An Open-Label, One-Arm Phase II Extension Study to Evaluate Safety and Tolerability of MIV-711 in Patients With Knee Joint Osteoarthritis
Phase: PHASE2
Conditions: Osteoarthritis, Knee
Sponsor: Medivir

An Open-Label, One-Arm Phase II Extension Study to Evaluate Safety 
and Tolerability of MIV-711 in Patients with Knee Joint Osteoarthritis
Sponsor:
Medivir AB
Blasieholmsgatan 2,
111 48 Stockholm, Sweden
Clinical Research Organization:
PAREXEL International (IRL) Limited,
70 Sir John Rogerson’s Quay, Dublin 2, Ireland.
Principal/Global Coordinating 
Investigator
Prof. Philip Conaghan
University of Leeds
Leeds Institute of Rheumatic and Musculoskeletal 
Medicine
Chapel Allerton Hospital
Chapeltown Road
Leeds LS7 4SA, United Kingdom
Sponsor Protocol No.:
MIV-711-202
EudraCT No.:
2016-001096-73
Study Drug Name:
MIV-711
Development Phase:
Phase II
Date of Protocol:
01 July 2016
The study will be conducted according to the protocol and in compliance with Good 
Clinical Practice (GCP), with the Declaration of Helsinki [1] and with other applicable 
regulatory requirements.
CONFIDENTIAL
This document contains confidential information of Medivir AB.
Do not copy or distribute without written permission from the Sponsor.

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Declaration of the Investigator
Title: An Open-Label, One-Arm Phase II Extension Study to Evaluate Safety and Tolerability 
of MIV-711 in Patients with Knee Joint Osteoarthritis
All documentation for this study that is supplied to me and that has not been previously 
published will be kept in the strictest confidence. This documentation includes this study 
protocol, Investigator's Brochure, electronic Case Report Form (eCRF), Patient-Reported 
Outcomes (PRO),patient diaries and other scientific data.
The study will not be commenced without the prior written approval of a properly constituted 
Independent Ethics Committee (IEC). No changes will be made to the study protocol without 
the prior written approval of the Sponsor and the IEC, except where necessary to eliminate an 
immediate hazard to the patients.
I have read and understood and agree to abide by all the conditions and instructions contained 
in this protocol.
Responsible Investigator of the local study centre
Signature
Date
Name (block letters)
Title (block letters)
Institution (block letters)
Country

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PROTOCOL SYNOPSIS
Title
An Open-Label, One-Arm Phase II Extension Study to Evaluate 
Safety and Tolerability of MIV-711 in Patients with Knee Joint 
Osteoarthritis
Sponsor Study No.
MIV-711-202
Phase
Phase II
Sponsor
Medivir AB
Blasieholmsgatan 2, 111 48 Stockholm, Sweden
Principal or Global 
Coordinating 
Investigator
Prof. Philip Conaghan
University of Leeds
Leeds Institute of Rheumatic and Musculoskeletal Medicine
Chapel Allerton Hospital
Chapeltown Road, Leeds LS7 4SA, United Kingdom
Study Centers
Five sites distributed in 5 European countries.
1) PAREXEL Berlin Early Phase Clinical Unit, PAREXEL 
International GmbH, Spandauer Damm 130, 14050 Berlin, 
Germany
2) MC Comac Medical, 13 Urvich Str, 1612 Sofia, Bulgaria
3) LLC ARENSIA Exploratory Medicine, Research Institute of 
Clinical Medicine, 13a, Tevdore Mgvdeli Str. 0112 Tbilisi,
Georgia
4) LLC ARENSIA Exploratory Medicine, Republican Clinical 
Hospital, 29 Testemitanu Str. 2025 Chisinau,
Republic of Moldova
5) SC ARENSIA Exploratory Medicine SRL
Spitalul Clinic Colentina, Sectia de Medicina Interna III, Sos. 
Stefan cel Mare Nr. 19-21,
Sector 2 Bucharest 020125, Romania
Objective
The primary objective is to assess the safety and tolerability of 
200 mg MIV-711 q.d. over 52 (26+26) weeks in patients with 
symptomatic and radiographic knee osteoarthritis (OA).
Design
This is a multicentre, open-label, one-arm Phase II extension study to evaluate the safety 
and tolerability of MIV-711 for up to 52 (26+26) weeks in patients with knee joint OA.
Patients to be enrolled will be selected from the patients in Study MIV-711-201 (a 
randomised, double-blind, placebo-controlled Phase IIa study to evaluate efficacy, safety 
and tolerability of MIV-711 in knee joint osteoarthritis). 
Patients treated with 200 mg MIV-711 once daily (q.d.) in Study MIV-711-201 whose 
symptoms did not clinically significantly deteriorate as defined by a numeric rating scale 
(NRS) increase of ø4" eqorctgf" vq" Daseline will be offered to roll over for 26 weeks’
extended treatment primarily evaluating longer term safety and tolerability. The 
52 (26+26) weeks total treatment also allows for a more suitable treatment length for the 
exploratory study of any structural effects of MIV-711 on joint cartilage thickness. In this 
protocol, this population is referred to as Study Population A.
The second objective of this study is the exploratory assessment of the treatment effect in a 

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group of OA patients that has confirmed symptom progression over the last 6 months. This
means that patients receiving placebo in Study MIV-711-201 and that had experienced a 
clinical worsening as defined by increased NRS versus Bcugnkpg" qh" œ4"will be offered to 
receive 200 mg MIV-711 q.d. for the next 6 months. In this protocol, this population is 
referred to as Study Population B. The safety and tolerability in Study Population B
constitutes a secondary objective whereas all other analyses are exploratory.
All patients in Study MIV-711-201 (Eudract No. 2015-003230-26) at the participating sites 
included in Study MIV-711-202 will be given the opportunity to participate provided that 
they meet the eligibility criteria.
To ensure the patients will have sufficient time to consider their participation in the study 
the informed consent form will be given to the patients prior to Visit 8 in Study 
MIV-711-201. Visit 8 of Study MIV-711-201 will ideally be conducted on the same day as 
Visit 1 of the present study. If these visits are conducted on the same day, the results of the 
following assessments will be recorded in the electronic case report form (eCRF) for both 
studies; urine and blood sampling for safety, vital signs, physical examination and 
electrocardiogram (ECG).
A central person, independent from the study, with access to the randomisation list and the 
eCRF for the MIV-711-201 study will confirm Inclusion Criterion 1. The confirmation will 
be communicated to the site staff and the study team via fax/email without revealing the 
treatment in MIV-711-201 or the change in NRS score.
All enrolled patients will receive 200 mg q.d. oral dose of MIV-711 for 26 weeks in 
addition to their current medication. MIV-711 200 mg will be provided as identical 
capsules to those used in Study MIV-711-201.
The patients will take the last dose of IMP in Study MIV-711-201 at Visit 8 and dosing in 
the present study will be started at Visit 2 after a screening period of 10±5 days.
Patients who are not eligible to participate in the present study will return for the safety 
follow up visit (Visit 9) in Study MIV-711-201. 
Patients will be permitted to remain on their current analgesic regimen with any changes in 
concomitant medications reported and recorded at study visits as well as in a 
patient-reported daily e-diary for two 2-week periods prior to Visit 4 and Visit 5.
The study consists of a Screening period of approximately 2 weeks (Visit 1), eligibility at 
Visit 2, an open-label treatment period of 26 weeks from Visit 2 through Visit 5, and a 
follow-up period of 4 weeks (Visit 6) after the last dose of study treatment is administered.
Telephone calls will be made 5-9 days after all dosing visits for safety and tolerability.
There will be additional phone calls at Week 10 and Week 20 for safety and tolerability.
A Data Monitoring and Ethics Committee will meet to review the unblinded safety and 
tolerability data after the first 25 patients complete Visit 4 and Visit 5.
Treatment
All patients will receive a 200 mg oral dose of MIV-711 q.d. for 
26 weeks in addition to their current medication.
Number of Patients
All patients in Study MIV-711-201 at the participating sites 
included in Study MIV-711-202 will be given the opportunity to 
participate provided that they meet the eligibility criteria. However, 
based on the inclusion and exclusion criteria it is anticipated that 
50-80 patients will be eligible for participation. The patients will be 
recruited from up to 5 centres in up to 5 countries for this study. 
Population
The study population will consist of patients with symptomatic and 
radiographic knee joint OA who have participated in Study 
MIV-711-201. Patients must be able to provide written consent, be 

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approved by the investigator for eligibility as well as meeting all the 
inclusion criteria and none of the exclusion criteria.
Criteria for inclusion and exclusion
Inclusion:
Patients must meet all of the following criteria to be eligible for enrolment in this study:
1. Previously enrolled in the MIV-711-201 study including completion of Visit 8 either by 
‚
Receiving MIV-711 200 mg and had non-significant clinical worsening on the 
primary endpoint as defined by NRS increase of ø2
OR by
‚
Receiving placebo and had a clinically significant worsening on the primary 
endpoint as defined by NRS increase of œ4
The NRS result will be derived using the primary endpointfrom Study MIV-711-201: NRS average knee 
pain in the target knee with 7days recall: increase from Baseline (Visit 2 of Study MIV-711-201) to 
Visit 8 of Study MIV-711-201.
2. Female patients must be non-pregnant, non-lactating and of non-childbearing potential 
either as naturally (spontaneously) post-menopausal or due to hysterectomy and/or 
bilateral oophorectomy/salpingo-oophorectomy (as determined by patient medical 
history). Naturally (spontaneously) post-menopausal is defined as being amenorrhoeic 
for 12 months without an alternative medical cause and with a Screening follicle 
stimulating hormone test indicating post-menopausal state.
3. Male patients should avoid fathering a child by either of the following methods:
‚
True sexual abstinence: meaning that heterosexual abstinence is in line with the 
preferred and usual lifestyle of the patient (periodic abstinence such as that based 
on calendar, ovulation, symptothermal, post-ovulation methods, declaration of 
abstinence for the duration of a trial, or withdrawal/coitus interruptus are not 
acceptable methods of contraception).  
‚
Willingness to use two effective means of contraception with their partner from 
the time of first IMP administration until 3 months after the last dose of IMP. Two 
or more of the following methods are acceptable and must include at least one 
barrier method: i) Surgical sterilisation (i.e., bilateral tubal ligation for female 
partners; vasectomy for male), ii) placement of an intrauterine device or 
intrauterine system, iii) hormonal contraception (implantable, patch, oral), iv) 
barrier methods including condom or occlusive cap (diaphragm or cervical/vault 
caps) with spermicidal foam/gel/film/cream/suppository. Male patients who have 
been sterilised are required to use one barrier method of contraception (condom).
4. The patient’s usual analgesic regimen (in case of use) should remain the same as for 
Visit 8 in the MIV-711-201 study (i.e., Visit 1 in the MIV-711-202 study).
NOTE: If a patient is experiencing increased or decreased pain and requires an increase or a decrease in 
the dose of analgesics, or an occasional change of analgesics medication during his/her participation in 
the study, then this will be allowed and should be properly documented in the patient file and the eCRF.
5. Needs to be able to communicate well with the investigators and staff.
6. Able to comply with the requirements of the study procedures and provide written 
informed consent prior to any study related procedures.

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Exclusion:
Patients will be excluded from enrolment in this study if they meet any of the following 
criteria:
1. The presence of any inflammatory arthritis (e.g., gout, reactive arthritis, rheumatoid 
arthritis, psoriatic arthritis, seronegative spondylarthropathy) or any underlying 
condition, other than OA, that may result in abnormal cartilage and bone metabolism.
2. Any generalised pain condition that may interfere with the evaluation of the target knee 
pain (e.g., fibromyalgia) as judged by the investigator.
3. Ongoing or a history of atrial fibrillation.
4. Currently receiving medication that affects cartilage or bone metabolism (other than 
study drug; hormone replacement therapy taken for more than 6 months is allowed).
5. Current or recurrent disease that could affect the action, absorption or disposition of 
MIV-711, or could affect clinical assessments or clinical laboratory assessments.
6. Any clinically severe or significant uncontrolled concurrent illness, which, in the 
opinion of the Investigator, would impair ability to give informed consent or take part in 
or complete this clinical study.
7. Any medical condition, adverse event (AE), clinical or laboratory finding from 
Study MIV-711-201 that, in the opinion of the Investigator, would preclude inclusion in
the present clinical study.
8. Known or suspected intolerance or hypersensitivity to the investigational medicinal 
product, closely related compounds, or any of the stated ingredients.
9. History of alcohol or other substance abuse within the last year.
10. Use of an investigational product other than MIV-711 during participation in the 
MIV-711-201 study and /or active enrolment in another drug or vaccine clinical study.
11. Significant target knee injury or surgery during participation in the MIV-711-201 study.
12. A history of partial or complete joint replacement surgery in the target knee at any time, 
listed for knee surgery, or anticipating knee surgery during the study period.
13. Any factor which, in the opinion of the investigator, would jeopardise the evaluation or
safety of the patient or be associated with poor adherence to the clinical study protocol
(e.g., inability to complete study diary, poor tolerability of venepuncture or lack of 
adequate venous access for required blood sampling during the study period).
14. Use of intra-articular hyaluronic acid in the target knee during participation in the 
MIV-711-201 study.
15. Use of intra-articular, intra-muscular or oral corticosteroids during participation in the 
MIV-711-201 study.
16. Commencement of non-pharmacological OA interventions during participation in the 
MIV-711-201 study. 
17. Vulnerable patients, e.g., patients kept in detention, soldiers, and employees of the 
sponsor or the Contract Research Organisation (CRO) with direct involvement in the 
proposed study or other studies under the direction of the investigator or the CRO, as 
well as family members of the employees or the investigator.
18. Lack of MRI of the knee from Visit 8 in the MIV-711-201 study due to special 
circumstances, such as claustrophobia or difficulties to fit the knee coil.
19. Patients with contra-indication to MRI of the knee.

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Outcome variables
Safety:
The primary outcome variables for this study are related to safety:
•
Incidence and severity of adverse events 
•
Incidence and severity of clinical laboratory abnormalities
•
Physical examination findings by the patient
•
Incidence and severity of ECG abnormalities
•
Mean change from Baseline (Visit 2 of Study MIV-711-201) in vital signs (blood 
pressure, heart rate, temperature) and oxygen saturation
•
Categorical summary of observed vital signs and vital sign changes compared to 
Baseline (Visit 2 of Study MIV-711-201), by patient
Efficacy:
The secondary outcome variables are related to efficacy:
•
The effect of MIV-711 on MRI cartilage thickness loss
•
The effect of MIV-711 on MRI bone marrow lesion volume
•
The effect of MIV-711 in the semi quantitative MRI Osteoarthritis Knee Score 
(MOAKS) parameters
•
To assess the effect of MIV-711 on MRI knee joint bone area.
Note: all MRI assessments refer to the target knee unless stated otherwise.
Exploratory outcome variables:
•
The effect of MIV-711 on worst target knee pain (1 week recall)
•
The effect of MIV-711 on average contralateral knee pain (1 week recall)
•
The effect of MIV-711 on constant and intermittent OA pain
•
The effect of MIV-711 on global improvements in knee problem, knee pain and knee 
function
•
The effect of MIV-711 on knee joint OA symptoms (function, pain, stiffness) 
•
The effect of MIV-711 on global disease activity 
•
The effect of MIV-711 on quality of life (QoL)
•
The effect of MIV-711 on patient reported e-diary daily recall knee joint pain
•
The effect of MIV-711 on patient reported e-diary daily recall analgesics use
•
Serum and urinary biomarkers (C-terminal telopeptide of collagen type I [CTX-I], 
procollagen type I N-terminal propeptide [PINP],bone specific alkaline phosphatase
[BSAP], C-terminal telopeptide of collagen type II [CTX-II], N-terminal telopeptide 
of collagen type I [NTX-I], gCTX-I and tartrate-resistant acid phosphatase 5b
[TRAP5b])
•
Compound index of MRI bone area and cartilage volume
•
Pharmacokinetics: MIV-711 Pharmacokinetic (PK) parameters and their relationship 
to covariates such as age, weight, gender, liver function and concomitant 
medications.
All of the above denoted secondary and exploratory parameters are considered as 
exploratory objectives in Study Population B and will be evaluated over 26 weeks.

