418
488
604
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14.0
QUALITY CONTROL AND QUALITY ASSURANCE
14.1
Study-Site Monitoring Visits
Monitoring visits to the study site will be made periodically during the study to ensure that all
aspects of the protocol are followed. Source documents will be reviewed for verification of data
recorded on the eCRFs. Source documents are defined as original documents, data, and records.
The investigator and the study site guarantee access to source documents by the sponsor or its
designee, the Contract Research Organization, and by the ethics committee.
All aspects of the study and its documentation will be subject to review by the sponsor or sponsor’s
designee (as long as blinding is not jeopardized), including but not limited to the Investigator’s
Binder, study drug, subject medical records, informed consent documentation, documentation of
subject authorization to use personal health information (if separate from the informed consent
forms), and review of eCRFs and associated source documents. It is important that the investigator
and other study personnel are available during the monitoring visits and that sufficient time is
devoted to the process.
14.2
Protocol Deviations
The investigator should not deviate from the protocol, except where necessary to eliminate an
immediate hazard to study subjects. Should other unexpected circumstances arise that will require
deviation from protocol-specified procedures, the investigator should consult with the sponsor or
designee (and ethics committee, as required) to determine the appropriate course of action. There
will be no exemptions (a prospectively approved deviation) from the inclusion or exclusion
criteria.
The site should document all protocol deviations in the subject’s source documents. In the event of
a significant deviation, the site should notify the sponsor or its designee (and ethics committee, as
required). Significant deviations include, but are not limited to, those that involve fraud or
misconduct, increase the health risk to the subject, or confound interpretation of primary study
assessment. A protocol deviation form should be completed by the site and signed by the sponsor
or designee for any significant deviation from the protocol. Significant protocol violations are
entered on the eCRF.
14.3
Quality Assurance Audits and Regulatory Agency Inspections
The study site also may be subject to quality assurance audits by the sponsor or designees. In this
circumstance, the sponsor-designated auditor will contact the site in advance to arrange an
auditing visit. The auditor may ask to visit the facilities where laboratory samples are collected,
where the medication is stored and prepared, and any other facility used during the study. In
addition, there is the possibility that this study may be inspected by regulatory agencies. If the
study site is contacted for an inspection by a regulatory body, the sponsor should be notified
immediately. The investigator and study site guarantee access for quality assurance auditors to all
study documents as described in Section 14.1.
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15.0
ETHICAL ASPECTS OF THE STUDY
This study will be conducted with the highest respect for the individual participants (ie, subjects)
according to the protocol, the ethical principles that have their origin in the Declaration of
Helsinki, and the ICH Harmonised Tripartite Guideline for GCP. Each investigator will conduct
the study according to applicable local or regional regulatory requirements and align his or her
conduct in accordance with the “Responsibilities of the Investigator” that are listed in Appendix B. 
The principles of Helsinki are addressed through the protocol and through appendices containing
requirements for informed consent and investigator responsibilities.
15.1
Ethics Committee Approval
Ethics committees must be constituted according to the applicable local requirements of each
participating region. The sponsor or designee will require documentation noting all names and
titles of members who make up the respective ethics committee. If any member of the ethics
committee has direct participation in this study, written notification regarding his or her abstinence
from voting must also be obtained.
The sponsor or designee will supply relevant documents for submission to the respective I ethics
committee for the protocol’s review and approval. This protocol, the Investigator’s Brochure, a
copy of the informed consent form, and, if applicable, subject recruitment materials and/or
advertisements and other documents required by all applicable laws and regulations, must be
submitted to a central or local ethics committee for approval. The ethics committee’s written
approval of the protocol and subject informed consent must be obtained and submitted to the
sponsor or designee before commencement of the study (ie, before shipment of the sponsor-
supplied drug or study specific screening activity). The ethics committee approval must refer to 
the study by exact protocol title, number, and version date; identify versions of other documents
(eg, informed consent form) reviewed; and state the approval date. The sponsor will notify site 
once the sponsor has confirmed the adequacy of site regulatory documentation and, when
applicable, the sponsor has received permission from competent authority to begin the study. Until
the site receives notification, no protocol activities, including Screening, may occur.
Study sites must adhere to all requirements stipulated by their respective ethics committee. This
may include notification to the ethics committee regarding protocol amendments, updates to the
informed consent form, recruitment materials intended for viewing by subjects, local safety
reporting requirements, reports, and updates regarding the ongoing review of the study at intervals
specified by the respective ethics committee, and submission of the investigator’s final status
report to the ethics committee. All ethics committee approvals and relevant documentation for
these items must be provided to the sponsor or its designee.
Subject incentives should not exert undue influence for participation.
15.2
Subject Information, Informed Consent, and Subject Authorization
Written consent documents will embody the elements of informed consent as described in the
Declaration of Helsinki and the ICH Guidelines for GCP and will be in accordance with all
applicable laws and regulations. The informed consent form, subject authorization form (if
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applicable), and subject information sheet (if applicable) describe the planned and permitted uses,
transfers, and disclosures of the subject’s personal and personal health information for purposes of
conducting the study. The informed consent form and the subject information sheet (if applicable)
further explain the nature of the study, its objectives, and potential risks and benefits, as well as the
date informed consent is given. The informed consent form will detail the requirements of the
participant and the fact that he or she is free to withdraw at any time without giving a reason and
without prejudice to his or her further medical care.
The investigator is responsible for the preparation, content, and ethics committee approval of the
informed consent form and if applicable, the subject authorization form. The informed consent
form, subject authorization form (if applicable), and subject information sheet (if applicable) must
be approved by both the ethics committee and the sponsor before use.
The informed consent form, subject authorization form (if applicable), and subject information
sheet (if applicable) must be written in a language fully comprehensible to the prospective subject.
It is the responsibility of the investigator to explain the detailed elements of the informed consent
form, subject authorization form(if applicable), and subject information sheet (if applicable) to the
subject. Information should be given in both oral and written form whenever possible and in the
manner deemed appropriate by the ethics committee. In the event the subject is not capable of
rendering adequate written informed consent, then the subject’s legally acceptable representative
may provide such consent for the subject in accordance with applicable laws and regulations.
The subject, or the subject’s legally acceptable representative, must be given ample opportunity to: 
(1) inquire about details of the study and (2) decide whether or not to participate in the study. If the
subject, or the subject’s legally acceptable representative, determines he or she will participate in
the study, then the informed consent form and subject authorization form (if applicable) must be
signed and dated by the subject, or the subject’s legally acceptable representative, at the time of
consent and before the subject entering into the study. The subject or the subject’s legally
acceptable representative should be instructed to sign using their legal names, not nicknames,
using a pen with blue or black ink. The investigator must also sign and date the informed consent
form and subject authorization (if applicable) at the time of consent and before the subject 
entering into the study; however, the sponsor may allow a designee of the investigator to sign to 
the extent permitted by applicable law.
Once signed, the original informed consent form, subject authorization form (if applicable), and
subject information sheet (if applicable) will be stored in the investigator’s site file. The
investigator must document the date the subject signs the informed consent in the subject’s
medical record. Copies of the signed informed consent form, the signed subject authorization form
(if applicable), and subject information sheet (if applicable) shall be given to the subject.
All revised informed consent forms must be reviewed and signed by relevant subjects or the 
relevant subject’s legally acceptable representative in the same manner as the original informed
consent. The date the revised consent was obtained should be recorded in the subject’s medical
record, and the subject should receive a copy of the revised informed consent form.
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15.3
Subject Confidentiality
The sponsor and designees affirm and uphold the principle of the subject’s right to protection
against invasion of privacy. Throughout this study, a subject’s source data will only be linked to
the sponsor’s clinical trial database or documentation via a subject identification number. As
permitted by all applicable laws and regulations, limited subject attributes, such as sex, date of
birth, and subject initials may be used to verify the subject and accuracy of the subject’s unique
identification number.
To comply with ICH Guidelines for GCP and to verify compliance with this protocol, the sponsor
requires the investigator to permit the monitor or the sponsor’s designee, representatives from any
regulatory authority(eg, Ministry of Health of Russian Federation, Food and Drug Administration,
Medicines and Healthcare products Regulatory Agency, Pharmaceuticals and Medical Devices
Agency), the sponsor’s designated auditors, and the appropriate ethics committee to review the
subject’s original medical records (source data or documents), including, but not limited to, 
laboratory test result reports, ECG reports, admission and discharge summaries for hospital
admissions occurring during a subject’s study participation, and autopsy reports. Access to a
subject’s original medical records requires the specific authorization of the subject as part of the
informed consent process (see Section 15.2).
Copies of any subject source documents that are provided to the sponsor must have certain
personally identifiable information removed (ie, subject name, address, and other identifier fields
not collected on the subject’s eCRF).
15.4
Publication, Disclosure, and Clinical Trial Registration Policy
15.4.1 Publication and Disclosure
The investigator is obliged to provide the sponsor with complete test results and all data derived by
the investigator from the study. During and after the study, only the sponsor may make study
information available to other study investigators or to regulatory agencies, except as required by
law or regulation. Except as otherwise allowable in the study site agreement, any public disclosure
(including publicly accessible websites) related to the protocol or study results, other than study
recruitment materials and/or advertisements, is the sole responsibility of the sponsor.
The sponsor may publish any data and information from the study (including data and information
generated by the investigator) without the consent of the investigator. Manuscript authorship for
any peer-reviewed publication will appropriately reflect contributions to the production and
review of the document. All publications and presentations must be prepared in accordance with
this section and the study site agreement. In the event of any discrepancy between the protocol and
the study site agreement, the study site agreement will prevail.
The investigator needs to obtain a prior written approval from the sponsor to publish any
information from the study externally such as to a professional association.
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15.4.2 Clinical Trial Registration
In order to ensure that information on clinical trials reaches the public in a timely manner and to
comply with applicable laws, regulations and guidance, Takeda will, at a minimum register all
interventional clinical trials it sponsors anywhere in the world on ClinicalTrials.gov and/or other
publicly accessible websites before start of study, as defined in Takeda Policy/Standard. Takeda
contact information, along with investigator’s city, country, and recruiting status will be registered
and available for public viewing.
For some registries, Takeda will assist callers in locating study sites closest to their homes by
providing the investigator name, address, and phone number to the callers requesting trial
information. Once subjects receive investigator contact information, they may call the site
requesting enrollment into the trial. The investigative sites are encouraged to handle the trial
inquiries according to their established subject screening process. If the caller asks additional
questions beyond the topic of trial enrollment, they should be referred to the sponsor.
Any investigator who objects to the sponsor providing this information to callers must provide the
sponsor with a written notice requesting that their information not be listed on the registry site.
15.4.3 Clinical Trial Results Disclosure
Takeda will post the results of clinical trials on ClinicalTrials.gov and/or other publicly accessible
websites, as required by Takeda Policy/Standard, applicable laws and/or regulations.
15.5
Insurance and Compensation for Injury
Each subject in the study must be insured in accordance with the regulations applicable to the site
where the subject is participating. If a local underwriter is required, then the sponsor or sponsor’s
designee will obtain clinical study insurance against the risk of injury to study subjects. Refer to
the study site agreement regarding the sponsor’s policy on subject compensation and treatment for
injury. If the investigator has questions regarding this policy, he or she should contact the sponsor
or sponsor’s designee.
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16.0
REFERENCES
1.
Bordeaux L, Reich L, Hirsch A. The epidemiology and natural history of peripheral arterial 
disease. In: Coffman JD, Eberhardt RT, editors. Contemporary Cardiology: Peripheral 
Arterial Disease: Diagnosis and Treatment. Totowa, NJ: Humana Press Inc.; 2010, p. 21-
34.
2.
Fowkes FG, Rudan D, Rudan I, Aboyans V, Denenberg JO, McDermott MM, et al. 
Comparison of global estimates of prevalence and risk factors for peripheral artery disease 
in 2000 and 2010: a systematic review and analysis. Lancet 2013;382(9901):1329-40.
3.
Dhaliwal G, Mukherjee D. Peripheral arterial disease: epidemiology, natural history, 
diagnosis and treatment. Int J Angiol 2007;16(2):36-44.
4.
Buchmayer F, Pleiner J, Elmlinger MW, Lauer G, Nell G, Sitte HH. Actovegin(R): a 
biological drug for more than 5 decades. Wien Med Wochenschr 2011;161(3-4):80-8.
5.
Kuninaka T, Senga Y, Senga H, Weiner M. Nature of enhanced mitochondrial oxidative 
metabolism by a calf blood extract. J Cell Physiol 1991;146(1):148-55.
6.
Bachmann W, Forster H, Mehnert H. Experimental studies in animals on the effect of a 
protein-free blood extract on the metabolism of glucose [in German]. Arzneimittel-
Forschung/Drug Research 1968;18:1023-7.
7.
Jacob S, Dietze GJ, Machicao F, Kuntz G, Augustin HJ. Improvement of glucose 
metabolism in patients with type II diabetes after treatment with a hemodialysate. 
Arzneimittelforschung 1996;46(3):269-72.
8.
Meilin S, Machicao F, Elmlinger M. Treatment with Actovegin improves spatial learning 
and memory in rats following transient forebrain ischaemia. J Cell Mol Med 
2014;18(8):1623-30.
9.
Elmlinger MW, Kriebel M, Ziegler D. Neuroprotective and anti-oxidative effects of the 
hemodialysate actovegin on primary rat neurons in vitro. Neuromolecular Med 
2011;13(4):266-74.
10.
Machicao F, Muresanu DF, Hundsberger H, Pfluger M, Guekht A. Pleiotropic 
neuroprotective and metabolic effects of Actovegin's mode of action. J Neurol Sci 
2012;322(1-2):222-7.
11.
Dieckmann A, Kriebel M, Andriambeloson E, Ziegler D, Elmlinger M. Treatment with 
Actovegin(R) improves sensory nerve function and pathology in streptozotocin-diabetic 
rats via mechanisms involving inhibition of PARP activation. Exp Clin Endocrinol 
Diabetes 2012;120(3):132-8.
12.
Fedorovich AA. Non-invasive evaluation of vasomotor and metabolic functions of 
microvascular endothelium in human skin. Microvasc Res 2012;84(1):86-93.
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13.
Kanowski S, Kinzler E, Lehmann E, Schweizer A, Kuntz G. Confirmed clinical efficacy of 
Actovegin in elderly patients with organic brain syndrome. Pharmacopsychiatry 
1995;28(4):125-33.
14.
Guekht A, Skoog I, Edmundson S, Zakharov V, Korczyn AD. ARTEMIDA Trial (A 
Randomized Trial of Efficacy, 12 Months International Double-Blind Actovegin): A 
Randomized Controlled Trial to Assess the Efficacy of Actovegin in Poststroke Cognitive 
Impairment. Stroke 2017;48(5):1262-70.
15.
Ziegler D, Movsesyan L, Mankovsky B, Gurieva I, Abylaiuly Z, Strokov I. Treatment of 
symptomatic polyneuropathy with actovegin in type 2 diabetic patients. Diabetes Care 
2009;32(8):1479-84.
16.
Angelkort B, Blume J, de la Haye R, Kuntz G. Metabolically active calves blood extract in 
welltrained patients with AVD in stage II. A placebo-controlled doubleblind study. VASA 
- J Vasc Dis 1988(Suppl 23):141-3.
17.
Horsch S, Claeys L, Diehm C, Rieger H, Cachovan M, Baitsch C. [Assessment of the 
clinical effectiveness of actihaemyl in Fontaine stage IIb intermittent claudication]. Vasa 
Suppl 1992;37:64-5.
18.
Muller-Buhl U, Ruhlmann KU, Meister K, Diehm C, Kuntz G. Increase of walking 
distance by intra-arterial infusions of hemodialysate. Therapiewoche 1991;41:188-96.
19.
Angelkort B, Ruhlmann KU, de la Haye R, Kuntz G. Influence of deproteinized 
hemodialysate on rest pain and walking distance in the presence of peripheral chronic 
arterial occlusive disease. Angiology 1992;43(1):47-58.
20.
Blume J. Peripheral arterial occlusive disease – Intravenous and intraarterial infusion 
therapy with Actovegin (In German). Therapiewoche 1986;36:5355-58.
21.
Uchkin IG, Zudin AM, Bagdasarian AG, Fedorovich AA. Effect of drug therapy for 
chronic obliterating diseases of lower-limb arteries on the state of the microcirculatory bed. 
Angiol Sosud Khir 2014;20(2):27-36.
22.
Garratt AM, Ruta DA, Abdalla MI, Buckingham JK, Russell IT. The SF36 health survey 
questionnaire: an outcome measure suitable for routine use within the NHS? BMJ 
1993;306(6890):1440-4.
23.
Ware J, Kosinski M. Improvements in the content and scoring of the SF-36 Health Survey 
Version 2. Accessed 16 July 2014. Available at: http://www.sf-36.org/.
24.
Guriyeva IV, Begma IV, Kuzina IV, et al. Patogenetic treatment with Actovegin of 
neuroishemic pain syndrome in lower extremirties in patients with diabetes mellitus [In 
Russian]. RMJ 2009;17(10):670-2.
25.
Adhoute G, Bacourt F, Barral M, Cardon JM, Chevalier JM, Cuny A, et al. Naftidrofuryl in 
chronic arterial disease. Results of a six month controlled multicenter study using 
Naftidrofuryl tablets 200 mg. Angiology 1986;37(3 Pt 1):160-7.
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26.
Julious SA. Sample Sizes for Clinical Trials. Boca Raton, FL.: Chapman & Hall/CRC. ; 
2010.
27.
Chow S-C, Shao J, Wang H. Sample Size Calculations in Clinical Research (Second 
Edition). Boca Raton, FL: Chapman & Hall/CRC; 2008.
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Appendix A
Schedule of Study Procedures
Day
Screening
Period
Treatment Period
Follow- up Period
Randomization
(Baseline)
Infusion Treatment (IV)
Oral Treatment
Day -7-14
to -1
Day 1
Start of IV
treatment Day 1
IV 
treatment
Day 2-Day 
13
End of IV
treatment
Day 14
V2+28
±2 days
(Day 42)
V3+28
±2 days
(Day 70)
End of
treatment
V4+14
±2 days
(Day 84) (a)
Interim
Follow-up (4
weeks interval
±5 days)
(Day 112)
Interim
Follow-up (4
weeks interval
±5 days)
(Day 140)
Final Follow-up
V7+28
±2 days
(Day 168) (b)
Visit No.
V0
V1
V1
V2
V3
V4
V5
V6
V7
V8
Informed consent
X
Inclusion/ exclusion criteria
X
X
Demographics
X
Medication history
X
X
Medical history and
concurrent medical
conditions
X
Smoking status and physical 
activity
X
X
X
X
X
X
X
X
X
Pretreatment events
X
X
AEs
X (c)
X (c)
X (c)
X
X
X
X
X
X
Physical examination
X
X
X
X
Vital signs
X
X
X
X
Height and weight (d)
X
X
X
Concomitant medications
X
X
X (e)
X
X
X
X
X
X
12-lead ECG
X
Clinical laboratory tests
X
X
X
Pregnancy test (f) and 
assessment of subject 
compliance with 
contraception requirements.
X (g) 
X
X
X
X
X
X
X
X
Footnotes are on last table page.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
le
pli
p
ap
28
days
ays
(Day
Day 70)
70)
End
End of
o
treatm
treat
V4
V
he
t t
V4
V4
bje
ub
ub
ub
ub
su
d s
nd
a
yly
s
y
se
us
al
X (
X
ci
er
e
m
om
co
n
no
no
no
no
X
r
ed
ed
ed
CCI


