Conditions: Osteoarthritis, Knee
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 244
Healthy volunteers: no

Brief summary:
This is a multicentre, randomised, placebo-controlled, double-blind, three-arm parallel, Phase IIa study to evaluate the efficacy, safety and tolerability of MIV-711 in patients with knee osteoarthritis (OA).

Detailed description:

Arms:
arm 1: MIV-711 for a total of 26 w arm 2: MIV-711 for a total of 26 w arm 3: Placebo for a total of 26 w

Interventions: intervention 1: MIV-711 intervention 2: Placebo
Intervention descriptions: intervention 1: MIV-711 administered orally once daily intervention 2: Placebo manufactured to mimic MIV-711 capsule.

Protocol document:
Prot_000.pdf: 
 
 
A Randomised, Double-blind Placebo-controlled Phase IIa Study to 
Evaluate Efficacy, Safety and Tolerability of MIV-711 in 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-711-201 
EudraCT No.: 
2015-003230-26 
Study Drug Name: 
MIV-711 
Development Phase: 
Phase IIa 
Date of Protocol: 
20 July 2016  
Date of Previous Protocols: 
09 September 2015 (original) 
13 January 2016 (Version 2, Amendment 1) 
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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SIGNATURE PAGE 
 
Declaration of Sponsor or Responsible Medical Officer 
Title: A Randomised, Double-blind Placebo-controlled Phase IIa Study to Evaluate Efficacy, 
Safety and Tolerability of MIV-711 in Knee Joint Osteoarthritis 
 
This study protocol was subjected to critical review. The information it contains is consistent 
with current knowledge of the risks and benefits of the investigational product, as well as with 
the moral, ethical, and scientific principles governing clinical research as set out in the 
Declaration of Helsinki, 1996 and the guidelines on GCP. 
 
 
 
_____________________________________ 
_____________________ 
John Öhd, MD PhD 
Date 
Director Clinical R&D 
Medivir AB 
 
 


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Declaration of the National Coordinating Investigator 
Title: A Randomised, Double-blind Placebo-controlled Phase IIa Study to Evaluate Efficacy, 
Safety and Tolerability of MIV-711 in Knee Joint Osteoarthritis 
 
This study protocol was subjected to critical review and has been approved by the Sponsor. 
The information it contains is consistent with the current risk/benefit evaluation of the 
investigational product as well as with the moral, ethical, and scientific principles governing 
clinical research as set out in the Declaration of Helsinki, as amended in 1996 and the 
guidelines on GCP. 
 
 
 
National Coordinating Investigator 
 
 
 
 
Signature 
Date 
 
 
PHILIP CONAGHAN 
 
Name (block letters) 
 
 
 
PROFESSOR 
 
Title (block letters) 
 
 
 
LEEDS INSTITUTE OF RHEUMATIC AND MUSCULOSKELETAL MEDICINE 
Institution (block letters) 
 
 
UNITED KINGDOM 
 
Country 
 
 
 
 


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Declaration of the Investigator 
Title: A Randomised, Double-blind Placebo-controlled Phase IIa Study to Evaluate Efficacy, 
Safety and Tolerability of MIV-711 in 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), subject 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 subjects. 
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 center 
 
 
 
 
 
Signature 
Date 
 
 
 
 
Name (block letters) 
 
 
 
 
 
Title (block letters) 
 
 
 
 
Institution (block letters) 
 
 
 
 
Country 
 


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PROTOCOL SYNOPSIS 
Title 
A Randomised, Double-blind Placebo-controlled Phase IIa Study to 
Evaluate Efficacy, Safety and Tolerability of MIV-711 in Knee 
Joint Osteoarthritis 
Sponsor Study No. 
MIV-711-201 
Phase 
Phase IIa 
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 
Six sites distributed in 6 European countries. 
1) University of Leeds, Leeds Institute of Rheumatic and 
Musculoskeletal Medicine, Chapel Allerton Hospital, 
Chapeltown Road, Leeds LS7 4SA, United Kingdom 
2) PAREXEL Berlin Early Phase Clinical Unit, PAREXEL 
International GmbH, Spandauer Damm 130, 14050 Berlin, 
Germany 
3) MC Comac Medical, 13 Urvich Str, 1612 Sofia, Bulgaria 
4) LLC ARENSIA Exploratory Medicine, Research Institute of 
Clinical Medicine, 13a, Tevdore Mgvdeli Str. 0112 Tbilisi, 
Georgia 
5) LLC ARENSIA Exploratory Medicine, Republican Clinical 
Hospital, 29 Testemitanu Str. 2025 Chisinau, 
Republic of Moldova 
6) SC ARENSIA Exploratory Medicine SRL 
Colentina Clinical Hospital, Spitalul Clinic Colentina Pavilion 
K, etaj III Sos. Stefan cel Mare Nr. 19-21, 
Sector 2 Bucharest 020125, 
Romania 
Objective 
To assess the effect of MIV-711 on knee pain (week 26), as 
measured by an 11-point numerical rating scale in patients with 
symptomatic and radiographic knee osteoarthritis 
Design 
This is a multicentre, randomised, placebo-controlled, double-blind, three-arm parallel, 
Phase IIa study to evaluate the efficacy, safety and tolerability of MIV-711 in patients with 
symptomatic and radiographic knee osteoarthritis (OA). 
A total of 240 patients with knee OA meeting the eligibility criteria and who provide 
written informed consent will be randomised on a 1:1:1 basis to the intervention (MIV-711 
low dose 100 mg or high dose 200 mg) or placebo. 
 


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Patients who are eligible and agree to continue with the study will return for the baseline 
visit within 30 days of the screening visit. 
After baseline assessments have been completed, patients will be randomised in a 1:1:1 
ratio via a central secure 24-hour randomisation service to the intervention (MIV-711) arms 
or the placebo-controlled arm. The study will include 26 weeks of treatment, with patients 
followed for a total of 30 weeks as per Study procedure. Study visits for clinical assessment 
and questionnaires will occur at visit 2 (baseline) and visit 5 and at visit 6 and visit 8, 
regardless of treatment group. Patients will have a magnetic resonance imaging (MRI) of 
the target knee at visit 2 (baseline) and visit 8. 
Main study visits for efficacy and safety will occur at visit 2 (baseline), visit 5, visit 6 and 
visit 8. At these visits, patients will undergo a full physical examination (target examination 
only at visit 3, visit 4 and visit 7) and vital signs will be recorded. Full haematology and 
biochemistry panels, parathyroid hormone and urinalysis will be performed at all visits. 
Additional biological sub study samples (blood/urine) will be taken at these visits for 
assessment of the biomarker response to MIV-711. Knee MRI (of the worst/target knee) 
will be undertaken at visit 2 (baseline) and visit 8. Patient-reported outcomes will be 
recorded at visit 2 (baseline), visit 5, visit 6 and visit 8. First dose will be initiated following 
completion of all baseline assessments and following randomisation. 
Additional clinic visits for safety will be conducted at visit 3 and visit 4 and at visit 7 and 
visit 9. At these visits, patients will undergo a targeted physical examination, vital signs 
will be recorded, clinical laboratory samples assessed and an ECG conducted. Patients will 
be questioned about the occurrence of any adverse events since the last study visit. At the 
final visit 9, knee pain will be assessed using a numeric rating scale (NRS) to determine any 
carry-over effects of the investigational medicinal product (IMP) post-cessation of dosing. 
Follow-up telephone calls to assess safety and tolerability will occur 5-9 days after visit 2, 
visit 3, visit 4, visit 5, visit 6, and visit 7. 
In addition to the normal visit schedule, unscheduled visits will be undertaken if the patient 
is unwell or there are any concerns as to the progress. Patient visits will be considered valid 
if they take place within ±2 days of the scheduled day for the visit 4 and visit 5 and within 
±7 days of the scheduled day for visit 6, visit 7, visit 8, and visit 9, but will revert to the 
original schedule for the next visit. 
Patients will be followed for 30 weeks in total, including 4 weeks after the dosing period, 
when final safety checks will be made. 
A patient pain diary and analgesia questionnaire will be completed in an e-diary format 
daily during three two-week periods before visit 2 (baseline), visit 6 and visit 8. 
The end of the study is defined as the last visit (visit 9, week 30) of the last patient or, if 
applicable, when the last patient has rolled over to study MIV-711-202 and having finalized 
visit 2 of that study. 
 
Treatment 
Patients will receive a once-daily 100 mg or 200 mg oral dose of 
MIV-711, or placebo for 26 weeks in addition to their current 
medication. 
Number of Patients A total of 240 patients  
MIV-711 100 mg: 80 patients 
MIV-711 200 mg: 80 patients 
Placebo: 80 patients 
Population 
The study population is defined as knee OA patients with chronic 
pain and Kellgren and Lawrence classification grade (K-L) ≥2 or 3. 
 
 


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Criteria for inclusion and exclusion 
Inclusion: 
1. Current average knee pain, defined as pain in either knee, within 1 week before visit 1, 
for which the patient gives a severity score of ≥4, <10 on a 0-10 NRS. 
2. Inclusive of 40-80 years old. 
3. Diagnosis of primary knee osteoarthritis, based upon the following: 
• Fulfilling the American College of Rheumatology Clinical and Radiographic (ACR) 
criteria for OA defined as knee pain for most days of the prior month and at least one 
of the following three factors: age >50 years, morning stiffness of less than 30 
minutes and knee crepitus on motion. 
• X-ray evidence within the last 12 months for Kellgren and Lawrence (K-L) 
classification grade 2 or 3. 
4. 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 amenorrhoic 
for 12 months without an alternative medical cause and with a screening follicle 
stimulating hormone indicating a post-menopausal state. 
5. 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). 
6. The patient’s usual analgesic regimen (in case of use) should remain the same for 
4 weeks prior to signature of the informed consent form. 
7. Needs to be able to communicate well with the investigators and staff. 
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: 
1. The presence of any inflammatory arthritis (e.g., gout, reactive arthritis, rheumatoid 
arthritis, psoriatic arthritis, seronegative spondylarthropathy) or any underlying 
condition, other than osteoarthritis, 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. A history of cancer within the previous 5 years (except for cutaneous basal-cell or 
squamous-cell cancer resolved by excision and cancer in situ which are allowed). 
4. Ongoing or a history of atrial fibrillation. 
5. Currently receiving medication that affects cartilage or bone metabolism (hormone 
replacement therapy taken for more than 6 months is allowed). 
6. Current or recurrent disease that could affect the action, absorption or disposition of 
MIV-711, or could affect clinical assessments or clinical laboratory assessments. 
7. 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. 
8. Known or suspected intolerance or hypersensitivity to the investigational product, 
closely related compounds, or any of the stated ingredients. 
9. A positive human immunodeficiency virus (HIV) antibody screen, a positive Hepatitis 
B surface antigen (HBsAg) screen, and/ or a positive Hepatitis C virus (HCV) antibody 
screen. A positive total Hepatitis B core antibody (anti-HBc) test in conjunction with a 
negative antibody to Hepatitis B Surface Antigen (anti-HBs) test. 
10. History of alcohol or other substance abuse within the last year. 
11. Use of an investigational product within 4 weeks prior to receiving the first dose of 
investigational product or active enrolment in another drug or vaccine clinical study. 
12. Significant target knee injury or surgery within the 6 months preceding enrolment in the 
study. 
13. 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. 
14. 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 venipuncture or lack of 
adequate venous access for required blood sampling during the study period). 
15. Use of intra-articular hyaluronic acid in the target knee within the 3 months preceding 
enrolment in the study. 
16. Use of intra-articular, intra-muscular or oral corticosteroids in the 2 months preceding 
enrolment. 
17. Commencement of non-pharmacological OA interventions within two months 
preceding enrolment. 
18. 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. 
19. Patients with contra-indication to MRI of the knee. 
 


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Outcome variables 
Efficacy: 
Primary efficacy endpoint: 
• Change from visit 2 (baseline) to visit 8 in NRS average target knee pain score  
Key secondary efficacy endpoint: 
• Change from visit 2 (baseline) to visit 8 in knee joint MRI bone area 
Secondary efficacy endpoints: 
• Change from visit 2 (baseline) to visit 8 in NRS worst target knee pain score 
• Change from visit 2 (baseline) to visit 8 in NRS average contralateral knee pain score 
• Change from visit 2 (baseline) to visit 8 in constant and intermittent OA pain 
• Change from visit 2 (baseline) to visit 8 in knee joint OA symptoms; WOMAC 
(function, pain, stiffness) 
• Change from visit 2 (baseline) to visit 8 in global disease activity 
• Change from visit 2 (baseline) to visit 8 in global improvements in knee problem, 
knee pain and knee function 
• Change from visit 2 (baseline) to visit 8 in quality of life (QOL) 
• Change from visit 2 (baseline) to visit 8 in MRI bone marrow lesion volume 
• Change from visit 2 (baseline) to visit 8 in MRI cartilage thickness loss 
• Change from visit 2 (baseline) to visit 8 in the semi quantitative MRI Osteoarthritis 
Knee Score (MOAKS) parameters  
• Change from visit 2 (baseline) to visit 8 in patient-reported e-diary daily recall knee 
joint pain 
• Change from visit 2 (baseline) to visit 8 in patient-reported e-diary daily recall 
analgesics use 
• Changes from visit 2 (baseline) to visit 8 in serum biomarkers C-terminal telopeptide 
of collagen type I (sCTX-I for bone resorption assessment) and urinary C-terminal 
telopeptide of collagen type II (uCTX-II for cartilage degradation assessment) 
•  
Exploratory endpoints: 
• Changes from visit 2 (baseline) to visit 8 in the serum and urinary biomarkers 
(Procollagen type I N-terminal propeptide [sPINP], bone specific alkaline 
phosphatase [sBSAP], N-terminal telopeptide of collagen type I [uNTX-I], uCTX-I, 
uαCTX-I and Tartrate-resistant acid phosphatase 5b [sTRAP5b]) 
• Pharmacokinetics: MIV-711 Pharmacokinetic (PK) parameters and their relationship 
to covariates such as age, weight, gender, liver function and concomitant 
medications. 
• Change from visit 2 (baseline) to visit 8 in compound index of MRI bone area and 
cartilage thickness 
Safety: 
Safety endpoints: 
• Incidence and severity of adverse events  
• Incidence and severity of clinical laboratory abnormalities 
• Summary of changes in physical examination compared to baseline by patient 
• Mean change from visit 2 (baseline) in vital signs (blood pressure, heart rate and 
temperature) 


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• Categorical summary of absolute vital signs and vital sign changes compared to 
visit 2 (baseline) by patient 
Statistical Methods 
Primary Efficacy analysis 
Change from baseline in NRS pain score will be analysed using a linear mixed model 
analysis based on the full analysis set (FAS) (modified intention to treat [mITT]). Only 
post-baseline NRS values will be used as the dependent variables. Baseline NRS will be 
included as a covariate. The model will include treatment group, baseline value, chronic 
analgesic use, minimization factors, week and week treatment group interaction as fixed 
effects and site as random effect. Development over time will be summarised by graphs 
(Least square means [LSmeans] and 95%-confidence limits as appropriate). 
Secondary Efficacy analysis 
All analyses of secondary endpoints will be conducted using same statistical model as 
specified in the primary efficacy analysis, adjusting for the same covariates as the primary 
analysis. The mITT population will be used for all secondary analyses.  
Secondary efficacy endpoints recorded at visit 2 (baseline) and visit 8 will be analysed 
using an analysis of covariance (ANCOVA). The model will include treatment group, 
baseline value, chronic analgesic use, minimization factors and site. Least square means 
(LSmeans) and the estimate of the difference between the treatment groups will be provided 
along with a 95% confidence interval (CI) and p-value. In the analysis of biomarkers that 
are sampled at multiple visits, all sampled time points will be considered for change from 
baseline and comparison to placebo in the respective cases. 
All secondary outcomes will be summarised descriptively (mean, standard deviation [SD], 
median, minimum and maximum for continuous data and counts and percentages for 
categorical data). 
For the analysis of all primary and secondary efficacy 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. 
Exploratory analysis 
The exploratory analysis of additional bone and cartilage biomarkers, PK and imaging 
above are not part of the statistical analysis set and will therefore be listed and may 
therefore be reported separately. 
The biological samples used for possible exploratory analysis (above) 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. 
Safety analysis 
Safety summaries will be presented by treatment group and scheduled assessment for the 
Safety Analysis Set (SAF). Summary statistics (number of observations, mean, standard 
deviation, median and minimum and maximum values) will be presented by treatment 
group for continuous variables, and number and percentages (n, %) will be presented by 
treatment group for categorical variables. Treatment-emergent adverse events (TEAEs) will 
be summarised according to the coded Medical Dictionary for Regulatory Activities 
(MedDRA), preferred term and system organ class.  
Clinical laboratory tests (hematology, serum chemistry, ECG and vital signs) will be 
summarised by treatment group for the SAF at each applicable scheduled assessment for 
the SAF. Potentially clinically important findings will be summarised by treatment group 
and listed. 


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No formal interim analysis to allow early stopping of the study on the basis of 
demonstrating efficacy or futility is planned. Unblinded Interim safety analyses (i.e. no 
efficacy analyses) will be undertaken after 50, 100, 150 and 200 patients have completed 
visit 6. 


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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 ................................................................................... 12 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS .............................. 16 
1 
INTRODUCTION ............................................................................................... 19 
1.1 
Abstract ........................................................................................................... 19 
1.2 
Background ..................................................................................................... 19 
1.3 
Pharmacokinetic, Pharmacodynamic and Safety results from MIV-711 
first in man study ............................................................................................ 20 
1.4 
Study rationale ................................................................................................ 21 
1.5 
Study design rationale .................................................................................... 21 
1.6 
Dosing rationale .............................................................................................. 22 
1.7 
Risk-Benefit Assessment ................................................................................ 23 
2 
STUDY OBJECTIVES ....................................................................................... 25 
2.1 
Primary Objective .......................................................................................... 25 
2.2 
Key Secondary Objective ............................................................................... 25 
2.3 
Secondary Objectives ..................................................................................... 25 
2.4 
Exploratory Objectives .................................................................................. 25 
3 
OVERALL DESIGN AND PLAN OF THE STUDY ....................................... 26 
4 
STUDY POPULATION ...................................................................................... 27 
4.1 
Inclusion Criteria ............................................................................................ 27 
4.2 
Exclusion Criteria ........................................................................................... 28 
4.3 
Patient Withdrawal and Replacement .......................................................... 30 
4.4 
Planned Sample Size and Number of Study Centers .................................. 31 
4.5 
Patient Identification and Randomization ................................................... 31 
4.5.1 
Patient Identification ........................................................................... 31 
4.5.2 
Randomisation Scheme ....................................................................... 31 
4.5.3 
Allocation/Randomisation of Patients to Treatment ........................... 31 
4.5.4 
Procedures for Handling of Incorrectly Included Subjects ................. 31 
4.6 
Extension Protocol .......................................................................................... 32 
5 
STUDY DRUG ..................................................................................................... 33 
5.1 
Investigational Drug ....................................................................................... 33 
5.2 
Administration ................................................................................................ 33 
5.3 
Packaging, Labeling and Storage .................................................................. 33 
5.4 
Drug Accountability ....................................................................................... 34 
5.5 
Blinding and Breaking the Blind ................................................................... 34 
5.6 
Compliance ...................................................................................................... 34 
5.7 
Other Medications .......................................................................................... 35 
5.7.1 
Rescue Medication .............................................................................. 35 
5.7.2 
Concomitant Medications ................................................................... 35 
5.7.3 
NSAIDs and other analgesics .............................................................. 35 
5.7.4 
Prohibited concomitant medications ................................................... 35 
5.7.5 
Chondroitin and glucosamine .............................................................. 36 
5.8 
RESTRICTIONS ............................................................................................ 36 
6 
ENDPOINT AND METHODS OF ASSESSMENT ......................................... 37 