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Statistical Methods
Primary Analysis
The primary outcome will be to study the safety and tolerability of MIV-711 in OA patients 
who have received treatment for up to 52 (26+26) weeks. Safety and tolerability will be 
assessed descriptively in summary tables presented over time. All data presentations 
addressing the primary outcome will use Study Population A.
Secondary Analysis
For Study Population B, the safety and tolerability of 200 mg MIV-711 will be studied for 
26 weeks. Safety and tolerability will be assessed descriptively in summary tables presented 
over time. 
All other secondary analyses will be undertaken using Study Population A while they will 
be undertaken as exploratory analyses on Study Population B.
For Study Population A all secondary outcome variables will be analysed using descriptive 
summary tables presenting statistics for, number of non-missing values means, medians, 
standard deviations, minimum and maximum values. Frequency tables (counts and 
percentages) will be presented in tables where appropriate. Figures of secondary response 
over time will be presented as appropriate.
For all outcome variables analysed using a linear model, distributional assumptions will be 
checked using examination of empirical distributions and model residuals. If necessary, 
data will be transformed prior to analysis if this improves the model fit, or normalises the 
distribution of the residuals. Non-parametric methods may be applied if appropriate.
For the analysis of secondary endpoints, alternate statistical methods maybe considered that 
will include the use of generalised linear models that account for the response variable 
having a “non-normal” distribution.  Additional details will be provided in the Statistical 
Analysis Plan.
All secondary outcomes will be summarised descriptively (mean, SD, median, minimum 
and maximum for continuous data and counts and percentages for categorical data). 
No comparisons between Study Populations A and B will be undertaken.
Exploratory Analysis
The exploratory analysis of patient-reported outcomes, bone and cartilage biomarkers, MRI 
imaging and PK assessments will be listed and summarised using descriptive statistics only
or presented in separate reports. The pharmacokinetic measurements in this study will be 
performed using sparse sampling in which the date/time of sample collection as well as the 
date/time of the most recent dose will be collected in the eCRF to allow for a future 
population pharmacokinetic analysis of these data. For the purpose of this study, the plasma 
concentrations of parent and potential metabolites of MIV-711 will be an additional 
exploratory endpoint and will be reported as outlined above. In the analysis of biomarkers
that are sampled at multiple visits, all sampled time points will be considered for change 
from Baseline in the respective cases. In applicable cases PK and biomarker data may be 
analysed using area under the curve calculations.

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LIST OF STUDY PERSONNEL
Sponsor
Medivir AB
Blasieholmsgatan 2
111 48 Stockholm, Sweden
Principal or Global 
Coordinating Investigator
Prof. Philip Conaghan
University of Leeds
Leeds Institute of Rheumatic and Musculoskeletal 
Medicine
Chapel Allerton Hospital
Chapeltown Road
Leeds LS7 4SA, United Kingdom
Contract Research 
Organization
PAREXEL International (IRL) Limited,
70 Sir John Rogerson’s Quay, Dublin 2, Ireland.
Adverse Event Reporting
PAREXEL International
Medical Monitor: Francois Burger
Medical hotline: +49 30 30685 274
SAE Fax: +49 30 315118 7777 (24-hour service)
Email: Medical_Berlin@parexel.com
Central Imaging Reader
Imorphics
Kilburn House, Lloyd Street North, Manchester Science 
Park, Manchester M15 6SE,United Kingdom
Laboratory for safety 
testing and urinalysis
ACM Global Central Laboratory
23 Hospital Fields Road
York, YO10 4DZ, United Kingdom
Laboratory for biomarker 
analysis
Nordic Bioscience Laboratory A/S
Herlev Hovedgade 207
2730 Herlev, Denmark
Laboratory for drug 
concentration  analysis
York Bioanalytical Solutions
Cedar House, Northminster Business Park
Upper Poppleton
York, YO26 6QR, United Kingdom
eDiary provider:
CRF Health
Brook House - 3rd Floor
229-243 Shepherds Bush Road Hammersmith
London, W6 7AN, United Kingdom

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TABLE OF CONTENTS
PROTOCOL SYNOPSIS............................................................................................5 
LIST OF STUDY PERSONNEL..............................................................................11 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS............................15 
1 
ABSTRACT...................................................................................................18 
2 
INTRODUCTION.........................................................................................19 
2.1 
Background...............................................................................................19 
2.2 
Pharmacokinetic, Pharmacodynamic and Safety results from MIV-711
First Time in Man Study and Blinded Safety and Tolerability Summary 
from MIV-711-201 ....................................................................................20 
2.3 
Study Rationale .........................................................................................21 
2.4 
Study Design and Dosing Rationales.........................................................22 
2.5 
Risk-Benefit Assessment...........................................................................23 
3 
STUDY OBJECTIVES..................................................................................25 
3.1 
Primary Objective Study Population A* ..................................................25 
3.2 
Secondary Objectives Study Population A................................................25 
3.3 
Secondary Objective Study Population B* ...............................................25 
3.4 
Exploratory Objectives Study Population A.............................................25 
3.5 
Exploratory Objectives Study Population B.............................................26 
4 
OVERALL DESIGN AND PLAN OF THE STUDY....................................27 
5 
STUDY POPULATION ................................................................................29 
5.1 
Inclusion Criteria......................................................................................29 
5.2 
Exclusion Criteria.....................................................................................30 
5.3 
Patient Withdrawal and Replacement......................................................31 
5.4 
Planned Sample Size and Number of Study Centres................................32 
5.5 
Patient Identification.................................................................................32 
5.5.1 
Patient Identification....................................................................... 32 
5.5.2 
Investigational Drug Administration Scheme................................... 32 
5.5.3 
Allocation of Patients to Treatment ................................................. 32 
5.5.4 
Procedures for Handling of Incorrectly Included Patients................. 33 
6 
STUDY DRUG ..............................................................................................34 
6.1 
Investigational Drug..................................................................................34 
6.2 
Administration..........................................................................................34 
6.3 
Packaging, Labelling and Storage.............................................................34 
6.4 
Drug Accountability..................................................................................35 
6.5 
Compliance ...............................................................................................35 
6.6 
Other Medications.....................................................................................35 
6.6.1 
Rescue Medication ......................................................................... 35 
6.6.2 
Concomitant Medications ............................................................... 35 
6.6.3 
NSAIDs and other analgesics.......................................................... 36 
6.6.4 
Prohibited Concomitant Medications............................................... 36 
6.6.5 
Chondroitin and Glucosamine ......................................................... 36 
6.7 
RESTRICTIONS......................................................................................36 
7 
ENDPOINT AND METHODS OF ASSESSMENT......................................37 
7.1 
Primary Endpoint (Study Population A) ..................................................37 

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7.2 
Secondary Endpoints (Study Population A) .............................................37 
7.3 
Secondary Endpoints (Study Population B)..............................................38 
7.4 
Exploratory Endpoints..............................................................................38 
7.4.1 
Exploratory Endpoints (Study Population A)................................... 38 
7.4.2 
Exploratory Endpoints (Study Population B) ................................... 39 
7.5 
Physical Examination................................................................................40 
7.6 
Vital Signs .................................................................................................40 
7.7 
12-lead Electrocardiograms (ECG)...........................................................40 
7.8 
Imaging Assessments.................................................................................40 
7.9 
Self-report Parameters..............................................................................41 
7.10 
Pharmacokinetic Sampling .......................................................................42 
7.11 
Biomarker Sampling .................................................................................42 
7.12 
Optional Pharmacogenomics Sampling ....................................................43 
7.13 
Adverse Events..........................................................................................43 
7.13.1 
Definitions of Adverse Events (AEs)............................................... 43 
7.13.2 
Assessment of Adverse Events........................................................ 43 
8 
STUDY CONDUCT.......................................................................................48 
8.1 
Study Schedule..........................................................................................48 
8.1.1 
Screening Visit (Visit 1, Day -10 ± 5 days)...................................... 48 
8.1.2 
Enrolment (Visit 2, Day 1).............................................................. 49 
8.1.3 
Safety Visit (Visit 3 [Week 4 ± 2 days]) .......................................... 49 
8.1.4 
Safety and Treatment Visit (Visit 4 [Week 14 ± 7 days], and Visit 5
[Week 26 ± 7 days]) ....................................................................... 49 
8.1.5 
Additional Telephone Calls to Assess Safety and Tolerability .......... 50 
8.1.6 
Safety Follow-up Visit (Visit 6, Week 30 ± 7 days) ......................... 50 
8.2 
Early Termination Visit............................................................................55 
8.3 
Discontinuation of the Study.....................................................................55 
9 
STATISTICAL METHODS..........................................................................56 
9.1 
Study Patients ...........................................................................................56 
9.1.1 
Disposition of Patients.................................................................... 56 
9.1.2 
Protocol Deviations ........................................................................ 56 
9.1.3 
Analysis Sets.................................................................................. 56 
9.2 
General Consideration..............................................................................57 
9.2.1 
Power and Sample Size Consideration............................................. 57 
9.2.2 
Analysis and Data Conventions:...................................................... 57 
9.3 
Demographics, Medical History, Baseline Characteristics, and 
Concomitant Medications .........................................................................57 
9.4 
Treatment Compliance .............................................................................57 
9.5 
Statistical Methodology.............................................................................58 
9.5.1 
Primary Endpoint (Study Population A) .......................................... 58 
9.5.2 
Secondary Endpoints ...................................................................... 58 
9.5.3 
Exploratory Endpoints .................................................................... 59 
9.5.4 
Safety............................................................................................. 59 
9.6 
Interim Analyses.......................................................................................60 
10 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS ........................61 
10.1 
Data Quality Assurance ............................................................................61 
10.1.1 
Database Management and Quality Control..................................... 61 
10.2 
Case Report Forms and Source Documentation.......................................61 
10.2.1 
Data Collection .............................................................................. 61 

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10.3 
Access to Source Data ...............................................................................62 
10.4 
Data Processing.........................................................................................62 
10.5 
Data Monitoring........................................................................................62 
10.6 
Safety Monitoring Plan .............................................................................63 
10.7 
Archiving Study Records..........................................................................63 
10.8 
Good Clinical Practice ..............................................................................63 
10.9 
Informed Consent.....................................................................................63 
10.10 Protocol Approval and Amendment.........................................................63 
10.11 Duration of the Study................................................................................64 
10.12 Confidentiality ..........................................................................................64 
10.13 Other Ethical and Regulatory Issues........................................................64 
10.14 Liability and Insurance.............................................................................64 
10.15 Publication Policy......................................................................................64 
11 
REFERENCE LIST.......................................................................................65 
12 
APPENDICES...............................................................................................68 
12.1 
APPENDIX 1: Total Blood Volumes ........................................................69 
Tables in Text
Table 1: Clinical Laboratory Testing......................................................................... 50 
Table 2: Study Schedule ........................................................................................... 52 
Figure in Text
Figure 1: Transition from Study MIV-711-201 to Study MIV-711-202......................... 27 
Figure 2: Study Design ............................................................................................... 28 

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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS
The following abbreviations and special terms are used in this Clinical Study Protocol.
g"EVZ-I
g C-terminal telopeptide of collagen type I
AE
Adverse event
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
AUC0-24h
Area under the concentration-time curve from zero to 24 hours
AUCı
Area under the concentration-time curve from zero to infinity
BSAP
Bone specific alkaline phosphatase
BML
Bone marrow lesions
DMEC
Data Monitoring and Ethics Committee
DMOAD
Disease modifying OA drug
CI
Confidence interval
Cmax
Observed maximum measured plasma concentration
CRA
Clinical research associate
CRO
Contract research organisation
CTX-I
C-terminal telopeptide of collagen type I
CTX-II
C-terminal telopeptide of collagen type II
eCRF
Electronic case report form
ECG
Electrocardiogram
EOT
End of Treatment
EQ-5D-5L
EQ-5D is a standard measure of health status developed by the EuroQol
Group in order to provide a simple, generic measure of health for clinical 
and economic appraisal
FTIM
First time in man
FSE
Fast spin echo
GCP
Good Clinical Practice
GMP
Good Manufacturing Practice
IB
Investigator’s brochure
ICF
Informed consent form
ICOAP
Intermittent and constant osteoarthritis pain
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IMP
Investigational medicinal product
IRT
Interactive Response Technology
IWRS
Interactive Web Response System

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LSmeans
Least square means
MedDRA
Medical Dictionary for Regulatory Activities
MOAKS
MRI Knee Osteoarthritis Score
MRI
Magnetic resonance imaging
mITT
modified intention to treat
NSAID
Nonsteroidal anti-inflammatory drug
NOAEL
No observed adverse effect level
NRS
Numeric rating scale
NTX-I
N-terminal telopeptide of collagen type I
OA
Osteoarthritis
OARSI
Osteoarthritis Research Society International
OMERACT
Outcome Measures in Rheumatoid Arthritis Clinical Trials
PD
Proton density
PINP
Procollagen type I N-terminal propeptide
PK
Pharmacokinetic
PPS
Per-Protocol Set
PRO
Patient-reported outcomes
q.d.
Once daily
QoL
Quality of Life
QTcF
QTc interval (Fridericia’s correction)
SAE
Serious adverse event
SAF
Safety analysis set
SAP
Statistical analysis plan
SD
Standard Deviation
PINP
Procollagen type I N-terminal propeptide
SUSAR
Suspected unexpected serious adverse reaction
Target Knee
Identified by knee pain on a numeric rating scale and Kellgren and 
Lawrence classification grade. If patients have knee pain in both sides
with equal regard to these two criteria, the right knee should always be 
prioritized.
TE
Time-to-echo
TEAE
Treatment-emergent adverse event
TRAP5b
Tartrate-resistant acid phosphatase 5b
TSC
Trial Steering Committee
ULN
Upper limit of normal
UV
Ultra violet

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WOMAC
Western Ontario and McMaster Universities Osteoarthritis Index

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1
ABSTRACT
Knee osteoarthritis (OA) represents a major health burden with few effective analgesic 
therapies and no approved structure modification drugs. The subchondral bone is integral to 
the OA process with modern imaging studies showing that subchondral bone pathology is 
associated with both the symptoms and progressive loss of cartilage in knee OA. The 
available data support the hypothesis that a potent and selective inhibitor of cathepsin K such 
as MIV-711 will have both anti-resorptive effects on subchondral bone and protective effects 
on cartilage and animal models demonstrate reduced structural joint degradation. One Phase I 
study with MIV-711 is completed and a three-arm, 240 patient, 6 month, Phase IIa, 
randomised, placebo-controlled study to assess the efficacy of MIV-711 in treating painful, 
radiographic knee OA, both in terms of symptoms and structural progression is currently in 
progress. The present protocol details the intention to conduct an extension of the ongoing 
Phase IIa study. The purpose is to establish 52 weeks safety and tolerability data in a subset of 
the study population. 

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2
INTRODUCTION
2.1
Background
Osteoarthritis is the fastest growing chronic pain disease worldwide.[2, 3] Radiographic knee 
OA is the most frequent site and affects about one in four middle age and older men and 
women.[4] Symptomatic knee OA (defined as frequent knee pain and an X-ray showing OA) 
affects about 12% of persons aged 55 years and over. Current treatments for OA are aimed at 
controlling pain, and all major contemporary evidence-based guidelines recommend a range 
of pharmacological and non-pharmacological therapies.[5, 6, 7, 8] Other than surgery, there 
are no current safe, long-term, effective analgesic treatments for established OA; 
consequently 70% of people with OA report to being in constant pain and 12.5% live with 
daily unbearable pain. [5, 9, 10]
A growing literature has suggested benefits for agents targeting OA subchondral 
bone.[11, 12] Bisphosphonates are commonly used for treating conditions with exaggerated 
osteoclastic bone resorption including osteoporosis, but also indicate beneficial effects in 
OA.[13, 14, 15] Treatment with strontium ranelate, another anti-resorptive bone acting agent 
which enhances pre-osteoblast replication, promotes osteoblastic differentiation and inhibits 
osteoclastic activity, was associated with a significant effect on structure, with a smaller loss 
of joint space width over 3 years compared with placebo.[16, 17, 18] Current studies of 
structure modification for regulatory approval typically use radiographic joint space width as 
the primary outcome which requires large numbers of patients over long periods of time.
Magnetic resonance imaging (MRI) has provided new insights into the multi-tissue pathology 
underlying typical clinical OA, and has also provided novel imaging biomarkers.[19, 20, 21]
While cartilage quantification and morphology have been well studied, semi-quantitative 
measures of other tissues are slowly accruing evidence for their metric properties in clinical 
studies.[22] Recently, a publication showed that accurate 3D quantification of MRI bone area 
provides a valid and highly responsive measure of OA progression and in a small study which 
selected for typical clinical study patients, bone area was more responsive to change at 3 and 
6 months than quantitative cartilage measures.[23, 24, 25]
Cathepsin K is a cysteine protease predominantly expressed in the osteoclast and intimately 
involved in bone resorption. It is also expressed in chondrocytes and synovial fibroblasts. 
Under normal physiological conditions, cathepsin K degrades key bone matrix proteins such 
as type I collagen. Cathepsin K is also expressed in chondrocytes in cartilage where it is able 
to cleave collagen type II and aggrecan, the main components of the cartilage matrix, leading 
to cartilage destruction. Consistent with these observations, transgenic mice that over-express 
cathepsin K spontaneously develop synovitis and cartilage degeneration.[26] Some fragments 
resulting from cathepsin K cleavage serve as biomarkers for its activity both in vitro and 
in vivo as further described below.
Cleavage of type I collagen results in release of the C-terminal telopeptide of collagen type I
(CTX-I), a biomarker that has been used extensively as a surrogate measure of bone 
resorption.[27] Cartilage degradation can be assessed by measuring the C-terminal telopeptide 
of collagen type II (CTX-II), which is a fragment released during cartilage degeneration in 
OA. In OA patients, increased CTX-II levels are associated with loss of cartilage integrity and 
are linked to disease burden, progression and radiographic scoring.[12, 28, 29] Bone-acting 
agents do not solely affect CTX-I but also CTX-II, most likely indirectly due to their 
anti-resorptive effects on subchondral bone. Reductions in CTX-II levels of 20-40% by 
anti-resorptive drugs are associated with attained pain and structural primary endpoints in OA 
patient studies.[14, 16, 30, 31] To summarise the relevance of these two biomarkers, the 