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Appendix A
Schedule of Study Procedures (continued)
Day
Screening
Period
Treatment Period
Follow- up Period
Randomization
(Baseline)
Infusion Treatment (IV)
Oral Treatment
Day -7-14
to -1
Day 1
Start of IV
treatment
Day 1
IV 
treatment 
Days 2-13
End of IV
treatment
Day 14
V2+28
±2 days
(Day 42)
V3+28
±2 days
(Day 70)
End of
treatment
V4+14
±2 days
(Day 84) (a)
Interim
Follow-up (4
weeks interval
±5 days)
(Day 112)
Interim
Follow-up (4
weeks interval
±5 days)
(Day 140)
Final Follow-up
V7+28
±2 days
(Day 168) (b)
Visit No.
V0
V1
V1
V2
V3
V4
V5
V6
V7
V8
Glycosylated hemoglobin 
HbA1c
X
Treadmill test
X
X (h)
X (e)
X
X
Ultrasound color duplex
imaging
X
SF-36
X
X
X
Dispense study drug for oral
treatment
X (e)
X
X
Return study drug for oral
treatment
X
X
X
Study drug compliance
check
X
X
X
V=visit.
(a) Early Termination Visit for subjects who terminate the study before completing the Oral Treatment Period.
(b) Early Termination Visit for subjects who terminate the study during the Follow-up Period.
(c) On Day 1 Visit 1, AEs should be checked after infusion. Starting on Day 2, AEs should be checked before (since previous infusion) and after the infusion.
(d) Height and weight will be measured at V1. Only weight will be measured at V5 and V8.
(e) Following the final infusion.
(f) Female subjects of childbearing potential only. Serum pregnancy test will be performed at Screening visit. Urine pregnancy test will be performed at all other visits. 
(g) Assessment of compliance with contraception requirements not needed at this visit.
(h) The time interval from the first test must be of ≥1 week (ie, 7 days).
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use
le
lic
p
ap
ys
y 70)
70)
End
End of
of
treatm
eatmen
V4+
V
±2
±
(D
he
ct
V4
V4
je
ubj
d s
d
an
nly
on
X (e)
(e)
o
us
iaiaiaia
me cia
before
fore com
c
dy during
durin
. Starting o
arting
ght will
will be 
Serum preg
rum pre
on requirem
requ
be of 
e of ≥1 w
≥1
CCI