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6.1 
Efficacy Endpoint ........................................................................................... 37 
6.1.1 
Primary Efficacy Endpoint .................................................................. 37 
6.1.2 
Key Secondary Endpoint ..................................................................... 37 
6.1.3 
Secondary Imaging Endpoints ............................................................ 37 
6.1.4 
Secondary Endpoints ........................................................................... 38 
6.1.5 
Exploratory Endpoints ......................................................................... 39 
6.1.5.1 
Biomarkers and biobanking .......................................................... 39 
6.1.5.2 
Imaging .......................................................................................... 39 
6.1.5.3 
Pharmacokinetics .......................................................................... 39 
6.2 
Safety Endpoints ............................................................................................. 39 
6.3 
Physical Examination ..................................................................................... 40 
6.4 
Vital Signs ........................................................................................................ 40 
6.5 
12-lead Electrocardiograms (ECG) .............................................................. 40 
6.6 
Imaging Assessments ...................................................................................... 40 
6.6.1 
K-L Scoring ......................................................................................... 40 
6.6.2 
MRI Assessments ................................................................................ 40 
6.7 
Self-report Parameters ................................................................................... 41 
6.8 
Pharmacokinetics Sampling .......................................................................... 42 
6.9 
Biomarker Sampling ...................................................................................... 43 
6.10 
Optional Pharmacogenomics Sampling ....................................................... 43 
6.11 
Adverse Events ................................................................................................ 43 
6.11.1 
Definitions of Adverse Events (AEs) .................................................. 43 
6.11.2 
Assessment of Adverse Events ........................................................... 44 
6.11.2.1 
Seriousness .................................................................................... 44 
6.11.2.2 
Intensity ......................................................................................... 44 
6.11.2.3 
Causality ........................................................................................ 44 
6.11.2.4 
Adverse Events of Special Interest ................................................ 44 
6.11.2.5 
Recording Adverse Events ............................................................. 45 
6.11.2.6 
Reporting Serious Adverse Events ................................................ 45 
6.11.2.7 
Follow-up of Adverse Events ......................................................... 46 
6.11.2.8 
Suspected Unexpected Serious Adverse Reactions ....................... 46 
6.11.2.9 
Pregnancy ...................................................................................... 46 
6.11.2.10 Abuse, Misuse, Overdose or Medication Error ............................. 47 
7 
STUDY CONDUCT ............................................................................................ 48 
7.1 
Study Schedule ................................................................................................ 48 
7.1.1 
Screening Visit (Visit 1, Day -30) ....................................................... 48 
7.1.2 
Randomisation/Baseline (Visit 2, Day 1) ............................................ 48 
7.1.3 
Safety Visit (Visit 3 [Week 2 ± 2], Visit 4 [Week 4 ± 2] and Visit 7 
[Week 20 ± 7 days]) ............................................................................ 49 
7.1.4 
Treatment visit (Visit 5 [Week 8 ± 2], Visit 6 [Week 14 ± 7 days], and 
Visit 8 [Week 26 ± 7 days]) ................................................................ 49 
7.1.5 
Safety Follow-up Visit (Visit 9, Week 30 ± 7 days) ........................... 50 
7.2 
Early Termination Visit ................................................................................. 56 
7.3 
Discontinuation of the study .......................................................................... 56 
8 
STATISTICAL METHODS............................................................................... 57 
8.1 
Study Patients ................................................................................................. 57 
8.1.1 
Disposition of Patients ........................................................................ 57 
8.1.2 
Protocol Deviations ............................................................................. 57 
8.1.3 
Analysis Set ......................................................................................... 57 


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8.2 
General Consideration ................................................................................... 58 
8.3 
Demographics, Medical History, Baseline Characteristics, and 
Concomitant Medications .............................................................................. 58 
8.4 
Treatment Compliance .................................................................................. 58 
8.5 
Statistical Methodology .................................................................................. 59 
8.5.1 
Hypothesis to be Tested ...................................................................... 59 
8.5.2 
Efficacy ............................................................................................... 59 
8.5.2.1 
Statistical Methodology for Primary Efficacy Endpoints ............. 59 
8.5.2.2 
Statistical Methodology for Secondary Efficacy Endpoints .......... 59 
8.5.2.3 
Statistical Methodology for Exploratory Endpoints ...................... 60 
8.5.3 
Safety ................................................................................................... 60 
8.6 
Interim Analyses ............................................................................................. 60 
8.7 
Sample Size and Sample Size Calculation .................................................... 60 
8.7.1 
Primary Endpoint consideration .......................................................... 60 
8.7.2 
Key Secondary Endpoint power consideration ................................... 61 
9 
ETHICAL, LEGAL, AND ADMINISTRATIVE ASPECTS .......................... 62 
9.1 
Data Quality Assurance ................................................................................. 62 
9.1.1 
Database Management and Quality Control ....................................... 62 
9.2 
Case Report Forms and Source Documentation ......................................... 62 
9.2.1 
Data collection ..................................................................................... 62 
9.3 
Access to Source Data..................................................................................... 63 
9.4 
Data Processing ............................................................................................... 63 
9.5 
Data Monitoring ............................................................................................. 63 
9.6 
Safety Monitoring Plan .................................................................................. 64 
9.7 
Archiving Study Records ............................................................................... 64 
9.8 
Good Clinical Practice ................................................................................... 64 
9.9 
Informed Consent ........................................................................................... 64 
9.10 
Protocol Approval and Amendment ............................................................. 65 
9.11 
Duration of the Study ..................................................................................... 65 
9.12 
Confidentiality ................................................................................................ 65 
9.13 
Other Ethical and Regulatory Issues ............................................................ 65 
9.14 
Liability and Insurance .................................................................................. 65 
9.15 
Publication Policy ........................................................................................... 65 
10 
REFERENCE LIST ............................................................................................ 67 
11 
APPENDICES ..................................................................................................... 70 
11.1 
APPENDIX 1,Total Blood Volumes ............................................................. 71 
 
Tables in Text 
Table 1: Clinical Laboratory Testing .............................................................................. 50 
Table 2: Study Schedule ................................................................................................. 52 
Figure in Text 
Figure 1: Schematic of study design ................................................................................ 26 
 
List of Appendix 
• Total blood volumes  
 


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LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
The following abbreviation and special terms are used in this Clinical Study Protocol. 
ACLT 
Anterior cruciate ligament transection  
ACR 
American College of Rheumatology 
AE 
Adverse event 
ANCOVA 
Analysis of covariance 
Anti-HBc 
Total Hepatitis B core antibody 
Anti-HBs 
Antibody to Hepatitis B Surface Antigen 
AST 
Aspartate aminotransferase 
AUC0-24h 
Area under the concentration-time curve from zero to 24 hours 
AUC∞ 
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 
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 
EDC 
electronic data capture 
ECG 
Electrocardiogram 
EMA 
European Medicines Agency 
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 
FAS 
Full analysis set 
FTIM 
First time in man 
FSE 
Fast spin echo 
GCP 
Good Clinical Practice 
HADS 
Hospital Anxiety and Depression Scale 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 


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IB 
Investigator’s brochure 
ICF 
Informed consent form 
ICOAP 
Intermittent and constant osteoarthritis pain 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
JSN 
Joint space narrowing 
K-L grade 
Kellgren and Lawrence grade 
LSmeans 
Least square means 
M1 
MIV-711 metabolite MV078617 
M2 
MIV-711 metabolite MV077555 
MedDRA 
Medical Dictionary for Regulatory Activities 
MF 
Medial femoral 
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 
OAQoL 
Osteoarthritis Quality of Life questionnaire  
OARSI 
Osteoarthritis Research Society International 
OD 
Once-daily 
OMERACT 
Outcome Measures in Rheumatoid Arthritis Clinical Trials 
OP 
Osteoporosis 
OVX 
Ovariectomy 
PD 
Proton density 
PINP 
Procollagen type I N-terminal propeptide 
PK 
Pharmacokinetic 
PPS 
Per-Protocol Set 
PRO 
Patient-reported outcomes 
QoL 
Quality of Life 
QTcF 
QTc interval (Fridericia’s correction) 


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SAE 
Serious adverse event 
SAF 
Safety analysis set 
SAP 
Statistical analysis plan 
sBSAP 
serum Bone specific alkaline phosphatase 
SD 
Standard Deviation 
sPINP 
serum Procollagen type I N-terminal propeptide 
sCTX-I 
serum C-terminal telopeptide of collagen type I 
sTRAP5b 
serum Tartrate-resistant acid phosphatase 5b 
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 
t1/2 
half-life time 
uα CTX-I 
Urine α C-terminal telopeptide of collagen type I 
uCTX-I 
urine C-terminal telopeptide of collagen type I 
uCTX-II 
Urine C-terminal telopeptide of collagen type II 
ULN 
Upper limit of normal 
uNTX-I 
urine N-terminal telopeptide of collagen type I 
WOMAC 
Western Ontario and McMaster Universities Osteoarthritis Index 
 
 


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1 
INTRODUCTION 
1.1 
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. MIV-711 
has now completed Phase I and the intention is to conduct a three-arm 240 patient, 6 month, 
Phase IIa, randomised, placebo-controlled study to determine the efficacy of MIV-711 in 
treating painful, radiographic knee OA, both in terms of symptoms and structural progression. 
1.2 
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 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 


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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 
reduction of CTX-I and CTX-II in blood and urine are used as indicators of reduced bone 
resorption and collagen 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 (ACLT). [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 1.3 and in dosing 
rationale section), 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 further detailed in the Investigator’s brochure (IB). 
1.3 
 Pharmacokinetic, Pharmacodynamic and Safety results from MIV-711 first in 
man study 
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 (OD) for 7 days and in healthy post-menopausal female volunteers at multiple 
doses of 100 mg OD for 28 days. The single dose part enrolled 18 males and 9 females with 
the age range 19-64 years. The multiple dose parts enrolled 15 males and 24 females with the 
age range 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 (AUC∞) of MIV-711. The mean terminal half-life (t½) was 3.3 to 
5.2 hours over the 20 to 200 mg dose range. Observed maximum measured plasma 
concentration (Cmax) and AUC∞ increased in close proportion to dose over the single dose 
range 100-600 mg. Following multiple oral administration of 50 to 200 mg OD for 7 days or 


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100 mg OD 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 AUC∞ 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 (see further section 1.6 and the IB). 
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 routine 
ECG to have asymptomatic atrial fibrillation after 3 OD 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. 
1.4 
Study rationale 
As stated in section 1.2, there are no 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 and animal models demonstrate reduced structural joint degradation. This 
first in patient study has the potential to establish a first indication of disease modifying 
efficacy for MIV-711 in OA and as such constitutes a first step to addressing a major unmet 
medical need. 
1.5 
Study design rationale 
Since OA is a chronic, lifelong disorder of slow joint deterioration, disease modifying 
treatments would be expected to counteract the gradual structural worsening over longer 
periods of time which in turn makes a parallel design necessary. At the same time, the 
expected treatment lengths for efficacy in the clinical setting constitute one of two important 
limitations for early development OA patient in disease modifying osteoarthritis drug 
(DMOAD) trials. The second limitation is constituted by the long response time and poor 
sensitivity of presently used joint structure measures. Joint space narrowing (JSN) attenuation 
together with analgesic/symptom efficacy are currently requirements for putative structure 
modifying therapies in OA  in that an analgesic effect could be expected to be concomitant to 
structural improvement (note the present study is not for pivotal purposes).[35] 
It has been shown that previous studies employing either JSN-or magnetic resonance imaging 
(MRI-based cartilage thickness endpoints), require at least 300 patients/arm to have sufficient 
powered (Bowes et al. already in ref list) with treatment lengths of 12 months or more. This 
makes a limited size Proof of Concept (PoC) type study impossible with the associated 
difficulty in transitioning from Phase I to Phase II for a new entity drug in this indication.  
Considering what is described above, pain has been chosen as the primary endpoint of this 
6-month study since it could be expected to be an earlier read-out than the mentioned typical 
radiological endpoints, as well as being less demanding in terms of sample size. In order to 
get the possibility for a joint structural read-out, none of the typical radiological endpoints 


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would provide reliable data considering the sample size and treatment length of the present 
study. Instead, as key secondary endpoint this design employs an innovative and potentially 
more sensitive MRI joint bone surface measurement (see sections 6.1.2).[23] MRI bone 
surface measurements are untried in the interventional setting, but epidemiological data 
suggests a sensitivity of measure that in fact is sufficient for the present sample size.[23] 
The suggested future application of MIV-711 in OA is that of a disease modifying drug which 
will be assessed in the present study as efficacy on knee joint pain and MRI joint structure as 
outlined above, which in turn governs the population selection rationale. The patients who 
enter this study therefore need to have a clinically significant chronic OA knee pain which is 
included on the basis of average pain symptoms ≥4 on the numeric rating scale (NRS) as well 
as a manifest radiographic OA expressed as K-L grade 2-3.[36] K-L grade 1 is excluded due 
to the very mild type of OA changes and long progression time that are indicative of this 
grade, whereas K-L grade 4 is judged to be too far along for the study of disease modification 
at least in the time frame of this study. 
1.6 
Dosing rationale 
The single dose ranges of 20-600 mg and multiple dose ranges 50-200 mg MIV-711 given 
OD for 7 days have been explored in healthy volunteers. In addition, the 100 mg dose was 
administered OD 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. At 200 mg OD, AUC0-24 was on average 2.4 µM*h, i.e. 6 times 
lower than the no observed adverse effect level (NOAEL) in the 6 months monkey study. 
Based on data from other bone acting agents (as described below), it is hypothesised that 
higher doses of bone-modifying agents may be required to achieve cartilage protection in OA 
compared to treatment of osteoporosis (OP).  
• 
It has been shown that the bisphosphonate alendronate produces bone-protective effects in 
the ovariectomised (OVX) rat model (a model of estrogen-deficient OP) at relatively low 
doses, while higher doses are required to produce cartilage protective effects in the rat 
ACLT model (a model of OA). Briefly, 30 µg/kg/week alendronate (which is close to the 
clinical dose of 70 mg/week for OP) was sufficient to protect against bone loss in OVX-
rats [37] while only providing mild cartilage-protective effects in ACLT rats. [38] By 
contrast, 240 µg/kg/week alendronate was required for optimal cartilage protection and 
prevention of osteophyte formation. [38] 
• 
A similar pattern was found when using the cathepsin K inhibitor L-006235 in rabbit 
models of OP and OA. An oral dose of 10 mg/kg L-006235, given OD, provided complete 
bone protection in OVX-rabbits while a dose of 50 mg/kg was required to provide 
cartilage protection in ACLT-rabbits. [32,39] 
• 
Similar findings have been demonstrated with strontium ranelate. A dose of 
625 mg/kg/day was sufficient for bone protection in rats with or without OVX-evoked 
OP. [40] However, in an animal model of OA (medial meniscal tear, MMT), a dose of 
1800 mg/kg/day was required to reduce subchondral bone remodelling and prevent 
articular cartilage degeneration.[41] 
In summary, data from preclinical models indicate that higher doses of alendronate, strontium 
ranelate and the cathepsin K inhibitor L-006235 are required in order to achieve cartilage 
protection in OA compared to the treatment of OP. 
While serum CTX-I levels are primarily a marker of bone resorption, urine CTX-II levels 
reflect cartilage degradation. In the clinical study MIV-711 reduced serum CTX-I levels were 


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observed in a dose-dependent manner by up to 79% after single doses of 20-600 mg, and by 
up to 55% after multiple (7 days) doses of 50-200 mg, compared to baseline. The effects were 
statistically significant at all dose levels, compared to placebo. The effect on CTX-I was 
closely related to the MIV-711 plasma concentrations. For CTX-II a dose-dependent decrease 
in urinary excretion after 7 days of dosing was observed. The mean decrease was 31%, 58% 
and 72% in subjects receiving 50, 100 and 200 mg MIV-711, respectively, compared to 
baseline, and the effects were statistically significant compared to placebo. After 28 days 
dosing at 100 mg OD the mean decrease was 67% for serum CTX-I and 55% for urine 
CTX-II compared to baseline. 
MIV-711 has shown a higher reduction in CTX-II excretion at 200 mg compared with 100 mg 
OD. Based on the established link in literature and preclinical models, 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 above and section 1.2), it is judged that the 200 mg dose 
should be studied in addition to the 100 mg dose since it has the highest potential to 
contribute to a disease modifying effect in OA. Both dose levels have been shown to be safe 
and tolerable in man as described above. 
1.7 
Risk-Benefit Assessment 
The presently proposed Phase IIa, first-in-disease study will be the second clinical study with 
MIV-711 and as such it has the potential to determine the efficacy of MIV-711 in treating 
painful, radiographic knee OA, both in terms of symptoms and structural progression. 
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*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 NOAEL was 15 µM*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 
OD for 7 days have been explored in healthy volunteers. In addition, the 100 mg dose was 
administered OD 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 OD in man (highest dose in present study) resulted in a 
2.4 µM*h average AUC0-24 which concludes to an expected 6 times margin to the NOAEL 
level in the cynomolgus monkey.  
In the multiple doses part of the Phase I study, MIV-711 was administered at dose of 100 mg 
OD for one month and 200 mg OD for one week. In the present study, both doses are given 
for a total duration of 6 months, which constitutes a significantly longer exposure compared 
to the Phase I study. The treatment length is driven primarily by the nature of OA and it is 
judged that 6 months is the minimum time needed to assess any effect of a bone acting agent 
in this disease. Considering the gap in existing safety data from one week up to 6 months, 
frequent visits and intermittent telephone contacts that include safety follow-up procedures 
have been scheduled as well as recurring Data Monitoring and Ethics Committee (DMEC) 
meetings reviewing the safety and tolerability data. The DMEC will reconvene at least at 
4 occasions as 50, 100, 150 and 200 patients reach 14 weeks treatment (the DMEC may 
decide on more frequent meetings at its discretion). 
MIV-711 has consistently shown efficacy in the Phase I study on the biomarkers that correlate 
strongly with efficacy on joint structure in the pre-clinical models. The doses of MIV-711 to 
be used in this study are estimated to provide an exposure sufficient to produce an 


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improvement in joint structure and symptoms, as has been shown for other bone-acting agents 
(see section 1.2 and section 1.6). There is a potential symptom and structure improvement 
benefit for patients participating in this study even though the treatment length is limited to 
6 months. There is a potential for benefit together with the favorable safety and toxicology 
profile converge into a favorable Benefit/Risk assessment for present study. 
With regard to previous clinical experience (see IB for further information), there are in 
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 conduct of the present study. 
On the basis of the pre-clinical and clinical data on MIV-711 up to this point and the result of 
Benefit/Risk balance, it is considered appropriate to proceed with the Phase IIa clinical study 
which is proposed in the present protocol. 


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2 
STUDY OBJECTIVES 
2.1 
Primary Objective 
To assess the effect of MIV-711 on target knee average pain over 26 weeks as measured by an 
11-point numerical rating scale (1 week recall) in patients with symptomatic and radiographic 
knee osteoarthritis. 
2.2 
Key Secondary Objective 
To assess the effect of MIV-711 on MRI target knee bone area in patients with symptomatic 
and radiographic knee OA over 26 weeks. 
2.3 
Secondary Objectives 
To assess, in patients with symptomatic and radiographic knee OA, over 26 weeks: 
• 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 MRI bone marrow lesion volume 
• The effect of MIV-711 on MRI cartilage thickness loss 
• The effect of MIV-711 in the semi quantitative MRI Osteoarthritis Knee Score 
(MOAKS) parameters 
• 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 
• The safety and tolerability of MIV-711 
• The effect of MIV-711 on biomarkers for bone resorption (serum CTX-I) and for 
cartilage degradation (urine CTX-II) assessment 
2.4 
Exploratory Objectives 
In addition, the study will address the following exploratory parameters: 
• 
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 
(sPINP), bone specific alkaline phosphatase (sBSAP), N-terminal telopeptide of collagen 
type I (uNTX-I), uCTX-I, uαCTX-I and tartrate-resistant acid phosphatases(TRAP5b). 
• 
Baseline (visit 2) and steady state treatment (visit 8) blood and urinary samples will be 
stored for patients who sign a separate voluntary Informed Consent Form (ICF) for 
potential 
future 
pharmacogenomics 
and 
disease-related 
proteomic, 
genomics, 
metabolomics and lipidomics analyses. 
• 
The effect of MIV-711 on a compound index of MRI bone area and cartilage thickness 
• 
The pharmacokinetics and metabolism of MIV-711 and the relationship to patient factors 
and concomitant medications. 


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3 
OVERALL DESIGN AND PLAN OF THE STUDY 
This is a multicentre, randomised, placebo-controlled, double-blind, three-arm parallel, 
Phase IIa study to evaluate the efficacy, safety and tolerability of MIV-711 in patients with 
symptomatic and radiographic knee 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. 
This Clinical Trial of an Investigational Medicinal Product - the data monitoring, clinical 
governance, quality assurance and ethical considerations will be performed in accordance 
with the Medicines for Human Use (Clinical Trials) Regulations (2004 and subsequent 
amendments) and principles of GCP.  
 
A total of 240 patients with knee OA meeting the eligibility criteria and who provide written 
informed consent will be randomised on a 1:1:1 basis to the intervention (MIV-711 low dose 
100 mg or high dose 200 mg) or placebo. 
 
Interventions 
The study will consist of two intervention arms and one control arm: 
Intervention arm I: Patients will receive an once-daily 100 mg oral dose of MIV-711 for 
26 weeks in addition to their current medication. 
Intervention arm II: Patients will receive an once-daily 200 mg oral dose of MIV-711 for 
26 weeks in addition to their current medication. 
Control arm: Patients will receive an once-daily oral dose of matching placebo for 26 weeks 
in addition to their current medication. 
MIV-711 (100 mg and 200 mg) and placebo will be provided as identical capsules. 
All arms: Patients will be permitted to remain on their current analgesic regimen (patient’s 
usual dose should remain the same for at least 4 weeks prior to study entry), with 
any changes in concomitant medications reported and recorded at study visits as 
well as in a patient reported daily e-diary for two week periods prior to visit 2 
(baseline), visit 6 and visit 8. 
 
The study consists of a screening period of approximately 4 weeks (visit 1), a baseline 
assessment period at visit 2, a double-blind treatment period of visit 2 through visit 8, and a 
follow-up period of 4 weeks (visit 9) after the last dose of study treatment is administered (see 
Figure 1).  
 