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reduction of CTX-I and CTX-II in blood and urine are used as indicators of reduced bone 
resorption and cartilage degradation, respectively, which are believed to translate into 
beneficial effects counteracting joint degeneration in OA.
Besides effects on biomarkers under physiological conditions, pharmacological studies 
performed in surgically-induced OA models in vivo have demonstrated that cathepsin K 
inhibition reduces cartilage degeneration, prevents subchondral bone loss and attenuates 
osteophytosis in rabbits subjected to anterior cruciate ligament transection. [32] In addition, 
cathepsin K inhibition reduces cartilage degeneration in dogs subjected to partial medial 
meniscectomy, another experimental model of OA.[33] Cathepsin K inhibition also reduces 
the mechanosensitivity of knee afferent nerve activity in a guinea pig model of spontaneous 
OA, thus suggesting a role for cathepsin K in joint nociception during disease 
progression.[34]
The investigational product intended for the present study, MIV-711, is a potent, selective and 
reversible inhibitor of the cathepsin K enzyme with an attractive preclinical profile. A 
consistent relationship is observed between the magnitude of MIV-711-evoked reductions on 
CTX-I and CTX-II and effects on disease progression in different animal models of 
OA.[32, 33] The MIV-711 biomarker results in man (described briefly in Section 2.2,
Section 2.4 and Section 2.5), show changes in CTX-I and CTX-II levels of similar 
magnitudes to those that are associated with disease modification in the animal models of OA. 
Hence, a positive effect of MIV-711 treatment on structurally relevant readouts in OA may be 
expected. More detailed information of MIV-711’s pharmacology, pre-clinical studies 
including OA animal models and Phase I clinical testing are included in the Investigator’s 
Brochure (IB).
2.2
Pharmacokinetic, Pharmacodynamic and Safety results from MIV-711 First 
Time in Man Study and Blinded Safety and Tolerability Summary from 
MIV-711-201
A First Time in Man (FTIM) study with MIV-711 has been conducted in male and female 
healthy volunteers including single doses up to 600 mg, multiple doses up to 200 mg 
once-daily (q.d.) for 7 days and in healthy post-menopausal female volunteers at multiple 
doses of 100 mg q.d. for 28 days. The single dose part enrolled 18 males and 9 females with 
an age range of 19-64 years. The multiple dose parts enrolled 15 males and 24 females with 
an age range of 18-65 years. The primary objective was to determine the safety and 
tolerability of ascending single and multiple oral doses of MIV-711 in healthy volunteers.
MIV-711 was rapidly absorbed after oral administration with peak concentrations typically 
occurring 1 hour after administration. A high fat meal prolonged the absorption but had no 
apparent effect on systemic exposure measured by area under the concentration-time curve 
from zero to infinity (AUCı) of MIV-711. The mean terminal half-life was 3.3 to 5.2 hours 
over the 20 to 200 mg dose range. Observed maximum measured plasma concentration (Cmax)
and AUCı increased in close proportion to dose over the single dose range 100-600 mg. 
Following multiple oral administration of 50 to 200 mg q.d. for 7 days or 100 mg q.d. for 28 
days, no accumulation of MIV-711 was observed. MIV-711 was indicated to be extensively
metabolised with less than 1% excreted unchanged by the kidney. No gender differences in 
dose normalised Cmax or AUCı for MIV-711 were observed. Further details on MIV-711 
metabolism can be found in the IB.
A dose-dependent reduction in the biomarkers serum CTX-I and urinary CTX-II was 
observed after single and multiple doses of MIV-711, by down to 55 and 72% from Baseline 
respectively at multiple dosing (for further details see Section 2.4, Section 2.5 and the IB).

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No clinically meaningful effects on vital signs, laboratory parameters or electrocardiogram 
(ECG) time intervals: including QTc interval (Fridericia’s correction; QTcF) were observed. 
Adverse events (AEs) assessed as related to investigational medicinal product (IMP) had a 
similar incidence for active treatment and for placebo. One subject was found on a per 
protocol ECG to have asymptomatic atrial fibrillation after 3 q.d. doses of MIV-711 200 mg. 
Spontaneous conversion to sinus rhythm occurred within 24 hours after the last dose. 
Investigations by an independent cardiologist supported that the post-dose atrial fibrillation 
observed was possibly drug induced. Further details of the results of the FTIM study are 
provided in the IB.
The ongoing MIV-711-201 study, from which the patients in the current protocol will be 
recruited, will include 240 patients under 1:1:1 randomisation to placebo: 100 mg MIV-711: 
200 mg MIV-711. The first patient was randomised in March 2016 and recruitment is 
ongoing; as of 21 June 2016, 102 patients have been enrolled. No treatment-related serious 
adverse events (SAEs) have been reported to date. One unrelated SAE was reported before the 
start of dosing. Seven patients were withdrawn from the study due to the following reasons: 
increased liver function tests; severe polymyalgia; suspected macular-papular rash; 
angioedema; non-compliance; lost to follow-up; withdrawal of consent. No safety-related 
trends have been identified in the ongoing Study MIV-711-201 and it is believed that 
MIV-711 has acceptable safety and tolerability based on blinded results in OA patients.
2.3
Study Rationale
As stated in Section 2.1, there are no pharmacological treatments available today that provide 
long term relief of OA symptoms nor are there any treatments that counteract its structural 
progression. Disease modifying OA drugs (DMOADs) would potentially address both these 
features which highlights the importance of evaluating candidate drugs such as MIV-711.
The available data support the hypothesis that a potent and selective inhibitor of cathepsin K 
such as MIV-711 will have both anti-resorptive effects on subchondral bone and protective 
effects on cartilage; this is supported by relevant animal models which demonstrate reduced 
structural joint degradation after treatment with MIV-711.
Whilst the first study of MIV-711 in patients, Study MIV-711-201, has the potential to 
establish a first indication of disease modifying efficacy for MIV-711 in OA, it is also 
important to consider the chronic nature of OA which often leads to life-long disease 
symptoms from the time of diagnosis. The life-long course of OA highlights the need to 
assess long-term safety for a prospective DMOAD, which is therefore the main rationale of 
the current extension study.  While further outlining the current study MIV-711-202 in the 
following sections, the study population pertaining to the 12 month safety assessment in 
Study MIV-711-202 is henceforth described as Study Population A.
There are two further rationales for this study:
‚
It is known that cartilage structural changes are not expected to be apparent over a 
6-month period using MRI [35] which constitutes the reason for using knee joint bone 
area as the main structural read-out in Study MIV-711-201. In the current study, 
patients will be treated for 52 (26+26) weeks (Study Population A) which will enable 
the secondary analysis of cartilage changes versus Baseline in Study MIV-711-201. 
‚
Furthermore, there is no available method to predict OA progression. In 
Study MIV-711-201 there is a potential to identify patients treated with placebo that
exhibit signs of clinical progression over the course of 26 weeks. Patients with
manifest symptomatic progression of OA would constitute the most justifiable patient 
population to receive a DMOAD. It is believed that the proposed extension study 
would be the first opportunity to explore the effects of a potential DMOAD in OA 

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patients with verified progressive symptoms (based on symptoms reported from Study
MIV-211-201). While further outlining study MIV-711-202 in the following sections,
the study population pertaining to the 6 month treatment assessment in patients with 
progressive symptoms is henceforth described as Study Population B.
2.4
Study Design and Dosing Rationales
The present study is a 6-month open-label one-arm extension study evaluating safety and 
tolerability as well as the efficacy of 200 mg MIV-711 q.d. in two separate patient populations
denoted as Study Populations A and B. 
Study Population A will be recruited from patients treated with 200 mg MIV-711 q.d. in 
Study MIV-711-201 and whose symptoms did not clinically significantly deteriorate as 
defined by an increase in the numeric rating scale (NRS) of ø4"eqorctgf"vq"Baseline. Patients 
eligible for Study Population A will be offered to roll over for 6 months’ extended treatment,
primarily evaluating longer term safety and tolerability. The total treatment duration of 
52 weeks also allows a more suitable treatment length for the exploratory study of any 
structural effects of MIV-711 on joint cartilage thickness. [23, 24, 25].
There will be no continuation of the 100 mg dose from Study MIV-711-201 because from a 
safety and tolerability perspective, using the 200 mg dose in this extension study allows
exposure to the highest dose previously tested for MIV-711. MIV-711 has also shown a 
higher reduction in CTX-II excretion at 200 mg compared with 100 mg q.d. Based on the 
established link between CTX-II and the levels that are predictive for structural effects on
bone only, and the higher levels that are indicative of cartilage protection (see Section 2.1), it 
is judged that the 200 mg dose should be studied in this extension study since it has the 
highest potential to contribute to a disease modifying effect in OA. Extending the 200 mg 
dose in those patients that did not significantly deteriorate clinically in their OA on that dose 
during the first 26 weeks, allows a balanced assessment of the 52-week safety and tolerability 
of MIV-711 while at the same time maximizing the opportunity of measuring structural 
change on joint cartilage thickness versus Baseline. Joint cartilage thickness is believed to 
require an observational period of at least 12 months as described in the literature.[23, 24, 25]
A further rationale of this study is to explore the treatment effect in a group of OA patients 
that have confirmed symptom progression over the last 6 months (Study Population B). Study 
Population B will be recruited from patients receiving placebo in Study MIV-711-201 having
experienced a clinical worsening as defined by an increase in PTU" qh" œ4 versus Baseline.
Patients eligible for Study Population B will be offered 200 mg MIV-711 q.d. for the next 
26 weeks. In addition to offering the treatment to appropriate patients, this also enables the 
assessment of the effects of MIV-711 based on MRI imaging, symptoms and biomarkers in 
patients with progressing symptoms and, as such, has the potential to provide valuable 
information for future patient selection in OA trials. Similar to Study MIV-711-201, the joint 
structural endpoint of choice over 6 months treatment constitutes MRI joint bone surface 
measurement (see Section 7.2).[23] All analyses, with the exception of safety and tolerability, 
will be conducted as exploratory with regards to Study Population B.
All patients in Study MIV-711-201 at the participating sites included in Study MIV-711-202 
will be given the opportunity to participate. Patients, investigators and site staff will not be 
made aware of the preceding treatment allocation in Study MIV-711-201 and treatment will 
remain blinded until database lock of study MIV-711-201. The actual roll-over of individual 
patients to Study MIV-711-202 is based on the criteria for Study Populations A and B 
detailed above and is executed by a central person independent from the study with access to 
the randomisation list and eCRF for Study MIV-711-201. The patients will be considered for 
roll-over one by one as they complete the last treatment visit in Study MIV-711-201 and upon 
blinded approval of the investigator as well as provision of informed consent. Based on the 

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selection criteria for Study Population A and B described earlier in this section, it is 
anticipated that 50-80 patients will be eligible for participation. Patients will be recruited from 
up to 5 centres in up to 5 countries for this study. Recruitment may be terminated if 
considered appropriate or necessary by the sponsor.
The analysis of data from the proposed study will not be based on a formal statistical analysis 
since the primary endpoint constitutes safety and tolerability. All efficacy parameters 
measured in Study MIV-711-201 will also be measured in the proposed study. However, the 
important difference is that any comparisons will be made from baselines within but not 
between Study Population A and B. In contrast, in Study MIV-711-201, comparisons will be 
made between treatment groups with a formally powered analysis regarding the primary 
endpoint.
2.5
Risk-Benefit Assessment
The presently proposed Phase II study (MIV-711-202) is the third clinical study with 
MIV-711 and as such it has the potential to determine the 12 month safety of MIV-711 in 
treating painful, radiographic knee OA, as well as the effect over 6 months in patients with 
progressing symptomatology.
The toxicity of MIV-711 has been studied in mouse and monkey up to 6 months. In the mouse
6 month study, MIV-711 was well tolerated to systemic exposures of 58 µM x h (mean) in 
terms of AUC0-t with no treatment-related microscopic findings. In the 6-month cynomolgus 
monkey study, the majority of the observed findings were related to MIV-711 pharmacology 
and the systemic exposure at the no observed adverse effect level (NOAEL) was 15 µM x h
(mean) in terms of AUC0-24. Further data is provided in the IB.
The single dose ranges 20-600 mg and multiple dose ranges 50-200 mg of MIV-711 given 
q.d. for 7 days have been explored in healthy volunteers. In addition, the 100 mg dose was 
administered q.d. in a 28-day open care cohort consisting of healthy post-menopausal female 
volunteers. In these settings, MIV-711 showed acceptable safety and tolerability in
conjunction with no clinically significant changes in haematology, clinical chemistry, vital 
signs or ECG parameters. The study of 200 mg MIV-711 q.d. in man, which constitutes the 
highest dose in Study
MIV-711-201 as well as the only dose administered in
Study MIV-711-202 resulted in a 2.4 µM x h average AUC0-24 which corresponds to an 
expected 6 times margin to the NOAEL level in the cynomolgus monkey.
MIV-711 has consistently shown biomarker effects in the Phase I study that correlates
strongly with efficacy on joint structure in the pre-clinical models. The doses of MIV-711 
used in Study MIV-711-201 were estimated to provide an exposure sufficient to produce an 
improvement in joint structure and symptoms, as has been shown for other bone-acting agents
(see Section 2.1). There is further potential symptom and structure improvement benefit for 
patients in Study Population A in the present study as the treatment length is extended to a 
total of 52 (26+26) weeks on 200 mg q.d. MIV-711. This potentially allows measurable 
changes in cartilage to occur. Furthermore, patients in Study Population B are selected based 
on clinically significant symptom progression and may therefore benefit more from a 
potential DMOAD compared to stable patients. The potential for benefit together with the
hitherto favourable safety and toxicology profile converge into a favourable Benefit/Risk 
assessment for the present study.
No safety-related trends have been identified in the ongoing Study MIV-711-201 and it is 
believed that MIV-711 has acceptable safety and tolerability in OA patients based on the 
blinded results so far. By the start of enrolment into the present study, at least one Data 
Monitoring and Ethics Committee (DMEC) meeting reviewing the safety data of 

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Study MIV-711-201 will have been finalized. For the present study, the DMEC will
reconvene to review the unblinded safety and tolerability data after the first 25 patients 
complete Visit 4 and Visit 5.
With regard to previous clinical experience (see IB for further information), there are at
present time no approved cathepsin K inhibitors on the market, although several have 
been/are in clinical stages of development. The clinical data on these other compounds are 
only available in part from meeting abstracts and published progress reports. However it is 
judged that there is no indication of any class effect, or otherwise collectively significant 
findings in the available data that would infer any added risk to the Benefit/Risk assessment 
for the present study.
On the basis of the pre-clinical and clinical data on MIV-711 to date and the favourable
Benefit/Risk balance, it is considered appropriate to proceed with the Phase II extension study 
which is proposed in the present protocol.

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3
STUDY OBJECTIVES
3.1
Primary Objective Study Population A*
To assess the safety and tolerability of 200 mg MIV-711 q.d. over 52 (26+26) weeks in 
patients with symptomatic and radiographic knee osteoarthritis.
* Study Population A will be recruited from patients treated with 200 mg MIV-711 q.d. in Study MIV-711-201 
and whose symptoms did not clinically significantly deteriorate as defined by an increase in PTU" qh" ø4"
compared to Baseline.
3.2
Secondary Objectives Study Population A
To assess, in patients with symptomatic and radiographic knee OA, over 52 (26+26) weeks:
•
The effect of MIV-711 on MRI cartilage thickness loss
•
The effect of MIV-711 on MRI bone marrow lesion volume
•
The effect of MIV-711 in the semi quantitative MRI Osteoarthritis Knee Score 
(MOAKS) parameters
•
To assess the effect of MIV-711 on MRI knee joint bone area.
Note: all MRI assessments refer to the target knee unless stated otherwise.
Target knee is identified by knee pain on a numeric rating scale and Kellgren and Lawrence classification 
grade. If patients have knee pain in both sides with equal regard to these two criteria, the right knee should 
always be prioritized. The target knee in Study MIV-711-202 must be the same as in Study MIV-711-201.
3.3
Secondary Objective Study Population B*
To assess the effect of 200 mg MIV-711 q.d. on safety and tolerability over 26 weeks in 
patients with symptomatic and radiographic knee osteoarthritis.
* Study Population B will be recruited from patients receiving placebo in Study MIV-711-201 having 
gzrgtkgpegf"c"enkpkecn"yqtugpkpi"cu"fghkpgf"d{"cp"kpetgcug"kp"PTU"qh"œ4"xgtuwu"Dcugline.
3.4
Exploratory Objectives Study Population A
In addition, the study will address the following exploratory parameters:
•
The effect of MIV-711 on worst target knee pain (1 week recall)
•
The effect of MIV-711 on average contralateral knee pain (1 week recall)
•
The effect of MIV-711 on constant and intermittent OA pain
•
The effect of MIV-711 on global improvements in knee problem, knee pain and knee 
function
•
The effect of MIV-711 on knee joint OA symptoms (function, pain, stiffness) 
•
The effect of MIV-711 on global disease activity 
•
The effect of MIV-711 on quality of life (QoL)
•
The effect of MIV-711 on patient reported e-diary daily recall knee joint pain
•
The effect of MIV-711 on patient reported e-diary daily recall analgesics use
•
Assessment of the effect of MIV-711 on exploratory serum and urinary biomarkers of 
relevance for OA including but not limited to procollagen type I N-terminal propeptide
(PINP), bone specific alkaline phosphatase (BSAP), N-terminal telopeptide of collagen 
type I (NTX-I), CTX-K."gEVZ-I, CTX-II and tartrate-resistant acid phosphatases
(TRAP5b).
•
Baseline and steady state treatment blood and urinary samples will be stored for 
patients who sign a separate voluntary Informed Consent Form (ICF) for potential 

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future pharmacogenomics and disease-related proteomics, genomics, metabolomics and 
lipidomics analyses.
•
The effect of MIV-711 on a compound index of MRI bone area and cartilage thickness
•
The pharmacokinetics of MIV-711 and the relationship to patient factors and 
concomitant medications
3.5
Exploratory Objectives Study Population B
All of the above denoted secondary and exploratory parameters described in Section 3.2 and 
Section 3.4 for Study Population A, are considered as exploratory objectives in Study 
Population B and will be evaluated over 26 weeks.