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Appendix B
Responsibilities of the Investigator
Clinical research studies sponsored by the sponsor are subject to ICH GCP and all the 
applicable local laws and regulations.
The investigator agrees to assume the following responsibilities:
1. Conduct the study in accordance with the protocol.
2. Personally conduct or supervise the staff that will assist in the protocol.
3. Ensure that study related procedures, including study specific (nonroutine/nonstandard panel)
screening assessments, are NOT performed on potential subjects before the receipt of written
approval from relevant governing bodies/authorities.
4. Ensure that all colleagues and employees assisting in the conduct of the study are informed of
these obligations.
5. Secure prior approval of the study and any changes by an appropriate ethics committee that
conform to ICH and local regulatory requirements.
6. Ensure that the ethics committee will be responsible for initial review, continuing review, 
and approval of the protocol. Promptly report to the ethics committee all changes in research
activity and all anticipated risks to subjects. Make at least yearly reports on the progress of
the study to the ethics committee, and issue a final report within 3 months of study
completion.
7. Ensure that requirements for informed consent, as outlined in ICH and local regulations, are
met.
8. Obtain valid informed consent from each subject who participates in the study, and document
the date of consent in the subject’s medical chart. Valid informed consent is the most current 
version approved by the ethics committee. Each informed consent form should contain a
subject authorization section that describes the uses and disclosures of a subject’s personal
information (including personal health information) that will take place in connection with
the study. If an informed consent form does not include such a subject authorization, then 
the investigator must obtain a separate subject authorization form from each subject or the
subject’s legally acceptable representative.
9. Prepare and maintain adequate case histories of all persons entered into the study, including
eCRFs, hospital records, laboratory results, etc, and maintain these data for a minimum of 2
years following notification by the sponsor that all investigations have been discontinued or
that the regulatory authority has approved the marketing application. The investigator should
contact and receive written approval from the sponsor before disposing of any such
documents.
10. Allow possible inspection and copying by the regulatory authority of GCP-specified essential
documents.
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11. Maintain current records of the receipt, administration, and disposition of sponsor-supplied
drugs, and return all unused sponsor-supplied drugs to the sponsor.
12. Report adverse reactions to the sponsor promptly. In the event of an SAE, notify the sponsor
within 24 hours. The investigator should also comply with the applicable regulatory
requirements related to the reporting of adverse reactions to the Regulatory Authority and
Ethics Committee.
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Appendix C
Elements of the Subject Informed Consent
In seeking informed consent, the following information shall be provided to each subject:
1. A statement that the study involves research.
2. An explanation of the purposes of the research.
3. The expected duration of the subject’s participation.
4. A description of the procedures to be followed, including invasive procedures.
5. The identification of any procedures that are experimental.
6. The estimated number of subjects involved in the study.
7. A description of the subject’s responsibilities.
8. A description of the conduct of the study.
9. A statement describing the treatment(s) and the probability for random assignment to each
treatment.
10. A description of the possible side effects of the treatment that the subject may receive.
11. A description of any reasonably foreseeable risks or discomforts to the subject and, when
applicable, to an embryo, fetus, or nursing infant.
12. A description of any benefits to the subject or to others that reasonably may be expected from
the research. When there is no intended clinical benefit to the subject, the subject should be
made aware of this.
13. Disclosures of appropriate alternative procedures or courses of treatment, if any, that might be
advantageous to the subject and their important potential risks and benefits.
14. A statement describing the extent to which confidentiality of records identifying the subject
will be maintained, and a note of the possibility that regulatory agencies, auditor(s), ethics
committee, and the monitor may inspect the records. By signing a written informed consent
form, the subject or the subject’s legally acceptable representative is authorizing such access.
15. For research involving more than minimal risk, an explanation as to whether any compensation
and an explanation as to whether any medical treatments are available if injury occurs and, if
so, what they consist of or where further information may be obtained.
16. The anticipated prorated payment(s), if any, to the subject for participating in the study.
17. The anticipated expenses, if any, to the subject for participating in the study.
18. An explanation of whom to contact for answers to pertinent questions about the research
(investigator), subject’s rights, and ethics committee and whom to contact in the event of a
research-related injury to the subject.
19. A statement that participation is voluntary, that refusal to participate will involve no penalty or
loss of benefits to which the subject otherwise is entitled, and that the subject or the subject’s
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Study No. Actovegin-3001
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Protocol Incorporating Amendment No. 04
19 February 2019
legally acceptable representative may discontinue participation at any time without penalty or
loss of benefits to which the subject is otherwise entitled.
20. The consequences of a subject’s decision to withdraw from the research and procedures for
orderly termination of participation by the subject.
21. A statement that the subject or the subject’s legally acceptable representative will be informed
in a timely manner if information becomes available that may be relevant to the subject’s
willingness to continue participation in the study.
22. The foreseeable circumstances or reasons under which the subject’s participation in the study
may be terminated.
23. A written subject authorization (either contained within the informed consent form or provided
as a separate document) describing to the subject the contemplated and permissible uses and
disclosures of the subject’s personal information (including personal health information) for
purposes of conducting the study. The subject authorization must contain the following
statements regarding the uses and disclosures of the subject’s personal information:
a) that personal information (including personal health information) may be processed by or
transferred to other parties in other countries for clinical research and safety reporting
purposes, including, without limitation, to the following: (1) Takeda, its affiliates, and
licensing partners; (2) business partners assisting Takeda, its affiliates, and licensing
partners; (3) regulatory agencies and other health authorities; and (4) ethics committee;
b) it is possible that personal information (including personal health information) may be
processed and transferred to countries that do not have data protection laws that offer 
subjects the same level of protection as the data protection laws within this country;
however, Takeda will make every effort to keep your personal information confidential,
and your name will not be disclosed outside the clinic unless required by law;
c) that personal information (including personal health information) may be added to
Takeda’s research databases for purposes of developing a better understanding of the
safety and effectiveness of the study drug(s), studying other therapies for patients,
developing a better understanding of disease, and improving the efficiency of future 
clinical studies;
d) that subjects agree not to restrict the use and disclosure of their personal information
(including personal health information) upon withdrawal from the study to the extent that
the restricted use or disclosure of such information may impact the scientific integrity of
the research; and
e) that the subject’s identity will remain confidential in the event that study results are
published.
24. Female subjects of childbearing potential (eg, nonsterilized, premenopausal female subjects) 
who are sexually active must use highly effective or effective contraception (as defined in the 
informed consent) from Screening throughout the duration of the study or for 30 days after the 
last dose (in case of early study termination). If a subject is found to be pregnant during study,
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19 February 2019
study drug will be discontinued and the investigator will offer the subject the choice to 
receive unblinded treatment information.
25. Male subjects agree to use barrier method of contraception (condom with or without 
spermicide) (as defined in the informed consent) from signing the informed consent 
throughout the duration of the study or for 30 days after the last dose (in case of early study 
termination). If the partner or wife of the subject is found to be pregnant during the study, the
investigator will offer the subject the choice to receive unblinded treatment information.
26. A statement that clinical trial information fromthis trial will be publicly disclosed in a publicly
accessible website, such as ClinicalTrials.gov.
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Appendix D
Investigator Consent to Use of Personal Information
Takeda will collect and retain personal information of investigator, including his or her name,
address, and other personally identifiable information. In addition, investigator’s personal
information may be transferred to other parties located in countries throughout the world (eg, the
United Kingdom, United States, and Japan), including the following:

Takeda, its affiliates, and licensing partners.

Business partners assisting Takeda, its affiliates, and licensing partners.

Regulatory agencies and other health authorities.

Ethics committees.
Investigator’s personal information may be retained, processed, and transferred by Takeda and
these other parties for research purposes including the following:

Assessment of the suitability of investigator for the study and/or other clinical studies.

Management, monitoring, inspection, and audit of the study.

Analysis, review, and verification of the study results.

Safety reporting and pharmacovigilance relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to
regulatory agencies relating to the study.

Preparation and submission of regulatory filings, correspondence, and communications to
regulatory agencies relating to other medications used in other clinical studies that may contain
the same chemical compound present in the study drug.

Inspections and investigations by regulatory authorities relating to the study.

Self-inspection and internal audit within Takeda, its affiliates, and licensing partners.

Archiving and audit of study records.