Figure 1: Schematic of study design 
Double-blind treatment
Visit 2 to Visit 8
MIV-711 100 mg
MIV-711 200 mg
Visit 9
Follow-up
Week 30 ±7 days
Placebo
Week 2
Week 4
Week 8
Week 14
Visit 5
Visit 7
Visit 8
Visit 6
Visit 3
Visit 4
Visit  2
Randomization
Week 1
Screening
Days -30 to 1
Week 20
Week 26
Visit 1


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4 
STUDY POPULATION 
The study population will consist of patients with symptomatic and radiographic knee OA. 
Patients must be able to provide written consent and meet all the inclusion criteria and none of 
the exclusion criteria. 
4.1 
Inclusion Criteria 
Patients must meet all of the following criteria to be eligible for enrolment in this study: 
1. Current average knee pain, defined as pain in either knee, within 1 week before Visit 1, 
for which the patient gives a severity score of ≥4, <10 on a 0-10 NRS. 
2. Inclusive of 40-80 years old.  
3. Diagnosis of primary knee osteoarthritis, based upon the following: 
• Fulfilling the American College of Rheumatology Clinical and Radiographic (ACR) 
criteria for OA defined as knee pain for most days of the prior month and at least one of 
the following three factors: age >50 years, morning stiffness of less than 30 minutes 
and knee crepitus on motion. 
• X-ray evidence within the last 12 months for Kellgren and Lawrence (K-L) 
classification grade 2 or 3. 
4. 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 amenorrhoic for 
12 months without an alternative medical cause and with a screening follicle stimulating 
hormone indicating post-menopausal state. 
5. 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). 
6. The patient’s usual analgesic regimen (in case of use) should remain the same for 4 weeks 
prior to the signature of the informed consent form. 
7. Needs to be able to communicate well with the investigators and staff. 
8. 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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4.2 
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. A history of cancer within the previous 5 years (except for cutaneous basal-cell or 
squamous-cell cancer resolved by excision and cancer in situ which are allowed). 
4. Ongoing or a history of atrial fibrillation. 
5. Currently receiving medication that affects cartilage or bone metabolism (hormone 
replacement therapy taken for more than 6 months is allowed). 
6. Current or recurrent disease that could affect the action, absorption or disposition of 
MIV-711, or could affect clinical assessments or clinical laboratory assessments. 
7. 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. 
8. Known or suspected intolerance or hypersensitivity to the investigational product, closely 
related compounds, or any of the stated ingredients. 
9. A positive human immunodeficiency virus (HIV) antibody screen, a positive Hepatitis B 
surface antigen (HBsAg) screen, and/ or a positive Hepatitis C virus (HCV) antibody 
screen. A positive total Hepatitis B core antibody (anti-HBc) test in conjunction with a 
negative antibody to Hepatitis B Surface Antigen (anti-HBs) test. 
10. History of alcohol or other substance abuse within the last year. 
11. Use of an investigational product within 30 days prior to receiving the first dose of 
investigational product or active enrolment in another drug or vaccine clinical study. 
12. Significant target knee injury or surgery within the 6 months preceding enrolment in the 
study. 
13. 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. 
14. 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 venipuncture or lack of 
adequate venous access for required blood sampling during the study period). 
15. Use of intra-articular hyaluronic acid in the target knee within the 3 months preceding 
enrolment in the study. 
16. Use of intra-articular, intra-muscular or oral corticosteroids in the 2 months preceding 
enrolment. 
17. Commencement of non-pharmacological OA interventions within two months preceding 
enrolment. 
18. 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 


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study or other studies under the direction of the investigator or the CRO, as well as family 
members of the employees or the investigator. 
19. Patients with contra-indication to MRI of the knee. 
 
 


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4.3 
Patient Withdrawal and Replacement 
In accordance with the Declaration of Helsinki, GCP, and International Conference on 
Harmonization (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 adverse events (AEs) and will be asked to return for a follow-up visit (visit 9). An MRI 
scan should be competed if withdrawal is after visit 6. 
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 CRA should be informed as soon as possible. 
If the patient has not yet received any IMP 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 reasons, 
including: 
• The occurrence of pregnancy in a patient. 
• Use of a non-permitted concomitant drug, as defined in Section 5.7.4 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 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 (ALT and/or 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 msec or increase > 60 ms from time matched baseline (confirmed by repeat 
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. 


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In order to perform the modified intention to treat (mITT) analysis, and to enable safety 
analyses, all patients who discontinue their randomised medication will be asked to still 
complete their follow-up visit (visit 9) 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). 
4.4 
Planned Sample Size and Number of Study Centers 
It is planned to recruit 240 patients at 6 centers in 6 countries for this study. 
Recruitment will be completive across all 6 sites. 
4.5 
Patient Identification and Randomization 
4.5.1 Patient Identification 
The Principal Investigator 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 
screening number. Enrolled patients who drop out of the study before randomisation will 
retain their screening number. 
4.5.2 Randomisation Scheme 
A total of 240 patients with knee OA meeting the eligibility criteria and who provide written 
informed consent will be randomised on a 1:1:1 basis to the intervention (MIV-711 low dose 
100 mg or high dose 200 mg) or placebo. 
The randomization allocation will be assigned through a centralized automated code holder 
that distributes the next available randomisation number on the randomisation list to the 
requesting site as described below.  
Allocation of patients to the treatment groups will proceed through the use of an Interactive 
Response Technology (IRT) System [Interactive Web Response (IWR)/Interactive Voice 
Response (IVR) system]. 
The study site will obtain the randomization number and container number assignment from 
the IRT system. The randomization number and the date on which the randomization number 
was assigned will be recorded on the eCRF. Once patient screening numbers, container 
numbers, and randomization numbers have been assigned, they cannot be reassigned. 
4.5.3 Allocation/Randomisation of Patients to Treatment 
Randomisation of patient to treatment will occur at visit 2 (baseline) after all screening 
procedures have been performed and eligibility for the study confirmed. Each randomised 
patient will receive a unique randomisation number. Randomization 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.  
Once patient screening numbers, container numbers, and randomisation numbers have been 
assigned, patients cannot be reassigned. 
4.5.4 Procedures for Handling of Incorrectly Included Subjects 
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 incorrectly 
randomised, or where patients subsequently fail to meet the criteria for the study post 


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enrolment, the procedures in the protocol for the discontinuation of such patients must be 
followed (see section 4.3). 
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. 
4.6 
Extension Protocol 
All patients in the current study at the participating sites included in Extension Study 
MIV-711-202 will be given the opportunity to participate in the extension protocol provided 
that they meet the MIV-711-202 eligibility criteria. 
 
 


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5 
STUDY DRUG 
5.1 
Investigational Drug 
MIV-711 is provided as the hydrochloride (HCl) salt of MIV-711. The pre-clinical 
development laboratory code was MV076159. MIV-711 is manufactured by Niels 
Clauson-Kaas A/S, Farum, Denmark. 
MIV-711 is formulated in hard gelatin capsules (size 0) at the strengths of 100 and 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. 
For the placebo formulation, the excipient composition of the MIV-711 hard gelatin capsule is 
used, but the active substance is substituted with microcrystalline cellulose and Starcap 1500. 
The placebo formulation is manufactured by Galenica AB, Malmö, Sweden. 
MIV-711 (100 mg and 200 mg) and placebo are provided as identical capsules. 
5.2 
Administration 
Patients will receive OD 100 mg or 200 mg oral dose of MIV-711, or placebo for 26 weeks in 
addition to their current medication. 
The IMP should be taken OD 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 is administered at the site during visit 2 
(baseline).  
IMP should be dispensed during the visits and returned by the patients for drug accountability 
at visit 5, visit 6, and visit 8. 
On days when the patient will visit the site the IMP must be taken at the site fasting (and not 
at home) and the time of the intake must be recorded in the source documents. 
5.3 
Packaging, Labeling and Storage 
The capsules will be packaged in the white Duma high-density polyethylene (HDPE) 
containers with polypropylene (PP) caps. 
The proposed shelf life for the IMP in this packaging is 24 months at room temperature 15 to 
25°C.  
The packaging and labeling of the blinded patient packages will be performed in accordance 
with GMP and national requirements. The labeling 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 


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- 
The following standard statements: 
“for clinical study use only” 
“keep 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. 
A temperature record must be maintained and the max/min temperature must be recorded 
during working days. 
The investigator must immediately inform the clinical research associate (CRA) in case of any 
temperature excursions. 
Shorter (≤ 24 hours) periods of storage outside this range is accepted if maximum temperature 
does not exceed 40°C. 
5.4 
Drug Accountability 
The Investigator is responsible for maintaining accurate IMP accountability records 
throughout the study. The clinical research 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 protocol section 5.3. 
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. 
5.5 
Blinding and Breaking the Blind 
The study will be performed in a double-blind manner. All supplied IMP will be identical 
packaging and will be similar in color, smell, taste, and appearance, thereby enabling double-
blind conditions. 
The study blind should not be broken except in a medical emergency (where knowledge of the 
IMP received would affect the treatment of the emergency) or as a result of a regulatory 
requirement.  
If possible, the Investigator should attempt to notify the Sponsor/Medical Monitor prior to 
contacting Interactive Web Response System (IWRS). All calls resulting in an unblinding 
event will be recorded and reported by the IWRS to the Medical Monitor and the Sponsor. 
If the blind is broken, the date, time, and reason must be recorded in the patient’s eCRF 
system, and any associated AE reported.  
The overall randomisation code will be broken only for reporting purposes. This will occur 
once all interim/final clinical data have been entered onto the database and all data queries 
have been resolved, and the assignment of patients to the analysis sets has been completed. 
5.6 
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 randomisation. Drug accountability will be performed and compliance 
of drug accountability will also be discussed with the patient. 


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Treatment compliance will be analysed via capsule count. More details will be given in the 
Statistical Analysis Plan (SAP). 
5.7 
Other Medications 
5.7.1 Rescue Medication 
Where possible, patients will be asked to continue with the same analgesic or anti-
inflammatory medication that 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.  
5.7.2 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 OD 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 metabolism 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 document. All 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 within 4 weeks of 
the screening visit will be documented as prior medication. Medication taken after the first 
dose of IMP will be documented as concomitant medication. Patients will be permitted to 
reinstate prohibited concomitant medications on completion of their final study visit. All 
patients will be asked about concomitant medication use and any changes to use of 
concomitant medications at all study visits. 
5.7.3 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 for 4 weeks prior to starting the study. 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.  
5.7.4 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 (RANKL) inhibiting antibodies and 


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calcitonin. Apart from combinations with mild opioids as specified in section 5.7.3, all 
opioids are prohibited unless for occasional rescue medication purposes. In case of 
uncertainty regarding prohibited medications please contact the medical monitor. 
5.7.5 Chondroitin and glucosamine 
Patients will be permitted to continue current use of chondroitin and glucosamine; however 
their use must be clearly documented in the CRF. Chondroitin or glucosamine therapy may 
not be started during the study.  
5.8 
RESTRICTIONS 
Due to the lack of data on the phototoxicity potential of MIV-711 when the study was started, 
patients participating in this study should be advised to take sun and UV-light protective 
measures for the duration of the study. Such measures include for example, 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. 
After this study started, further evaluation of MIV-711 in laboratory tests have meanwhile 
been undertaken and concluded that there is no phototoxicity risk for patients taking MIV-711. 
However, since this study is ongoing, patients will still be advised to follow the above 
described sunlight protective measures because it is important to keep as many conditions as 
possible similar during the course of the study. 


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6 
ENDPOINT AND METHODS OF ASSESSMENT 
6.1 
Efficacy Endpoint 
6.1.1 Primary Efficacy Endpoint 
The primary outcome will be the change in the assessment of average pain score over the past 
1 week for the target knee, between visit 2 (baseline) and visit 8, on a 0 - 10 NRS. The scale 
ranges from 0 indicating “no pain”, to 10 indicating “pain as bad as it could be”. Pain has 
been chosen as the primary outcome because according to regulatory guidelines, an 
admissible disease modifying effect in OA needs either to result in symptom efficacy 
(together with structural benefit) or decreased events in terms of surgical treatment. The latter 
cannot be determined in the present study due to insufficient length of follow up. 
The Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) suggests that 
outcome measures for OA studies should include pain, function and QOL. The use of an 
11 - point pain NRS as the primary outcome for OA pain studies is recommended by the 
Initiative on Methods, Measurement, and Pain Assessment in Clinical Trials (IMMPACT) [42, 
43, 44, 45], as they have been found to be reliable and to demonstrate good face and criterion 
validity. [46] 
6.1.2 Key Secondary Endpoint 
The key secondary endpoint will be the MRI of bone area. Bone parameters will be measured 
for MRIs of the target knee taken at visit 2 (baseline) and visit 8. 
6.1.3 Secondary Imaging Endpoints 
MRIs will be analysed semi-quantitatively by a central experienced musculoskeletal 
radiologist using the MOAKS [47] and quantitatively using statistical shape modelling (SSM, 
Imorphics Ltd) for the features below. [23, 48, 49] 
MOAKS scoring will be used to assess the following features: 
- 
Bone Marrow Lesions (BMLs) and cysts - 15 subregions graded for BML (including 
ill-defined lesion and cysts) size in regard to the total volume of the subregion 
occupied by BML(s). Grade 0= none, grade 1<33% of subregional volume, 
grade 2=33–66% of subregional volume and grade 3>66% of subregional 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 subregion 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. 
Statistical shape modelling 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 [50] 
- 
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 patellaBone 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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6.1.4 Secondary Endpoints 
Patient-Reported Outcomes (PRO) 
PRO 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 [51] -
a 24-item OA-specific, tri-dimensional self-administered questionnaire, for assessing 
health status and health outcomes in OA of the knee. The five responses are 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 
[52, 53] 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 ≥50% and absolute change ≥20 or  
2) Improvement in at least two of the following: 
i) pain ≥20% and absolute change ≥10,  
ii) function ≥20% and absolute change ≥10 and  
iii) patients’ global assessment ≥20% and absolute change ≥10 
• Intermittent and constant osteoarthritis pain (ICOAP) [52] - 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 [54] into a constant pain 
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) [55] - 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 [56]. 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.[57]  
• In an e-diary format, a patient knee pain diary (NRS) and analgesia questionnaire will 
be completed daily during three two-week periods prior to visit 2 (baseline), visit 6 and 
visit 8. Baseline 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) 


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3) Adherence to usual analgesics regimen 
4) Intake of IMP (note: in case the e-diary device is kept by the patients for the 
full duration of the study, intake of IMP will be registered daily throughout the 
study) 
 
Laboratory assessments: 
Blood and urine samples will be taken at visit 2 (baseline) and visit 4, visit 6, visit 8, and 
visit 9 for analysis of serum CTX-I and urinary CTX-II biomarkers. 
6.1.5 Exploratory Endpoints 
6.1.5.1 Biomarkers and biobanking 
Blood and urine samples will be taken at visit 2 (baseline), visit 4, visit 6, visit 8, and visit 9 
for analysis of exploratory bone and cartilage markers of relevance for OA disease such as 
sPINP, sBSAP and s(TRAP5b) in blood and uNTX-I, uCTX-I and uαCTX-I in urine. 
Pharmacogenomic samples will also be collected and stored to enable further profiling 
(proteomic, genomic).  
A blood and urine sample from visit 2 and visit 8 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. 
6.1.5.2 Imaging 
Change from visit 2 (baseline) to visit 8 in a calculated compound index of MRI bone area 
(key secondary endpoint) and cartilage thickness. 
6.1.5.3 Pharmacokinetics 
The pharmacokinetics and metabolism of MIV-711 and the relationship to patient factors and 
concomitant medications will be analyzed following the sampling procedures as described in 
section 6.8. 
6.2 
Safety Endpoints 
• Incidence and severity of adverse events  
• Incidence and severity of clinical laboratory abnormalities 
• Summary of changes in physical examination compared to baseline by patient 
• Mean change from baseline in vital signs (blood pressure, heart rate, and temperature) 
• Categorical summary of absolute vital signs and vital sign changes compared to 
baseline by patient 
 
 


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6.3 
Physical Examination 
A standard complete physical examination will be performed at visit 1 (screening), visit 2 
(baseline), visit 5, visit 6 and visit 8. 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 (HEENT), lungs (auscultation), heart (auscultation for 
presence of murmurs, gallops, rubs), extremities exam for the presence of peripheral edema, 
abdominal (palpation and auscultation), neurologic (mental status, station, gait, reflexes, 
motor and sensory function, coordination) and lymph nodes.  
A targeted physical examination will be performed at visit 3, visit 4, and visit 7 assessing the 
following: lungs, heart, abdomen, extremity exam for the presence of peripheral oedema and 
lymph nodes. A standard clinical examination of both knees will be undertaken at all visits. 
Any clinically significant changes from visit 2 (baseline) should be recorded as AEs. 
6.4 
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. 
Height will be measured at visit 1 (screening) and weight will be measured at visit 1 
(screening) and visit 8. 
6.5 
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 (baseline) pre-dosing and after 30 minutes, 1 
hour and 2 hours post-dosing (± 10 minutes).  
Standard 12-lead ECG will be performed at all other visits 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. 
6.6 
Imaging Assessments 
6.6.1 K-L Scoring 
K-L scoring based on target knee radiographs no older than 12 months is required to assess 
inclusion criterion 3. This could be performed by a local radiologist and in order to ensure 
comparability and accuracy of study data and to evaluate variability between study sites, an 
independent consultant radiologist will review the K-L scoring on all patients from digitized 
images. In some instances there may be adjudication between the local and the independent 
radiologist’s assessments, which is further detailed in the Imaging Investigator Site 
Operations Manual. 
6.6.2 MRI Assessments 
At visit 2 (baseline) and visit 8, MRI acquisition will be performed on the target knee using 
1.5/3T systems using the following sequences, which have been optimised for visualization of 


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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 at both visit 2 and 
visit 8. 
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. 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 phantom scan 
image quality issues the phantom scans will be sent to PAREXEL Imaging for evaluation. If a 
site has an imaging-related upgrade (hardware/software) then a phantom scan will be 
requested before and after upgrade to confirm the protocol has not changed. 
Each set of patient images will be quality controlled to allow for a repeat MRI to be captured 
if required. 
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. 
6.7 
Self-report Parameters 
Patient-reported outcomes will be recorded using questionnaires at visit 2 (baseline) and at 
visit 5, visit 6, and visit 8, as follows: 
Pain, function and disease activity 
At visit 2 (baseline), visit 5, visit 6, and visit 8: 
• 11-point NRS scales  for:  
- 
Average overall knee pain severity in the target knee over the past 1 week (also 
recorded at visit 9) 
- 
Average overall knee pain severity in the contralateral knee over the past 1 week (also 
recorded at visit 9) 
- 
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 three two-week periods prior to visit 2 (baseline), visit 6 and visit 8. 
 
At visit 2 (baseline) only: 
• Duration of knee pain over the past 12 months (within the last 7 days, 8-30 days, 31-92 
days, >92 days)  
• Onset of knee pain (within the last 12 months, >1 - 5 years, >5 - 10 years, >10 years) 
 
At visit 5, visit 6, and visit 8 only: 
Using a 6 - point Likert scale (completely better, much better, better, no change, worse, much 
worse) we will record patient-reported: 


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• 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  
At visit 2 (baseline) and visit 8: 
• 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.  
 
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 adverse events since the last visit, or the outcome of any adverse 
events 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 5, visit 6, and visit 8 and 
drug accountability will be conducted. The Brief Medication Questionnaire self-reported 
measure [58] for the use of concomitant medication will be included at visit 5, visit 6, and 
visit 8. 
6.8 
Pharmacokinetics Sampling 
Three blood samples will be collected at visit 4 and visit 8 to measure plasma concentrations 
of MIV-711. On each of these visits, 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 a 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 1500g for 10 minutes at approximately 
4°C. 
For each sample, the separated plasma will be equally split into 4 aliquots and transferred into 
4 suitably labelled polypropylene tubes, and stored within 2 hours of collection at at 
least -70°C until shipped on dry-ice. Three aliquots will be dispatched to the Bioanalytical 
Laboratory for analysis of MIV-711 and for potential exploratory metabolite analysis. The 
forth aliquot will remain at the clinical site. 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 analyzing 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. 