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4
OVERALL DESIGN AND PLAN OF THE STUDY
This is a multicentre, open-label, one-arm Phase II extension study to evaluate the safety and 
tolerability of MIV-711 in patients with knee joint OA. 
The clinical study, which involves the use of an IMP, has been designed and will be run in 
accordance with the principles of Good Clinical Practice (GCP) and the current regulatory 
requirements as detailed in the Clinical Trial Directive 2001/20EC and any subsequent 
amendments of the clinical study regulations.
All patients in Study MIV-711-201 (Eudract No. 2015-003230-26) at the participating sites 
included in Study MIV-711-202 will be given the opportunity to participate provided that 
they meet the eligibility criteria. The transition from Study MIV-711-201 to MIV-711-202 is 
shown in Figure 1.
Figure 1: Transition from Study MIV-711-201 to Study MIV-711-202
To ensure the patients will have sufficient time to consider their participation in the study the 
informed consent form will be given to the patients prior to Visit 8 in Study MIV-711-201. 
Visit 8 of Study MIV-711-201 will ideally be conducted on the same day as Visit 1 of the 
present study. If these visits are conducted on the same day the results of the following 
assessments will be recorded in the electronic Case Report Form (eCRF) for both studies; 
urine and blood sampling for safety, vital signs, physical examination and ECG. See 
Section 8.1.1 for a full list of assessments required at Visit 1.
A central person, independent from the study, with access to the randomisation list and the
eCRF for Study MIV-711-201 study will confirm Inclusion Criterion 1. The confirmation will 
be communicated to the site staff and the study team via fax/email without revealing the 
treatment in MIV-711-201 or the change in NRS score.
All enrolled patients will receive 200 mg q.d. oral dose of MIV-711 for 26 weeks in addition 
to their current medication. MIV-711 200 mg will be provided as identical capsules to those 
used in Study MIV-711-201.
The patients will take the last dose of IMP in Study MIV-201-711 at Visit 8 and dosing in the 
present study will be started at Visit 2 after a screening period of 10±5 days. Patients who are 

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not eligible to participate in the present study will return for the safety follow up visit (Visit 9) 
in Study MIV-711-201. 
Patients will be permitted to remain on their current analgesic regimen with any changes in 
concomitant medications reported and recorded at study visits as well as in a patient reported 
daily e-diary for two 2-week periods prior to Visit 4 and Visit 5.
The study consists of a Screening period of approximately 2 weeks (Visit 1), eligibility at 
Visit 2, an open-label treatment period of 26 weeks from Visit 2 through Visit 5, and a 
follow-up period of 4 weeks (Visit 6) after the last dose of study treatment is administered.
Telephone calls will be made 5-9 days after all dosing visits for safety and tolerability. There 
will be additional phone calls at Week 10 and Week 20 for safety and tolerability.
A DMEC will meet to review the unblinded safety and tolerability data after the first
25 patients complete Visit 4 and Visit 5.
The study design is summarised in Figure 2.
Figure 2: Study Design

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5
STUDY POPULATION
The study population will consist of patients with symptomatic and radiographic knee joint 
OA who have participated in Study MIV-711-201. Patients must be able to provide written 
consent and meet all the inclusion criteria and none of the exclusion criteria.
5.1
Inclusion Criteria
Patients must meet all of the following criteria to be eligible for enrolment in this study:
1. Previously enrolled in Study MIV-711-201 including completion of Visit 8 either by 
‚
Receiving MIV-711 200 mg and had non-significant clinical worsening on the 
primary endpoint as defined by NRS increase of ø2
OR by
‚
Receiving placebo and had a clinically significant worsening on the primary 
endpoint as defined by NRS increase of œ2
The NRS result will be derived using the primary endpointfrom Study MIV-711-201: NRS average knee 
pain in the target knee with 7days recall: increase from Baseline (Visit 2 of Study MIV-711-201) to Visit 8 
of Study MIV-711-201.
2. Female patients must be non-pregnant, non-lactating and of non-childbearing potential 
either as naturally (spontaneously) post-menopausal or due to hysterectomy and/or 
bilateral oophorectomy/salpingo-oophorectomy (as determined by patient
medical 
history). Naturally (spontaneously) post-menopausal is defined as being amenorrhoeic for 
12 months without an alternative medical cause and with a Screening follicle stimulating 
hormone test indicating post-menopausal state.
3. Male patients should avoid fathering a child by either of the following methods:
‚
True sexual abstinence: meaning that heterosexual abstinence is in line with the 
preferred and usual lifestyle of the patient (periodic abstinence such as that based on 
calendar, ovulation, symptothermal, post-ovulation methods, declaration of 
abstinence for the duration of a trial, or withdrawal/coitus interruptus are not 
acceptable methods of contraception).  
‚
Willingness to use two effective means of contraception with their partner from the 
time of first IMP administration until 3 months after the last dose of IMP. Two or 
more of the following methods are acceptable and must include at least one barrier 
method: i) Surgical sterilisation (i.e., bilateral tubal ligation for female partners; 
vasectomy for male), ii) placement of an intrauterine device or intrauterine system, 
iii) hormonal contraception (implantable, patch, oral), iv) barrier methods including 
condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal 
foam/gel/film/cream/suppository. Male patients who have been sterilised are 
required to use one barrier method of contraception (condom).
4. The patient’s usual analgesic regimen (in case of use) should remain the same as for 
Visit 8 in Study MIV-711-201 (i.e., Visit 1 in Study MIV-711-202).
NOTE: If a patient is experiencing increased or decreased pain and requires an increase or 
a decrease in the dose of analgesics, or an occasional change of analgesics medication 
during his/her participation in the study, then this will be allowed and should be properly 
documented in the patient file and the CRF.
5. Needs to be able to communicate well with the investigators and staff.

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6. Able to comply with the requirements of the study procedures and provide written 
informed consent prior to any study related procedures.
5.2
Exclusion Criteria
Patients will be excluded from enrolment in this study if they meet any of the following 
criteria:
1. The presence of any inflammatory arthritis (e.g., gout, reactive arthritis, rheumatoid 
arthritis, psoriatic arthritis, seronegative spondylarthropathy) or any underlying condition, 
other than OA, that may result in abnormal cartilage and bone metabolism.
2. Any generalised pain condition that may interfere with the evaluation of the target knee 
pain (e.g., fibromyalgia) as judged by the investigator.
3. Ongoing or a history of atrial fibrillation.
4. Currently receiving medication that affects cartilage or bone metabolism (other than study 
drug; hormone replacement therapy taken for more than 6 months is allowed).
5. Current or recurrent disease that could affect the action, absorption or disposition of 
MIV-711, or could affect clinical assessments or clinical laboratory assessments.
6. Any clinically severe or significant uncontrolled concurrent illness, which, in the opinion 
of the Investigator, would impair ability to give informed consent or take part in or 
complete this clinical study.
7. Any medical condition, AE, clinical or laboratory finding from Study MIV-711-201 that,
in the opinion of the Investigator, would preclude inclusion in the present clinical study.
8. Known or suspected intolerance or hypersensitivity to the investigational medicinal 
product, closely related compounds, or any of the stated ingredients.
9. History of alcohol or other substance abuse within the last year.
10. Use of an investigational product other than MIV-711 during participation in Study
MIV-711-201 and /or active enrolment in another drug or vaccine clinical study.
11. Significant target knee injury or surgery during participation in Study MIV-711-201.
12. A history of partial or complete joint replacement surgery in the target knee at any time, 
listed for knee surgery, or anticipating knee surgery during the study period.
13. Any factor which, in the opinion of the investigator, would jeopardise the evaluation or 
safety of the patient or be associated with poor adherence to the clinical study protocol
(e.g., inability to complete study diary, poor tolerability of venepuncture or lack of 
adequate venous access for required blood sampling during the study period).
14. Use of intra-articular hyaluronic acid in the target knee during participation in Study
MIV-711-201.
15. Use of intra-articular, intra-muscular or oral corticosteroids during participation in Study
MIV-711-201.
16. Commencement of non-pharmacological OA interventions during participation in Study
MIV-711-201. 
17. Vulnerable patients, e.g., patients kept in detention, soldiers, and employees of the sponsor 
or the Contract Research Organisation (CRO) with direct involvement in the proposed 
study or other studies under the direction of the investigator or the CRO, as well as family 
members of the employees or the investigator.

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18. Lack of MRI of the knee from Visit 8 in Study MIV-711-201 due to special 
circumstances, such as claustrophobia or difficulties to fit the knee coil.
19. Patients with contra-indication to MRI of the knee.
5.3
Patient Withdrawal and Replacement
In accordance with the Declaration of Helsinki, GCP, and International Conference on 
Harmonisation (ICH) Guidelines and applicable regulations governing human subject 
protections, individual patients have the right to withdraw consent at any time without 
prejudice. At the time of withdrawal of consent, a full efficacy and safety evaluation will be 
performed if the patient consents. 
Patients who withdraw will be asked about the reason(s) for withdrawal, and the presence of 
any AEs and will be asked to return for a follow-up visit (similar to Visit 6) within 4 weeks 
following the withdrawal. An MRI scan should be completed if withdrawal is after Visit 4.
If a patient is being withdrawn due to a suspected infection, no biological samples from this 
patient are allowed to be sent to the laboratory. Samples will be managed according to 
standard routines at the study site. 
In case of discontinuation, the clinical research associate (CRA) should be informed as soon 
as possible.
If the patient has not yet received any IMP in the current protocol and discontinues from the 
study, the patient should not participate in any further study related procedure.
Patients who withdraw will return to routine care.
Patients must also be removed from the study by the Sponsor or Investigator for any of the 
reasons listed below:
‚
The occurrence of pregnancy in a patient.
‚
Use of a non-permitted concomitant drug, as defined in Section 6.6.4 where the 
predefined consequence is withdrawal from the IMP.
‚
Taking another investigational medicinal agent during patients involvement in the study 
i.e., from qualification to end of treatment (EOT).
‚
Any violation of, or deviation from study protocol procedures which, in the judgment of 
the responsible physician, could adversely affect the patients or the integrity of the study 
including missing more than 7 consecutive doses or other evidence of significant non-
compliance (excluding drug holidays or interruptions that were medically warranted).
‚
Any clinical AE, laboratory abnormality, inter-current illness or significant worsening of 
inter-current illness which, in the opinion of the investigator, indicates that continued 
participation in the study is not in the best interest of the patient.
‚
Patients who undergo target knee joint replacement during the treatment period will be 
withdrawn from the study and classified as treatment failures.
‚
Serum transaminases (alanine aminotransferase [ALT] and/or aspartate aminotransferase 
[AST]) > 3 x upper limit of normal (ULN) AND total bilirubin > 2 x ULN (confirmed 
by subsequent repeat).
‚
ALT or AST > 3 x ULN (confirmed by repeat visit) with the appearance or worsening of 
symptoms felt by the Investigator to be potentially related to hepatic inflammation, such 
as fatigue, nausea, vomiting, right upper quadrant pain or tenderness, fever, rash, or 
eosinophilia.
‚
QTcF > 500 ms or increase > 60 ms from time matched baseline (confirmed by repeat 

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ECG).
‚
Occurrence of an exclusion criterion which is clinically relevant and affects the patient’s 
safety, if discontinuation is considered necessary by the Principal Investigator and/or 
Sponsor.
In order to perform the modified intention to treat (mITT) analysis, and to enable safety 
analyses, all patients who discontinue their medication will be asked to still complete their 
follow-up visit (Visit 6) as outlined in the study schedule. 
Patients who withdraw from the study will not be replaced.
In all cases, the reason(s) for withdrawal must be recorded on the electronic CRF (eCRF).
5.4
Planned Sample Size and Number of Study Centres
All patients in Study MIV-711-201 at the participating sites in Study MIV-711-202 will be 
given the opportunity to participate provided that they meet the eligibility criteria.
It is expected that approximately 50-80 patients based on the normal progression rate of OA
symptoms, as well as the study selection criteria, will be eligible for participation. However 
due to unpredictable factors such as perceived benefits or burdens for the patients 
participating in the study the estimated total number of patients may deviate from the range 
above.
The patients will be recruited from up to 5 centres in up to 5 countries for this study. 
Recruitment could be terminated if considered appropriate.
5.5
Patient Identification 
5.5.1
Patient!Identification
The Principal Investigator or qualified designee will obtain signed, informed consent from the 
potential study patient before any study-specific procedures are performed.
After written informed consent has been obtained, each patient will receive a unique patient 
number. Screened patients who drop out of the study before the first administration of IMP in 
Study MIV-711-202 will retain their patient number. The MIV-711-202 study will be an 
open-label study and distribution of IMP will proceed through the use of an Interactive 
Response Technology (IRT) System [Interactive Web Response System (IWRS)].
5.5.2
Investigational!Drug!Administration!Scheme
From the patients with knee joint OA participating in Study MIV-711-201, those who meet 
the eligibility criteria for the extension study and who provide written informed consent will 
be included in the extension study. In Study MIV-711-202, all patients will receive 200 mg
q.d. oral dose of MIV-711 for 26 weeks in addition to their current medication. MIV-711 
200 mg will be provided as identical capsules to those used in Study MIV-711-201.
The study site will obtain the patient number and container number assignment from the IRT 
system. The date on which the patient number was assigned will be recorded on the eCRF.
Once patient numbers and container numbers have been assigned, they cannot be reassigned.
5.5.3
Allocation!of!Patients!to!Treatment
Allocation of patients to treatment will occur at Visit 2 (Enrolment) after the patient has 
signed the informed consent form and the Investigator has confirmed the patient’s eligibility 
based on screening procedures performed. All patients will receive a unique patient number. 
The patient number allocated to any patient will not be reallocated to other patients if he/she
terminates the study participation for any reason, regardless of whether IMP was taken or not.

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5.5.4
Procedures!for!Handling!of!Incorrectly!Included Patients
Patients who fail to meet the inclusion/exclusion criteria for this study should not, under any 
circumstances, be enrolled into the study. There can be no exceptions to this rule. 
Where patients who do not meet the study criteria are enrolled in error or where patients 
subsequently fail to meet the criteria for the study post enrolment, the procedures in the 
protocol for the discontinuation of such patients must be followed (see Section 5.3).
Once the error is identified a discussion must occur between the Sponsor, the Medical 
Monitor and the Investigator regarding whether to continue or discontinue the patient from the 
study. It needs to be ensured that all such decisions are appropriately documented.

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6
STUDY DRUG
6.1
Investigational Drug
MIV-711 is provided as the hydrochloride (HCl) salt. The pre-clinical development laboratory 
code was MV076159. MIV-711 is manufactured by NCK A/S, Farum, Denmark.
MIV-711 is formulated in hard gelatin capsules (size 0) at the strength of 200 mg, expressed 
as MIV-711 free base. The included excipients are microcrystalline cellulose; Starcap 1500; 
magnesium stearate and anhydrous colloidal silica. The capsule formulation is manufactured 
by Galenica AB, Malmö, Sweden.
6.2
Administration
Patients will receive q.d. 200 mg oral dose of MIV-711 for 26 weeks in addition to their 
current medication.
The IMP should be taken q.d. in the morning approximately 24 hours apart and swallowed 
whole together with a glass of water (approximately 200 ml) before breakfast; breakfast can 
be taken approximately one hour later. The first dose in Study MIV-711-202 is administered 
at the site during Visit 2 (Enrolment). All patients must stay at the site 2 hours after 
administration of the first dose.
IMP should be dispensed during the Visits 2 and 4 and returned by the patients for drug 
accountability at Visit 4 and Visit 5.
On days when the patient is visiting the site the IMP must be taken at the site under fasting
conditions (and not at home) and the time of the intake must be recorded in the source 
documents.
6.3
Packaging, Labelling and Storage
The capsules will be packaged in the white Duma high-density polyethylene containers with 
polypropylene caps.
The packaging and labelling of the patient packages will be performed in accordance with 
Good Manufacturing Practice (GMP) and national requirements. The labelling will fulfil 
GMP Annex 13 requirements and be translated into local language.
The label will include the following information:
-
Name and address of the sponsor (Medivir) 
-
Dosage form, route of administration and quantity of dosage units
-
Study code
-
Kit ID
-
Directions for use
-
The name of the Investigator 
-
Storage conditions
-
Batch number
-
Expiry date
-
The following standard statements:
ｗfor clinical study use only”
ｗkeep out of reach of children”
Additional local requirement will be adhered to the country-specific labels in accordance with 
local regulations for each participating countries.