Posting investigator site contact information, study details and results on publicly accessible
clinical trial registries, databases, and websites.
Investigator’s personal information may be transferred to other countries that do not have data
protection laws that offer the same level of protection as data protection laws in investigator’s own
country.
Investigator acknowledges and consents to the use of his or her personal information by Takeda
and other parties for the purposes described above.
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Appendix E
Detailed Description of Amendments to Text
The primary sections of the protocol affected by the changes in Amendment No. 04 are 
indicated. The corresponding text has been revised throughout the protocol.
Change 1: Revised number of participating sites and countries.
The primary change occurs in Section 6.1 Study Design.
Initial 
wording:
Study Design:
This is a randomized, multicenter, parallel group, double-blind, placebo-controlled 
phase 3b study to evaluate the efficacy and safety of actovegin 12-week treatment 
given intravenously and subsequently orally in subjects with peripheral arterial 
disease (PAD) Fontaine Stage IIB.
A total of 366 subjects with PAD Fontaine Stage IIB will be enrolled in 
approximately 15 to 20 sites in 5 countries (Russia, Ukraine, Belarus, Kazakhstan, 
and Georgia)
Amended 
or new 
wording:
Study Design:
This is a randomized, multicenter, parallel group, double-blind, placebo-controlled 
phase 3b study to evaluate the efficacy and safety of actovegin 12-week treatment 
given intravenously and subsequently orally in subjects with peripheral arterial 
disease (PAD) Fontaine Stage IIB.
A total of 366 subjects with PAD Fontaine Stage IIB will be enrolled in 
approximately 15 17 to 20 25 sites in 5 3 countries (Russia, Ukraine, Belarus, 
Kazakhstan, and Georgia).
Rationale for Change:
To revise the numbers of study sites and countries participating in the study.
Section 2.0 STUDY SUMMARY (Study Design and Number of Sites) also includes this change.
Change 2: Clarified inclusion criterion #11.
The primary change occurs in Section 7.1 Inclusion Criteria.
Added text: 11. The subject has a history of stable PAD therapy for at least 2 weeks before 
Screening and is not newly diagnosed with PAD.
Rationale for Change:
To clarify inclusion criterion # 11 that the subject must not be newly diagnosed with PAD. 
Section 2.0 STUDY SUMMARY (Main Criteria for Inclusion) also includes this change.
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Change 3: Clarified early discontinuation procedures.
The primary change occurs in Section 7.6 Procedures for Discontinuation or Withdrawal of a 
Subject.
Added text: The investigator may discontinue a subject’s study participation at any time during
the study when the subject meets the study termination criteria described in Section 
7.5. In addition, efforts should be made to perform all procedures scheduled for the 
Early Termination Visit at the earliest possible date. The Early Termination Visit 
for subjects who discontinue the study before completing the Oral Treatment 
Period will be identical to Visit 5. The Early Termination Visit for subjects 
who discontinue the study after completing the Oral Treatment Period will be 
identical to the Final Follow-up visit. The Follow-up Period is not required for 
subjects who discontinue the study early. Discontinued or withdrawn subjects 
will not be replaced.
Rationale for Change:
To clarify procedures for subjects who discontinue the study early.
Change 4: Clarified that subjects should continue companion medications for peripheral arterial 
disease (PAD) and prevention of cardiovascular events.
The primary change occurs in Section 8.1.1.2 Companion Medication.
Initial 
wording:
Subjects may continue their current treatment for PAD and for prevention of 
cardiovascular events.
Amended 
or new 
wording:
Subjects may should continue their current treatment for PAD and for prevention 
of cardiovascular events.
Rationale for Change:
To clarify that subjects should continue companion medications for PAD and prophylaxis of 
cardiovascular events.
Change 5: Specified minimum infusion duration.
The primary change occurs in Section 8.1.3.1 IV Treatment Period (Week 0 to 2)
Added text: The infusion rate will be about 2 mL per minute (40 to 50 drops/minute). Total 
infusion duration should not be less than 112 minutes.
Rationale for Change:
To specify the minimum duration of infusion.
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Change 6: Corrected timing of oral treatment period.
The primary change occurs in Section 8.1.3.2 Oral Treatment Period (Week 3 to 12)
Initial 
wording:
8.1.3.2 Oral Treatment Period (Week 2 to 12)
Amended 
or new 
wording:
8.1.3.2 Oral Treatment Period (Week 2 3 to 12)
Rationale for Change:
To correct the beginning of the oral treatment period from Week 2 to Week 3.
Change 7: Deleted instruction to collect incorrect demographic information.
The primary change occurs in Section 9.1.2 Demographics, Medical History, and Medication 
History Procedure.
Initial 
wording:
Demographic information to be obtained will include date of birth, sex, race as 
described by the subject, height, weight, and smoking status of the subject at 
Screening.
Amended 
or new 
wording:
Demographic information to be obtained will include date of birth, sex, and race as 
described by the subject, height, weight, and smoking status of the subject at 
Screening.
Rationale for Change: To delete collection of incorrect demographic information.
Change 8: Specified timing of height and weight assessments.
The primary change occurs in Section 9.1.4 Weight and Height.
Added text: Weight and height of subjects should be measured while wearing indoor clothing 
and no shoes. Values are to be reported to 1 decimal place. Height will be 
measured at V1. Weight will be measured at V1, V5, and V8.
Rationale for Change: To clarify the timing of height and weight assessments.
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Change 9: Clarified that questionnaires should be provided to patients in a language in which 
they are fluent.
The primary change occurs in Section 9.1.5 Smoking Status and Physical Activity.
Initial 
wording:
Patients should be provided with the Physical Activity Questionnaire in their native 
language
Amended 
or new 
wording:
Patients should be provided with the Physical Activity Questionnaire in their native
a language in which they are fluent.
Rationale for Change:
To clarify that questionnaires provided to patients should be in a language in which they are 
fluent.
Section 9.1.7.2 SF-36 also includes this change (with reference to the SF-36). 
Change 10: Clarified fasting conditions and revised maximum blood volume collected.
The primary change occurs in Section 9.1.11Procedures for Clinical Laboratory Samples.
Initial 
wording:
All samples will be collected under fasting condition and in accordance with 
acceptable local laboratory procedures. The maximum volume of blood collected at 
any single visit will be approximately 10 mL, with an approximate total volume of 
blood collection over the course of the study of 30 mL.
Amended 
or new 
wording:
All samples will be collected under fasting conditions (at least 8 hours after the 
last meal) and in accordance with acceptable local laboratory procedures. The 
maximum volume of blood collected at any single visit will be approximately 10 15
mL, with an approximate total volume of blood collection over the course of the 
study of 30 45 mL.
Rationale for Change: To specify that fasting conditions are considered as at least 8 hours after 
the last meal, and to revise the maximum amount of blood collected at each visit and over the 
entire course of the study.
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Change 11: Specified details of white blood cell count.
The primary change occurs in Table 9.a
Clinical Laboratory Tests Clinical Laboratory Tests.
Description 
of change:
A footnote was added for white blood cell count:

White blood cell count (d)
o
(d) Must include numbers of segmented neutrophils and band cells. 
Rationale for Change: To specify that the white blood cell count should include numbers of 
segmented neutrophils and band cells.
Change 12: Added requirement to document lost or damaged tablets and defined the nature of 
returned tablets.
The primary change occurs in Section 9.2 Monitoring Subject Treatment Compliance.
Added text: During the Oral Treatment Period, the investigator must check subject compliance 
by counting the number of returned tablets at time points specified in the clinical 
study overview. Subjects will be required to bring the dispensed study medication 
bottles to each site visit. All cases of lost or damaged tablets must be 
documented.
Treatment compliance will be calculated by the investigator at Visits 3, 4, and 5 
using the formula:
Compliance in % = 
100 × (number of tablets dispensed – number of tablets returned*) / (expected 
number of tablets to be taken)
Whereby expected number of tablets to be taken = 
6 × (date of last dose – date of first dose + 1) - 2 × (3 - time of last dose) - 2 × 
(time of first dose - 1)
Where time of first/last dose of medication equal to

1 for Morning dose

2 for Daytime dose

3 for Evening dose
* Returned tablets include lost/damaged tablets, those that were expected to be returned. 
Rationale for Change: To include a requirement to document lost or damaged tablets and to 
define the nature of returned tablets.
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Protocol Incorporating Amendment No. 04
19 February 2019
Change 13: Added AESIs.
The primary change occurs in Section 10.1.5 AESIs.
Added text: 10.1.5 AESIs
AESIs in this study include the following.

Hypersensitivity:
Hypersensitivity or AEs relating to hypersensitivity.

Transmission of bovine infective agents:
Prion-associated disorders, iatrogenic infections, suspected 
transmission or transmission of an infectious agent via product, and 
encephalopathy.

Transmission of infectious agents – lack of sterility:
All AEs of infections.

Off-label use as an athletic performance enhancer:
Intentional product misuse.
Rationale for Change: To include AESIs in the protocol.
Change 14: Clarified method of signing the informed consent.
The primary change occurs in Section 15.2 Subject Information, Informed Consent, and Subject 
Authorization.
Initial 
wording:
The subject or the subject’s legally acceptable representative should be instructed to 
sign using their legal names, not nicknames, using blue or black ballpoint ink.
Amended 
or new 
wording:
The subject or the subject’s legally acceptable representative should be instructed to 
sign using their legal names, not nicknames, using a pen with blue or black 
ballpoint ink.
Rationale for Change: To clarify that the informed consent should be signed with a pen. 
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Study No. Actovegin-3001
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Protocol Incorporating Amendment No. 04
19 February 2019
Change 15: Removed specific assessments from the Schedule of Study Procedures.
The primary change occurs in Appendix A Schedule of Study Procedures.
Description 
of change:
The following assessments were removed for the start of IV treatment, Day 1:

Smoking status and physical activity.

Concomitant medications.