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6.9 
Biomarker Sampling 
Blood and urine samples will be taken at visit 2 (baseline), visit 4, visit  6, visit 8 and visit 9 
for analysis of serum CTX-I and urinary CTX-II, as well as for exploratory bone and cartilage 
markers of relevance for OA disease (such as sPINP, sBSAP and s(TRAP5b) in blood and 
NTX-I, CTX-I and αCTX-I 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 each of these visits. 
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 labeled 
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 labeled 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. 
Further details on the provider and handling of the biomarker samples will be provided in the 
Laboratory Manual. 
6.10 Optional Pharmacogenomics Sampling 
Blood and urine samples will be collected at visit 2 (baseline) and visit 8 under voluntary ICF 
for preparation of samples to provide 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. 
6.11 Adverse Events 
6.11.1 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 unfavorable 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 
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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. 
6.11.2 Assessment of Adverse Events 
Each AE will be assessed by the Investigator with regard to the following categories. 
6.11.2.1 Seriousness 
A serious AE (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 
• 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. 
6.11.2.2 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. 
6.11.2.3 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 
6.11.2.4 Adverse Events of Special Interest 
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6.11.2.5 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 9) 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. 
6.11.2.6 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 9) 
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. 
The following information is required for an initial report: 
• An identifiable reporter (i.e., name, address of Investigator) 
• An identifiable patient (i.e., screening/randomization 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 center 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 
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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  
6.11.2.7 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 
stabilised 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. 
6.11.2.8 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. 
• If the SUSAR is fatal or life-threatening, associated with the use of the IMP, and 
unexpected, Regulatory Authorities and Independent Ethics Committees (IECs) will be 
notified within 7 calendar days after the 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 but is otherwise serious, associated with 
the use of the IMP, and unexpected, Regulatory Authorities and IECs will be notified 
within 15 calendar days after the PAREXL 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. 
6.11.2.9 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 and followed until outcome 
(completion/termination) of the pregnancy. 
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 report form. 
 


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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 6.11.2.6. 
6.11.2.10 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 6.9.2.6.  
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: 
- 
The administration and/or use of the unassigned treatment are always reportable as a 
medication error. 
- 
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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7 
STUDY CONDUCT 
7.1 
Study Schedule 
Newly diagnosed and existing patients with symptomatic knee OA consulting their 
rheumatologist, musculoskeletal physician, orthopaedic surgeon, physiotherapist, or general 
practitioner will be invited to consent to further contact by the research team. The patient 
information will be provided and the study will be discussed. Any questions from the patient 
will be answered. The patient will then have at least 24 hours to discuss the information with 
whoever they choose. The Screening Phase will last for a maximum of 30 days, during which 
patients will be checked for eligibility. The clinical laboratory testing will be performed at 
scheduled visit (Table 1). The patients´ eligibility will be determined by the laboratory results 
obtained during the screening visit. The study will include 26 weeks of treatment, with 
patients followed for 30 weeks as per Study Schedule (Table 2). 
7.1.1 Screening Visit (Visit 1, Day -30) 
The below are the activities 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. 
• assessing inclusion and exclusion criteria 
• obtaining demographic data (including age, gender and race) 
• obtaining medical and surgical history  
• performing full physical examination 
• performing vital signs assessments including weight and height performing 12-lead 
electrocardiogram assessment  
• sampling for urinalysis  
• sampling for urine drug screen 
• sampling for blood post-menopausal assessments (only post-menopausal or sterile 
women will be enrolled) 
• sampling for blood clinical chemistry and hematology testing  
• sampling for blood HBsAg, anti-HBc, HCV, anti-HBs, and HIV testing 
• complete NRS (to assess inclusion criterion 1) 
• evaluation of existing X-ray (not older than 12 months) of the target knee 
• K-L identification of target knee is primarily based on pain, secondarily on K-L grade, 
and if both sides should be equal with regard to these two criteria, the right knee should 
always be prioritized 
• e-diary dispensing and training 
• dispense Patient Emergency Card 
7.1.2 Randomisation/Baseline (Visit 2, Day 1) 
The below are the activities at the randomization/baseline visit which will be documented in 
eCRF: 
• confirming inclusion and exclusion criteria 
• monitoring for AEs, SAEs and concomitant medication 
• performing randomization in a 1:1:1 ratio via  Interactive Web Response System 
(IWRS) 
• performing full physical examination 


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• performing vital signs assessments  
• performing serial electrocardiogram assessment at pre-dosing, and at 0.5, 1 and 2 h 
post-dosing 
• sampling for urinalysis 
• sampling for urinalysis (biomarker) 
• sampling for blood clinical chemistry and hematology testing  
• sampling for blood biomarker testing 
• performing target knee MRI (-7 days) 
• NRS, WOMAC, ICOAP 
• completing Quality of Life questionnaire: EuroQoLEQ-5D-5L 
• dispensing the first IMP at the site. Patient must stay at the clinic for 2 hours after 
taking the IMP. 
• obtaining optional ICF preparation of samples to provide for for pharmacogenomics, 
proteomics, genomics, metabolomics and lipidomics 
• phone call to assess safety and tolerability (completed 5-9 days after the visit) 
• e-diary review and training 
7.1.3 Safety Visit (Visit 3 [Week 2 ± 2], Visit 4 [Week 4 ± 2] and Visit 7 [Week 20 ± 
7 days]) 
The below are the activities at the safety visits which will be documented in eCRF: 
• monitoring for AEs, SAEs and concomitant medication 
• performing vital signs assessments  
• performing targeted physical examination 
• performing 12-lead electrocardiogram assessment 30 minutes post-dose 
• sampling for urinalysis  
• sampling for urinalysis (biomarker) (at visit 4 only) 
• sampling for blood biomarker testing (at visit 4 only) 
• sampling for blood clinical chemistry and hematology testing  
• sampling for blood PK assessment (at visit 4 only) 
• phone call to assess safety and tolerability (completed 5-9 days after the visits) 
• dispense IMP at the site (the capsule should be taken from the bottle currently in use by 
the patient). 
7.1.4 Treatment visit (Visit 5 [Week 8 ± 2], Visit 6 [Week 14 ± 7 days], and Visit 8 
[Week 26 ± 7 days]) 
The below are the activities at the treatment visits which will be documented in eCRF: 
• monitoring for AEs, SAEs and concomitant medication 
• performing vital signs assessments 
• measuring weight (at visit 8 only) 
• performing full physical examination  
• performing 12-lead electrocardiogram assessment  
• sampling for urinalysis  
• sampling for urinalysis (biomarker) (at visit 6 and visit 8 only) 
• sampling for urine drug screen (at visit 5 only) 


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• sampling for blood clinical chemistry and hematology testing  
• sampling for blood PK assessment (at visit 8 only) 
• sampling for blood biomarker testing (at visit 6 and visit 8 only) 
• performing knee MRI (at visit 8 only) 
• completion of NRS, WOMAC, ICOAP, and Global Improvement 
• completing Quality of Life questionnaire: EuroQoL EQ-5D-5L (at visit 8 only) 
• dispense IMP at the site (the capsule should be taken from the bottle currently in use by 
the patient)  
• drug accountability 
• phone call to assess safety and tolerability (completed 5-9 days after the visits, except 
for visit 8) 
• obtaining blood sample for  pharmacogenomics, proteomics, genomics, metabolomics 
and lipidomics and urine sample for proteomics and metabolomics (at visit 8 only) 
 
7.1.5 Safety Follow-up Visit (Visit 9, Week 30 ± 7 days) 
The below are the activities at the safety follow-up visit which will be documented in eCRF: 
• monitoring for AEs, SAEs and concomitant medication 
• performing vital signs assessments  
• performing 12-lead electrocardiogram assessment  
• sampling for urinalysis  
• sampling for urinalysis (biomarker) 
• sampling for blood clinical chemistry and hematology testing  
• sampling for blood biomarker testing 
• delivering NRS for average overall knee pain severity 
 
The end of the study is defined as the last visit 9 (week 30) of the last patient or, if applicable, 
when the last patient has rolled over to study MIV-711-202 and having finalized visit 2 of that 
study. 
 
Table 1: 
Clinical Laboratory Testing 
Screening only 
Post-menopausal determination: Follicle stimulation hormone (FSH)  
Female patients must be 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 amenorrhoic for 
12 months without an alternative medical cause and with a screening follicle stimulating hormone 
indicating post-menopausal state. 
Fasting samples are required at all study visits as fasting glucose is required as part of the chemistry 
samples. 
Hematology: WBC and differential, % and absolute for: neutrophils, lymphocytes, monocytes, 
eosinophils, basophils; hemoglobin, hematocrit, 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 (at screening only) 


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Urinalysis: with microscopic: specific gravity, pH , protein, glucose, ketones, nitrites, blood and leukocyte 
esterase 
Urine Drug Screen: Amphetamine, Benzodiazepines, THC, Cocaine, Oxycodone and Opiate 
Hepatitis B surface antigen, total Hepatitis B Core antibodies, antibodies to Hepatitis B Surface 
antigen, Hepatitis C virus, HIV 1/2 
PTH (parathyroid hormone) 
 
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 
V7 
V8 
V9 
Weeks 
-4 
1 
2 
4 
8 
14 
20 
26 
30 
Day 
up to 
30  days 
Day 1 
day 15 
±2 days 
day 29 
±2 days 
day 57 
±2 days 
±7 days 
±7 days 
±7 days 
± 7 days 
Visit Description 
Screening 
Randomisation
/Baseline 
Treatment period 
Safety 
follow-
up 
Signed informed consent 
X 
 
 
 
 
 
 
 
 
Randomisation 
 
X 
 
 
 
 
 
 
 
Inclusion/exclusion criteria 
X 
X 
 
 
 
 
 
 
 
Target knee identificationA  
X 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
Weight 
X 
 
 
 
 
 
 
X 
 
Height 
X 
 
 
 
 
 
 
 
 
Medical & Surgical history 
X 
 
 
 
 
 
 
 
 
Physical examination 
X 
X 
XB 
XB 
X 
X 
XB 
X 
 
Vital signs, including body 
temperature 
X 
X 
X 
X 
X 
X 
X 
X 
X 
12-Lead ECGC 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Clinical chemistry/ 
Haematology 
X 
X 
X 
X 
X 
X 
X 
X 
X 
UrinalysisD 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Urine drug screen 
X 
 
 
 
X 
 
 
 
 
Post-menopausal assessment 
(females only) 
X 
 
 
 
 
 
 
 
 


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Study Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Weeks 
-4 
1 
2 
4 
8 
14 
20 
26 
30 
Day 
up to 
30  days 
Day 1 
day 15 
±2 days 
day 29 
±2 days 
day 57 
±2 days 
±7 days 
±7 days 
±7 days 
± 7 days 
Visit Description 
Screening 
Randomisation
/Baseline 
Treatment period 
Safety 
follow-
up 
HBsAg, anti-HBc, anti-HBs, 
HCV, and HIV test 
X 
 
 
 
 
 
 
 
 
e-diary dispensing and 
training 
X 
 
 
 
 
 
 
 
 
Patient Emergency Card 
dispense 
X 
 
 
 
 
 
 
 
 
MRI of target kneeE 
 
X 
 
 
 
 
 
X 
 
e-diary for pain and 
analgesicF 
 
X 
 
 
 
X 
 
X 
 
Duration and onset of knee 
pain 
 
X 
 
 
 
 
 
 
 
NRS, ICOAP, WOMAC 
XG 
X 
 
 
X 
X 
 
X 
XG 
Global improvement 
(6-point Likert scale) 
 
 
 
 
X 
X 
 
X 
 
EuroQoL EQ-5D-5L 
 
X 
 
 
 
 
 
X 
 
Brief Medication 
Questionnaire 
 
 
 
 
X 
X 
 
X 
 
Dispense IMPI 
 
XH 
 
 
X 
X 
 
 
 
Drug accountability 
 
X 
 
 
X 
X 
 
X 
 
PK sampling (blood) 
 
 
 
X 
 
 
 
X 
 


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Study Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Weeks 
-4 
1 
2 
4 
8 
14 
20 
26 
30 
Day 
up to 
30  days 
Day 1 
day 15 
±2 days 
day 29 
±2 days 
day 57 
±2 days 
±7 days 
±7 days 
±7 days 
± 7 days 
Visit Description 
Screening 
Randomisation
/Baseline 
Treatment period 
Safety 
follow-
up 
Biomarker samplesJ 
 
X 
 
X 
 
X 
 
X 
X 
AEs/SAEs monitoring 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Concomitant Medication 
 
X 
X 
X 
X 
X 
X 
X 
X 
Phone call to assess safety 
and tolerabilityK 
 
X 
X 
X 
X 
X 
X 
 
 
Blood sample for 
pharmacogenomics, 
proteomics, genomics, 
metabolomics and 
lipidomics and urine sample 
for proteomics and 
metabolomicsL 
 
X 
 
 
 
 
 
X 
 
A) Selection of target knee is primarily based on pain, secondarily on K-L grade, and if both sides should be equal with regard to these two criteria, the right knee should 
always be prioritized. 
B) Targeted physical examination. Full physical examination at all other visits. 
C) At visit 2 at pre-dosing, 0.5, 1 and 2 h post dosing (± 10 minutes). At all other visits 30 minutes post-dose (± 10 minutes). 
D) If urinalysis is positive for blood, nitrites, leukocyte esterase, and/or protein, additional microscopic analysis may be performed. 
E) MRI should be performed at visit 2 (- 7 days) and at visit 8 (± 5 days). 
F) To be completed at home during the 2 weeks prior to the marked visit. 
G) Only NRS for average overall knee pain severity (1 week recall) for both knees 
H) The first dose of IMP will be dispensed to the patient at the site. Date and time should be recorded in the eCRF. The first dose should be given to the patient after all 
baseline assessments has been performed including completion of PROs. Patients take the IMP in the clinic in a fasting state and must stay at the clinic for 2 hours after 
intake of  the IMP. 
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 8. 
J) 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. 
K) The phone call should be made 5-9 days after all dosing visits. 
L) Blood will be collected for pharmacogenomics, proteomics, genomics, metabolomics and lipidomics and urine will be collected for proteomics and metabolomics pre-dose 


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Study Visit 
V1 
V2 
V3 
V4 
V5 
V6 
V7 
V8 
V9 
Weeks 
-4 
1 
2 
4 
8 
14 
20 
26 
30 
Day 
up to 
30  days 
Day 1 
day 15 
±2 days 
day 29 
±2 days 
day 57 
±2 days 
±7 days 
±7 days 
±7 days 
± 7 days 
Visit Description 
Screening 
Randomisation
/Baseline 
Treatment period 
Safety 
follow-
up 
at Visit 8 from patients who provide additional written consent. 


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7.2 
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 9) as outlined in the study schedule (Table 2). 
In addition to the assessments described in Section 7.1.5, the following should also be 
completed: 
• drug accountability 
• return of eDiary 
• physical examination 
• performing knee MRI (±5 days) (if withdrawal is after visit 6) 
• obtaining optional blood samples for pharmacogenomics, proteomics, genomics, 
metabolomics and lipidomics and urine samples for proteomics and lipidomics. 
7.3 
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 Data Monitoring and Ethics Committee 
(DMEC). Any serious adverse event 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 50, 100, 150 and 200 patients have completed the visit 6. No formal 
statistical tests will be undertaken but adverse events will be summarised and tabulated for 
each group separately. If, in the view of the DMEC, the number or severity of adverse events 
in one of the groups 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 unfavorable 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 unfavorable 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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8 
STATISTICAL METHODS 
The statistical considerations summarized in this section outline the plan for data analysis of 
this study.  
Before unblinding and 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. 
8.1 
Study Patients 
8.1.1 Disposition of Patients 
The number and percentage of patients entering and completing each phase of the study will 
be presented, stratified by treatment. Reasons for withdrawal pre--and post-randomization 
will also be summarized. 
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. 
8.1.2 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 unblinding. 
8.1.3 Analysis Set 
• The Intention-to-Treat population (ITT): all randomised patients in the treatment group 
to which they were randomised, regardless of whether treatment was received as 
planned. 
• The full analysis set (modified ITT approach; mITT): all patients having both a 
baseline and at least one post-baseline value for the primary variable (NRS pain score).   
• PPS: those patients who adhered to the treatment regimen of the program to which they 
were allocated, provided sufficient assessment of primary outcomes, and did not violate 
the study protocol in any substantial way.  
Major protocol violators and exclusions from the per-protocol set 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 per-protocol set: 
- 
Incorrect diagnosis 
- 
Arthroscopy in the target knee during the study period 
- 
Missing more than 5 doses of MIV-711 
The panel will review these criteria using blinded data prior to data analysis. 
• The safety analysis set (SAF): all patients receiving at least one dose of either MIV-711 
or placebo, analysed according to treatment actually received. 


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The primary and secondary efficacy analysis will be based on mITT and PPS, to assess the 
sensitivity of the analysis to the choice of analysis set. All safety analyses will be based upon 
the SAF. 
Demographic and baseline characteristics will be evaluated for the ITT and for the PPS. If one 
or more patients received incorrect IMP, these data will also be presented for the SAF. 
8.2 
General Consideration 
All statistical tests will be one-sided and will be performed at the 5% level of significance 
(Type I error α=0.05). 
Continuous data will be summarised by treatment group 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). 
Analysis and data conventions: 
Definition of baseline 
The baseline assessment to be used for calculating change from baseline will be the last valid 
assessment prior to first dose administration. 
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 hemolysed 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. 
8.3 
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, overall and stratified by treatment. 
8.4 
Treatment Compliance 
Treatment compliance as measured in Section 5.6 will be summarised by means of descriptive 
statistics (n, mean, SD, median, minimum, and maximum) and/or frequency tables and 
stratified by treatment. 


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8.5 
Statistical Methodology 
8.5.1 Hypothesis to be Tested 
The primary hypothesis of this study is that MIV-711 will reduce pain in patients with 
moderate knee osteoarthritis diagnosed based on symptomatic and radiologic criteria. 
8.5.2 Efficacy 
8.5.2.1 Statistical Methodology for Primary Efficacy Endpoints 
In order to test the hypothesis, the change from baseline in NRS pain score will be analysed 
using a linear mixed model using the FAS (mITT). Only post-baseline NRS values will be 
used as dependent variable. Baseline NRS will be included as a covariate. The model will 
include fixed effects for treatment group, baseline value, chronic analgesic use minimization 
factors, week and week-by-treatment group interaction; site will be modeled as a random 
effect. 
The contrast of primary interest will be the treatment difference at visit 8. Least Square means 
(LSmeans) at visit 8 for the change from baseline score will be reported from the mixed 
model. LSmeans for the overall effect of treatment, estimates of the pair-wise treatment 
differences, two-sided 95% confidence intervals (CI), and p-value (one-sided) will be 
provided. 
Development over time will be summarised by graphs of LSmeans and 95%-confidence limits 
as appropriate.  
As a sensitivity analysis, the primary endpoint will also be analysed by using the PP subset, 
following the same conventions as in the primary analysis on the FAS population. 
8.5.2.2 Statistical Methodology for Secondary Efficacy Endpoints 
All secondary endpoints will be analysed using the same statistical model specified for the 
primary endpoint, adjusting for the same factors as the primary analysis. The mITT 
population will be used for all secondary analyses.  
Some secondary endpoints such as QoL will be obtained at visit 2 (baseline) and visit 8 only. 
In the analysis of biomarkers that are sampled at multiple visits, all sampled time points will 
be considered for change from baseline and comparison to placebo in the respective cases.  
For all outcomes 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 all primary and secondary efficacy 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).  
No subgroup analyses are planned in this Phase IIa study.  
No interim analysis will be conducted for any efficacy endpoint.  
An unblinded interim safety analysis will be conducted after 50, 100, 150 and 200 patients 
have completed the visit 6. No formal statistical tests will be undertaken. Adverse events will 
be summarised descriptively and tabulated by treatment group (see section 8.6). The DMEC 
will consider the results of the AE summaries when making decisions regarding dosing of 


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subsequent cohorts (i.e. need for dose stoppages) or the need for formal interm analysis of 
non-safety data. 
8.5.2.3 Statistical Methodology for Exploratory Endpoints 
The exploratory analysis of additional bone and cartilage biomarkers, imaging and PK 
assessments are not part of the statistical analysis set, and may therefore 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 metabolite forms 
of MIV-711 will be an additional exploratory endpoint and will be reported as outlined above. 
Any subsequent analysis of the biomarker samples stored will not be part of the present study 
reporting. 
8.5.3 Safety 
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 treatment 
group and scheduled assessment for the SAF. Summary statistics (number of observations, 
mean, SD, median, minimum and maximum values) will be presented by treatment group for 
continuous variables, and number and percentages (n, %) will be presented by treatment 
group for categorical variables. Where applicable, changes from baseline will also be 
summarised for each treatment group.  
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, preferred term and treatment group in the SAF. Treatment-emergent adverse 
events will be further summarised by treatment group 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 by treatment group. 
Clinical laboratory tests (hematology, serum chemistry, ECG, and vital signs) will be 
summarised by treatment group for the SAF at each scheduled assessment. Potentially 
clinically important findings will also be summarised by treatment group and listed. 
The number of patients taking rescue medication, the amount of rescue medication taken and 
the reason for use will be tabulated and summarised descriptively by treatment. 
8.6 
Interim Analyses 
No formal interim analysis to allow early stopping of the study on the basis of demonstrating 
efficacy or futility is planned. Unblinded Interim safety analyses (i.e. no efficacy analyses) 
will be undertaken after 50, 100, 150 and 200 patients have completed visit 6. 
8.7 
Sample Size and Sample Size Calculation 
8.7.1 Primary Endpoint consideration 
The sample size is based on the primary efficacy outcome of change in pain score from 
baseline, measured using the 0-10 numerical rating score and comparing MIV-711 and 
placebo groups. The following were input to the calculation.  
- 
A clinically important effect for changes in chronic musculoskeletal pain severity has 
been estimated as 1.0 point. [59]  


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- 
The between-patient SD for change in pain score of 2.256 was obtained from a review 
of the literature of clinical studies in patients with knee OA. This was the average SD 
reported in a large study of similar patients assessed at 12 months after treatment. [60] 
- 
Using a Bayesian decision-theoretic approach Stallard recommended that operating 
characteristics for Phase IIa studies can be relaxed with maximum (one-sided) type I 
and type II errors of 0.2 and 0.4 respectively.[61] For this study a stricter approach 
was considered requiring the power of the test to be at least 80% and the one-sided 
type I error rate to be fixed at 0.05 
- 
Loss to follow-up is expected to be 20% at by visit 8. 
Based upon the assumptions above we require a sample size of 80 patients per group, or 
240 patients in total, with 192 patients providing the primary outcome measurement at visit 8.  
Statistical analysis will be carried out using mITT and per-protocol populations. All data 
analysis and statistical programming will be conducted using the SAS software (Version 9.1 
or higher). Significance tests will be one-sided at the 5% level (Type I error α=0.05).  
For the primary endpoint, change from visit 2 (baseline) to visit 8 in NRS pain score, the type 
I error for the tests of the two doses will be protected by performing a fixed-sequence 
multiple-testing procedure. The order of steps is defined below: 
1. 200 mg versus placebo 
2. 100 mg versus placebo 
To adjust for the multiple testing of two doses, the second step will only be considered as 
confirmatory providing the previous step is successful at one-sided 5%-level (p<0.05). If the 
previous step is not successful, the analysis of the following step will be considered 
descriptive. 
The study will be blinded until the final analysis. 
8.7.2 Key Secondary Endpoint power consideration 
The sample size is based on the change of bone area (mm2) of the medial femoral (MF) 
condyle from baseline, which was found to be the most responsive region in a study of bone 
area.[23] 
The following were input to the calculation.  
- 
In a comparable group of patients within an observational clinical study, the mean 
change found in MF area was 13.5mm2 in 6 months 
- 
Standard deviation for change in MF bone area over 6 months for this study was 
16.0 mm2 
- 
With the present trial design we will have 80% power to detect an improvement in 
bone surface area of the order of 0.45 (between-patient) SD, with a 1-sided 
significance of 5% and allowing for 20% loss to follow up. This equates to 7.2mm2 of 
change in area, approximately half of the expected bone area change in 6 months 
(13.5mm2) 


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9 
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. 
9.1 
Data Quality Assurance 
PAREXEL will conduct a site visit to verify the qualifications of each Investigator, inspect 
the site facilities, and inform the Investigator of responsibilities and the procedures for 
ensuring adequate and correct documentation. 
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 system for this study must be consistent with the 
patients’ source documentation (i.e., medical records). 
9.1.1 Database Management and Quality Control 
All data generated by the site personnel will be captured electronically at each study center 
using eCRFs. Data from external sources (such as laboratory 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 application (DataLabs). 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. Once all source data verification is 
complete and all queries are closed, the CRA will freeze the eCRF page. 
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. 
9.2 
Case Report Forms and Source Documentation 
All data obtained during this study should be entered in the EDC system 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.  
 