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The proposed shelf life for the IMP in this packaging is 24 months at room temperature 15 to
25°C.
A temperature record must be maintained and the max/min temperature must be recorded 
during working days.
The investigator must immediately inform the CRA in case of any temperature excursions.
Shorter (ø 24 hours) periods of storage outside the 15°C to 25°C range is accepted if 
maximum temperature does not exceed 40°C.
6.4
Drug Accountability
The Investigator is responsible for maintaining accurate IMP accountability records 
throughout the study. The CRA will review the accountability records.
Each dispensing of IMP will be documented in the eCRF system.
The drug accountability log will include information such as amount dispensed and amount 
returned to the site. IMP returned to the site will be stored as outlined in Section 6.3. The 
returned products should be marked as “returned” and kept separate from the IMP not yet 
dispensed.
The destruction of IMP will be performed according to local requirements following sponsor 
approval.
6.5
Compliance
The administration of all medication (including IMP) must be recorded in the appropriate 
sections of the eCRF. The Investigator is responsible for discussing the treatment compliance 
with the patient before enrolment in the study. Drug accountability will be performed and 
compliance of drug accountability will also be discussed with the patient.
Treatment compliance will be analysed via capsule count. More details will be given in the 
Statistical Analysis Plan (SAP).
6.6
Other Medications
6.6.1
Rescue!Medication
Where possible, patients
will be asked to continue with the same analgesic or 
anti-inflammatory medication they are taking at Screening throughout the study. However, if 
a patient is experiencing increased or decreased pain and requires an increase or a decrease in 
the dose of analgesics, or an occasional change of analgesics medication, then this will be 
allowed, but the reason for the dose change, the new dose and or medication used, must be 
documented in the eCRF. 
6.6.2
Concomitant Medications
In vitro studies have shown no significant inhibition of drug metabolic CYP enzymes at 
MIV-711 concentrations up to 10 µM. In a previous clinical study, mean Cmax at steady-state 
for the dose 200 mg q.d. was 0.58 µM and the highest individual value was 0.80 µM. It is 
therefore considered unlikely that MIV-711 will affect the metabolism of other drugs through 
CYP inhibition and there are no specific restrictions on concomitant medications for 
pharmacokinetic (PK) reasons.
Furthermore, clinical data indicate that MIV-711 is 
extensively metabolised potentially by several routes, making it less likely that other drugs 
should significantly affect the elimination of MIV-711.
In addition to the periodical e-diary, use of concomitant medication and any 
non-pharmacological interventions will be recorded in the source documents and eCRF. All 

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concomitant medications taken during the study will be recorded with generic name, 
indication, daily dose, and start and stop dates of administration at each visit. For this study, 
prescription medicines, other than those prohibited by the study protocol are permitted as 
concomitant medications to manage ongoing or chronic, stable medical conditions. 
Medications taken at the time of Visit 1 will be documented as prior medication. Medication 
taken after the first dose of IMP in the current (MIV-711-202) study will be documented as 
concomitant medication. All patients will be asked about concomitant medication use and any 
changes to use of concomitant medications at all study visits. Patients will be permitted to 
reinstate prohibited concomitant medications on completion of their follow up study visit.
6.6.3
NSAIDs!and!other!analgesics
Patients will be allowed to continue any analgesic medication they are taking at the Screening 
visit for the duration of the study. The patients’ usual analgesics regimen should remain the 
same as at Visit 8 in Study MIV-711-201. Typical OA analgesics are allowed such as: 
nonsteroidal anti-inflammatory drugs (NSAIDs), paracetamol and tramadol, as well as 
NSAID and paracetamol combinations with mild opioids such as codeine and 
dextropropoxyphene. In addition to the periodical e-diary, use of concomitant medication will 
be recorded in the source document at each visit.
6.6.4
Prohibited!Concomitant!Medications
Patients should not use any form of steroids (oral, intravenous, intra-articular or intra-
muscular) during the study period; except for inhaled/intranasal steroids for the treatment of 
allergic rhinitis and/or asthma and topical steroids for the treatment of eczema. Medications 
purposed to affect bone or cartilage metabolism are also prohibited as exemplified (albeit not 
exhaustively) by antiresorptive medications such as bisphosphonates, receptor activator of 
nuclear factor kappa-B ligand inhibiting antibodies and calcitonin. Apart from combinations 
with mild opioids as specified in Section 6.6.3, all opioids are prohibited unless for occasional 
rescue medication purposes. In case of uncertainty regarding prohibited medications please 
contact the medical monitor.
6.6.5
Chondroitin! and!Glucosamine
Patients will be permitted to continue current use of chondroitin and glucosamine; however
their use must be clearly documented in the eCRF. Chondroitin or glucosamine therapy may 
not be started during the study.
6.7
RESTRICTIONS
The present study, MIV-711-202 is an extension to the main study MIV-711-201. The main 
study was started with limited available data on phototoxicity for the study drug MIV-711 
which necessitated protective sunlight measures for participating patients. Further evaluation 
of MIV-711 in laboratory tests have since been undertaken which concluded that there is no 
phototoxicity risk for patients taking MIV-711. However, since the present study is an 
extension, it is advised that patients follow similar sunlight protective measures in order to 
maintain consistency in study conditions for patients in the two studies. Such sun and ultra 
violet (UV)-light protective measures include avoiding indoor tanning and direct sun 
exposure, especially between 10 am and 4 pm. If sun/UV light cannot be avoided, suitable 
protective clothing and use of appropriate sunscreen on uncovered areas of the skin are 
advised.

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7
ENDPOINT AND METHODS OF ASSESSMENT
7.1
Primary Endpoint (Study Population A)
The primary objective is to study the safety and tolerability of MIV-711 in OA patients who 
have received treatment for up to 52 (26+26) weeks.
Safety endpoints:
•
Incidence and severity of AEs
•
Incidence and severity of clinical laboratory abnormalities
•
Physical examination findings by patient
•
Incidence and severity of ECG abnormalities
•
Mean change from Baseline (Visit 2 of Study MIV-711-201) in vital signs (blood 
pressure, heart rate, temperature) and oxygen saturation
•
Categorical summary of observed vital signs and vital sign changes compared to
Baseline (Visit 2 of Study MIV-711-201), by patient
7.2
Secondary Endpoints (Study Population A)
Bone parameters will be measured from MRIs of the bone area taken at Visit 2 (Enrolment)
and Visit 8 of Study MIV-711-201 as well as the MRI of the bone area taken at Visit 5 in 
Study MIV-711-202.
MRIs will be analysed semi-quantitatively by a central experienced musculoskeletal 
radiologist using the MOAKS [36] and quantitatively using statistical shape modelling (SSM, 
Imorphics Ltd) for the features below. [23, 37, 38]
MOAKS scoring will be used to assess the following features:
-
Bone marrow lesions (BMLs) and cysts: 15 sub-regions graded for BML (including 
ill-defined lesions and cysts) size in regard to the total volume of the sub-region 
occupied by BML(s). Grade 0=none, grade 1<33% of sub-regional volume, 
grade 2=33–66% of sub-regional volume and grade 3>66% of sub-regional volume. 
-
Articular cartilage: 14 articular cartilage regions graded for size of any cartilage loss 
(including partial and full thickness loss) as a % of surface area as related to the size of 
each individual region surface and % of loss in this sub-region that is full-thickness 
loss.
-
Osteophytes: 12 sites scored for presence and size of osteophytes. Grade 0=none; 
Grade 1=small; Grade 2= medium; Grade 3= large.
Bone shape modelling of MRI will be used to assess:
-
Mean cartilage thickness (mm) for each of the anterior, posterior and central regions, 
with areas denuded of cartilage included as having zero thickness [39]
-
Bone marrow lesion volume (mm3) by anatomical region: medial and lateral 
femorotibial region of femur, medial and lateral patellofemoral region of femur,
medial and lateral tibia, and patella
-
Bone area (mm2) for anatomical regions: lateral and medial femur (patellofemoral); 
lateral and medial femur (femorotibial); lateral and medial patella, lateral and medial 
tibial condyle
-
Bone shape by distance along an OA shape vector for femur, tibia and patella
-
Index bone area/cartilage thickness.

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7.3
Secondary Endpoints (Study Population B)
These are the same as the primary endpoints for Study Population A (see Section 7.1).
7.4
Exploratory Endpoints
7.4.1
Exploratory!Endpoints!(Study!Population!A)
Patient-reported outcomes (PROs)
At Visit 4 and 5 the following PROs will be recorded using questionnaires as specified in 
Table 2.
•
Average overall knee pain severity in the target knee over the past 1 week (0-10 NRS)
•
Worst knee pain severity in the target knee over the past 1 week (0-10 NRS)
•
Global disease activity over the past 1 week (0-10 NRS)
•
Average overall knee pain severity in the contralateral knee over the past 1 week (0-10
NRS)
•
Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC) 3.1 [40] -
a 24-item OA-specific, tri-dimensional self-administered questionnaire, for assessing 
health status and health outcomes in OA of the knee. The response to each question is 
scored as 0=none, 1=mild, 2=moderate, 3=severe, 4=extreme. The 24 questions are 
divided into 3 subscales; pain (questions 1-5, score range 0-20), stiffness (questions 6 
and 7, score range 0-8) and physical function (questions 8-24, score range 0-68). 
Higher scores indicate worse pain, stiffness and physical function. The subscale scores 
are derived by summing the assigned values on component items. The study joint 
referred in the WOMAC questionnaire corresponds to the target knee (as referenced 
elsewhere in this protocol).
•
Osteoarthritis Research Society International (OARSI)-OMERACT Responder index 
[41, 42] will be calculated using the WOMAC pain and function subscales and the 
patient’s global assessment score. Response will be defined as:
1) Improvement in pain or function œ72'"cpf"cduqnwvg"ejcpig œ42"qt"
2) Improvement in at least two of the following:
i) pain œ42'"cpf"cduqnwvg" ejcpig œ32."
ii) function œ42'"cpf"cduqnwvg"ejcpig œ32"cpf"
iii) patients’ global assessment œ42'"cpf"cduqnwvg" ejcpig œ32
•
Intermittent and constant osteoarthritis pain (ICOAP) [42] - an 11-item tool designed to 
assess constant and intermittent OA pain. The tool will be self-reported. (The tool was 
designed for telephone or interview administration but self-reporting is allowed.) The 
questions will be scored according to the User Manual [43] into a constant pa in 
subscale, intermittent pain subscale and total pain score. These scores will be 
transformed to a 0-100 scale for analysis.
•
Global improvements in knee problem, knee pain and knee function recorded on a 
6-point likert scale: completely better, much better, better, no change, worse, much 
worse.
•
EuroQol-5 Dimensions (EQ-5D-5L) [44] (Visit 5 only) - a generic measure of self-
reported health status that defines health status in terms of five dimensions – mobility; 
self-care; usual activity; pain or discomfort; and anxiety or depression [45]. EQ-5D-5L
has been extensively validated and shown to be sensitive, internally consistent, and 
reliable in the general population and other patient groups, including for inflammatory 
arthritis.[46]

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•
In an e-diary format, a patient knee pain diary (NRS) and analgesia questionnaire will 
be completed daily during two 2-week periods prior to Visit 4 and Visit 5. Baseline 
(Visit 2 of Study MIV-711-201) will be defined as the last observation prior to the first 
dose of investigational product. The assessments in the e-diary comprise.
1) Average overall knee pain severity in the target knee over the past 12 h (0-10
NRS)
2) Worst knee pain severity in the target knee over the past 12 h (0-10 NRS)
3) Adherence to usual analgesics regimen
4) Intake of IMP
Biomarkers, imaging and pharmacokinetics:
•
Serum and urinary biomarkers (CTX-I, PINP, BSAP and TRAP5b in serum and NTX-I, 
CTX-K."gEVZ-I, and CTX-II in urine).
•
Compound index of MRI bone area and cartilage volume
•
Pharmacokinetics: MIV-711 PK parameters and their relationship to covariates such as 
age, weight, gender, liver function and concomitant medications.
7.4.1.1
Biomarkers and biobanking
Blood and urine samples will be taken at Visits 2, 4, 5 and 6, for analysis of exploratory bone 
and cartilage markers of relevance for OA disease, such as CTX-I, PINP, BSAP and TRAP5b
in serum and NTX-I, CTX-I, gEVZ-I and CTX-II in urine.
A blood and urine sample from Visit 5 will be collected and stored in a biobank according to 
local biobanking regulations and under a separate voluntary ICF, to enable further profiling 
(pharmacogenomics, proteomics, genomics, metabolomics and lipidomics). In addition, 
potential susceptibility genes and genes related to underlying disease may be explored using 
the same samples. Aliquots of each sample will be retained for up to 5 years by the sponsor or 
its subcontractor for biobank storage, in line with GCP/Good laboratory practice and 
biobanking policies. Biological samples used for possible exploratory analysis may be 
retained at Medivir, Huddinge, Sweden, or at an affiliated storage location detailed in the 
Laboratory Manual, for a maximum of 5 years following the finalisation of the Clinical Study 
Report. The results from such analysis will be reported separately from the Clinical Study 
Report.
7.4.1.2
Imaging
Change from Visit 8 in Study MIV-711-201 to Visit 5 in the current study in a calculated 
compound index of MRI bone area (key secondary endpoint) and cartilage thickness.
7.4.1.3
Pharmacokinetics
The pharmacokinetics and potential metabolites of MIV-711 and their relationship to patient 
factors and concomitant medications will be analysed following the sampling procedures as 
described in Section 7.10.
7.4.2
Exploratory!Endpoints!(Study!Population!B)
All secondary and exploratory endpoints described in Section 7.2 and Section 7.4.1,
respectively, for Study Population A will be assessed as exploratory endpoints for Study 
Population B and will be evaluated over 26 weeks.

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7.5
Physical Examination
A standard complete physical examination will be performed at Visit 1 (Screening), Visit 2
(Enrolment), Visit 3, Visit 4 and Visit 5. The following parameters and body systems will be 
examined and any abnormalities will be described: general appearance, skin (presence of 
rash), head, eye, ears, nose, and throat, lungs (auscultation), heart (auscultation for presence 
of murmurs, gallops, rubs), extremities exam for the presence of peripheral oedema,
abdominal (palpation and auscultation), neurologic (mental status, station, gait, reflexes, 
motor and sensory function, coordination) and lymph nodes. 
A standard clinical examination of both knees will be undertaken at all visits. Any clinically 
significant changes from Visit 2 (Enrolment) should be recorded as AEs.
7.6
Vital Signs 
Vital signs (body temperature, heart rate, blood pressure, oxygen saturation) will be 
performed at all clinic visits prior to IMP dosing.
Blood pressure and heart rate measurements will be performed after the patient has been 
resting in a supine position for at least 5 minutes.
Weight will be measured at Visit 1 (Screening).
7.7
12-lead Electrocardiograms (ECG)
A 12-lead ECG will be performed at all clinic visits. 12-lead serial ECGs will be recorded at 
Visit 2 (Enrolment) pre-dosing and after 30 minutes, 1 hour and 2 hours post-dosing 
(± 10 minutes).
On dosing days, ECG should be performed 30 minutes after dosing (± 10 minutes).
The 12-lead ECG will be performed after the patient has been resting in a supine position for 
at least 10 minutes.
All ECGs will be assessed by the investigator, and the data will be recorded in the eCRF. The 
clinical significance of ECG results will be determined by the investigator after review of the 
ECG report in relation to the patient’s medical history, physical examination findings, and 
concomitant medications.
7.8
Imaging Assessments
At Visit 5 MRI acquisition will be performed on the bone area using 1.5/3T systems using the 
following sequences, which have been optimised for visualization of bone, cartilage and 
BML:
•
High resolution 3D sagittal proton density (PD) fast spin echo (FSE) with fat saturation
•
Sagittal PD FSE intermediate-weighted with fat-saturation
•
Sagittal PD FSE without fat-suppression.
The total scanning time for this set of sequences is approximately 15 minutes. 
When obtaining the MRI scan the sites must use the same scanner and coil as used during 
Visit 2 and Visit 8 in Study MIV-711-201.
Based on experience from Study MIV-711-201 it will be the responsibility of each site to 
ensure robustness of MRI acquisition. At each centre, phantoms will be scanned and visually 
assessed for distortion, warping and double shadowing along with protocol compliance prior 
to study initiation and then regularly re-tested. Each set of images will be quality controlled to 
allow for a repeat MRI to be captured if required. It is the responsibility of the sites to perform 
these phantom scans on a regular basis throughout the study and these scans will not be
evaluated centrally. In case of image quality issues the central reader may request the 

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phantom scans. If a site has an upgrade (hardware/software) then a phantom scan will be 
requested before and after upgrade to confirm the protocol has not changed.
Further details are provided in the imaging acquisition guidelines provided to each site.
Upon study completion the MRI measures from the images gathered for this study will be 
repeated using automated image analysis to enable future methodological improvements.
7.9
Self-report Parameters
Patient-reported outcomes will be recorded using questionnaires at Visit 4 and at Visit 5, as 
follows:
Pain, function and disease activity
•
11-point NRS scales for: 
-
Average overall knee pain severity in the target knee over the past 1 week
-
Average overall knee pain severity in the contralateral knee over the past 1 week
-
Worst knee pain severity in the target knee over the past 1 week 
-
Global disease activity over the past 1 week 
•
ICOAP – an 11-item tool designed to assess constant and intermittent pain
•
WOMAC 3.1 – a 24-item OA - specific, tri-dimensional self-administered 
questionnaire, for assessing health status and health outcomes in OA of the knee 
•
In an e-diary format, a patient pain diary and analgesia questionnaire will be completed 
daily during two 2-week periods prior to Visit 4 and prior to Visit 5.
Using a 6-point Likert scale (completely better, much better, better, no change, worse, much 
worse) we will record patient-reported:
•
Global improvement in knee problem at follow-up
•
Global improvement in knee pain at follow-up
•
Global improvement in knee function at follow-up
Quality of life 
EuroQol-5 Dimensions (EQ-5D-5L) - a generic measure of self-reported health status that 
defines health status in terms of five dimensions – mobility; self-care; usual activity; pain or 
discomfort; and anxiety or depression. This will be performed at Visit 5 only.
Clinical Safety Evaluation/Adverse Events
During each visit patients will be monitored and questioned by a member of the clinical staff 
for the occurrence of new AEs since the last visit, or the outcome of any AEs reported at 
previous visits. Incidence, severity, expectedness, relation to the study intervention and 
outcome of each adverse event will be documented and reported.
Adherence to Study Medication and Concomitant Medication
Patients will be asked to return any unused study medication at Visit 4 and Visit 5 and drug
accountability will be conducted. The Brief Medication Questionnaire self-reported measure 
[47] for the use of concomitant medication will be included at Visit 4 and Visit 5.