Pregnancy test and assessment of subject compliance with contraception 
requirements.
Rationale for Change: These assessments will be performed at the screening and baseline visits.
Property of Takeda: For non-commercial use only and subject to the applicable Terms of Use


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PPD

SAP_001.pdf: 


Other information as needed to protect confidentiality of Takeda or partners, personal
information, or to otherwise protect the integrity of the clinical study.
Title: A Randomized, International, Multicenter, Parallel Group, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of Actovegin 12-Week Treatment Given 
First Intravenously and Subsequently Orally in Subjects With Peripheral Arterial Occlusive 
Disease Fontaine Stage IIB
NCT Number: NCT03469349
SAP Approve Date: 11 November 2019
Certain information within this Statistical Analysis Plan has been redacted (ie, specific content is masked 
irreversibly from view with a black/blue bar) to protect either personally identifiable (PPD) information 
or company confidential information (CCI). 
This may include, but is not limited to, redaction of the following: 
Named persons or organizations associated with the study.
Proprietary information, such as scales or coding systems, which are considered confidential 
information under prior agreements with license holder.


1.0
TITLE PAGE
STATISTICAL ANALYSIS PLAN
STUDY NUMBER: Actovegin-3001
A Randomized, International, Multicenter, Parallel Group, Double-Blind, Placebo-
Controlled Study to Evaluate the Efficacy and Safety of Actovegin 12-Week Treatment 
Given First Intravenously and Subsequently Orally in Subjects with Peripheral Arterial 
Occlusive Disease Fontaine Stage IIB
PHASE 3
Version: 1.0 (Final)
Date: 11 November 2019
Prepared by:
Based on:
Protocol Version: Amendment 4
Protocol Date: 19 Feb. 2019
 
 
Property of Takeda: For n
rcial use only and subject to the applicable Terms of Use
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PPD
PPD


Actovegin-3001
Page 2 of 23
Statistical Analysis Plan (Final V1.0)
11NOV2019
1.1
Approval Signatures
Electronic signatures can be found on the last page of this document.
Study Title:
A Randomized, International, Multicenter, Parallel Group, Double-
Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of
Actovegin 12-Week Treatment Given First Intravenously and 
Subsequently Orally in Subjects with Peripheral Arterial Occlusive
Disease Fontaine Stage IIB
Reviewers/Approvals:
Prope
ct to the applicable Terms of Use
uble
ble-
nd Safet
nd Saf
y and 
and 
rial Occ
al Oc
PPD


Actovegin-3001
Page 3 of 23
Statistical Analysis Plan (Final V1.0)
11NOV2019
Property of Takeda: For non-commercial use only and subject to the applicable Ter
se
PPD


Actovegin-3001
Page 4 of 23
Statistical Analysis Plan (Final V1.0)
11NOV2019
2.0
TABLE OF CONTENTS
1.0
TITLE PAGE ..................................................................................................................1
1.1
Approval Signatures ..................................................................................................2
2.0
TABLE OF CONTENTS.................................................................................................4
3.0
LIST OF ABBREVIATIONS..........................................................................................6
4.0
OBJECTIVES .................................................................................................................7
4.1
Primary Objectives ....................................................................................................7
4.2
Secondary Objectives.................................................................................................7
4.3
Safety Objectives.......................................................................................................7
4.4
Study Design .............................................................................................................7
5.0
ANALYSIS ENDPOINTS...............................................................................................8
5.1
Primary Endpoint.......................................................................................................8
5.2
Secondary Endpoints .................................................................................................8
5.3
Additional Endpoints: Safety .....................................................................................9
6.0
DETERMINATION OF SAMPLE SIZE.........................................................................9
7.0
METHODS OF ANALYSIS AND PRESENTATION...................................................10
7.1
General Principles....................................................................................................10
7.1.1
Study Definitions ...............................................................................................11
7.1.2
Definition of Study Days....................................................................................11
7.1.3
Definition of Study Visit Windows ....................................................................11
7.1.4
Conventions for Missing Adverse Event Dates...................................................11
7.1.5
Conventions for Missing Concomitant Medication Dates...................................12
7.2
Analysis Sets ...........................................................................................................12
7.3
Disposition of Subjects ............................................................................................13
7.4
Demographic and Other Baseline Characteristics.....................................................14
7.5
Medical History and Concurrent Medical Conditions...............................................14
7.6
Prior and Concomitant Medications, Concomitant Procedures .................................14
7.7
Study Drug Exposure and Compliance.....................................................................15
7.8
Efficacy Analysis.....................................................................................................16
7.8.1
Primary Efficacy Endpoint(s).............................................................................16
7.8.2
Secondary Efficacy Endpoint(s).........................................................................16
7.8.3
Additional Efficacy Endpoint(s).........................................................................17
7.9
Pharmacokinetic/Pharmacodynamic Analysis ..........................................................17
7.9.1
Pharmacokinetic Analysis ..................................................................................17
7.9.2
Pharmacodynamic Analysis ...............................................................................17
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Actovegin-3001
Page 5 of 23
Statistical Analysis Plan (Final V1.0)
11NOV2019
7.10
Other Outcomes.......................................................................................................17
7.11
Safety Analysis........................................................................................................18
7.11.1 Adverse Events ..................................................................................................18
7.11.2 Clinical Laboratory Evaluations .........................................................................19
7.11.3 Vital Signs .........................................................................................................20
7.11.4 12-Lead ECGs ...................................................................................................20
7.11.5 Other Observations Related to Safety.................................................................21
7.12
Interim Analysis ......................................................................................................21
7.13
Changes in the Statistical Analysis Plan...................................................................21
8.0
REFERENCES..............................................................................................................21
9.0
APPENDIX...................................................................................................................22
LIST OF IN-TEXT TABLES
Table 6
Sample Sizes Under Different Values of Power....................................................9
LIST OF IN-TEXT FIGURES
Figure 4.4
Schematic of Study Design ..................................................................................7
LIST OF APPENDICES
Appendix A
Schedule of Study Procedures............................................................................21
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Actovegin-3001
Page 6 of 23
Statistical Analysis Plan (Final V1.0)
11NOV2019
3.0
LIST OF ABBREVIATIONS
ACD
absolute claudication distance
AE
adverse event
ALT
alanine aminotransferase
ANCOVA
analysis of covariance
ANOVA
analysis of variance
AST
aspartate aminotransferase
BMI
body mass index
BUN
blood urea nitrogen
ECG
electrocardiogram
eCRF
electronic case report form
FAS
full analysis set
GGT
-glutamyl transferase
IC
intermittent claudication
ICD
initial claudication distance
ICH
International Conference on Harmonisation
IMP
investigational medicinal product
IP
investigational product
IV
intravenous
LFT
liver function tests
LDH
lactate dehydrogenase
LLN
lower limit of normal
MedDRA
MMRM
Medical Dictionary for Regulatory Activities
mixed model for repeated measures
PAD
peripheral arterial disease
PD
pharmacodynamics
PK
pharmacokinetics
PPS
per-protocol set
QOL
quality-of-life
PRO
patient-reported outcome
SAE
serious adverse event
SAF
safety set
SAP
statistical analysis plan
SF-36
36-item Short Form Survey
TID
3 times daily
TLGs
tables, listings, and graphs
ULN
upper limit of normal
WHODrug
World Health Organization Drug Dictionary
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Statistical Analysis Plan (Final V1.0)
11NOV2019
4.0
OBJECTIVES
4.1
Primary Objectives
The primary objective is to investigate the efficacy of actovegin for the symptomatic treatment of
PAD Fontaine Stage IIB.
4.2
Secondary Objectives

To investigate the effect of actovegin in sustained improvement in claudication distance of
subjects with PAD Fontaine Stage IIB.

To investigate the effect of actovegin on patients’ quality of life.
4.3
Safety Objectives

To evaluate the safety of actovegin compared with placebo.
4.4
Study Design
This is a randomized, multi-center, parallel group, double-blind, placebo-controlled phase 3b
study to evaluate the efficacy and safety of actovegin 12-week treatment given intravenously and
subsequently orally in subjects with PAD Fontaine Stage IIB.
A total of 366 subjects with PAD Fontaine Stage IIB will be enrolled in approximately 17 to
25 sites in 3 countries (Russia, Kazakhstan, and Georgia).
The study will consist of a 1- to 2-week Screening Period, Randomization, 12-week Treatment
Period, and 12-week Follow-up Period. The overall study duration will be 25 to 26 weeks.
Subjects will enter a 1- to 2-week Screening Period during which, the stability of the subject’s
condition will be verified, a diagnosis of PAD will be confirmed, and subjects with high
variability in the claudication distance will be detected and excluded. For this purpose, 2 treadmill
tests will be performed within a time interval of ≥1 week (ie, 7 days). Subjects having a change of
more than 25% in the ACD during the Screening Period will be excluded.
Subjects with a history of stable intermittent claudication with symptoms that have been present 
continuously for at least 6 months at the time of Screening. A diagnosis of PAD (ICD of
<200 meters) will be confirmed by ultrasound color duplex imaging and treadmill test.
Eligible subjects will be randomized to receive either actovegin or placebo in a 1:1 ratio. The
treatment period will include 2 weeks of IV infusions of actovegin (deproteinized hemoderivate)
at a dose of 1200 mg/day, followed by 10 weeks of oral treatment in tablets at a dose of
1200 mg/day (two 200 mg tablets 3 times daily [TID]). Matched placebo (placebo ampoules and
placebo tablets) will be used throughout the treatment period to maintain blinding. The overall
treatment duration will be 12 weeks.
A 12-week follow-up period with no investigational medicinal product (IMP) treatment will
follow the 12-week treatment period to examine sustained efficacy after treatment as well as safety
once actovegin treatment has stopped.
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Statistical Analysis Plan (Final V1.0)
11NOV2019
A schematic of the study design is included as Figure 4.4. A schedule of assessments is listed in
Appendix A.
Figure 4.4
Schematic of Study Design
V=visit
5.0
ANALYSIS ENDPOINTS
5.1
Primary Endpoint
The primary endpoint is the percent change in initial claudication distance (ICD) from Baseline to
12 weeks of study treatment.
5.2
Secondary Endpoints

The percent change in ICD from Baseline to 2 and 24 weeks after randomization.

The change in absolute claudication distance (ACD) from Baseline to 2, 12, and 24 weeks 
after randomization.

Proportion of patients having rest pain at 12 and 24 weeks after randomization.

Proportion of patients having revascularization procedures at 24 weeks after randomization.