9.2.1 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 and 
right 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 


Sponsor Name 
Clinical Study Protocol 
MIV-711-201 
CONFIDENTIAL 
Amendment 2 
63 of 71 
20 July 2016 
 
 
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 
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 
9.3 
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 CRA 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 audit 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. 
9.4 
Data Processing 
All data will be entered by site personnel into the eCRF (as detailed in Section 9.2.1). 
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. 
9.5 
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 50, 100, 150 and 200 patients have completed visit 6. 
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 include an independent chair 
having specialist osteoarthritis expertise and experience of studies in this area, an independent 


Sponsor Name 
Clinical Study Protocol 
MIV-711-201 
CONFIDENTIAL 
Amendment 2 
64 of 71 
20 July 2016 
 
 
statistician and one other member will also be appointed. 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. 
9.6 
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. 
9.7 
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. 
9.8 
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.  
9.9 
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. 


Sponsor Name 
Clinical Study Protocol 
MIV-711-201 
CONFIDENTIAL 
Amendment 2 
65 of 71 
20 July 2016 
 
 
9.10 Protocol Approval and Amendment 
Before the start of the study, the study protocol and/or other relevant documents will be 
approved by the IEC/Competent 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. 
This protocol is to be followed exactly. To alter the protocol, amendments must be written, 
receive approval from the appropriate personnel, and receive IEC/Competent 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. 
9.11 Duration of the Study 
The study will be conducted from November 2015 to 31 March 2017. 
9.12 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. 
9.13 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 IRB/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. 
9.14 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. 
9.15 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. 


Sponsor Name 
Clinical Study Protocol 
MIV-711-201 
CONFIDENTIAL 
Amendment 2 
66 of 71 
20 July 2016 
 
 
An Investigator shall not publish any data (poster, abstract, paper, etc.) without having 
consulted with the sponsor in advance. Details are provided in a separate document. 
 


Sponsor Name 
Clinical Study Protocol 
MIV-711-201 
CONFIDENTIAL 
Amendment 2 
67 of 71 
20 July 2016 
 
 
10 REFERENCE LIST
 
 
 
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World Medical Association Declaration of Helsinki. Recommendations guiding physicians in biomedical 
research involving human subjects. Adopted by the 18th WMA General Assembly, Helsinki, Finland, 
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1989 48th WMA General Assembly, Somerset West, Republic of South Africa, October 1996 
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Murray, C. J., et al. (2012). "Disability-adjusted life years (DALYs) for 291 diseases and injuries in 21 
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Vos, T., et al. (2012). "Years lived with disability (YLDs) for 1160 sequelae of 289 diseases and injuries 
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4  
Peat, G., et al. (2001). "Knee pain and osteoarthritis in older adults: a review of community burden and 
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Conaghan, P. G., et al. (2008). "Care and management of osteoarthritis in adults: summary of NICE 
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6  
Hochberg, M. C., et al. (2012). "American College of Rheumatology 2012 recommendations for the use 
of nonpharmacologic and pharmacologic therapies in osteoarthritis of the hand, hip, and knee." Arthritis 
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7  
Zhang, W., et al. (2010). "OARSI recommendations for the management of hip and knee osteoarthritis: 
part III: Changes in evidence following systematic cumulative update of research published through 
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Pendleton, A., et al. (2000). "EULAR recommendations for the management of knee osteoarthritis: report 
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Conaghan, P. G., et al. (2012). "The personal impact of osteoarthritis on individuals and how they use 
therapies: the arthritis care OA Nation 2012 Survey." Ann Rheum Dis 71(Suppl3): 584. 
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Conaghan, P. G., et al. (2014). "Impact and therapy of osteoarthritis: the Arthritis Care OA Nation 2012 
survey." Clinical Rheumatology. 
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Herrero-Beaumont, G. and J. A. Roman-Blas (2013). "Osteoarthritis: Osteoporotic OA: a reasonable 
target for bone-acting agents." Nat Rev Rheumatol 9(8): 448-450. 
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Karsdal, M. A., et al. (2014). "The coupling of bone and cartilage turnover in osteoarthritis: opportunities 
for bone antiresorptives and anabolics as potential treatments?" Annals of the Rheumatic Diseases 73(2): 
336-348. 
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marrow edema) with intravenous ibandronate." Osteoporosis International 16(12): 2063-2068. 
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Laslett, L. L., et al. (2012). "Zoledronic acid reduces knee pain and bone marrow lesions over 1 year: a 
randomised controlled trial." Ann Rheum Dis 71(8): 1322-1328. 
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randomized, controlled HORIZON Pivotal Fracture Trial." Journal of Bone and Mineral Research 26(5): 
984-992. 
16  
Reginster, J. Y., et al. (2013). "Strontium ranelate in the treatment of knee osteoarthritis: new insights and 
emerging clinical evidence." Therapeutic advances in musculoskeletal disease 5(5): 268-276. 
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Reginster, J. Y. (2014). "Efficacy and safety of strontium ranelate in the treatment of knee osteoarthritis: 
results of a double-blind randomised, placebo-controlled trial." Annals of the Rheumatic Diseases 73(2): 
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18  
Reginster, J. Y., et al. (2012). "Efficacy and safety of strontium ranelate in the treatment of knee 
osteoarthritis: results of a double-blind, randomised placebo-controlled trial." Annals of the Rheumatic 
Diseases. 
19  
Tan, Y. K. and P. G. Conaghan (2012). "Insights into osteoarthritis from MRI." International journal of 
rheumatic diseases 15(1): 1-7. 
20  
Guermazi, A., et al. (2013). "MRI-based semiquantitative scoring of joint pathology in osteoarthritis." Nat 
Rev Rheumatol 9(4): 236-251. 


Sponsor Name 
Clinical Study Protocol 
MIV-711-201 
CONFIDENTIAL 
Amendment 2 
68 of 71 
20 July 2016 
 
 
                                                                                                                                                                                     
21  
Roemer, F. W., et al. (2009). "Magnetic resonance imaging-based semiquantitative and quantitative 
assessment in osteoarthritis." Rheumatic Diseases Clinics of North America 35(3): 521-555. 
22  
Conaghan, P. G., et al. (2011). "Summary and recommendations of the OARSI FDA osteoarthritis 
Assessment of Structural Change Working Group." Osteoarthritis and cartilage / OARS, Osteoarthritis 
Research Society 19(5): 606-610. 
23  
Bowes, M. A., et al. (2013). "A novel method for bone area measurement provides new insights into 
osteoarthritis and its progression." Annals of the Rheumatic Diseases. In press. 
24  
Neogi, T., et al. (2013). "Magnetic resonance imaging-based three-dimensional bone shape of the knee 
predicts onset of knee osteoarthritis: data from the osteoarthritis initiative." Arthritis and Rheumatism 
65(8): 2048-2058. 
25  
Bowes, M. A. and P. G. Conaghan ( 2014). "Bone area demonstrates change in 3 months in a very small 
OA cohort." Osteoarthritis and Cartilage 22(suppl 1): 488. 
26  
Morko, J., et al. (2005). "Spontaneous development of synovitis and cartilage degeneration in transgenic 
mice overexpressing cathepsin K." Arthritis and Rheumatism 52(12): 3713-3717. 
27  
Schaller, S., et al. (2005). "In vitro, ex vivo, and in vivo methodological approaches for studying 
therapeutic targets of osteoporosis and degenerative joint diseases: how biomarkers can assist?" Assay 
Drug Dev Technol 3(5): 553-580. 
28  
Kraus, V. B., et al. (2011). "Application of biomarkers in the development of drugs intended for the 
treatment of osteoarthritis." Osteoarthritis and Cartilage 19(5): 515-542. 
29  
Van Spil, W. E., et al. (2010). "Serum and urinary biochemical markers for knee and hip-osteoarthritis: a 
systematic review applying the consensus BIPED criteria." Osteoarthritis and Cartilage 18(5): 605-612. 
30  
Pelletier, J. P., et al. (2013). "Disease-modifying effect of strontium ranelate in a subset of patients from 
the Phase III knee osteoarthritis study SEKOIA using quantitative MRI: reduction in bone marrow lesions 
protects against cartilage loss." Annals of the Rheumatic Diseases. 
31  
Reginster, J. Y., et al. (2013). "Efficacy and safety of strontium ranelate in the treatment of knee 
osteoarthritis: results of a double-blind, randomised placebo-controlled trial." Annals of the Rheumatic 
Diseases 72(2): 179-186. 
32  
Hayami, T., et al. (2012). "Inhibition of cathepsin K reduces cartilage degeneration in the anterior cruciate 
ligament transection rabbit and murine models of osteoarthritis." Bone 50(6): 1250-1259. 
33  
Connor, J. R., et al. (2009). "Protective effects of a cathepsin K inhibitor, SB-553484, in the canine partial 
medial meniscectomy model of osteoarthritis." Osteoarthritis and Cartilage 17(9): 1236-1243. 
34  
McDougall, J. J., et al. (2010). "Cathepsin K inhibition reduces CTXII levels and joint pain in the guinea 
pig model of spontaneous osteoarthritis." Osteoarthritis and Cartilage 18(10): 1355-1357. 
35  
"Guideline on Clinical Investigation of Medicinal Products Used in the Treatment of Osteoarthritis, 1 
August 2010, Doc. Ref. CPMP/EWP/784/97 Rev. 1." 
36  
Kellgren, J. H. and J. S. Lawrence (1957). "Radiological assessment of osteo-arthrosis." Ann Rheum Dis 
16(4): 494-502. 
37  
Seedor JG, Quartuccio HA, Thompson DD. The bisphosphonate alendronate (MK-217) inhibits bone loss 
due to ovariectomy in rats. J Bone Miner Res. 1991 Apr; 6(4):339-346. 
38  
Hayami T, Pickarski M, Wesolowski GA, McLane J, Bone A, Destefano J, et al. The role of subchondral 
bone remodeling in osteoarthritis: reduction of cartilage degeneration and prevention of osteophyte 
formation by alendronate in the rat anterior cruciate ligament transection model. Arthritis Rheum. 2004 
Apr; 50(4):1193-1206. 
39  
Pennypacker BL, Duong le T, Cusick TE, Masarachia PJ, Gentile MA, Gauthier JY, et al. Cathepsin K 
inhibitors prevent bone loss in estrogen-deficient rabbits. J Bone Miner Res. 2011 Feb; 26(2):252-262. 
40  
Bain SD, Jerome C, Shen V, Dupin-Roger I, Ammann P. Strontium ranelate improves bone strength in 
ovariectomized rat by positively influencing bone resistance determinants. Osteoporos Int. 2009 Aug; 
20(8):1417-1428. 
41  
Yu DG, Ding HF, Mao YQ, Liu M, Yu B, Zhao X, et al. Strontium ranelate reduces cartilage 
degeneration and subchondral bone remodeling in rat osteoarthritis model. Acta pharmacologica Sinica. 
2013 Mar; 34(3):393-402. 
42  
Dworkin, R. H., et al. (2005). "Core outcome measures for chronic pain clinical trials: IMMPACT 
recommendations." Pain 113(1-2): 9-19. 


Sponsor Name 
Clinical Study Protocol 
MIV-711-201 
CONFIDENTIAL 
Amendment 2 
69 of 71 
20 July 2016 
 
 
                                                                                                                                                                                     
43  
Dworkin, R. H., et al. (2014). "Outcome measures in placebo-controlled trials of osteoarthritis: 
responsiveness to treatment effects in the REPORT database." Osteoarthritis and Cartilage 19(5): 483-
492. 
44  
Turk, D. C., et al. (2003). "Core outcome domains for chronic pain clinical trials: IMMPACT 
recommendations." Pain 106(3): 337-345. 
45  
Turk, D. C., et al. (2008). "Identifying important outcome domains for chronic pain clinical trials: an 
IMMPACT survey of people with pain." Pain 137(2): 276-285. 
46  
Chang, L. (1994). "A Psychometric Evaluation of 4-Point and 6-Point Likert-Type Scales in Relation to 
Reliability and Validity " Applied psychological measurements 18(3): 205-215. 
47  
Hunter, D. J., et al. "Evolution of semi-quantitative whole joint assessment of knee OA: MOAKS (MRI 
Osteoarthritis Knee Score).[Erratum appears in Osteoarthritis Cartilage. 2011 Sep;19(9):1168]." 
Osteoarthritis & Cartilage 19(8): 990-1002. 
48  
Heimann, T. and H. P. Meinzer (2009). "Statistical shape models for 3D medical image segmentation: a 
review." Medical Image Analysis 13(4): 543-563. 
49  
Heimann, T., et al. (2007). "Automatic generation of 3D statistical shape models with optimal landmark 
distributions." Methods of Information in Medicine 46(3): 275-281. 
50  
Hunter, D. J., et al. (2010). "Can cartilage loss be detected in knee osteoarthritis (OA) patients with 3-6 
months' observation using advanced image analysis of 3T MRI?" Osteoarthritis and cartilage /OARS, 
Osteoarthritis Research Society 18(5): 677-683. 
51  
Murphy, L. B., et al. (2010). "Estimating medical costs attributable to osteoarthritis in the US population: 
comment on the article by Kotlarz et al." Arthritis and Rheumatism 62(8): 2566-2567; author reply 2567-
 2568. 
52  
Hawker, G. A., et al. (2008). "Development and preliminary psychometric testing of a new OA pain 
measure-an OARSI/OMERACT initiative." Osteoarthritis Cartilage 16(4): 409-414. 
53  
Dougados, M., et al. (2000). "Response criteria for clinical trials on osteoarthritis of the knee and hip: a 
report of the Osteoarthritis Research Society International Standing Committee for Clinical Trials 
response criteria initiative." Osteoarthritis Cartilage 8(6): 395-403. 
54  
(2007). "User’s Guide for the Measure of Intermittent and Constant Osteoarthritis Pain: ICOAP. Version 
3. December 2007." from http://www.osteoarthritisresearch.ca/pdf/ICOAP-user-guide.pdf. 
55  
Hurst, N. P., et al. (1994). "Validity of Euroqol--a generic health status instrument--in patients with 
rheumatoid arthritis. Economic and Health Outcomes Research Group." Br J Rheumatol 33(7): 655-662. 
56  
Brooks, R. (1996). "EuroQol: the current state of play." Health Policy 37(1): 53-72. 
57  
Harrison, M. J., et al. (2010). "Exploring the validity of estimating EQ-5D and SF-6D utility values from 
the health assessment questionnaire in patients with inflammatory arthritis." Health Qual Life Outcomes 
8: 21. 
58  
Svarstad, B. L., et al. (1999). "The Brief Medication Questionnaire: a tool for screening patient adherence 
and barriers to adherence." Patient Educ Couns 37(2): 113-124. 
59  
Salaffi, F., et al. (2004). "Minimal clinically important changes in chronic musculoskeletal pain intensity 
measured on a numerical rating scale." European journal of pain 8(4): 283-291. 
60  
Bennell, K. L., et al. (2011). "Lateral wedge insoles for medial knee osteoarthritis: 12 month randomised 
controlled trial." BMJ 342: d2912. 
61  
Stallard, N. (2012). "Optimal sample sizes for phase II clinical trials and pilot studies." Stat Med 31(11-
12): 1031-1042. 