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7.10
Pharmacokinetic Sampling
Three blood samples will be collected at Visit 5 to measure plasma concentrations of 
MIV-711 and potential metabolites. On this visit, one of these three samples will be collected
at pre-dose and the other two samples will be collected post-dose. The two post-dose samples 
should be separated by two of the following time intervals, if possible; 0.25-1h, 1-2h, 2-4h, 
4-6h, 6-8h and 8-10h. For example, if the first post-dose sample is taken at 1-2h the second 
should be taken at 6-8h.
The 3 blood samples (approximately 5 mL each) will be taken by venipuncture or cannulation 
from a forearm vein(s) and collected into lithium heparin tubes, and will be mixed. After 
mixing, blood samples will be placed in a cool box containing crushed ice/water. The samples 
will be centrifuged, within 1 hour of collection, at 1500 g for 10 minutes at approximately 
4°C.
For each sample, the separated plasma will be equally split into 2 aliquots and transferred into 
2 suitably labelled polypropylene tubes, and stored within 2 hours of collection at at 
least -70°C until shipped on dry-ice. The 2 aliquots should be shipped in two separate 
shipments to the Bioanalytical Laboratory for further shipment and analysis of MIV-711 and
for potential metabolite analysis. Refer to the Laboratory Manual for further details.
The date/time of sample collection as well as the date/time of the most recent dose will be 
collected in the eCRF. A separate sub-protocol for the Population pharmacokinetics (PK)
analysis will be established aiming at analysing MIV-711 PK parameters and their 
relationship to covariates such as age, weight, gender, liver function, and concomitant 
medications. Exploratory PK-Pharmacodynamic
analyses for efficacy variables and 
biomarkers may be performed based on the study results. 
Further details on the provider and handling of the pharmacokinetic samples will be provided 
in the Laboratory Manual.
7.11
Biomarker Sampling
Blood and urine samples will be taken at Visits 2, 4, 5 and 6 for analysis of exploratory bone 
and cartilage biomarkers of relevance for OA disease, such as CTX-I, PINP, BSAP and 
TRAP5b in serum and NTX-I, CTX-I, gEVZ-I and CTX-II in urine. Patients should be fasted 
overnight (no meals after 11 pm, but water allowed) and restrained from extensive exercise 
and smoking the previous day. Blood and urine samples will be collected at pre-dose in the 
morning (between 7-10 am) on the visit.
Blood samples (approximately 15 mL) will be taken by venipuncture or cannulation from a 
forearm vein(s) and collected into serum separator tubes. The samples will be centrifuged, 
within 1 hour of collection, at 1800g for 10 minutes at room temperature. For each sample the 
separated serum will be divided into 3 aliquots and transferred into suitably labelled
polypropylene tubes and stored within 1.5 hours of collection at at least -70°C until analysis.
The first void of morning urine should have occurred before the urine sample (approximately 
10 mL) is taken from a later void. The urine samples will be divided into 3 aliquots into 
suitably labelled polypropylene tubes. The samples will be stored within 1.5 hours of 
collection at at least -70°C until analysis.
The date/time of sample collection as well as the date/time of the most recent dose will be 
collected in the eCRF.
Aliquot 1 and 2 of each blood and urine sample should be shipped together to the Central 
Laboratory. The third aliquot should remain at the site and be shipped separately.
Further details on the provider and handling of the biomarker samples will be provided in the 
Laboratory Manual.

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7.12
Optional Pharmacogenomics Sampling
Blood and urine samples will be collected at Visit 5
under voluntary ICF for 
pharmacogenomics, proteomics, genomics, metabolomics and lipidomics.
Blood samples (approximately 19 mL) will be taken by venipuncture or cannulation from a 
forearm vein(s) and collected into a DNA PAXgene (approximately 8.5 mL), RNA PAXgene 
(approximately 2.5 mL) or EDTA tube (approximately 8 mL) for preparation of DNA, RNA 
and protein, respectively. The DNA and RNA PAXgene tubes will be frozen and stored at at 
least -70°C until analysis. The EDTA tube will be processed into plasma by centrifugation 
within 1 hour of collection, at 1500 g for 10 minutes at approximately 4°C. The plasma will 
be separated into 2 aliquots and transferred into suitably labelled cryovials and stored at at 
least -70°C until analysis. 
A urine sample (approximately 5 mL) will be collected for protein isolation. The urine sample 
is centrifuged within 1 hour of collection at 1500 g for 5 min at approximately 4°C and the 
sample is separated into 2 aliquots and transferred into suitably labelled cryovials and stored 
at at least -70°C until analysis.
The 2 aliquots of each blood and urine sample should be shipped in two separate shipments to 
the Central Laboratory.
7.13
Adverse Events
7.13.1 Definitions of!Adverse!Events (AEs)
An AE is any untoward medical occurrence that occurs in a patient or clinical investigation 
patient administered a pharmaceutical product, and which does not necessarily have to have a 
causal relationship with this treatment. An AE can therefore be any unfavourable and 
unintended sign (including abnormal laboratory finding), symptom, or disease temporally 
associated with the use of an investigational product, whether or not considered related to the 
product.
All AEs, including undercurrent illnesses, occurring during the study will be documented in 
the eCRF system. Concomitant illnesses, which existed before entry into the study, will not be 
considered AEs unless they worsen during the treatment period. All AEs, regardless of the 
source of identification (e.g., physical examination, laboratory assessment, ECG, reported by 
patient), must be documented. Worsening of the underlying disease is not considered an AE
and should be reported as such only if deemed by the Investigator to be beyond the expected 
progression for OA.
Pre-existing conditions will be recorded in the eCRF system on the Medical History page.
A treatment-emergent AE (TEAE) will be defined as an AE that begins or that worsens in 
severity after at least one dose of IMP has been administered.
7.13.2 Assessment!of!Adverse!Events
Each AE will be assessed by the Investigator with regard to the following categories.
7.13.2.1 Seriousness
An SAE is defined as any untoward medical occurrence that at any dose:
•
Results in death
•
Is life-threatening
This means that the patient is at risk of death at the time of the event; it does not mean 
that the event hypothetically might have caused death if it were more severe.
•
Requires inpatient hospitalization or prolongation of existing hospitalization

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•
Results in persistent or significant disability or incapacity
•
Is a congenital anomaly or birth defect
•
Is an important medical event(s) that may not be immediately life-threatening or result 
in death or hospitalization but that may jeopardise the patient or require intervention to 
prevent one of the above outcomes.
Medical and scientific judgment should be exercised in deciding whether a case is serious 
and whether expedited reporting is appropriate.
7.13.2.2 Intensity
The intensity of each AE must be assessed by the Investigator using one of the following 
categories, and recorded in the eCRF system:
•
Mild: An AE that is easily tolerated and does not interfere with usual activities;
•
Moderate: An AE that interferes with usual activities;
•
Severe: An AE that prevents usual activities.
7.13.2.3 Causality
The Investigator will assess the causality/relationship between the AE and the IMP as well as 
the study procedure and record that assessment in the eCRF system.
The causal relationship of the AE to IMP will be described in terms of:
•
Related
•
Unrelated
7.13.2.4 Adverse Events of Special Interest
No Adverse Events of Special Interest monitoring is applicable for this study.
7.13.2.5 Recording Adverse Events
All AEs and SAEs must be recorded, whether or not considered causally related to the IMP or 
to the study procedure(s). All AEs and SAEs will be recorded in the eCRF system from the 
date the Informed Consent Form is signed (Visit 1) until the safety follow-up visit (Visit 6) is 
completed. All AE reports should contain a brief description of the event, date and time of 
onset, date and time of resolution, intensity, treatment required, relationship to IMP, action 
taken with the IMP, outcome, and whether the event is classified as serious. The information 
related to the AEs will be captured in the eCRF within the normal data entry timelines.
Whenever feasible, AEs should be documented as medical diagnoses. When AEs do not 
appear clearly inter-related, individual signs or symptoms may be reported as separate AEs.
7.13.2.6 Reporting Serious Adverse Events
The Investigator will complete the SAE report and will evaluate the seriousness and the 
causal relationship of the event to study treatment. In addition, sponsor will evaluate the 
relatedness and expectedness according to the reference document (IB). Based on the 
Investigator and sponsor’s assessment of the event, a decision will be made concerning the 
need for further action.
All SAEs that occur from the time of signature of informed consent until 4 weeks (Visit 6)
after the last dose of IMP, whether considered to be associated with the IMP or not, must be 
reported within 24 hours of awareness to the PAREXEL Safety Contact using the numbers in 
the List of Study Personnel.
SAEs occurring after the end of the study should be reported to the sponsor by the 
Investigator, if the Investigator considers there is a causal relationship with the IMP.

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The following information is required for a valid report:
•
An identifiable reporter (i.e., name, address of Investigator)
•
An identifiable patient (i.e., patient number, but NOT patient name)
•
A suspect IMP or clinical study procedure
•
A serious adverse event or outcome associated with the use of IMP or clinical study
procedure
As far as possible all points on the SAE report form should be covered in the initial report, or 
the completed SAE form itself must be faxed to the PAREXEL Safety Contact. If important 
relevant information is missing, PAREXEL will immediately initiate follow-up. The 
investigator or other site personnel must inform PAREXEL of any follow-up information on a 
previously reported SAE within 24 hours of when he or she becomes aware of it. The original 
SAE form must then be sent by mail to the PAREXEL Safety Contact. In addition, the event 
must be documented in the eCRF system.
In the event that the Investigator is unable to enter the SAE in the eCRF or to complete the 
paper SAE form to report the event within 24 hours of their awareness of the event, the 
investigator may report the SAE over the telephone via the SAE answering service, and then 
provide the completed paper SAE form via fax/email. In any case the Investigator also has to 
record the event in the eCRF. If questions arise regarding the reporting procedures or the 
specifics of the reporting of an event, sites may call utilizing the numbers specified in the list 
of Study Personnel.
After receipt of the initial report, the safety centre will review the information and, if 
necessary, contact the Investigator, to obtain further information for assessment of the event. 
PAREXEL will be responsible for all information processing and reporting according to local 
legal requirements. 
PAREXEL International
Medical Monitor: Francois Burger
Medical hotline: +49 30 30685 274
SAE Fax: +49 30 315118 7777 (24-hour service)
Email: Medical_Berlin@parexel.com
7.13.2.7 Follow-up of Adverse Events
All AEs experienced by a patient, irrespective of the suspected causality, will be monitored 
until the AE has resolved, any abnormal laboratory values have returned to baseline or 
stabilized at a level acceptable to the Investigator and Medical Monitor, until there is a 
satisfactory explanation for the changes observed, until the patient is lost to follow-up, or until 
the patient has died.
The Sponsor will actively follow-up and collect information on any AE that occurs during the 
course of a clinical study, however while this activity will continue for any serious AEs until 
stabilization or until the outcome is known, it will be discontinued at the time of database lock 
for non-serious AEs.
7.13.2.8 Suspected Unexpected Serious Adverse Reactions
Any adverse event that is serious, associated with the use of the IMP, and suspected 
unexpected serious adverse reaction (SUSAR) has additional reporting requirements, as 
described below. For the assessment of expectedness, further information is found in the IB 
Section 6 ‘Summary of Data and Guidance for the investigator’.

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•
If the SUSAR is fatal or life-threatening Regulatory Authorities and Independent Ethics 
Committees (IECs) will be notified within 7 calendar days after PAREXEL learns of 
the event. Additional follow-up (cause of death, autopsy report, and hospital report) 
information should be reported within an additional 8 days (15 days total).
•
If the SUSAR is not fatal or life-threatening Regulatory Authorities and IECs will be 
notified within 15 calendar days after PAREXEL learns of the event.
The Sponsor will notify the Investigators in a timely fashion of relevant information about 
SUSARs that could adversely affect the safety of patients. Follow-up information may be 
submitted if necessary. 
The Sponsor will also provide annual safety updates to the Regulatory Authorities and IECs
responsible for the study. These updates will include information on SUSARs and other 
relevant safety findings.
7.13.2.9 Pregnancy
Women of childbearing potential are not allowed to be included in this study. Should a 
pregnancy still occur during study treatment, the patient must be discontinued from the study 
immediately and the pregnancy must be reported to the sponsor by providing the completed 
Pregnancy Reporting and Outcome Form within 24 hours of awareness and followed until 
outcome (completion/termination) of the pregnancy.
7.13.2.10 Paternal Exposure
Pregnancy of the patient's partner is not considered to be an AE. However, the outcome of all 
pregnancies from the date of the first dose until 6 month after the last dose must be reported to 
the Sponsor and, be followed and documented by completion of the Pregnancy Reporting and 
Outcome Form.
Any pregnancy must be reported to the Sponsor according to the SAE reporting procedure 
whether or not associated with an AE/SAE as described in section 7.13.2.6.
7.13.2.11 Abuse, Misuse, Overdose or Medication Error
Any abuse, misuse, overdose, or medication error must be reported to the Sponsor according 
to the SAE reporting procedure whether or not associated with an AE/SAE as described in 
Section 7.13.2.6.
Note: The 24 hour reporting requirement for SAEs does not apply to reports of abuse, misuse, 
overdose, or medication errors unless these result in an SAE.
The categories below are not mutually exclusive; the event can meet more than 1 category.
•
Abuse – Persistent or sporadic intentional intake of IMP when used for a non-medical 
purpose in a manner that may be detrimental to the individual and/or society.
•
Misuse – Intentional use of IMP other than as directed or indicated at any dose (Note: 
this includes a situation where the investigational product is not used as directed at the 
dose prescribed in this protocol). 
•
Overdose – Intentional or unintentional intake of a dose of an investigational product 
exceeding 15% over the total daily mg of MIV-711 as defined in the dosing charts 
developed per protocol. 
•
Medication Error – An error made in prescribing, dispensing, administration, and/or 
use of an IMP. Medication errors should be collected/reported for all investigational 
products under investigation.
The following medication errors are defined as reportable to the sponsor in this study:

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-
The administration and/or use of an expired product should be considered as a 
reportable medication error.
A blood sample for determination of plasma MIV-711 concentration should be obtained, if at 
all possible, as soon as possible after Investigator becomes aware of any above, if associated 
with an AE.
The information related to abuse, misuse, overdose, or medication error will be captured in 
the eCRF within the normal data entry timelines.