Change in 36-item Short Form Survey (SF-36) at 12 and 24 weeks after randomization.
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Statistical Analysis Plan (Final V1.0)
11NOV2019
5.3
Additional Endpoints: Safety

Safety and tolerability of actovegin will be evaluated by assessment of adverse events (AEs), 
clinical safety laboratory tests, vital signs, weight, electrocardiogram (ECG), and physical 
examination.
6.0
DETERMINATION OF SAMPLE SIZE
The primary endpoint of change from Baseline in ICD (initial claudication distance) is the most 
clinically important parameter for evaluation of effectiveness of Fontaine Stage II PAD 
treatment; this endpoint is recommended in the EMA guideline “Note for guidance on clinical
investigation of medicinal products for treatment of peripheral arterial occlusive disease.” 
Although several trials about actovegin have been done [1-5], none of them have the same 
primary endpoint as the proposed study. Additionally, the study design, study duration, primary 
endpoint, treadmill test setting and/or target subjects is also different in the proposed study.
The sample size justification is based on published data for Naftidrofuryl study [6]. This study is 
a randomized, double-blind, placebo-controlled, parallel-group study, including 154 subjects
with Stage II intermittent claudication. The 90-day examination data of Naftidrofuryl study is 
close to our 12-week treatment duration. The study design, measurement time, targeted subjects 
and treadmill test setting for [6] are similar to the proposed study. For the Naftidrofuryl study, 
the primary endpoint change from Baseline in ICD is similar to our primary endpoint (percent 
change from Baseline in ICD), the difference in percent change from Baseline in ICD between 
Naftidrofuryl and placebo is approximately 28%, while the corresponding pooled standard 
deviation is approximately 85%.
Two-sample t test with a 0.05 two-sided significance level is used for sample size calculation. 
Since the allocation ratio is 1:1, the sample size per each arm is calculated by the formula below 
[7, 8]:
 =  =
	(/	)	
∆	
,
where  is the sample size without drop-out for group i (i=1,2),  is the pooled standard 
deviation estimated from previous data, α is the two-sided significance level, 1-β is the power, ∆ 
is the difference in population means, and / and  are the z-values. 
Assuming σ=85% and ∆=28% for the percent change from Baseline in ICD, a total of 292 
subjects (146 per each arm) is sufficient to achieve at least 80% power. Considering 20% drop-
out rate, a total of 366 subjects (183 per each arm) should be randomized in the study.
Table 6 shows the sensitivity test for sample sizes (with and without drop-out) required for 
different values of power (from 70% to 95%) while 85% SD, 28% mean difference, 0.05 
significance level and 20% drop-out rate are assumed. 
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Statistical Analysis Plan (Final V1.0)
11NOV2019
Table 6
Sample Sizes Under Different Values of Power
Power (1-β)
70%
75%
80%
85%
90%
95%
Significant level (α)
0.05
0.05
0.05
0.05
0.05
0.05
Mean difference (∆=m1-m2)
28%
28%
28%
28%
28%
28%
Standard deviation ()
85%
85%
85%
85%
85%
85%
 (without drop-out)
115
129
146
167
195
241
Drop-out rate
20%
20%
20%
20%
20%
20%
 (considering drop-out)
144
162
183
209
244
302
N (total sample size)
288
324
366
418
488
604
7.0
METHODS OF ANALYSIS AND PRESENTATION
7.1
General Principles 
All statistical analyses will be conducted using SAS® Version 9.4, or higher.
All confidence intervals, statistical tests, and resulting P-values will be reported as 2-sided and 
will be assessed at α=0.05 significance level unless otherwise stated. P-values will be rounded to 
4 decimal places prior to assessment of statistical significance. 
Where appropriate, variables will be summarized descriptively by study visit. For the categorical 
variables, the count and proportions of each possible value will be tabulated by treatment group. 
The denominator for the proportion will be based on the number of subjects who provided non-
missing responses to the categorical variable. For continuous variables, the number of subjects 
with non-missing values, mean, median, SD, minimum, and maximum values will be tabulated. 
Means and medians will be presented to 1 more decimal place than the recorded data. The 
standard deviations (SDs) will be presented to 2 more decimal places than the recorded data. 
Confidence intervals about a parameter estimate will be presented using the same number of 
decimal places as the parameter estimate.
Baseline values are defined as the last observed value before the first dose of study medication. 
All subgroup analyses will be performed in an exploratory manner and are not powered or
designed to detect differences in subgroups. Categories within a subgroup will only be analyzed
if, within the study groups, the category contains at least 5% of the total number of subjects in
the subgroup. If this criterion is not met, a page for the category will be displayed stating:
“Analysis was not performed as this category does not contain at least 5% of the number of 
subjects in the subgroup within each study group.” Nevertheless, for all subgroups at least 
descriptive statistics will be presented.
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Statistical Analysis Plan (Final V1.0)
11NOV2019
7.1.1
Study Definitions
7.1.2
Definition of Study Days
Study Day 1 is defined as the date on which a subject is administered their first dose of the study 
medication. Other study days are defined relative to the Study Day 1 with Day 1 being Study 
Day 1 and Day -1 being the day prior to Study Day 1.
7.1.3
Definition of Study Visit Windows
All data will be categorized on the basis of the scheduled visit at which they are collected.  These 
visit designators are predefined values that appear as part of the visit tab in the electronic case 
report form (eCRF).  
7.1.4
Conventions for Missing Adverse Event Dates
Adverse events with start dates that are completely or partially missing will be imputed as follows:

If month and year are known but day is missing 
o
If month and year are the same as month and year of first dose date, then impute to
   first dose date 
o
If month and year are different than month and year of first dose date, then impute
   to first date of the month 

If year is known but day and month are missing 
o
If year is same as year of 1st dose date, then 1st dose date will be used instead
o
If year is different than year of 1st dose date, then 1st of January of the year will be 
   imputed. 
Imputing missing AE start date is mandatory. After the imputation, all imputed dates are checked 
against the start dates to ensure the stop date does not occur before start date. 
Adverse events with stop dates that are completely or partially missing will be imputed as follows:

If “ongoing” is checked, no imputation is necessary.

If month and year are known but day is missing, the last day of the month will be imputed 

If year is known, but day and month are missing,
o
If YYYY < year of last dose, then 31st of December will be imputed
o
If YYYY = year of last dose, then 31st of December will be imputed 
o
If YYYY > year of last dose, then 1st of January will be imputed 

If all are missing, no imputation is necessary. The event will be considered “ongoing”. 
If an AE is ongoing, AE stop date could be missing. Otherwise, AE stop date could be imputed per 
above rules. If a subject dies during the study and AE stop date is missing, then the death date will 
be used for AE stop date. After the imputation, all the imputed stop dates are compared with the 
start dates to ensure the stop date does not occur before the start date. If the imputed stop date 
occurs prior to the start date, then the imputed stop date will be the same as the start date. 
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Statistical Analysis Plan (Final V1.0)
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The imputed dates will not be populated on the data listing, they are used for derivation purpose
only. The actual and incomplete date will be on the data listing.
7.1.5
Conventions for Missing Concomitant Medication Dates
Concomitant medications with start dates that are completely or partially missing will be analyzed 
as follows:

If month and year are known, but day is missing, then impute day to first of the month

If year is known, but day and month are missing, then 1st of January of the year will be imputed
Concomitant medications with stop dates that are completely or partially missing will be analyzed 
as follows:

If “ongoing” is checked, no imputation is necessary.

If month and year are known but day is missing, the last day of the month will be imputed 

If year is known, but day and month are missing, 
o
If YYYY < year of last dose, then 31st of December will be imputed 
o
If YYYY = year of last dose, then 31st of December will be imputed 
o
If YYYY > year of last dose, then 1st of January will be imputed 

If all is missing, no imputation is necessary. It will be considered “ongoing”.
If a concomitant medication is ongoing, the stop date could be missing. Otherwise, concomitant 
medications stop date could be imputed per above rules. If a subject dies during the study and the 
concomitant medication stop date is missing, then the death date will be used for the stop date. 
After the imputation, all the imputed stop dates are compared with the start dates to ensure the 
stop date does not occur before the start date. If the imputed stop date occurs prior to the start date, 
then the imputed stop date will be the same as the start date.
The imputed dates will not be populated on the data listing, they are used for derivation purpose 
only. The actual and incomplete date will be on the data listing.
7.2
Analysis Sets
The Full Analysis Set (FAS) will include all subjects who were randomized, received at least 1
dose of study drug, and have at least 1 valid post-baseline value for assessment of primary 
endpoint. In FAS efficacy summaries and analyses, subjects will be analyzed by the treatment to 
which they were randomized.
The Per-Protocol Set (PPS) will consist of all subjects in the FAS who have no significant
protocol deviations as presented in Section 7.3. These criteria for exclusion of subjects from the
PPS will be reviewed, approved and documented (in a separate document) prior to database lock
and unblinding as part of the blinded data review. Any changes to these criteria after approval of
the SAP will be documented and approved in a separate document prior to database lock and
unblinding. The PPS will only be used for supportive analyses for primary and key secondary 
efficacy endpoints.
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Statistical Analysis Plan (Final V1.0)
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The Safety Set (SAF) will include all subjects who were randomized and received at least 1 dose 
of double-blind study medication. In safety summaries, subjects will be analyzed according to the
treatment they received. If a subject receives more than 1 treatment, the actual treatment will be
defined as the one that is used most frequently. If the 2 most common treatments are used with
equal frequency, then the randomized treatment will be used as the actual treatment.
7.3
Disposition of Subjects
The table of disposition of subjects includes the number of subjects in the following categories:  
subjects enrolled, subjects randomized, subjects treated, subjects completed treatment, subjects 
completed study, subjects discontinued of study, and primary reason for discontinuation study. 
Percentages will be presented.  
A listing will present data concerning subject disposition.
The significant protocol deviations captured on the eCRF or derived from programming will be 
summarized/listed by the standard protocol deviation (PV) terms (see below). The significant 
protocol deviation criteria will be reviewed, approved and documented (in a separate document) 
prior to database lock and unblinding as part of the blinded data review.
Significant protocol deviation criteria will be based on the Actovegin-3001 Clinical Study 
Protocol Deviations Management Plan (FORM-0002660):
Standardized Protocol Deviation Terms (eCRF):