Sponsor Name 
Clinical Study Protocol 
MIV-711-201 
CONFIDENTIAL 
Amendment 2 
70 of 71 
20 July 2016 
 
 
11 APPENDICES 
 
 


Sponsor Name 
Clinical Study Protocol 
MIV-711-201 
CONFIDENTIAL 
Amendment 2 
71 of 71 
20 July 2016 
 
 
11.1 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 
• Haematology 
 
9.5 
2 
 
9 
9 
 
85.5 
18 
Pharmacokinetic samples 
5 
6 
30 
Pharmacogenetic samples 
19 
2 
38 
Hepatitis B and C, HIV test, anti-HBs test, and 
anti-HBc test 
3 
1 
3 
Biomarker analysis 
15 
5 
75 
Additional unforeseeable samples 
 
 
50.5 
Total 
 
 
300.0 
 

SAP_001.pdf: 
PAREXEL International 
Statistical Analysis Plan 
 
Medivir 
Protocol: MIV-711-201 
Final 1.0 
22 June 2017 
 
Page 1 of 155 
 
STATISTICAL ANALYSIS PLAN 
 
Medivir AB 
 
 
Protocol 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 
 
 
PAREXEL Study Number: 226198 
 
 
 
Version: Final 1.0 
Date:  22 June 2017 
 
 
 
 
 
 
 
 
 
 






PAREXEL International 
Statistical Analysis Plan 
 
Medivir 
Protocol: MIV-711-201 
Final 1.0 
22 June 2017 
 
Page 4 of 155 
 
TABLE OF CONTENTS 
SIGNATURE PAGE - MEDIVIR .................................................................................................. 2 
SIGNATURE PAGE - PAREXEL ................................................................................................. 3 
TABLE OF CONTENTS ................................................................................................................ 4 
1. 
STATISTICAL ANALYSIS PLAN .................................................................................. 9 
2. 
STUDY OBJECTIVES AND HYPOTHESES ................................................................. 9 
2.1.1 
PRIMARY OBJECTIVE ................................................................................................... 9 
2.1.2 
HYPOTHESIS TO BE TESTED....................................................................................... 9 
2.2 
SECONDARY OBJECTIVES .......................................................................................... 9 
2.3 
EXPLORATORY OBJECTIVES ................................................................................... 10 
2.3.1 
BIOMARKERS ............................................................................................................... 10 
2.3.2 
PHARMACOKINETICS ................................................................................................ 10 
3. 
STUDY DESIGN ............................................................................................................ 11 
3.1 
STUDY ENDPOINTS ..................................................................................................... 11 
3.1.1 
PRIMARY ENDPOINT .................................................................................................. 11 
3.1.2 
SECONDARY ENDPOINT ............................................................................................ 12 
3.1.3 
OTHER SECONDARY ENDPOINTS ........................................................................... 12 
3.1.4 
SAFETY ENDPOINTS ................................................................................................... 12 
3.2 
STUDY POPULATION .................................................................................................. 13 
3.3 
SAMPLE SIZE ESTIMATION ....................................................................................... 13 
3.4 
DOSE ADMINISTRATION ........................................................................................... 13 
3.5 
RANDOMIZATION ....................................................................................................... 14 
3.6 
PATIENT REPLACEMENT........................................................................................... 14 
3.7 
TRIAL BLINDING ......................................................................................................... 14 
3.8 
PROTOCOL DEVIATIONS ........................................................................................... 14 
3.9 
INTERIM ANALYSIS .................................................................................................... 15 
3.10 
EXTENSION PROTOCOL ............................................................................................. 15 
4. 
STUDY ANALYSIS VARIABLES ................................................................................ 15 
4.1 
DEMOGRAPHIC AND BACKGROUND VARIABLES .............................................. 15 
4.2 
SAFETY VARIABLES ................................................................................................... 16 
4.2.1 
ADVERSE EVENTS ...................................................................................................... 16 
4.2.2 
CLINICAL LABORATORY TESTS ............................................................................. 16 


PAREXEL International 
Statistical Analysis Plan 
 
Medivir 
Protocol: MIV-711-201 
Final 1.0 
22 June 2017 
 
Page 5 of 155 
 
4.2.3 
OTHER LABORATORY TESTS ................................................................................... 16 
4.2.4 
VITAL SIGNS ................................................................................................................. 17 
4.2.5 
ELECTROCARDIOGRAMS .......................................................................................... 17 
4.2.6 
PHYSICAL EXAMINATION ........................................................................................ 17 
4.2.7 
PRIOR AND CONCOMITANT MEDICATIONS ......................................................... 17 
4.2.8 
ADHERENCE TO STUDY MEDICATIONS ................................................................ 18 
4.2.9 
PHONE CALL TO ASSESS SAFETY AND TOLERABILITY ................................... 18 
4.3 
PHARMACODYNAMIC VARIABLES - EFFICACY ................................................. 18 
4.3.1 
PAIN ................................................................................................................................ 18 
4.3.2 
MRI AND IMAGING ..................................................................................................... 18 
4.3.3 
PATIENT REPORTED OUTCOMES (PRO)................................................................. 20 
4.3.3.1 NRS SCORES - KNEE PAIN AND FUNCTION IN THE LAST WEEK ..................... 20 
4.3.3.2 ICOAP SCORES ............................................................................................................. 21 
4.3.3.3 WOMAC SCORES ......................................................................................................... 21 
4.3.3.4 OMERACT SCORES ...................................................................................................... 22 
4.3.3.5 GLOBAL IMPROVEMENT SCORES ........................................................................... 22 
4.3.3.6 QUALITY OF LIFE ........................................................................................................ 23 
4.3.3.7 BRIEF MEDICATION QUESTIONNAIRE .................................................................. 23 
4.3.3.8 E-DIARY ASSESSNMENT OF NRS AND ANALGESIC USE ................................... 23 
4.3.4 
SECONDARY EFFICACY PARAMETERS ................................................................. 24 
4.3.4.1 BIOMARKERS ............................................................................................................... 24 
4.3.4.2 OTHER IMAGING ASSESSMENTS ............................................................................ 24 
4.4 
ANALYSIS POPULATIONS ......................................................................................... 24 
4.4.1 
INTENT-TO-TREAT POPULATION (ITT) .................................................................. 24 
4.4.2 
MODIFIED INTENT-TO-TREAT POPULATION (MITT) .......................................... 24 
4.4.3 
PER PROTOCOL POPULATION (PPS) ....................................................................... 25 
4.4.4 
SAFETY ANALYSIS POPULATION (SAF) ................................................................ 25 
5. 
GENERAL CONSIDERATIONS FOR DATA PRESENTATIONS ............................. 25 
5.1 
SOFTWARE .................................................................................................................... 26 
6. 
PATIENT AND TREATMENT INFORMATION ......................................................... 26 
6.1 
PATIENT DISPOSITION ............................................................................................... 26 
6.2 
PATIENTS EXCLUDED FROM ANALYSIS POPULATIONS .................................. 27 
6.3 
ELIGIBILITY CRITERIA .............................................................................................. 27 


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6.4 
EXCLUSION TESTS ...................................................................................................... 27 
6.5 
PROTOCOL DEVIATIONS ........................................................................................... 27 
6.6 
DEMOGRAPHIC DATA ................................................................................................ 27 
6.7 
MEDICAL HISTORY ..................................................................................................... 27 
6.8 
PRIOR AND CONCOMITANT MEDICATION ........................................................... 28 
6.9 
DOSE ADMINISTRATION ........................................................................................... 28 
7. 
PHARMACODYNAMIC ANALYSIS - EFFICACY .................................................... 28 
7.1 
NRS PAIN DATA ........................................................................................................... 28 
7.2 
STATISTICAL ANALYSIS OF THE NRS PAIN DATA ............................................. 29 
7.2.1 
MULTIPLICITY ADJUSTMENT FOR THE PRIMARY ENDPOINT ........................ 31 
7.2.2 
VISUALIZATIONS FOR THE PRIMARY ENDPOINT .............................................. 31 
7.3 
KEY SECONDARY ANALYSIS: MRI OF BONE AREA IN TARGET 
KNEE ............................................................................................................................... 31 
7.3.1 
STATISTICAL ANALYSIS OF THE MRI OF BONE AREA IN TARGET 
KNEE ............................................................................................................................... 31 
7.4 
SECONDARY ANALYSIS: MRI OF CARTILAGE THICKNESS IN 
TARGET KNEE .............................................................................................................. 32 
7.4.1 
STATISTICAL ANALYSIS OF THE MRI OF CARTILAGE THICKNESS 
IN TARGET KNEE ......................................................................................................... 32 
7.5 
SECONDARY ANALYSIS: MRI OF TOTAL BML VOLUME IN 
TARGET KNEE .............................................................................................................. 32 
7.5.1 
STATISTICAL ANALYSIS OF THE MRI OF TOTAL BML VOLUME IN 
TARGET KNEE .............................................................................................................. 33 
7.6 
ANALYSIS OF OTHER SECONDARY IMAGING ASSESSMENTS ........................ 33 
7.7 
ANALYSIS OF OTHER PATIENT REPORTED OUTCOMES (PROS) ..................... 34 
7.7.1 
INTERMITTENT AND CONSTANT OSTEOARTHRITIS PAIN (ICOAP) 
KNEE VERSION ............................................................................................................ 34 
7.7.2 
ANALYSIS OF THE WOMAC ...................................................................................... 35 
7.7.3 
(OARSI)-OMERACT RESPONDER CRITERIA .......................................................... 35 
7.7.4 
GLOBAL IMPROVEMENTS ........................................................................................ 37 
7.7.5 
QUALITY OF LIFE PRO – EQ-5D-5L .......................................................................... 37 
7.7.6 
E-DIARY FOR PATIENT PAIN .................................................................................... 38 
7.7.7 
BIOMARKERS FROM SERUM AND URINE SAMPLES .......................................... 38 
8. 
SAFETY ANALYSIS ..................................................................................................... 39 
8.1 
ADVERSE EVENTS ...................................................................................................... 39 


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8.2 
CLINICAL 
SAFETY 
LABORATORY 
TESTS 
(HEMATOLOGY, 
CHEMISTRY, URINALYSIS) ....................................................................................... 40 
8.2.1 
HEMATOLOGY AND CHEMISTRY ........................................................................... 40 
8.2.2 
URINALYSIS ................................................................................................................. 41 
8.3 
OTHER BLOOD AND URINE SAMPLES ................................................................... 41 
8.4 
VITAL SIGNS ................................................................................................................. 41 
8.5 
12-LEAD SAFETY ECG ................................................................................................ 41 
8.6 
PHYSICAL EXAMINATION AND WEIGHT .............................................................. 42 
8.7 
PHONE CALL TO ASSESS SAFETY ........................................................................... 42 
9. 
REPORTING OUTPUT .................................................................................................. 43 
10. 
REFERENCES ................................................................................................................ 44 
11. 
SUMMARY TABLES .................................................................................................... 45 
12. 
FIGURES ......................................................................................................................... 48 
13. 
LISTINGS........................................................................................................................ 50 
14. 
TABLE SHELLS ............................................................................................................. 52 
15. 
LISTING SHELLS ........................................................................................................ 103 


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Abbreviations and definitions 
AE 
Adverse event 
BLQ 
Below the lower limit of quantification 
BMI 
Body Mass Index 
BML 
Bone Marrow Lesions 
CI 
Confidence interval 
CS 
Clinically significant 
CV 
Coefficient of variation 
ECG 
Electrocardiogram 
FAS 
Full analysis set 
h 
Hour 
HBsAg 
Hepatitis B surface antigen 
HCV 
Hepatitis C virus 
HIV 
Human immunodeficiency virus 
IMP 
Investigational Medicinal Product 
LLOQ 
Lower limit of quantification 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOAKS 
MRI Osteoarthritis Knee Score 
NCS 
Not clinically significant 
NRS 
Numeric Rating Scale 
NK 
Not known 
OA 
Osteoarthritis 
PK 
Pharmacokinetic 
QOL 
Quality of Life 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation  
SOC 
System Organ Class 
t½ 
Apparent terminal elimination half-life  
TEAE 
Treatment-emergent adverse event 
TIC 
Time Integrated Concentrations 
Tmax 
Time corresponding to occurrence of Cmax  
WHO-DD 
World Health Organisation - Drug Dictionary 
 
 
 
 


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1. 
Statistical Analysis Plan 
This Statistical Analysis Plan (SAP) is based on the final protocol, dated 09 September 
2015 as well as all protocol amendments finalized including: amendment 1 dated 13 
January 2016 and amendment 2 dated 20 July 2016. The SAP provides details on the 
planned statistical methodology for the primary and secondary analysis of the study data.  
The SAP also outlines the statistical programming specifications for the tables, listings 
and figures.  It describes the safety and pharmacodynamic (PD) data, the handling of that 
data; the anticipated data transformations and manipulations, and other details of the 
analyses not provided in the study protocol.  This SAP covers the planned analysis to be 
conducted by PAREXEL of all safety and efficacy data as described in the protocol, and 
as collected in the source data. 
2. 
Study Objectives and Hypotheses 
2.1.1 Primary Objective 
To assess the effect of MIV-711 on knee pain (at week 26), as measured by an 11-point 
numerical rating scale in patients with symptomatic and radiographic knee osteoarthritis 
2.1.2 Hypothesis to be Tested 
The primary hypothesis of this study is that MIV-711 will reduce pain in patients with 
moderate knee osteoarthritis diagnosed based on symptomatic and radiologic criteria.  
2.2 
Secondary Objectives 
To assess the effect of MIV-711 on MRI target knee bone area in patients with 
symptomatic and radiographic knee OA over 26 weeks.  
Other secondary objectives include: 
 
To assess, in patients with symptomatic and radiographic knee OA, over 26 weeks:  
- 
*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)  


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- 
*The effect of MIV-711 on MRI bone area in regions other than primary region   
- 
*The effect of MIV-711 on MRI bone marrow lesion volume 
- 
*The effect of MIV-711 on MRI cartilage thickness loss 
- 
The effect of MIV-711 in the semi quantitative MRI Osteoarthritis Knee Score 
(MOAKS) parameters 
- 
*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  
- 
The safety and tolerability of MIV-711  
- 
The effect of MIV-711 on biomarkers for bone resorption (serum CTX-I) and for 
cartilage degradation (urine CTX-II) assessment 
 
*Assessments on the target knee will be used to address these other secondary objectives. 
2.3 
Exploratory Objectives  
In addition, the study will address the following exploratory objectives. 
2.3.1 Biomarkers  
- Assessment of the effect of MIV-711 on serum and urinary biomarkers of relevance for 
OA  
 
- Serum CTXI and urine CTXII will be the only biomarkers covered in this SAP; all other 
biomarkers mentioned in the study protocol will not be included in this SAP.  
 
- Baseline (visit 2) and steady state treatment (visit 8) blood and urinary samples will be 
stored for patients who sign a separate voluntary Informed Consent Form (ICF) for 
potential future pharmacogenomics and disease-related proteomic, genomics, 
metabolomics and lipidomics analyses, and will not be considered in this SAP. 
 
The analysis of all serum biomarkers for: Procollagen type I N-terminal propeptide 
(sPINP), bone specific alkaline phosphatase (sBSAP), tartrate-resistant acid phosphatases 
(TRAP5b) will be described in a separate report (if analysed), and will not be considered 
in this SAP. 
 
 
2.3.2 Pharmacokinetics  
The pharmacokinetics and metabolism of MIV-711 and the relationship to patient factors 
and concomitant medications will be described in a separate report and will not be 
considered in this SAP.  


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3. 
Study Design 
This is a multicentre, randomised, placebo-controlled, double-blind, three-arm parallel, 
Phase IIa study to evaluate the efficacy, safety and tolerability of MIV-711 in patients 
with symptomatic and radiographic knee OA. A total of 240 patients with knee OA 
meeting the eligibility criteria and who provide written informed consent will be 
randomised on a 1:1:1 basis to the intervention (MIV-711 low dose 100 mg or high dose 
200 mg) or placebo. Six sites distributed in 6 European countries will be used to recruit 
patients. 
 
Patients who are eligible and agree to continue with the study will return for the baseline 
visit within 30 days of the screening visit. After baseline assessments have been 
completed, patients will be randomised in a 1:1:1 ratio via a central secure 24-hour 
randomisation service to the intervention (MIV-711) arms or the placebo-controlled arm.  
 
 Intervention arm I: Patients will receive a once-daily 100 mg oral dose of MIV-
711 for 26 weeks in addition to their current medication. 
 Intervention arm II: Patients will receive a once-daily 200 mg oral dose of MIV-
711 for 26 weeks in addition to their current medication.  
 Control arm: Patients will receive a once-daily oral dose of matching placebo for 
26 weeks in addition to their current medication.  
 
The study consists of a screening period of approximately 4 weeks (visit 1), a baseline 
assessment period at visit 2, a double-blind treatment period of visit 2 through visit 8, and 
a follow-up period of 4 weeks (visit 9) after the last dose of study treatment is 
administered.  Study visits for clinical assessment and questionnaires will occur at visit 2 
(baseline), visit 5, visit 6, and visit 8, regardless of treatment group. The end of the study 
is defined as the last visit (visit 9, week 30) of the last patient or, if applicable, when the 
last patient has rolled over to study MIV-711-202 and having finalized visit 2 of that 
study. 
3.1 
Study Endpoints 
The Outcome Measures in Rheumatoid Arthritis Clinical Trials (OMERACT) suggests 
that outcome measures for OA studies should include: 
- 
Pain 
- 
Function 
- 
Quality of Life (QOL)                        
3.1.1 Primary Endpoint 
The primary outcome variable is ‘Pain’ and will be measured using the change from 


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baseline in NRS “average” knee pain in the target knee with 7 days recall, between visit 2 
(baseline) and visit 8, using a 0 to 10 NRS. The scale ranges from 0 indicating —“no 
pain“, to 10 indicating —“pain as bad as it could be“.  
 
Other pain variables will include: 
 
 worst target knee pain 
 average contralateral knee pain 
 constant and intermittent OA pain. 
3.1.2 Secondary Endpoint 
The key secondary endpoint will be the MRI of bone area in the medial femoral condyle.  
Bone parameters will be measured for MRIs of the target knee taken at visit 2 (baseline) 
and visit 8. The MRI of bone area will be assessed for the target knee.  
3.1.3 Other Secondary Endpoints 
- 
*NRS e-diary assessment 
- 
Analegsics use e-diary assessment 
- 
*Bone Marrow Lesions (MOAKS) 
- 
*Articular Cartilage (MOAKS) 
- 
*Osteophytes (MOAKS) 
- 
*Mean Cartilage thickness (Imorphics, Ltd.) 
- 
*Combined Bone Marrow Lesion Volume (Imorphics, Ltd.) 
- 
Patient Reported Outcomes: to assess for pain, function, disease activity, and 
QOL 
- 
Laboratory assessments for blood and urine biomarkers (Serum CTXI and 
urine CTXII) 
 
*These other secondary endpoints will be assessed for the target knee.  
3.1.4 Safety Endpoints 
- 
Adverse events  
- 
Clinical laboratory tests (hematology, clinical chemistry, and urinalysis) 
- 
Vital signs (blood pressure, pulse, and body temperature) 
- 
12-lead ECGs: PR interval, QRS interval, RR interval, QT interval, and QTc 
interval (Bazett’s correction [QTcB], Fridericia’s Correction [QTcF]), heart 
rate  
- 
Concomitant medication  


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- 
Physical examination 
- 
Rescue medication use  
3.2 
Study Population 
 
The study population includes knee OA patients 40 to 80 years of age inclusive. 
The patient population fulfils the ACR criteria for OA and in addition must be 
radiographically confirmed as Kellgren and Lawrence (K-L) x-ray classification grade 2 
or 3 and with a current average knee pain of greater or equal to 4 and less than 10 on a 1 
to 10 NRS pain score. Patients must be able to provide written consent and meet all the 
inclusion criteria and none of the exclusion criteria.  
3.3 
Sample Size Estimation 
It is planned to recruit 240 patients at 6 centers in 6 countries for this 
study. Recruitment will be competitive across all 6 sites.  
The distribution of patients across treatment groups will be as: 
 
- 
MIV-711 100 mg: 80 patients  
- 
MIV-711 200 mg: 80 patients  
- 
Placebo: 80 patients.  
 
Details of the formal sample size calculation are provided in the 
protocol Section 8.7.  
3.4 
Dose Administration 
 
Patients will receive once-daily (OD) 100 mg or 200 mg oral dose of MIV-711, or 
placebo for 26 weeks in addition to their current medication.  The IMP should be taken 
OD in the morning approximately 24 hours apart, before breakfast; breakfast can be taken 
approximately one hour later. The first dose is administered at the site during visit 2 
(baseline). IMP should be dispensed during the visits and unused IMP returned by the 
patients for drug accountability at visit 5, visit 6, and visit 8. On days when the patient 
will visit the site the IMP must be taken at the site fasting (and not at home) and the time 
of the intake must be recorded in the source documents.  
 


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3.5 
Randomization 
A total of 240 patients with knee OA meeting the eligibility criteria and who provide 
written informed consent will be randomised on a 1:1:1 basis to the intervention (MIV-
711 low dose 100 mg or high dose 200 mg) or placebo.  
 
The randomization allocation will be assigned through a centralized automated code 
holder that distributes the next available randomisation number on the randomisation list 
to the requesting site as described below.  
 
Allocation of patients to the treatment groups will proceed through the use of an 
Interactive Response Technology (IRT) System [Interactive Web Response 
(IWR)/Interactive Voice Response (IVR) system].  
 
The study site will obtain the randomization number and container number assignment 
from the IRT system. The randomization number and the date on which the 
randomization number was assigned will be recorded on the eCRF. Once patient 
screening numbers, container numbers, and randomization numbers have been assigned, 
they cannot be reassigned.  
3.6 
Patient Replacement 
 
In order to perform the modified intent to treat (mITT) analysis, and to enable safety 
analyses, all patients who discontinue their randomised medication will be asked to still 
complete their follow-up visit (visit 9) as outlined in the study schedule.  
 
Patients who withdraw from the study will not be replaced. 
 
3.7 
Trial Blinding 
A double-blind/masking technique will be used. 
3.8 
Protocol Deviations 
The following criteria will be used to exclude a patient from the per-protocol analysis  
set:  
- 
Incorrect diagnosis  
- 
Arthroscopy in the target knee during the study period  
- 
Missing more than 5 doses of MIV-711 (based on accountability) 


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These criteria will be reviewed using blinded data prior to data analysis.  Note: this is not 
an exhaustive list of deviations, these are only the deviations specified per protocol. The 
discussion during the BDRM will review all deviations collected at each site. All protocol 
deviations will be reviewed, evaluated and discussed between CRO and Sponsor before 
DBL. 
3.9 
Interim Analysis 
No formal interim analysis that would allow early stopping of the study on the basis of 
demonstrating efficacy or futility is planned. Unblinded interim safety data (i.e. no 
efficacy analyses) will be reviewed during data monitoring committee (DMC) meetings 
held after 50, 100, 150 and 200 patients have completed visit 6.  
3.10 Extension Protocol  
All patients in the current study at the participating sites included in the extension study 
MIV-711-202 will be given the opportunity to participate in the extension protocol 
provided they meet the MIV-711-202 eligibility criteria.  
 
4. 
Study Analysis Variables 
4.1 
Demographic and Background Variables 
The following demographic and anthropometric information will be recorded at 
screening: 
 Date of informed consent 
 Medical and surgical history (including previous and current medical conditions and 
medications) 
 Age calculated as (date of informed consent – date of birth)/365.25 
 Gender 
 Ethnic origin 
 Race 
 Height (cm) 
 Body weight (kg) 
 Body mass index (BMI) (kg/m2) 
 


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4.2 
Safety Variables 
4.2.1 Adverse Events 
 
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 9) is completed. 
4.2.2 Clinical Laboratory Tests 
Blood samples for hematology and clinical chemistry, and urinalysis assessments will be 
collected during all study visits: Visit 1 (screening), Visit 2 (Week 1), Visit 3 (Week 2), 
Visit 4 (Week 4), Visit 5 (Week 8), Visit 6 (Week 14), Visit 7 (Week 20), Visit 8 (Week 
26), and Visit 9 (Week 30, follow-up). 
 