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8
STUDY CONDUCT
8.1
Study Schedule
Patients with symptomatic knee OA participating in Study MIV-711-201 will be invited to 
participate in the present study.
Visit 1 of the present study coincides with Visit 8 of Study MIV-711-201. To ensure the 
patients will have sufficient time to consider their participation in the study, the informed 
consent form will be given to the patients prior to Visit 8 in Study MIV-711-201. During 
Visit 1 of the present study the patient information will be discussed. Any questions from the 
patient will be answered. The Screening Phase will last for a maximum of 10±5 days, during 
which patients will be checked for eligibility by the investigator. The patient’s eligibility will 
be determined by the laboratory results obtained during the Screening visit (Visit 1). The 
study will include 26 weeks of treatment, with patients followed for 30 weeks as per Study 
Schedule (Table 2).
8.1.1
Screening!Visit!(Visit 1,!Day -10 ± 5 days)
The activities below are those performed at the Screening visit which will be documented in 
eCRF:
•
Obtaining written informed consent. Study details, risks and benefits will be reviewed 
and patients will be encouraged to ask questions and clarify any concerns. The patient
will have been provided with the consent form to read prior to Visit 8 in Study 
MIV-711-201.
•
Assessing inclusion and exclusion criteria
•
Obtaining demographic data (including age, gender and race)
•
Obtaining medical and surgical history 
•
Performing complete physical examination (assessed at Visit 8 in MIV-711-201, must 
only be re-assessed if Visit 8 does not occur on the same day as Visit 1 in the present 
study)
•
Performing vital signs assessments including weight and oxygen saturation (assessed at 
Visit 8 in MIV-711-201, must only be re-assessed if Visit 8 will not occur on the same 
day as Visit 1 in the present study)
•
Performing 12-lead electrocardiogram assessment (assessed at Visit 8 in MIV-711-201, 
must only be re-assessed if Visit 8 will not occur on the same day as Visit 1 in the 
present study)
•
Sampling for urinalysis (assessed at Visit 8 in MIV-711-201, must only be re-assessed 
if Visit 8 will not occur on the same day as Visit 1 in the present study)
•
Sampling for urine drug screen
•
Sampling for blood clinical chemistry and haematology testing (assessed at Visit 8 in 
MIV-711-201, must only be re-assessed if Visit 8 will not occur on the same day as 
Visit 1 in the present study)
•
Sampling for blood post-menopausal assessments (only post-menopausal or sterile 
women will be enrolled)
•
Dispensing new Patient Emergency Card
•
Monitoring for AEs, SAEs
•
Performing registration in the Interactive Web Response System (IWRS)

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8.1.2
Enrolment!(Visit 2,!Day 1)
The activities below are those performed at the enrolment visit which will be documented in 
eCRF:
•
Confirming inclusion and exclusion criteria
•
Monitoring for AEs, SAEs and concomitant medication
•
Performing complete physical examination
•
Performing vital signs assessments
•
Performing 12-lead serial ECGs at Visit 2 (Enrolment) pre-dosing and after 30 minutes, 
1 hour and 2 hours post-dosing (± 10 minutes)
•
Sampling for blood and urine biomarker testing
•
Sampling for blood clinical chemistry, haematology and urine testing
•
Dispensing the first IMP at the site. Patient must stay at the clinic for 2 hours after 
taking the IMP.
•
Dispense e-diary. Re-training of patients if required.
•
Obtaining optional ICF for pharmacogenomics, proteomics, genomics, metabolomics 
and lipidomics.
•
Phone call to assess safety and tolerability (completed 5-9 days after the visit)
8.1.3
Safety!Visit!(Visit!3![Week!4!±!2!days])
The activities below are those performed at the safety visit which will be documented in 
eCRF: 
•
Monitoring for AEs, SAEs and concomitant medication
•
Performing vital signs assessments  
•
Performing physical examination 
•
Performing 12-lead electrocardiogram assessment 30 minutes post-dose 
•
Sampling for urinalysis  
•
Sampling for blood clinical chemistry and haematology testing
•
Phone call to assess safety and tolerability (completed 5-9 days after the visit)
8.1.4
Safety!and!Treatment!Visit!(Visit 4 [Week 14 ±!7!days],!and!Visit 5 [Week 26 ±!
7 days])
The activities below are those performed at the safety and treatment visits which will be 
documented in eCRF:
•
Monitoring AEs, SAEs and concomitant medication
•
Performing vital signs assessments
•
Performing complete physical examination
•
Performing 12-lead electrocardiogram assessment 30 minutes post-dose (± 10 minutes)
•
Sampling for urinalysis 
•
Sampling for blood and urine biomarker testing
•
Sampling for blood clinical chemistry and haematology testing 
•
Sampling for blood PK assessment (at Visit 5 only)
•
Obtaining optional blood sample for pharmacogenomics, proteomics, genomics, 
metabolomics and lipidomics and urine sample for proteomics and metabolomics (at 
Visit 5 only)
•
Performing knee MRI (at Visit 5 only) ±5 days

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•
Completion of NRS, WOMAC, ICOAP, Global Improvement Questionnaire and Brief 
Medication Questionnaire
•
Completion of Quality of Life questionnaire: EuroQoL EQ-5D-5L (at Visit 5 only)
•
Dispense IMP at the site (the capsule should be taken from the bottle currently in use 
by the patient) (Visit 4 only)
•
Drug accountability
•
Review e-diary completion which has been done for a two-week period prior to the 
visits
•
Phone call to assess safety and tolerability (completed 5-9 days after the visits)
•
Return of e-diary (at Visit 5 only)
8.1.5
Additional!Telephone!Calls to!Assess!Safety!and!Tolerability
Additional telephone calls to assess safety and tolerability will be performed at Week 10 and 
Week 20.
8.1.6
Safety!Follow-up Visit (Visit 6,!Week 30 ±!7 days)
The activities below are those performed at the safety follow-up visit which will be 
documented in eCRF:
•
Monitoring AEs, SAEs and concomitant medication
•
Performing vital signs assessments 
•
Performing 12-lead electrocardiogram assessment 
•
Sampling for blood and urine biomarker testing
•
Sampling for blood clinical chemistry, haematology and urine testing 
The end of the study is defined as the last Visit 6 (Week 30) of the last patient.
Table 1:
Clinical Laboratory Testing
Post-menopausal determination:Follicle stimulation hormone (FSH) 
Female patients mustbe of non-childbearing potential either as naturally (spontaneously) post-menopausal 
or due to hysterectomy and/or bilateral oophorectomy/salpingo-oophorectomy (as determined by patient 
medical history). Naturally (spontaneously) post-menopausal is defined as being amenorrheic for 
12 months without an alternative medical cause and with a Screening FSH indicating post-menopausal 
state.
Fasting samples are required at all study visits as fasting glucose is required as part of the chemistry 
samples.
Haematology: WBC and differential, % and absolute for: neutrophils, lymphocytes, monocytes, 
eosinophils, basophils; haemoglobin,haematocrit, RBC, RBC indices (MCV, MCH and MCHC) and 
morphology, platelet count
Chemistry:urea nitrogen, creatinine, calcium, sodium, potassium, bicarbonate, chloride, total protein, 
fasting glucose, total bilirubin, direct bilirubin and indirect bilirubin, ALT, AST, alkaline phosphatase, 
GGT, CPK, CRP 
Urinalysis:with microscopic: specific gravity, pH , protein, glucose, ketones, nitrites, blood and leukocyte 
esterase
Urine Drug Screen:Amphetamine, Benzodiazepines, THC, Cocaine, Oxycodone and Opiate
PTH (parathyroid hormone)

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The above parameters will be analysed by a Central Laboratory. Total blood volumes to be 
collected are detailed in Appendix 1. Further details on the provider and handling of 
laboratory samples will be provided in the Laboratory Manual.
The study schedule is summarised in Table 2.

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Table 2:
Study Schedule
Study Visit
V1
V2
V3
V4
V5
V6
Weeks
-2
1
4 ±2 days
14 ±7 days
26 ± 7 days
30 ± 7 days
Day
-10 ± 5 days
Day 1
28 ±2 days
98 ±7 days
182 ± 7 days
210 ± 7 days
Visit Description
ScreeningA
Enrolment
Safety
Safety and Treatment
Safety follow-up
Signed informed consent
X
XB
Inclusion/exclusion criteria
X
X
Demographics
X
Weight
X
Medical & Surgical history
X
Physical examination
XC
X
X
X
X
Vital signs, including body 
temperature
XC
X
X
X
X
X
12-Lead ECGD
XC
XE
X
X
X
X
Clinical chemistry/Haematology
XC
X
X
X
X
X
UrinalysisF
XC
X
X
X
X
X
Urine drug screen
X
Post-menopausal assessment
(females only)
X
e-diary dispensing and training
X
e-diary for pain and analgesicG
X
X
Patient Emergency Card 
Dispensing
X
MRI of the bone area
XH

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Study Visit
V1
V2
V3
V4
V5
V6
Weeks
-2
1
4 ±2 days
14 ±7 days
26 ± 7 days
30 ± 7 days
Day
-10 ± 5 days
Day 1
28 ±2 days
98 ±7 days
182 ± 7 days
210 ± 7 days
Visit Description
ScreeningA
Enrolment
Safety
Safety and Treatment
Safety follow-up
Registration in the IWRS
X
NRS, ICOAP, WOMAC
X
X
Global improvement (6-point 
Likert scale)
X
X
EuroQoL EQ-5D-5L
X
Brief Medication Questionnaire
X
X
Dispense IMPI
XJ
X
Drug accountability
X
X
e-diary return
X
PK sampling (blood)
X
Biomarker samplesK
X
X
X
X
AEs/SAEs monitoring
X
X
X
X
X
X
Concomitant Medication
X
X
X
X
X
Phone call to assess safety and 
tolerabilityL
X
X
X
X
Blood sample for 
pharmacogenomics, proteomics, 
genomics, metabolomics and 
lipidomics and urine sample for 
proteomics and metabolomics
XM

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01 July 2016
Study Visit
V1
V2
V3
V4
V5
V6
Weeks
-2
1
4 ±2 days
14 ±7 days
26 ± 7 days
30 ± 7 days
Day
-10 ± 5 days
Day 1
28 ±2 days
98 ±7 days
182 ± 7 days
210 ± 7 days
Visit Description
ScreeningA
Enrolment
Safety
Safety and Treatment
Safety follow-up
Abbreviations: AE=adverse event; ECG=electrocardiogram; eCRF=electronic case report form; DNA=deoxyribose nucleic acid;  EuroQoL EQ-5D-5L= a standard measure of 
health status developed by the EuroQol Group in order to provide a simple, generic measure of health for clinical and economic appraisal; FSH=follicle stimulating hormone; 
ICF=informed consent form; ICOAP=intermittent and constant osteoarthritis pain; IMP=investigational medicinal product; IWRS= Interactive Web Response System;
MRI=magnetic resonance imaging; NRS=numeric rating scale; PK=pharmacokinetic; PRO=patient-reported outcomes; RNA=ribonucleic acid; SAE=serious adverse event; 
WOMAC= Western Ontario and McMaster Universities Osteoarthritis Index
A) The Screening visit (Visit 1) will coincide with 26-week End of Treatment visit of Study MIV-711-201 (Visit 8).
B) Optional ICF to be provided and signed at Visit 2.
C) Assessed at Visit 8 in Study MIV-711-201. Only need to be re-assessed if Visit 8 does not occur on the same day as Visit 1 in Study MIV-711-202
D) 30 minutes post-dose (± 10 minutes).
E) 12-lead serial ECGs will be recorded at Visit 2 (Enrolment) pre-dosing and after 30 minutes, 1 hour and 2 hours post-dosing (± 10 minutes).
F) If urinalysis is positive for blood, nitrites, leukocyte esterase, and/or protein, additional microscopic analysis may be performed.
G) To be completed at home during the 2 weeks leading up to the marked visit with final recording the day before.
H) ± 5 days
I) Patients take IMP in the clinic in a fasting state. Breakfast can be eaten 1 hour after IMP intake. The last dose of the IMP will be taken at the site during Visit 5.
J) The first dose of IMP will be dispensed to the patient at the site and the patient must stay at the clinic for 2 hours after intake of IMP. Date and time should be recorded in the 
eCRF. The first dose should be given to the patient after all assessments at Enrolment have been performed. 
K) Both blood and urine sample will be collected for biomarker. The first void of morning urine should have occurred before the urine sample is taken from a later void. The 
patients must be fasting when all biomarker samples are taken.
L) The phone call should be made 5-9 days after all dosing visits. There will be additional phone calls at Week 10 and Week 20. 
M) Blood will be collected for pharmacogenomics, proteomics, genomics, metabolomics and lipidomics and urine will be collected for proteomics and metabolomics pre-dose at 
Visit 5 from patients who provide additional written consent.

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8.2
Early Termination Visit
All patients who discontinue the IMP because of an AE, or for any other reason, will be asked 
to complete the safety follow-up visit (Visit 6) as outlined in the study schedule (Table 2). In 
addition to the assessments described in Section 8.1.6, the following should also be 
completed:
•
Drug accountability
•
Return of eDiary
•
Physical examination
•
Performing knee MRI (±5 days) (if withdrawal is after Visit 4)
•
Obtaining optional blood samples for pharmacogenomics, proteomics, genomics, 
metabolomics and lipidomics and urine samples for proteomics and meabolomics.
8.3
Discontinuation of the Study
No formal interim analysis to allow early stopping of the study on the basis of demonstrating 
efficacy or futility is planned.
The study will be monitored by the independent DMEC. Any SAE will be reported to the 
committee who may recommend stopping the study for safety reasons. Interim safety analyses 
(i.e. no efficacy analyses) will be undertaken after the first 25 patients have completed Visit 4
and 5. No formal statistical tests will be undertaken but AEs will be summarised and tabulated 
for each group separately. If, in the view of the DMEC, the number or severity of adverse 
events is of concern, consideration will be given to the future conduct and design of the study,
and to whether further formal interim analyses are required.
The study will be discontinued due to events such as exemplified below:
•
The Sponsor (following DMEC recommendation or in absence of such 
recommendation) judges it necessary for medical, safety, regulatory or any other 
reasons consistent with applicable laws, regulations and GCP.
•
If SAEs are assessed as causally related to IMP or in presence of other significant 
medical events as judged by the sponsor.
•
New information leading to unfavourable risk-benefit judgment of the IMP, as judged 
by the investigator and/or sponsor, e.g., due to:
1) Occurrence of significant previously unknown adverse reactions or 
unexpectedly high intensity or incidence of known adverse reactions, or
2) Other unfavourable safety findings.
•
If events are not considered to be consistent with continuation of the study.
•
Poor enrolment of patients making completion of the trial within an acceptable time 
frame unlikely.
•
Discontinuation of development of the sponsor’s IMP.

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9
STATISTICAL METHODS
The statistical considerations summarised in this section outline the plan for data analysis of 
this study. 
Before database lock, a separate SAP will be finalised, providing detailed methods for the 
analyses outlined below. 
Any deviations from the planned analyses will be described and justified in the final 
integrated study report.
9.1
Study Patients
9.1.1
Disposition!of!Patients
The number and percentage of patients entering and completing each phase of the study will 
be presented overall. Reasons for withdrawal pre- and post-randomisation will also be 
summarised.
The disposition of patients will also include information on the number and percentage of 
patients who:
•
Completed IMP and follow-up,
•
Withdrew from IMP but completed follow-up,
•
Withdrew from IMP and from follow-up.
9.1.2
Protocol!Deviations
Deviations from the protocol including violations of inclusion/exclusion criteria will be 
assessed as “minor” or “major” in cooperation with the sponsor. Major deviations from the 
protocol will lead to the exclusion of a patient from the Per Protocol Set (PPS). Deviations 
will be defined prior to data base hard lock.
9.1.3
Analysis!Sets
Study Population A
Patients treated with 200 mg MIV-711 q.d. in Study MIV-711-201 whose symptoms did not 
clinically significantly deteriorate as defined by an NRS increase of ø4"eqorctgf"vq"Daseline.
Study Population B
Patients receiving placebo in Study MIV-711-201 and that had experienced a clinical 
worsening as defined by increased NRS versus Bcugnkpg" qh"œ40
No comparisons between Study Populations A and B will be undertaken.
Major protocol violators and exclusions from the analysis sets will be identified by a panel,
including the clinical project manager, study statistician, and other appropriate clinical study 
team members.
The following criteria will be used to exclude a patient from the analysis set:
•
Incorrect diagnosis
•
Any of the prohibited interventions/injuries for the target knee
•
Missing more than 7 doses of MIV-711
The panel will review these criteria using soft-locked data prior to data analysis.
The safety analysis set (SAF): all patients receiving at least one dose of either MIV-711.
The primary analysis will be based on Study Population A.

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The secondary analysis will be based on Study Population B.
All safety analyses will be based upon the SAF.
Demographic and Baseline characteristics will be evaluated for the SAF.
9.2
General Consideration
Continuous data will be summarised using descriptive statistics (number, mean, median, 
standard deviation [SD], minimum, and maximum). Categorical data will be summarized by 
treatment group using frequency tables (frequencies and percents).
9.2.1
Power!and!Sample!Size!Consideration
This study is not powered for any confirmatory analyses.
9.2.2
Analysis!and!Data!Conventions:
Visit windows
Assessments taken outside of protocol allowable windows will be displayed according to the 
eCRF assessment recorded by the investigator.
Unscheduled assessments
Extra (repeat) assessments (laboratory data or vital signs associated with non-protocol clinical 
visits or obtained in the course of investigating or managing adverse events) will be included 
in data listings.
For repeat/unscheduled assessments collected prior to first dose administration, the last 
assessment taken for a time point will be used in data summaries (summary tables, figures, 
and statistical analysis). For repeat/unscheduled collected after the first dose administration 
the original assessment for any given time point will be used in the data summaries (summary 
tables, figures, and statistical analysis).
It is noted that invalid laboratory data may not be used (from haemolysed samples, 
mishandled samples, quantity not sufficient or other conditions that would render values 
invalid). 
Missing data conventions
In general, data will not be imputed for safety analysis. Efficacy analysis imputations will use 
last observation carried forward (LOCF) for patients in analysis populations as described. 
Additional details will be in the SAP.
Any outliers that are detected during the blind review of the data will be investigated. If 
necessary, queries will be issued to the Investigator to either correct or confirm the outlier.
9.3
Demographics, Medical History, Baseline Characteristics, and Concomitant 
Medications
Demographic data, medical history, concomitant disease, and concomitant medication will be 
summarised by means of descriptive statistics (n, mean, SD, median, minimum and 
maximum) or frequency tables, presented overall.
9.4
Treatment Compliance
Treatment compliance as measured in Section 6.5 will be summarised by means of descriptive 
statistics (n, mean, SD, median, minimum, and maximum) and/or frequency tables presented 
overall.