Inclusion/exclusion criteria not met

Missing informed consent

Use the prohibited medications during the treatment period 

Any missed/incorrect study procedure that directly impacts the primary study objectives 
or subject safety 

Dispensing of incorrect treatment and/or incorrect dose of study medication

PAD therapy is not stable
List the protocol deviations to be programmed from the clinical database (eCRF data). 
Programmable listings serve as a means to identify records missing from the Significant Protocol 
Deviation eCRF. 
Programming Protocol Deviation criteria:

Oral drug compliance is below 80% 

Inclusion/exclusion criteria not met

Doesn’t have the primary endpoint at week 12 or at baseline

Use the prohibited medications during the treatment period
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Statistical Analysis Plan (Final V1.0)
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CRO Protocol Deviation Tracking Log (CRO standard form SF-CL-10.02-01) will be used for 
collection of information about all (either significant and non-significant) protocol deviations 
revealed during the Study course.
7.4
Demographic and Other Baseline Characteristics
Demographics and baseline characteristics will be summarized for sex, age, age group (<65, 
>=65 years of age), race, BL height, BL weight, and BL BMI. The table will also include a 
summary of study subject baseline characteristics: duration of peripheral artery disease (years), 
class of medications taken to treat PAD, smoking history, diabetic status, and ABI index at 
screening. A listing of demographics and baseline characteristics will be provided.
Baseline values for efficacy and safety parameters will be presented in the standard tables 
(Takeda Global Template for Common Table Shells, 25MAR2017), summarized per visit.
7.5
Medical History and Concurrent Medical Conditions
General medical history data will be presented in a summary table by SOC/PT, and in a listing 
by subject. 
Physical examination data will be presented in a listing.
7.6
Prior and Concomitant Medications, Concomitant Procedures
Prior and concomitant medications and procedures will be coded by generic term using the 
World Health Organization (WHO) Drug Dictionary. The number and percentage of subjects 
taking concomitant medications will be tabulated by WHO drug preferred name (generic term)
from the first dose of study treatment through 30 days after the last dose of study medication. 
Concomitant medications will be summarized in a table and presented in by-subject listings, 
separately.
The medications for the treatment of PAD will be identified by ATC code and then summarized 
in a table according to the following categories and corresponding preferred names:
–
Antiplatelet drugs and anticoagulants (except medications listed in Section Error! Reference 
source not found.). (ATC code B01AA-B01AF: B01AA: Vitamin K antagonists, B01AB: 
Heparin group, B01AC: Platelet aggregation inhibitors excluding heparin, B01AE: Direct 
thrombin inhibitors, B01AF: Direct factor Xa inhibitors)
–
Lipid-lowering agents (ATC code C10: Lipid modifying agents)
–
Antihypertensive drugs (ATC codes C02-C09: C02: Antihypertensive drugs, C03: Diuretic 
drugs, C04: Peripheral vasodilators, C05: Vasoprotective drugs, C07: Beta blocking agents, 
C08: Calcium channel blockers, C09: Agents acting on the renin-angiotensin system)
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Statistical Analysis Plan (Final V1.0)
11NOV2019
Concomitant procedures will be summarized in a table.
7.7
Study Drug Exposure and Compliance
A subject will be considered as treated in a period as long as this subject received any amount of 
study drug in that period. A treatment period is defined as a period in which the subject received 
any amount of study drug. A treatment period for a specific drug is defined as a period in which 
the subject received any amount of that drug. 
The exposure to study drug will be summarized including the periods (IV period, Oral period), 
total number of doses taken, number and percentages of subjects by treatment periods, treatment 
duration category (i.e. 1-2 weeks, 3-4 weeks…, 10-12 weeks) by cumulatively (number of 
subjects will be decreased by time).  
Dosing data will also be presented in a by-subject listing.
The IV treatment compliance in % = 100 x (number of completed infusions / expected number of 
infusions to be taken). If a subject completed the IV treatment period, the expected number of 
infusions is 14 (received 1 infusion per day for 14 days).
The oral treatment compliance will be calculated by the investigator at Visits 3, 4, and 5 using the
formula:
Compliance in % = 100 × (number of tablets dispensed – number of tablets returned) / 
(expected number of tablets to be taken)
Whereby expected number of tablets to be taken = 6 × (date of last dose – date of first dose + 1) 
- 2 × (3 - time of last dose) - 2 × (time of first dose - 1)
Where time of first/last dose of medication equal to

1 for Morning dose

2 for Daytime dose

3 for Evening dose
These data will subsequently be recorded in the eCRF by site personnel.
Subjects will be considered to be non-compliance with study medication if they miss > 20% of 
doses required for the visit period, or to take more than 120% of the doses for the treatment period 
since last visit.
Treatment compliance percentages will be summarized descriptively as quantitative variables 
(number, mean, SD, median, min, and max). The percentage of patients whose compliance is 
<80% or >120% will be summarized.
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Statistical Analysis Plan (Final V1.0)
11NOV2019
7.8
Efficacy Analysis
The primary and secondary endpoints will be analyzed in randomized subjects who received at
least one dose of study drug. Efficacy analysis will use population FAS and PPS.
The percent change from baseline in ICD, the absolute change from baseline in ACD, the percent
change from baseline in ACD, the absolute change from baseline in ICD, and change from
baseline in SF-36 will be analyzed using a mixed model for repeated measures (MMRM) analysis 
of covariance with treatment, center, sex, age group, visit, treatment-by-visit interaction as fixed 
effects, baseline value as covariate, and subject as a random effect. Comparisons between 
actovegin and placebo will be performed on all assessment points, by reporting LSMeans and the 
difference in LSMeans along with p-values and 95% confidence intervals. The MMRM analysis 
will be performed using observed case data, and a missing at random assumption. The effect at 
each time point for each treatment is allowed to vary freely and an unstructured covariance
matrix is assumed. Risk factors (e.g. smoking status and diabetes status, etc) effect on the 
primary efficacy endpoint will be analyzed by stepwise regression, to determine whether these 
risk factors should be included in the MMRM model or not.
Proportion of subjects (i.e. patients) having rest pain at 12 and 24 weeks will be analyzed by
logistic regression and the odds ratio between Actovegin and Placebo will be determined 
along with p-value and 95% confidence intervals. The analysis for proportion of subjects 
having a revascularization procedure at any time during the 24 weeks will be analyzed similarly. 
The primary efficacy endpoint and the secondary efficacy endpoints will be analyzed using the 
PPS for supportive analyses purpose.
7.8.1
Primary Efficacy Endpoint(s)
The primary efficacy endpoint is the percent change in initial claudication distance (ICD) from
Baseline to 12 weeks of study treatment.
7.8.2
Secondary Efficacy Endpoint(s)

The percent change in ICD from Baseline to 2 and 24 weeks after randomization.

The change in absolute claudication distance (ACD) from Baseline to 2, 12, and 24 weeks 
after randomization.

Proportion of patients having rest pain at 12 and 24 weeks after randomization.

Proportion of patients having revascularization procedures at 24 weeks after randomization.

Change in 36-item Short Form Survey (SF-36) at 12 and 24 weeks after randomization.
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Statistical Analysis Plan (Final V1.0)
11NOV2019
7.8.3
Additional Efficacy Endpoint(s)
The following additional efficacy endpoints will be evaluated:

The absolute change in ICD from Baseline to 2, 12, and 24 weeks after randomization.

The percent change in ACD from Baseline to 2, 12, and 24 weeks after randomization.

Subgroup analysis for the efficacy endpoints (percent (or absolute) change in ICD (or ACD) 
from Baseline to 2, 12, and 24 weeks after randomization) will be performed by following for 
the exploratory analysis purpose:

Age group (<65 or >=65 years of old)

Diabetic and non-diabetic patients

Patients with aorto-iliac or femoro-popliteal lesions

Current smokers, former smokers, and never-smokers 

Following efficacy endpoints will be presented by figures: Percent change from baseline in 
ICD (or ACD) by time (BL, Week 2, Week 12, Week 24) – FAS; Absolute change from 
baseline in ICD (or ACD) by time (BL, Week 2, Week 12, Week 24) - FAS.
7.9
Pharmacokinetic/Pharmacodynamic Analysis
Not applicable.
7.9.1
Pharmacokinetic Analysis
Not applicable.
7.9.2
Pharmacodynamic Analysis
Not applicable.
7.10
Other Outcomes
Not applicable.
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Statistical Analysis Plan (Final V1.0)
11NOV2019
7.11
Safety Analysis
Safety and tolerability of actovegin will be evaluated by assessment of adverse events (AEs), 
clinical safety laboratory tests, vital signs, weight, electrocardiogram (ECG), and physical 
examination.
7.11.1 Adverse Events
The definition of treatment-emergent AEs (TEAE) is defined as any AE that occurs after 
administration of the first dose of any study treatment through 30 days after the last dose of any 
study treatment.
AEs will be coded using MedDRA (Medical Dictionary for Regulatory Activities) version 22.0 
or above, and will be summarized by system organ class and preferred term in the treatment
period (TEAEs) and in the entire study. Study period is from Day 1 (first dose date) to the end of 
study.
AEs that were reported more than once by a subject during the same period will be counted only
once for that subject and period at the maximum severity. For Tables by SOC/PT, SOC is sorted 
using alphabetical order and PTs are sorted in decreasing frequency based on the total number of 
subjects.
All AEs (include the verbatim terms) will be presented in a by-subject listing. 
Summary tabulations will include the following categories: 

Overview of Treatment-Emergent Adverse Events

Overview of Adverse Events during Study Period

Overview of Adverse Events by Study Period

Treatment-Emergent AEs by System Organ Class and Preferred Term

AEs by System Organ Class and Preferred Term during Study Period

Pre-treatment AEs by System Organ Class and Preferred Term

TEAEs by System Organ Class and Preferred Term During IV Treatment Period

TEAEs by System Organ Class and Preferred Term During Oral Treatment Period

AEs by System Organ Class and Preferred Term During Follow-Up Period

TEAEs by System Organ Class and Preferred Term by Events

Drug-Related Treatment-Emergent AEs by System Organ Class and Preferred Term

Intensity of Treatment-Emergent AEs by System Organ Class and Preferred Term

Intensity of Drug-Related Treatment-Emergent AEs by System Organ Class and 
Preferred Term
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Statistical Analysis Plan (Final V1.0)
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
The Most Commonly Reported Treatment-Emergent AEs by Preferred Term (i.e., those 
events reported by ≥1% of all subjects)