The following safety laboratory parameters will be measured: 
 
Hematology: WBC and differential, % and absolute for: neutrophils, lymphocytes, 
monocytes, eosinophils, basophils; hemoglobin, hematocrit, 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 (at screening only), PTH (parathyroid 
hormone). 
 
Urinalysis: with microscopic: specific gravity, pH, protein, glucose, ketones, nitrites, 
blood and leukocyte esterase  
 
4.2.3 Other Laboratory Tests 
 
 Post-menopausal determination at screening: Follicle stimulation hormone (FSH) 
in female patients. 
 
 Urine Drug Screen measured at screening and Visit 5 (Week 8): Amphetamine, 
Benzodiazepines, THC, Cocaine, Oxycodone and Opiate.  
 
 Serology Testing measured at screening: Hepatitis B surface antigen, total 
Hepatitis B core antibodies, antibodies to Hepatitis B Surface antigen, Hepatitis C 
virus, HIV 1 and 2.  


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4.2.4 Vital Signs 
 
Vital signs (body temperature, heart rate, blood pressure, oxygen saturation) will be 
performed at all clinic visits prior to IMP dosing: Visit 1 (screening), Visit 2 (Week 1), 
Visit 3 (Week 2), Visit 4 (Week 4), Visit 5 (Week 8), Visit 6 (Week 14), Visit 7 (Week 
20), Visit 8 (Week 26), and Visit 9 (Week 30, follow-up). All assessments will be 
collected in the supine position. 
 
Height will be measured at visit 1 (screening) and weight will be measured at visit 1 
(screening) and visit 8.  
 
4.2.5 Electrocardiograms 
 
A 12-lead ECG will be performed at all clinic visits.  12-lead serial ECGs will be 
recorded at visit 2 (baseline) pre-dosing and after 30 minutes, 1 hour and 2 hours post-
dosing (± 10 minutes). Standard 12-lead ECG will be performed at all other visits 30 
minutes after dosing (± 10 minutes).  
 
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.  
4.2.6 Physical Examination 
A standard complete physical examination will be performed at visit 1 (screening), visit 2 
(baseline), visit 5, visit 6 and visit 8.  
 
A targeted physical examination will be performed at visit 3, visit 4, and visit 7 assessing 
the following: lungs, heart, abdomen, extremity exam for the presence of peripheral 
oedema and lymph nodes. A standard clinical examination of both knees will be 
undertaken at all visits. Any clinically significant changes from visit 2 (baseline) should 
be recorded as AEs.  
4.2.7 Prior and Concomitant Medications 
All 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 


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permitted as concomitant medications to manage ongoing or chronic, stable medical 
conditions. Medications taken within 4 weeks of the screening visit will be documented 
as prior medication. Medication taken after the first dose of IMP will be documented as 
concomitant medication. Prior medications that are ongoing past Visit 2 IMP 
administration that involve a different dose level, frequency etc. from initial 
administration will be recorded as concomitant medication. Prior medications that are 
ongoing past Visit 2 IMP administration that do not involve a different dose level from 
initial administration will remain as prior medications. 
The Brief Medication Questionnaire self-reported measure for the use of concomitant 
medication will be included at visit 5, visit 6, and visit 8.  
4.2.8 Adherence to Study Medications 
Patients will be asked to return any unused study medication at visit 5, visit 6, and visit- 
8 and drug accountability will be conducted.  
4.2.9 Phone Call to Assess Safety and Tolerability 
Follow-up telephone calls to assess safety and tolerability will occur 5 to 9 days after 
visit 2, visit 3, visit 4, visit 5, visit 6, and visit 7. 
4.3 
Pharmacodynamic Variables - Efficacy 
4.3.1 Pain 
The primary efficacy outcome variable is ‘Pain’ and will be measured using the change 
from baseline in the average pain score for the target knee, between visit 2 (baseline) and 
visit 8, using a 0 to 10 NRS. The scale ranges from 0 indicating —“no pain“, to 10 
indicating —“pain as bad as it could be“.  
4.3.2 MRI and Imaging  
The key secondary endpoint will be the change from visit 2 (baseline) to visit 8 on MRI 
of bone area.  A secondary endpoint of interest will be the change from visit 2 (baseline) 
to visit 8 on MRI cartilage thickness, and the volume of bone marrow lesions. Below are 
the denominations of the data items that will provide the basis for bone area and cartilage 
thickness and bone marrow lesion volume. 
 
 MF_TAB: Area of bone in the medial femur region, MF 
 CM_FEMUR_THCTAB: Average thickness of cartilage in the central medial 
femur region 


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 CM_TIBIA_THCTAB: Average thickness of cartilage in the central medial tibia 
region 
 TOTAL_BML_VOLUME: Combined volume of all BML regions 
 
Other secondary endpoints will include the analysis of MRIs using MOAKS scoring.  
 
MRI assessment using MOAKS scoring will be used to assess the following features, as 
provided by PAREXEL MRI:  
 
 Bone Marrow Lesions (BMLs) and cysts. This involves 15 subregions graded for 
BML size (including ill-defined lesion and cysts) measuring the total volume of 
the subregion occupied by BML(s). Grade 0= none, grade 1 < 33% of subregional 
volume, grade 2 = 33 to 66% of subregional volume and grade 3 > 66% of 
subregional volume.  
 
 Articular Cartilage: This involves 14 articular cartilage regions graded for size of 
any cartilage loss (including partial and full thickness loss) as a percentage of 
surface area as related to the size of each individual region surface and percentage 
of loss in this subregion that is full-thickness loss.  
 
 Osteophytes: This involves 12 sites scored for presence and size of osteophytes. 
Grade 0=none, Grade 1= small, Grade 2 = medium, Grade 3 = large.  
 
The specific subregrions associated with the above three groups of MOAKS scoring are 
outlined in the table below: 
 
Bone Marrow Lesions (BMLs) and cysts 
Articular Cartilage 
Osteophytes 
Medial Patella  
Lateral Patella  
Medial Femur Trochlea 
Medial Femur Central 
Medial Femur Posterior 
Lateral Femur Trochlea 
Lateral Femur Central 
Lateral Femur Posterior 
Medial Tibia Anterior 
Medial Tibia Central 
Medial Tibia Posterior 
Subspinous 
Lateral Tibia Anterior 
Lateral Tibia Central 
Lateral Tibia Posterior  
Medial Patella 
Lateral Patella 
Medial Femur Trochlea 
Medial Femur Central 
Medial Femur Posterior 
Lateral Femur Trochlea 
Lateral Femur Central 
Lateral Femur Posterior 
Medial Tibia Anterior 
Medial Tibia Central 
Medial Tibia Posterior 
Lateral Tibia Anterior 
Lateral Tibia Central 
Lateral Tibia Posterior 
Superior Patella 
Inferior Patella 
Medial Patella  
Lateral Patella  
Medial Femur Trochlea 
Medial Femur Central 
Medial Femur Posterior 
Lateral Femur Trochlea 
Lateral Femur Central 
Lateral Femur Posterior 
Tibia Medial 
Tibia Lateral 
  
Bone Marrow Lesions (BMLs) and cysts: The 15 subregions will be assessed for: 


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 Size of BML 
 Number of BMLs 
 Percentage that is BML  
 
Articular Cartilage: The 14 subregions will be assessed for: 
 
 Size of any cartilage loss 
 Percentage of Full Thickness Loss 
 
4.3.3 Patient Reported Outcomes (PRO) 
Patient-reported outcomes will be recorded using questionnaires at visit 2 (baseline) and 
at visit 5, visit 6, and visit 8. These PRO data will be used as measures of pain, function 
and disease activity.  
4.3.3.1 
NRS Scores - Knee Pain and Function in the Last Week 
For the purposes of the questions below, the target knee is defined as the knee studied in 
this trial. Pain in your knee relates to any knee symptom you may experience for example 
pain or aching. 
 
The scale ranges for NRS pain scores range from 0 indicating —“no pain“, to 10 
indicating —“pain as bad as it could be“. The NRS scales will be used to assess for:  
 
1) NRS question 1: NRSPTO (Primary Endpoint). On average, how would you rate the 
overall pain severity in your target knee over the last week (7 days)? 
 
2) NRS question 2: NRSPAINW. How would you rate your worst pain severity in your 
target knee over the last week (7 days)? 
 
3) NRS question 3: NRSPAINS. On average, how would you rate the overall pain 
severity in your other knee over the last week (7 days)? 
 
4) NRS question 4: NRSACT. Over the last week (7 days), how active do you think 
your target knee arthritis has been? 
 
5) NRS question 5: NRSSAT. Over the last week (7 days), how satisfied have you been 
with your target knee function? 


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For purposes of this SAP NRS question 4 refers to the patients “Global Assessment 
Score”. 
4.3.3.2 
ICOAP Scores 
Intermittent and constant osteoarthritis pain (ICOAP): an 11-item tool designed to assess 
constant and intermittent pain. Higher scores indicate worse constant and intermittent 
pain. The items assessed include: 
 
 IP1- How intense has constant knee pain been  
 IP2-Constant knee pain affecting sleep 
 IP3-Constant knee pain - quality of life 
 IP4-Frustrated by your constant knee pain 
 IP5-Upset by your constant knee pain 
 IP6-Intensity of pain that comes and goes 
 IP7-Frequency pain that comes and goes 
 IP8-Pain comes and goes affecting sleep 
 IP9-Pain comes and goes quality of life 
 IP10-Frustration pain that comes and goes 
 IP11-Upset pain that comes and goes 
4.3.3.3 
WOMAC Scores 
Western Ontario and McMaster Universities Osteoarthritis Index (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. Using an 11-box NRS scale, higher scores 
indicate worse pain, stiffness and physical function. Items assessed include: 
 
 WOMAC1-Pain - walking on a flat surface 
 WOMAC2-Pain - going up or down stairs 
 WOMAC3-Pain - at night while in bed 
 WOMAC4-Pain - sitting or lying down 
 WOMAC5-Pain - while standing 
 WOMAC6-Stiffness after first woke up in morning 
 WOMAC7-Stiffness sitting or lying down 
 WOMAC8-Difficulty - When going down the stairs 
 WOMAC9-Difficulty - When going up the stairs 
 WOMAC10-Difficulty - Getting up from a sitting 
 WOMAC11-Difficulty - While standing 


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 WOMAC12-Difficulty - When bending to the floor 
 WOMAC13-Difficulty - Walking on a flat surface 
 WOMAC14-Difficulty - Getting in or out of a car 
 WOMAC15-Difficulty - While going shopping 
 WOMAC16-Difficulty - When putting on your socks 
 WOMAC17-Difficulty - When getting out of bed 
 WOMAC18-Difficulty - When taking off your socks 
 WOMAC19-Difficulty - While lying in bed 
 WOMAC20-Difficulty - Getting in or out of bath 
 WOMAC21-Difficulty - While sitting 
 WOMAC22-Difficulty - Getting on or off toilet 
 WOMAC23-Difficulty - Performing heavy duties 
 WOMAC24-Difficulty - Performing light duties 
4.3.3.4 
OMERACT Scores 
Osteoarthritis Research Society International (OARSI)-OMERACT Responder index [2, 
3] will be calculated using the WOMAC pain and function subscales and the patient‘s 
global assessment score. A responder will be defined as any subject that satisfies one of 
the following two overall conditions:  
 
CASE 1.  Improvement in pain or function ≥50% and absolute change ≥20 
 
CASE 2. Improvement in at least two of the following conditions: 
1. pain ≥20% and absolute change ≥10   
2. function ≥20% and absolute change ≥10  
3. patients‘ global assessment ≥20% and absolute change ≥10  
 
Higher scores indicate worse pain, stiffness and physical function so that an 
“improvement” is only concerned with negative changes (or decreases) from baseline. 
Positive increases in scores relative to baseline suggest a worsening of pain (scores 
increasing over time suggests pain is increasing in severity over time).  
4.3.3.5 
Global Improvement Scores 
Global improvements in knee problem, knee pain and knee function (Ability to use knee) 
recorded on a 6-point likert scale at visit 5, visit 6, and visit 8 only: (completely better, 
much better, better, no change, worse, much worse)   
 


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4.3.3.6 
Quality of Life 
At visit 2 (baseline) and visit 8:  EuroQol -5 Dimensions (EQ-5D-5L) - a generic measure 
of self-reported health status.  Items assessed include: 
 
 Usual Activities 
 Anxiety/Depression 
 Self-Care 
 Pain/Discomfort 
 Mobility 
 Health Rating 
4.3.3.7 
Brief Medication Questionnaire  
The Brief Medication Questionnaire is a self-reported measure for the use of concomitant 
medication and will be administered at visit 5, visit 6, and visit 8. Items assessed include: 
 
 How much did you take each time 
 How many days did you take it 
 The dosage times are inconvenient 
 How many times per day did you take it 
 It is hard to get my refill on time 
 How many times did you miss taking it 
 It is hard to open the container 
 Hard to read the print on the container 
 For what reason were you taking it 
 It is hard to remember all doses 
 Stop taking meds since(V5) or (V6, V8) 
 Medication Name 
4.3.3.8 
E-Diary Assessnment of NRS and Analgesic Use 
In an e-diary format, a patient knee pain diary (NRS) and analgesia questionnaire will be 
completed daily every 12 hours (AM, PM) during three two-week periods prior to visit 2 
(baseline), visit 6 and visit 8. Baseline will be defined as the last observation prior to the 
first dose of investigational product. The assessments in the e-diary comprise:  
 
 Average overall knee pain severity in the target knee over the past 12 h (0 -10 
NRS)  
 Adherence to usual analgesics regimen:  
o Has patient taken any pain medication over last 12 hours? (Yes, No). 


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o Classify your pain medication usage over the last 12 hours: (More than 
normal, Normal, Less than normal)  
 Intake of IMP (note: the e-diary device is kept by the patients for the  
full duration of the study, intake of IMP will be registered daily throughout the  
study)  
4.3.4 Secondary Efficacy Parameters 
4.3.4.1 
Biomarkers 
Secondary Endpoints: Blood and urine samples for the analysis of secondary and 
exploratory bone and cartilage markers of relevance for OA disease for analysis of serum 
CTX-I and urinary CTX-II biomarkers will be taken at visit 2 (baseline) and visit 4, visit 
6, visit 8, and visit 9.  
 
 urinary CTX-II biomarkers 
 serum CTX-I 
4.3.4.2 
Other Imaging Assessments 
K-L scoring based on target knee radiographs no older than 12 months is required to 
assess inclusion criterion 3.  
At visit 2 (baseline) and visit 8, MRI acquisition will be performed on the target knee for  
measurement of bone area, cartilage thickness and BML volume. 
 
 
 
4.4 
Analysis Populations 
4.4.1 Intent-to-Treat Population (ITT) 
All randomised patients in the treatment group to which they were randomised, 
regardless of whether treatment was received as planned.  
4.4.2 Modified Intent-to-Treat Population (mITT) 
mITT is the full analysis set (FAS) consisting of all patients having both a baseline and at 
least one post-baseline value for the primary variable (NRS pain score).   


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4.4.3 Per Protocol Population (PPS) 
Those patients who adhered to the treatment regimen of the program to which they were 
allocated, provided sufficient assessment of primary outcomes, and did not violate the 
study protocol in any substantial way.  
4.4.4 Safety Analysis Population (SAF) 
The safety analysis population will include all patients receiving at least one dose of 
either MIV-711 or placebo. These patients will be analyzed according to treatment 
actually received.  
5. 
General Considerations for Data Presentations 
In this study IMP refers to any amount of the treatments defined in section 3.4, regardless 
of the time or period of administration. 
Data for all enrolled patients who receive at least one dose of IMP will be presented in 
the data listings.  
 
A patient who is enrolled but does not receive IMP will be included in those data listings 
for which they have data but will be excluded from all data summaries. Data summaries 
will only include those patients that receive IMP.  
 
For those listings or data summaries where baseline and change from baseline 
measurements will be presented, unless stated otherwise, the baseline assessment to be 
used for calculating change from baseline will be the last valid assessment prior to first 
dose administration.  
 
All pre- and post-dose assessments including unscheduled assessments will be included 
in the data listings. For unscheduled assessments collected pre-dose, the last assessment 
taken for a time point will be used in the data summaries (summary tables, figures, and 
statistical analysis); for all post-dose time points, the original assessment for any given 
time point will be used in the data summaries (summary tables, figures, and statistical 
analysis). 
 
For summaries of safety data continuous variables will be summarized using descriptive 
statistics including: number of observations (n), mean (arithmetic), median, standard 
deviation (SD), minimum, and maximum. Frequencies and percentages will be used for 
summarizing discrete (categorical) data. In summaries for safety the denominator for all 
percentages will be the number of patients in a given treatment group.  
 


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Safety and efficacy data that are reported as missing will be excluded from all descriptive 
and non-descriptive data analysis. There will be no imputation of any data.  Observations 
that might be considered spurious (extreme relative to the majority of the data) will not 
be altered or removed from any presentation of the data, including the calculation of 
summary statistics (means, medians, etc.), unless approved by the sponsor.  
 
For data listings, all raw data will be reported/displayed exactly as provided. For 
summaries of quantitative safety data, the minimum and maximum value will be reported 
exactly as the raw data are reported; measures of central tendency (means, medians) will 
be reported to one more decimal place than the raw data; measures of variance (SD) will 
be reported to two more decimal places than the raw data.   
 
Unless stated otherwise there will be no adjustment for multiple comparisons. 
All statistical tests will be one-sided and will be performed at the 5% level of significance  
(Type I error =0.05). 
 
In all data persentations ‘Treatment’ will be defined as consisting of the three protocol 
defined categories: 200 mg, 100 mg, placebo. Listings will include all patients and will 
be sorted by treatment, patient number, and time point (where applicable). In all listings 
treatment will be grouped in the order: 200 mg, 100 mg, placebo.  All derived data used 
in a data summary or statistical analysis will be listed.   
 
5.1 
Software  
All statistical analyses will be performed using Statistical Analysis Software (SAS®) 
(SAS® Institute Inc., Cary, North Carolina, United States of America [USA]) Version 9.2 
or higher. 
6. 
Patient and Treatment Information 
6.1 
Patient Disposition 
The completion status, date of completion or discontinuation, the reason for 
discontinuation, and the study day of withdrawal will be listed. The number of patients 
enrolled and the frequency and percentage of patients completing the study, patients 
withdrawing early, and primary reason for withdrawal will be summarized by treatment 
and overall. Also included in this summary will be the numbers of patients in each of the 
analysis populations: ITT, mITT, PPS. 
 
Per protocol patients will take IMP until V8 and then they have a safety follow up visit 
(V9) 4 weeks after last IMP dose. If a patient is withdrawn IMP is stopped but the patient 


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is still asked to come for the safety follow up visit (V9) 4 weeks after last IMP. Some 
patients are withdrawn but refuse or are unable to attend the safety follow up visit (V9) 4 
weeks later. 
6.2 
Patients Excluded from Analysis Populations 
Each patient excluded from one of the analysis populations will be listed along with the 
reason for their exclusion. 
6.3 
Eligibility Criteria 
All enrolled patients who did not meet an inclusion criterion and all enrolled patients who 
met an exclusion criterion will be listed. 
6.4 
Exclusion Tests  
Results of the exclusion tests will be listed. These will include laboratory tests performed 
prior to dosing for: FSH testing, serology, and urine drug screen. 
6.5 
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 may lead to the exclusion of a patient from the Per Protocol Set (PPS). 
Deviations will be defined prior to unblinding. All reported protocol deviations will 
be listed.    
6.6 
Demographic Data  
Demographic and baseline characteristics will be evaluated for the ITT and for the PPS. 
Demographic information will be listed.  Descriptive statistics will be obtained for the 
continuous variables: height, age, BMI, and body weight and presented overall.  
Frequencies and percentage of patients will be tabulated for the categorical variables 
ethnicity, race, and gender.   
 
6.7 
Medical History 
Medical and surgical history data recorded prior to dosing will be listed for each patient. 
Medical history will be coded using the MedDRA (Version 18.1).  
 


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Only those body systems where a condition or abnormality has been reported will be 
listed. 
6.8 
Prior and Concomitant Medication 
Prior and concomitant medications will be coded using WHO Drug (September 2015 
version). These medications will be classified by Anatomical Therapeutic Chemical 
(ATC) categories.  
Prior and Concomitant Medications will be listed by patient. 
Summary tables of the number of percentage of patients by treatment and ATC 
classification will be provided for prior and concomitant medications. 
6.9 
Dose Administration 
Information collected per the dose administration CRF will be listed including patient 
number, treatment, visit, and the date and time of administration as well as the dose form, 
route of administration, number of capsules dispensed and number of capsules returned.  
 
The number and percentage of patients who received IMP will be summarized for each 
on site visit and by treatment. Descriptive statistics will be used to summarize drug 
accountability as the number of capsules returned for each on site study visit by 
treatment. 
 