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9.5
Statistical Methodology
9.5.1
Primary!Endpoint (Study!Population A)
The primary outcome will be to study the safety and tolerability of 200 mg MIV-711 q.d. over 
52 (26+26) weeks in patients with symptomatic and radiographic knee OA.
Safety endpoints:
•
Incidence and severity of AEs
•
Incidence and severity of clinical laboratory abnormalities
•
Physical examination findings by patient
•
Incidence and severity of ECG abnormalities
•
Mean change from Baseline (Visit 2 of Study MIV-711-201) in vital signs (blood 
pressure, heart rate, temperature) and oxygen saturation
•
Categorical summary of observed vital signs and vital sign changes compared to
Baseline (Visit 2 of Study MIV-711-201), by patient
Safety and tolerability will be assessed descriptively in summary tables presented over time. 
All data presentations addressing the primary outcome will use Study Population A.
9.5.2
Secondary!Endpoints
9.5.2.1
Definition of Baseline for Secondary Endpoints
For the efficacy parameters, for Study Population A, changes from Baseline will be assessed 
using the Visit 2 baseline data from MIV-711-201. For Study Population B, changes from 
Baseline will be assessed using the Visit 2 data from Study MIV-711-202.
9.5.2.2
Study Population A
The secondary endpoints are related to efficacy:
•
The effect of MIV-711 on MRI cartilage thickness loss
•
The effect of MIV-711 on MRI bone marrow lesion volume
•
The effect of MIV-711 in the semi quantitative MRI Osteoarthritis Knee Score 
(MOAKS) parameters
•
To assess the effect of MIV-711 on MRI knee joint bone area.
Note: all MRI assessments refer to the target knee unless stated otherwise.
9.5.2.3
Study Population B
The secondary endpoint for Study Population B is the same as the primary endpoint for Study 
Population A (see Section 9.5.1).
9.5.2.4
Statistical Methodology for Secondary Endpoints
For Study Population B, the safety and tolerability of 200 mg MIV-711 for 26 weeks will be 
studied in OA patients with clinical worsening during the placebo treatment in the 
MIV-711-201 study. Safety and tolerability will be assessed descriptively in summary tables 
presented over time. 
All other secondary analyses will be undertaken using Study Population A, while they will be 
undertaken as exploratory analyses on Study Population B.
For Study Population A all secondary outcome variables will be analysed using descriptive 
summary tables presenting statistics for, number of non-missing values means, medians, 
standard deviations, minimum and maximum values. Frequency tables (counts and 

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percentages) will be presented in tables where appropriate. Figures of secondary response 
over time will be presented as appropriate.
For all outcome variables analysed using a linear model, distributional assumptions will be 
checked using examination of empirical distributions and model residuals. If necessary, data 
will be transformed prior to analysis if this improves the model fit, or normalises the 
distribution of the residuals. Non-parametric methods may be applied if appropriate.
For the analysis of secondary endpoints, alternate statistical methods maybe considered that 
will include the use of generalised linear models that account for the response variable having 
a “non-normal” distribution.  Additional details will be provided in the SAP.
All secondary outcomes will be summarised descriptively (mean, SD, median, minimum and 
maximum for continuous data and counts and percentages for categorical data). 
9.5.3
Exploratory!Endpoints
The exploratory endpoints are detailed in Section 7.4.1 for Study Population A and 
Section 7.4.2 for Study Population B.
9.5.3.1 Definition of Baseline for Exploratory Endpoints
For the efficacy parameters, for Study Population A, changes from Baseline will be assessed 
using the Visit 2 baseline data from MIV-711-201. For Study Population B, changes from 
Baseline will be assessed using the Visit 8 data from Study MIV-711-201 which is expected 
to occur on the same calendar day as Visit 1 in Study MIV-711-202. For the biomarkers in 
Study Population B, the baseline will be Visit 2 in the present study (MIV-711-202).
9.5.3.2
Statistical Methodology for Exploratory Endpoints
The exploratory analysis of patient reported outcomes, bone and cartilage biomarkers, MRI 
imaging and PK assessments will be listed and summarised using descriptive statistics only or 
presented in separate reports. The pharmacokinetic measurements in this study will be 
performed using sparse sampling in which the date/time of sample collection as well as the 
date/time of the most recent dose will be collected in the eCRF to allow for a future 
population pharmacokinetic analysis of these data. For the purpose of this study, the plasma 
concentrations of parent and potential metabolites of MIV-711 will be an additional 
exploratory endpoint and will be reported as outlined above. In the analysis of biomarkers that 
are sampled at multiple visits, all sampled time points will be considered for change from 
Baseline in the respective cases. In applicable cases, PK and biomarker data may be analysed 
using area under the curve calculations.
9.5.4
Safety
The primary purpose and endpoint of the present study is safety and tolerability as described 
above. There will be no formal statistical hypothesis testing for safety data in this study,
therefore only summary statistics will be provided. Safety summaries will be presented by 
scheduled assessment for the SAF. Summary statistics (number of observations, mean, SD,
median, minimum and maximum values) will be presented for continuous variables, and 
number and percentages (n, %) will be presented for categorical variables. Where applicable, 
changes from Baseline will also be summarised over time.
Treatment-emergent adverse events will be summarised by preferred term and system organ 
class and classified according to the latest version of coded Medical Dictionary for Regulatory 
Activities (MedDRA). The number and percentage of TEAEs will be summarised by system 
organ class and preferred term in the SAF. Treatment-emergent adverse events will be further 
summarised with respect to severity and relationship to IMP. Treatment-emergent adverse 
events related to IMP, leading to withdrawal, serious TEAEs, and deaths will be summarised.

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Clinical laboratory tests (haematology, serum chemistry), ECG, and vital signs will be 
summarised for the SAF at each scheduled assessment. Potentially clinically important 
findings will also be summarised and listed.
The number of patients taking rescue medication (see definition in Section 6.6.1), the amount 
of rescue medication taken and the reason for use will be tabulated and summarised 
descriptively.
9.6
Interim Analyses
No interim analysis will be conducted for any efficacy endpoint.
An unblinded interim safety analysis may be conducted after the first 25 patients have 
completed Visit 4 and Visit 5. No formal statistical tests will be undertaken. Adverse events 
will be summarised descriptively and tabulated for all patients by treatment group (see 
Section 9.5.4). The DMEC will consider the results of the AE summaries when making 
decisions regarding dosing of subsequent cohorts (i.e. need for dose stoppages) or the need for 
formal interim analysis of non-safety data.

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10 ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS
This study will be conducted according to the protocol, European Union clinical trial directive 
(2001/20/EC), ICH E6 (R1), GCP guidelines, and applicable local or regional regulatory 
requirements.
10.1
Data Quality Assurance
The Investigator is required to prepare and maintain adequate and accurate source documents
designed to record all observations and other data pertinent to the study for each study patient.
All information recorded on the eCRF for this study must be consistent with the patients’ 
source documentation (i.e., medical records).
10.1.1 Database!Management!and!Quality!Control
All data generated by the site personnel will be captured electronically at each study centre
using eCRFs. Data from external sources (such as laboratory data and eDiary data) will be 
imported into the database. Once the eCRF clinical data have been submitted to the central 
server at the independent data centre, corrections to the data fields will be captured in an audit 
trail. The reason for change, the name of the person who performed the change, together with 
the time and date will be logged to provide an audit trail. 
If additional corrections are needed, the responsible CRA or data manger will raise a query in 
the eCRF. The appropriate staff at the study site will answer queries sent to the Investigator.
The name of the staff member responding to the query, and time and date stamp will be 
captured to provide an audit trail.
The specific procedures to be used for data entry and query resolution using the eCRF will be 
provided to study sites in an eCRF completion guideline. In addition, site personnel will 
receive training on the eCRF.
10.2
Case Report Forms and Source Documentation
All data obtained during this study should be entered in the eCRF promptly. All source 
documents from which eCRF entries are derived should be placed in the patient’s medical 
records. Measurements for which source documents are usually available include laboratory 
assessments, ECG, MRI scans, and X-rays.
The original eCRF entries for each patient will be checked against source documents at the 
study site by the CRA.
10.2.1 Data!Collection
The Investigators (and appropriately authorised staff) will be given access to an online web/
based eCRF system called DataLabs which is 21 CFR Part 11 compliant. DataLabs is 
specifically designed for the collection of the clinical data in electronic format. Access rights
to the eCRF system will be carefully controlled and configured according to each individual’s 
role throughout the study. In general, only the Investigator and authorised staff will be able to 
enter data and make corrections in the eCRFs.
The eCRF should be completed for each patient included in the study and should reflect the 
latest observations on the patients participating in the study. Therefore, the eCRFs are to be
completed as soon as possible during or immediately after the patient’s visit or assessment. 
The Investigator must verify that all data entries in the eCRF are accurate and correct. If some 
assessments cannot be done, or if certain information is unavailable, not applicable or 
unknown, the Investigator should indicate this in the eCRF.
Computerised data-check programs and manual checks will identify any clinical data 
discrepancies for resolution. Corresponding queries will be loaded into the system and the site 

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will be informed about new issues to be resolved on-line. All discrepancies will be solved on-
line directly by the Investigator or by authorised staff. Off-line edit checks will be done to 
examine relationships over time and across panels to facilitate quality data.
After completion, the Investigator will be required to electronically sign off the clinical data
entered into the eCRF.
10.3
Access to Source Data
During the study, a CRA will make site visits to review protocol compliance, compare eCRF
entries and individual patient’s medical records, assess drug accountability, and ensure that 
the study is being conducted according to pertinent regulatory requirements. eCRF entries 
will be verified with source documentation. The review of medical records will be performed 
in a manner to ensure that patient confidentiality is maintained.
Checking of the eCRF entries for completeness and clarity, and cross-checking with source 
documents, will be required to monitor the progress of the study. Moreover, Regulatory
Authorities of certain countries, IECs, and/or the Sponsor’s Clinical Quality Assurance Group 
may wish to carry out such source data checks and/or on-site audits or inspections. Direct 
access to source data will be required for these inspections and audits; they will be carried out 
giving due consideration to data protection and medical confidentiality. The Investigator
assures PAREXEL and the Sponsor of the necessary support at all times.
10.4
Data Processing
All data will be entered by site personnel into the eCRF (as detailed in Section 10.2.1).
Previous and concomitant medications will be coded using the World Health Organization 
(WHO) Drug Reference List (DRL), which employs the Anatomical Therapeutic Chemical 
(ATC) classification system. Medical history/current medical conditions and adverse events 
will be coded using the MedDRA terminology.
The versions of the coding dictionaries will be provided in the Clinical Study Report.
10.5
Data Monitoring
A Trial Steering Committee (TSC) will be established and will be blinded and responsible for 
providing overall supervision for the study in accordance with pre-agreed terms of reference, 
in particular to the progress of the study, adherence to the protocol and patient safety. 
Operationally this will include consultation regarding the study design, subsequent 
amendments and emerging data and research relevant to the study, including open DMEC 
reports and the results of other research that may have a direct bearing on the future conduct 
of the study. They will also ensure that any action taken protects the rights, safety and 
wellbeing of patients and the study is conducted to the rigorous standards of GCP. It is 
anticipated that the TSC will meet at approximately 6-12 monthly intervals and after each 
independent DMEC review as required. Any SAE will be reported to the DMEC who may 
recommend stopping the study for safety reasons. Interim safety analyses (i.e. no efficacy 
analyses) will be undertaken after the first 25 patients have completed Visit 4 and Visit 5.
The independent DMEC will be set up to monitor study safety which will be specified in a 
DMEC charter. The independent DMEC will be unblinded and will include three members:
an independent chair having specialist osteoarthritis expertise and experience of studies in this 
area, an independent statistician and a second physician. Specifically they will monitor AEs 
and serious SAEs related to the treatments received in accordance with the recommendations 
of performing a clinical study of an IMP. In addition the independent DMEC will make 
recommendations on continuation of the study based on interim safety analyses.

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10.6
Safety Monitoring Plan
A change in the value of a clinical laboratory investigation can represent an AE if the change 
is clinically relevant or if, during treatment with the investigational product, a shift of a 
parameter is observed from a normal value to an abnormal value, or a further worsening of an 
already abnormal value.  When evaluating such changes, the extent of deviation from the 
reference range, the duration until return to the reference range, either while continuing 
treatment or after the EOT with the investigational product, and the range of variation of the 
respective parameter within its reference range, must be taken into consideration.
If, at the end of the treatment phase, there are abnormal clinical laboratory values which were 
not present at Baseline, further clinical or laboratory investigations should be performed until 
the values return to within the reference range or until a plausible explanation (e.g.,
concomitant disease) is found for the abnormal clinical laboratory values.
The Investigator should decide, based on the above criteria and the clinical condition of a 
patient, whether a change in a clinical laboratory parameter is clinically significant and 
therefore represents an AE.
10.7
Archiving Study Records
According to ICH guidelines, essential documents should be retained for a minimum of 
2 years after the last approval of a marketing application in an ICH region and until there are 
no pending or contemplated marketing applications in an ICH region or at least 10 years have 
elapsed since the formal discontinuation of clinical development of the investigational 
product. However, these documents should be retained for a longer period if required by the 
applicable legal requirements.
No essential documents may be destroyed without prior written approval from the Sponsor.
10.8
Good Clinical Practice
The procedures set out in this study protocol are designed to ensure that the Sponsor and 
Investigator abide by the principles of the GCP guidelines of the ICH, and of the Declaration 
of Helsinki (1996). The study also will be carried out in accordance with local legal 
requirements. 
10.9
Informed Consent
Before each patient is admitted to the study, informed consent will be obtained from the 
patient according to the regulatory and legal requirements of the participating country. This 
consent form must be dated and retained by the Investigator as part of the study records. The 
Investigator will not undertake any investigation specifically required only for the clinical 
study until valid consent has been obtained. The terms of the consent and when it was 
obtained must also be documented in the eCRF system.
If a protocol amendment is required, the ICF may need to be revised to reflect the changes to 
the protocol. If the consent form is revised, it must be reviewed and approved by the 
appropriate IEC, and signed by all patients subsequently enrolled in the study as well as those 
currently enrolled in the study.
10.10
Protocol Approval and Amendment
Before the start of the study, the study protocol and/or other relevant documents will be 
approved by the IEC/Regulatory Authorities, in accordance with local legal requirements. The 
Sponsor must ensure that all ethical and legal requirements have been met before the first 
patient is enrolled in the study.

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This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IEC/Regulatory Authority 
approval prior to implementation (if appropriate). Administrative changes (not affecting the 
patient benefit/risk ratio) may be made without the need for a formal amendment. All 
amendments will be distributed to all protocol recipients, with appropriate instructions.
10.11
Duration of the Study
The study will be conducted from September 2016 to August 2017.
10.12
Confidentiality
All study findings and documents will be regarded as confidential. The Investigator and 
members of his/her research team must not disclose such information without prior written 
approval from the Sponsor.
The anonymity of participating patients must be maintained. Patients will be identified in the
eCRF system and other documents submitted to PAREXEL by their patient number and date
of birth, not by name. Documents that identify the patient (e.g., the signed informed consent) 
must be maintained in confidence by the Investigator and should never be submitted to 
PAREXEL or the Sponsor.
10.13
Other Ethical and Regulatory Issues
If a significant safety issue is identified, either from an individual case report or review of 
aggregate data, then the Sponsor will issue prompt notification to all parties – Regulatory 
Authorities, Investigators, and Institutional Review Boards/IECs.
A significant safety issue is one that has a significant impact on the course of the clinical 
study or program (including the potential for suspension of the development program or 
amendments to protocols) or warrants immediate update of informed consent.
10.14
Liability and Insurance
The Sponsor will take out reasonable third-party liability insurance cover in accordance with 
all local legal requirements. The civil liability of the Investigator, the persons instructed by 
him or her and the hospital, practice, or institute in which they are employed and the liability 
of the Sponsor with respect to financial loss due to personal injury and other damage that may 
arise as a result of the carrying out of this study are governed by the applicable law.
The Sponsor will arrange for patients participating in this study to be insured against financial 
loss due to personal injury caused by the pharmaceutical products being tested or by medical 
steps taken in the course of the study.
10.15
Publication Policy
By signing the study protocol, the Investigator agrees with the use of results of the study for 
the purposes of national and international registration, publication and information for 
medical and pharmaceutical professionals. If necessary, Regulatory Authorities will be 
notified of the Investigator's name, address, qualifications and extent of involvement.
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted with the sponsor in advance.

Sponsor Name
Clinical Study Protocol
MIV-711-202
CONFIDENTIAL
Final
65 of 69
01 July 2016
11 REFERENCE LIST
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Clinical Study Protocol
MIV-711-202
CONFIDENTIAL
Final
66 of 69
01 July 2016
20
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30
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31
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35
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39
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41
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Sponsor Name
Clinical Study Protocol
MIV-711-202
CONFIDENTIAL
Final
67 of 69
01 July 2016
42
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Sponsor Name
Clinical Study Protocol
MIV-711-202
CONFIDENTIAL
Final
68 of 69
01 July 2016
12 APPENDICES

Sponsor Name
Clinical Study Protocol
MIV-711-202
CONFIDENTIAL
Final
69 of 69
01 July 2016
12.1
APPENDIX 1: Total Blood Volumes
The total volume of blood that will be drawn from each patient in this study is as follows:
Assessment
Sample 
Volume 
(mL)
No of 
samples
Total 
Volume 
(mL)
Safety 
•
Clinical chemistry
9.5
6
57
•
Haematology
2
6
12
Pharmacokinetic samples
5
3
15
Blood samples for pharmacogenomics, 
proteomics, genomics, metabolomics and 
lipidomics
19
1
19
Biomarker analysis
15
4
60
Additional unforeseeable samples
37
Total
200