Serious Treatment-Emergent AEs by System Organ Class and Preferred Term

Serious AEs by System Organ Class and Preferred Term during Study Period

Treatment-Emergent AEs Leading to Study Drug Discontinuation by System Organ Class 
and Preferred Term

Listing of Deaths
Most commonly reported (≥1% of all subjects in each group) treatment-emergent AEs will be 
presented by preferred term only.  Subjects with the same AE more than once will have that 
event counted only once within each preferred term.
An overall summary AE table will include numbers and percentages of subjects who had any 
AE, AE by relationship (drug-related, not related), AE by severity (mild, moderate, and severe),
serious AE (SAE), drug-related SAE, not related SAE, AE leading to study drug discontinuation, 
and on-study deaths. 
In addition, a by-subject listing of the SAEs will be presented (the subject listing will contain all 
SAEs regardless of treatment-emergent AE status).
A by-subject listing of AEs leading to deaths occurring on-study will be presented.  
A by-subject listing of treatment-emergent AEs leading to discontinuation of any study drug will 
be presented.  All AEs resulting in discontinuation of any study drug occurring on-study will be 
displayed.
7.11.2 Clinical Laboratory Evaluations
Absolute values and changes from baseline in clinical safety laboratory tests will be summarized 
for each treatment group using descriptive techniques. Values outside normal ranges, potentially
clinically significant values, and the markedly abnormal values (MAV) will be flagged and
tabulated.
For the purposes of summarization in both the tables and listings, all laboratory values will be 
converted to standardized units. 
If a subject has repeated laboratory values for a given time point, the value from the last 
evaluation will be used.
Laboratory test results will be summarized according to the scheduled sample collection time 
point. Change from baseline will also be presented. Unscheduled laboratory test results will not 
be included in the tables by visit, but they will be listed in the listing. The parameters to be 
analyzed are as follows:
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Actovegin-3001
Page 20 of 23
Statistical Analysis Plan (Final V1.0)
11NOV2019

Hematology:  hemoglobin, hematocrit, erythrocytes, thrombocytes, leukocytes and white 
blood cell count.

Serum chemistry:  creatinine, total bilirubin, albumin, alkaline phosphatase (ALP), 
aspartate aminotransferase (AST), alanine aminotransferase (ALT), glucose, Gamma 
glutamyl transferase (GGT), Creatine kinase, sodium, potassium, Cholesterol (total, high-
density lipoprotein, and low-density lipoprotein), and Triglycerides.
The number and frequency of the potentially clinically significant values (PCS) for above 
Laboratory tests will be summarized by visit for following categories: Normal, Abnormal but not 
clinically significant, and Abnormal and clinically significant.
Shift tables will be constructed for laboratory parameters to tabulate changes by values of Low, 
Normal, High based on the local Lab normal ranges for scheduled visits, or criteria for markedly 
abnormal values (MAV) from baseline to post baseline worst value (includes unscheduled visit 
records) (see Takeda Guidance for Defining Markedly Abnormal Values Used in Statistical 
Analyses, TOOL-001387 (1.0), 02JUN2016). Parameters to be tabulated will include:

Hematology: hemoglobin, thrombocytes

Serum chemistry: ALT, AST, ALP, creatinine, total bilirubin.
Mean laboratory values and box plots over time for key lab parameters will be produced, 
including but not limited to the liver function tests (ALT, AST, alkaline phosphatase, and total 
bilirubin).
By-subject listings to be presented include results from the clinical laboratory tests for 
hematology, serum chemistry, and urinalysis.
7.11.3 Vital Signs
Absolute values and changes from baseline in vital signs and weight will be summarized for each 
treatment group using descriptive techniques. Values outside the criteria for markedly abnormal 
values will be flagged and tabulated (see Takeda Guidance for Defining Markedly Abnormal 
Values Used in Statistical Analyses, TOOL-001387 (1.0), 02JUN2016).
The actual values of vital sign parameters including blood pressure, heart rate, and body weight, 
will be summarized over time for each treatment arm.  Change from baseline will also be 
presented.  
A by-subject listing will also be presented.
7.11.4 12-Lead ECGs
An overall summary ECG table will include numbers and percentages of subjects who had ECG 
result of Normal, NCS, CS from CRF ECG page by treatment group. A by-subject listing of 
ECG result will also be presented.
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Actovegin-3001
Page 21 of 23
Statistical Analysis Plan (Final V1.0)
11NOV2019
7.11.5 Other Observations Related to Safety
Physical examination findings will be presented by a listing.
7.12
Interim Analysis
No interim analysis is planned.
7.13
Changes in the Statistical Analysis Plan 
{None}
8.0
REFERENCES
1.
Angelkort B, Blume J, de la Haye R, Kuntz G. Metabolically active calves blood extract in 
welltrained patients with AVD in stage II. A placebo-controlled doubleblind study. VASA 
- J Vasc Dis 1988(Suppl 23):141-3.
2.
Horsch S, Claeys L, Diehm C, Rieger H, Cachovan M, Baitsch C. [Assessment of the 
clinical effectiveness of actihaemyl in Fontaine stage IIb intermittent claudication]. Vasa 
Suppl 1992;37:64-5.
3.
Muller-Buhl U, Ruhlmann KU, Meister K, Diehm C, Kuntz G. Increase of walking 
distance by intra-arterial infusions of hemodialysate. Therapiewoche 1991;41:188-96.
4.
Angelkort B, Ruhlmann KU, de la Haye R, Kuntz G. Influence of deproteinized 
hemodialysate on rest pain and walking distance in the presence of peripheral chronic 
arterial occlusive disease. Angiology 1992;43(1):47-58.
5.
Guriyeva IV, Begma IV, Kuzina IV, et al. Patogenetic treatment with Actovegin of 
neuroishemic pain syndrome in lower extremirties in patients with diabetes mellitus [In 
Russian]. RMJ 2009;17(10):670-2.
6.
Adhoute G, Bacourt F, Barral M, Cardon JM, Chevalier JM, Cuny A, et al. Naftidrofuryl in 
chronic arterial disease. Results of a six month controlled multicenter study using 
Naftidrofuryl tablets 200 mg. Angiology 1986;37(3 Pt 1):160-7.
7.
Julious SA. Sample Sizes for Clinical Trials. Boca Raton, FL.: Chapman & Hall/CRC. ; 
2010.
8.
Chow S-C, Shao J, Wang H. Sample Size Calculations in Clinical Research (Second 
Edition). Boca Raton, FL: Chapman & Hall/CRC; 2008.
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9.0
APPENDIX
Appendix A
Schedule of Study Procedures
Day
Screening
Period
Treatment Period
Follow- up Period
Randomization
(Baseline)
Infusion Treatment (IV)
Oral Treatment
Day -7-14
to -1
Day 1
Start of IV
treatment Day 1
IV 
treatment
Day 2-
Day 13
End of IV
treatment
Day 14
V2+28
±2 days
(Day 42)
V3+28
±2 days
(Day 70)
End of
treatment
V4+14
±2 days
(Day 84) (a)
Interim
Follow-up (4
weeks interval
±5 days)
(Day 112)
Interim
Follow-up (4
weeks interval
±5 days)
(Day 140)
Final Follow-up
V7+28
±2 days
(Day 168) (b)
Visit No.
V0
V1
V1
V2
V3
V4
V5
V6
V7
V8
Informed consent
X
Inclusion/ exclusion criteria
X
X
Demographics
X
Medication history
X
X
Medical history and
concurrent medical
conditions
X
Smoking status and 
exercise habits
X
X
X
X
X
X
X
X
X
Pretreatment events
X
X
AEs
X (c)
X (c)
X(c)
X
X
X
X
X
X
Physical examination
X
X
X
X
Vital signs
X
X
X
X
Height and weight (d)
X
X
X
Concomitant medications
X
X
X(e)
X
X
X
X
X
X
12-lead ECG
X
Clinical laboratory tests
X
X
X
Pregnancy test (f) and 
assessment of subject 
compliance with 
contraception requirements.
X(g) 
X
X
X
X
X
X
X
X
Footnotes are on last table page.
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Actovegin-3001
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Statistical Analysis Plan (Final V1.0)
11NOV2019
Appendix A
Schedule of Study Procedures (continued)
Day
Screenin
g Period
Treatment Period
Follow- up Period
Randomization
(Baseline)
Infusion Treatment (IV)
Oral Treatment
Day -7-
14
to -1
Day 1
Start of
IV
treatment
Day 1
IV 
treatment 
Days 2-13
End of IV
treatment
Day 14
V2+28
±2 days
(Day 42)
V3+28
±2 days
(Day 70)
End of
treatment
V4+14
±2 days
(Day 84) (a)
Interim
Follow-up (4
weeks interval
±5 days)
(Day 112)
Interim
Follow-up (4
weeks interval
±5 days)
(Day 140)
Final Follow-
up V7+28
±2 days
(Day 168) (b)
Visit No.
V0
V1
V1
V2
V3
V4
V5
V6
V7
V8
Glycosylated hemoglobin 
HbA1c
X
Treadmill test
X
X(h)
X(e)
X
X
Ultrasound color duplex
imaging
X
SF-36
X
X
X
Dispense study drug for
oral treatment
X(e)
X
X
Return study drug for oral
treatment
X
X
X
Study drug compliance
check
X
X
X
V=visit.
(a) Early Termination Visit for subjects who terminate the study before completing the Oral Treatment Period.
(b) Early Termination Visit for subjects who terminate the study during the Follow-up Period.
(c) On Day 1 Visit 1, AEs should be checked after infusion. Starting on Day 1, AEs should be checked before (since last visit) and after the infusion.
(d) Height and weight will be measured at V1. Only weight will be measured at V5 and V8.
(e) Following the final infusion.
(f) Female subjects of childbearing potential only.
(g) Assessment of compliance with contraception requirements not needed at this visit.
(h) The time interval from the first test must be of ≥1 week and ≤2 weeks.
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