Compliance will be derived as the number of days patient was exposed to IMP. 100% 
compliance will be considered for dosing during the period Visit 2 to Visit 8.  
The number of capsules used will be derived as the number of capsules dispensed minus 
the number of capsules returned. Subjects with less than 100% compliance will be 
identified among those who have results for “Reason not all unused Capsules returned”. 
7. 
Pharmacodynamic Analysis - Efficacy 
The primary and secondary efficacy analysis will be based on the mITT population.  
7.1 
NRS Pain Data 
NRS data for knee pain will be listed for each patient, treatment, and time point. NRS 
results will be shown for the following: 
 
 Primary endpoint: Amount of pain severity in the target knee last week (SDTM: 
Overall pain severity in target knee 


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 Global Assessment Score: How active has the target knee arthritis has been in the 
past week (SDTM: How active was target knee arthritis) 
 Satisfaction with target knee function (SDTM:How satisfied are you with target 
knee function) 
 Worst pain severity in target knee (SDTM: Worst pain severity in target knee) 
 Overall pain severity in other knee (SDTM: Overall pain severity in other knee) 
 
Change from baseline will be derived for each of the above NRS pain scores. These 
changes from baseline scores will be descriptively summarized by visit and treatment. 
Frequency tables by treatment will be used to summarize the number and percent of 
patients in each of the categories observed for:  
 
 Duration of Knee Pain Past 12 Months: Within the last 7 Days, Days 8-30, Days 
31-92, More  than 92 Days 
 Onset of Knee Pain: Within the last 12 months, 1 to 5 years, 5 to 10 years, More 
Than 10 years 
 
Results for duration and onset of knee pain will be listed for each patient. 
 
Graphical presentation of the observed and change from baseline NRS pain scores will 
include: 
 
 Mean ± 95% CI Profiles of Observed NRS Scores by Treatment, mITT 
Population 
 Mean ± 95% CI Profiles of Change From Baseline NRS Scores by Treatment, 
mITT Population 
7.2 
Statistical Analysis of the NRS Pain Data 
To assess the sensitivity of the statistical analysis to the choice of analysis set, the 
primary efficacy analysis described below will be considered for both the mITT and the 
PPS populations.  
 
The primary hypothesis of this study is that MIV-711 will reduce pain in patients with 
moderate knee osteoarthritis diagnosed based on symptomatic and radiologic criteria. 
To statistically test this hypothesis, a linear mixed model via SAS PROC MIXED based 
on the FAS (mITT). The model will include fixed factors for treatment, time (measured 
in weeks), the interaction for treatment-by-time, baseline analgesic user (Yes/No), and 
random effect for clinical site. The baseline NRS score will be included as a covariate for 
adjustment.  
 


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Patients considered pain medication users at baseline will be identified via concomitant 
medication analgesic usage. Pain medication users will include any patient exposed to a 
prescribed analgesic at time of first IMP intake and the medication was ongoing at the 
time of visit 2. 
 
The dependent variable in the linear model is the change from baseline NRS pain score. 
Separate mixed model analyses will be considered for each of the change from baseline 
NRS pain scores. 
 
 Primary endpoint: Amount of pain severity in the target knee last week (SDTM: 
Overall pain severity in target knee 
 Global Assessment Score: How active has the target knee arthritis has been in the 
past week (SDTM: How active was target knee arthritis) 
 Satisfaction with target knee function (SDTM:How satisfied are you with target 
knee function) 
 Worst pain severity in target knee (SDTM: Worst pain severity in target knee) 
 Overall pain severity in other knee (SDTM: Overall pain severity in other knee) 
 
In this analysis the contrast of primary interest is the treatment difference (active versus 
placebo) at visit 8 week 26. LSmeans at visit 8 for the change from baseline score will be 
reported from the mixed model. LSmeans for the overall effect of treatment, estimates of 
the pair-wise treatment differences, two-sided 95% confidence intervals (CI), and p-value 
(one-sided) will be provided.  
 
The following SAS code maybe used as reference:  
 
PROC MIXED data=; 
CLASS patient  treatment week; 
MODEL NRS_chg= NRS_baseline treatment week treatment*week baseline_conmed_pain_use/ 
DDFM=KR ; 
RANDOM site ; 
REPEATED week / SUBJECT=patient TYPE=UN; 
LSMEAN treatment*week  treatment / diff CL ALPHA=0.1  ; 
RUN;   
 
 
In an alternate sensitivity analysis of the primary endpoint (Amount of pain severity in 
the target knee last week) that could be considered  as applicable, the linear model 
described in this section would include the PRO for e-diary analgesic use (Yes, No) as an 
additional independent factor. This analysis would be considered only if baseline pain 
medication usage could not be adequately identified via the concomitant medication 
records. The effect of whether or not a patient was an analgesic user at baseline as 
defined by the e-diary would then be considered as the additional factor. 
 


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7.2.1 Multiplicity Adjustment for the Primary Endpoint 
For the primary endpoint, change from visit 2 (baseline) to visit 8 in NRS pain score, the 
Type I error for the tests of the two doses will be protected by performing a fixed-
sequence multiple-testing procedure. The order of steps is defined below:  
Step 1. 200 mg versus placebo 
Step 2. 100 mg versus placebo 
 
To adjust for the multiple testing of two doses, the second step will only be considered as 
confirmatory providing the previous step is significant at a one-sided 5%-level (p<0.05). 
If the previous step is not significant, the analysis of the following step will be considered  
descriptive. 
 
7.2.2 Visualizations for the Primary Endpoint 
Mean profiles for treatments (MIV-711) will be compared with placebo for each 
treatment as well as the difference from placebo treatment, as obtained from the change 
from baseline NRS score estimated least squares means. The difference from placebo in 
least squares means obtained from the above mixed model (section 7.2) will be presented 
in the following figures: 
   
 NRS Change From Baseline (LSMean Difference ± 95% CI) Difference from 
Placebo by Treatment and Time Point, mITT Population 
 NRS Change From Baseline (LSMean Difference ± 95% CI) Difference from 
Placebo by Treatment and Time Point, PPS Population 
 
 
7.3 
Key Secondary Analysis: MRI of Bone Area in Target Knee 
The observed and change from baseline of the MRI of the bone area of the medial femur 
for the target knee will be listed for each patient and descriptively summarized by 
treatment and visit. 
 
7.3.1 Statistical Analysis of the MRI of Bone Area in Target Knee 
As the key secondary analysis of efficacy, the change from baseline in the MRI of bone 
area in the target knee will be analysed using the same statistical model described in 


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Section 7.2 above. This analysis will be based on the mITT population. Results will be 
summarized.  
 
Mean profiles for treatments (MIV-711) will be compared with placebo by plotting the 
difference from placebo using the change from baseline MRI bone area score:   
 
 MRI of Bone Area Change From Baseline (LSMean Difference ± 95% CI) 
Difference from Placebo by Treatment and Time Point, mITT Population 
7.4 
Secondary Analysis: MRI of Cartilage Thickness in Target Knee 
The observed and change from baseline of the MRI of the cartilage thickness for the 
target knee will be listed for each patient and descriptively summarized by treatment and 
visit. Source data for these analyses will be obtained from: 
 
 CM_FEMUR_THCTAB: Average thickness of cartilage in the central medial 
femur region 
 CM_TIBIA_THCTAB: Average thickness of cartilage in the central medial tibia 
region 
7.4.1 Statistical Analysis of the MRI of Cartilage Thickness in Target Knee 
As a secondary analysis of efficacy, the change from baseline in the MRI of cartilage 
thickness in the target knee will be analysed using the same statistical model described in 
Section 7.2 above. This analysis will be based on the mITT population. Results will be 
summarized.  
 
Mean profiles for treatments (MIV-711) will be compared with placebo by plotting the 
difference from placebo using the change from baseline MRI cartilage thickness score:   
 
- 
MRI of Cartilage Thickness Change From Baseline (LSMean Difference ± 95% 
CI) Difference from Placebo by Treatment and Time Point, mITT Population 
 
7.5 
Secondary Analysis: MRI of total BML Volume in Target Knee 
The observed and change from baseline of the MRI of the total bone marrow lesion 
volume for the target knee will be listed for each patient and descriptively summarized by 
treatment and visit. Source data for these analyses will be obtained from: 
 
- 
Total_BML_Volume 


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7.5.1 Statistical Analysis of the MRI of Total BML Volume in Target Knee 
As a secondary analysis of efficacy, the change from baseline in the MRI of total bone 
marrow lesion volume in the target knee will be analysed using the same statistical model 
described in Section 7.2 above. This analysis will be based on the mITT population. 
Results will be summarized.  
 
Mean profiles for treatments (MIV-711) will be compared with placebo by plotting the 
difference from placebo using the change from baseline MRI cartilage thickness score:   
 
- 
MRI of Total BML Volume Change From Baseline (LSMean Difference ± 95% 
CI) Difference from Placebo by Treatment and Time Point, mITT Population 
 
7.6 
Analysis of Other Secondary Imaging Assessments 
Other secondary imaging variables will be listed for each patient and descriptively 
summarized by treatment and visit. These other secondary imaging variables will include: 
 
MOAKS Variables 
 Bone Marrow Lesions (BMLs) and cysts 
o Size of BML: 0=’None’, 1=’<33%’, 2=’33-66%’, 3=’>66%’,9=’Not 
Evaluable’ 
o Number of BMLs: scored 9 to 99 
o Percentage that is BML: 0=’None’, 1=’<33%’, 2=’33-66%’, 3=’>66%’, 
9=’Not Evaluable’ 
 
 Articular Cartilage 
o Size of any Cartilage Loss: 0=’Normal’, 1=’<10% Area’, 2=’10-75% 
Area’, 3=’>75% Area’, 9=’Not Evaluable’ 
o Percentage Full Thickness Loss: 0=’Normal’, 1=’<10% Region’, 2=’10-
75% Region’, 3=’>75% Region’, 9=’Not Evaluable’ 
 
 Osteophytes: 0=’None’, 1=’Small’,  2=’Medium’, 3=’Large’, 9=’Not Evaluable’ 
 
For the MOAKS imaging variables collected quantitatively the change from baseline 
score will be derived and descriptively summarized by treatment and visit. For MOAKS 
variables with categorical response, the number and percentage of subjects in each 
treatment for each category will be summarized.  


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7.7 
Analysis of Other Patient Reported Outcomes (PROs) 
7.7.1 Intermittent and Constant Osteoarthritis Pain (ICOAP) Knee Version 
The observed raw ICOAP scores will be listed by treatment and visit for each patient. 
 
The observed results for the intermittent and constant osteoarthritis pain (ICOAP) score 
will be transformed to a 0-100 scale for analysis. The following methods will be used to 
transform the ICOAP scores: 
 
Constant pain subscale   
 
To calculate the Total constant pain subscale, sum the scores within each time point for 
items IP1 through IP5.  Maximum constant pain score ranges from 0 to 20.  
This score can be transformed to a score out of 100 using the following formula:    
(Total constant pain score / 20) x 100   
 Intermittent pain subscale 
 
To calculate the total intermittent pain subscale, sum the scores within each time point for 
items IP6 through IP11. Maximum intermittent pain subscale ranges from 0 to 24.   
This score can be transformed to a score out of 100 using the following formula:    
(Total intermittent pain score / 24) x 100   
 
 Total pain score 
 
To calculate the total ICOAP score, sum the constant and intermittent pain subscales 
within each time point.  Maximum total pain score ranges from 0 to 44.    
This score can be transformed to a score out of 100 using the following formula:    
(Total pain score / 44) x 100   
 
The three transformed ICOAP scores (Constant Pain, Intermittent Pain, and Total Pain) 
will be listed by patient for each scheduled time point.  Change from baseline will be 
derived for each of these transformed ICOAP scores. The observed and change from 
baseline values for these three transformed ICOAP scores will be listed and the change 
from baseline values will be descriptively summarized by treatment and time point.  
Figures of the mean change from baseline ICOAP response, using each transformed 
ICOAP score, will be used to visualize the behavior of the ICOAP response over time: 
 
 ICOAP Change From Baseline by Treatment and Time Point, mITT Population 


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7.7.2 Analysis of the WOMAC 
The observed WOMAC scores for pain, stiffness, and physical function will be listed. 
Change from baseline scores will be derived for each WOMAC item, listed by patient 
and descriptively summarized by treatment and visit.  
 
Mean profiles for treatments (MIV-711) will be compared with placebo by plotting the 
change from baseline WOMAC score:   
 
 WOMAC Pain Score Mean Change From Baseline (95% CI) by Treatment and 
Time Point, mITT Population. 
 WOMAC Stiffness Score Mean Change From Baseline (95% CI) by Treatment 
and Time Point, mITT Population 
 WOMAC Difficulty Score Mean Change From Baseline (95% CI) by Treatment 
and Time Point, mITT Population 
 
7.7.3  (OARSI)-OMERACT Responder Criteria 
The following steps will be used to derive OARSI-OMERACT response (Yes, No). This 
analysis will use the PROs from the WOMAC pain data, the WOMAC Function data, and 
the patient global assessment NRS observed at Visit 2 and Visit 8. It is expected Visit 8 
will be the last ‘on-treatment’ visit for each subject.  
 
Step 1. Derive Total Scores: 
a) Total WOMAC Pain (Sum of 5 questions): For each subject and each scheduled 
time point derive a total score by summing over all 5 pain responses. For each 
subject this will provide a total WOMAC Pain score out of 50 for each protocol 
scheduled time point. Denote this new variable in the data set as 
‘WOMAC_Pain_50’. 
b) Total WOMAC Function (Sum of 17 questions): For each subject and each 
scheduled time point derive a total score by summing over all 17  
difficulty responses. For each subject this will provide a Total WOMAC Function 
score out 170 for each protocol scheduled time point. Denote this new variable in 
the data set as ‘WOMAC_Func_170’. 
c) Patient Global Assessment (NRS question 4: Over the past week, how active do 
you think your knee arthritis has been?). Use this score as is, scored out of 10.  
 
Step 2. Transform the three scores from Step 1 to create three new scores, each out of 
100: 
a) Transformed WOMAC Pain Score: 
WOMAC_PAIN_100 = WOMAC_Pain_50  2.  


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b) Transformed WOMAC Function Score: 
WOMAC_FUNC_100 = WOMAC_Func_170 ÷1.7. 
c) Transformed Global Assessment Score:  
NRSACT_100 = (Global Assessment Score )  10. 
 
Step 3. Comparing Visit 8 against Visit 2: Use the transformed scores from step 2 to 
derive change between baseline and percentage change from baseline scores. 
  
Denote the change from baseline scores as: 
  
 CHG_WOMAC_PAIN_100 
 CHG_WOMAC_FUNC_100 
 CHG_NRSACT_100 
  
Denote the percentage change from baseline scores as: 
  
 PCHG_WOMAC_PAIN_100 
 PCHG_WOMAC_FUNC_100 
 PCHG_NRSACT_100 
 
Percentage change from baseline will be calculated as: 
((Visit 8 Score – Visit 2 Score) ÷ Visit 2 Score)  100 
 
The total scores and the transformed scores for each of WOMAC pain, WOMAC 
physical function, and global assessment will be listed by patient and visit along with 
their change from baseline scores and percentage change from baseline scores. Change 
from baseline scores will be presented for Visit 8 only. Percentage change from baseline 
scores will be derived from visit 2 and visit 8 data only.  
 
Step 4. Derive Responder OARSI-OMERACT (Yes, No): In all derived scores, low 
values are associated with less severe pain (0 = no pain) and high scores are associated 
with more severe pain (100 = worst pain). In assessing for a positive OMERACT 
response, patient improvement (Response = Yes) is associated with decreases (negative 
changes) from baseline and (negative) percentage (changes) decreases from baseline. The 
different criteria are quantified in the tables below. 
 
Case 1: using the change from baseline and percentage change from baseline scores  
for WOMAC pain and WOMAC function (from step 3), an OMERACT responder will 
be flagged as ‘Yes’ if either of the following 2 criteria are satisfied: 
 
 
Criteria 
 
 
Decrease from 
Baseline 
       
Percentage 
Decrease from 
Baseline 
 
OMERACT 
Responder 


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1 
WOMAC Pain 
 ≥ 20 
and 
≥ 50% 
Yes 
2 
WOMAC Function 
 ≥ 20 
and 
≥ 50% 
Yes 
 
Case 2: using the change from baseline and percentage change from baseline scores  
for WOMAC pain, WOMAC function, and global assessment score (from step 3), an 
OMERACT responder will be flagged as ‘Yes’ if at least 2 of the following 3 criteria are 
satisfied: 
 
 
Criteria 
 
Decrease 
from 
Baseline 
       
Percentage 
Decrease from 
Baseline 
 
OMERACT 
Responder 
3 
WOMAC Pain 
 ≥ 10 
and 
≥ 20% 
Yes 
4 
WOMAC Function 
 ≥ 10 
and 
≥ 20% 
Yes 
5 
Global Assessment NRS 
 ≥ 10 
and 
≥ 20% 
Yes 
 
A subject is a ‘Yes’ responder if either of criteria 1 or 2 are satisfied. If neither criteria 1 
or 2 are satisfied, criteria 3, 4 and 5 will be checked. 
 
A listing will be created that presents each patient’s responder status by treatment. 
Included in this listing will be the associated change from baseline and percent change 
from baseline values. 
 
The number and percentage of subjects with responder status will be summarized by 
treatment. 
7.7.4 Global Improvements 
Global improvements in knee problem, knee pain and knee function that were recorded 
on a 6-point likert scale: completely better, much better, better, no change, worse, much 
worse. 
 
Descriptive tables will be used to summarize the number and percentage of each global 
improvement response for each treatment group by time point. All data will be listed for 
each patient.  
7.7.5 Quality of Life PRO – EQ-5D-5L 
Observed results from the EQ-5D-5L will be listed for each patient.  
This will include results from the 5 dimensions: mobility; self-care; usual activity; pain or 
discomfort; and anxiety or depression, in addition to the reported health rating score. 
 
Change from baseline scores will be derived for each QOL response as Visit 8 Week 26 


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versus Visit 2 Day 1. The change from baseline scores will be summarized using 
descriptive statistics by treatment group. The observed mean scores with 95% CI will be 
plotted by treatment and time point to visualize the QOL response over time. 
7.7.6 E-diary for Patient Pain 
All data collected in e-diary format, will be listed for each patient. 
Data permitting summary tables by treatment and time point will be provided for the e-
diary information reported for NRS scores and pain medication usage.  
 
Separate summary tables will be provided for AM and PM response as well as a table for 
overall 24 hour response. The overall summary will use the mean of the AM and PM 
NRS scores provided for each visit, to obtain one record for that visit. 
 
The number and percentage of patients with ‘Yes/No’ response to pain medication usage 
on the e-diary will be provided separately for AM, PM as well as for 24 hours overall. 
For the overall table, at least one ‘Yes’ response, either for the AM or the PM response, 
will be interpreted as a ‘Yes’ response over the 24 hours.   
 
The number and percentage of patients with each pain medication usage response (‘More 
than Normal’, ‘Normal’, ‘Less than normal’) will be summarized by treatment and visit, 
with separate summaries for AM and PM response.  
 
Data permitting the average NRS e-diary score will be visualized using a plot of mean 
NRS response by treatment and time point. Separate figures will be provided for the AM 
and PM NRS scores as well as overall 24 hours for each visit. For the overall figure the 
mean of the AM and PM NRS scores will be used to obtain 1 record at each visit prior to 
computing descriptive statistics. 
 
7.7.7 Biomarkers from Serum and Urine Samples 
The serum CTX-I and urinary CTX-II biomarkers will be presented in data lisitngs by 
subject and time point and in descriptive summary tables by treatment and time point. 
Figures of mean response over time with +/- 95% CI will be used to visualize their 
distribution over time for each treatment. 
 
Time-Integrated-Concentrations (TIC) will be derived for each serum CTX-I and urinary 
CTX-II biomarkers. For each biomarker the mean TIC value and the standard deviation 
(SD) of the TIC will be derived. For each biomarker a Z- score will be derived by 
subtracting the mean and dividing by SD. TIC results and associated Z-scores will be 
listed for each subject. 


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8. 
Safety Analysis 
All safety analyses will be based upon the SAF. If one or more patients received incorrect 
IMP, these data will also be presented for the SAF.  
8.1 
Adverse Events 
 
All AEs reported will be coded and classified according to MedDRA version 18.1.   
 
A treatment-emergent AE (TEAE) will be defined as an AE that begins or that worsens in  
severity after IMP has been administered. 
 
Non-treatment emergent adverse events (NTEAE): AEs that occurred before the 
administration of IMP and did not worsen in severity or relationship after exposure to 
IMP. 
 
All AE data as captured on the CRF will be listed by patient. All serious AEs (SAEs) will 
be listed. A listing of all AEs leading to treatment discontinuation will be presented.  
 
Unless specified otherwise, all adverse event summaries will include the TEAEs only and 
adverse event summary counts of AEs will be the number of patients reporting adverse 
events and not the number of events reported. The number and percentage of patients 
with adverse events will be tabulated by body system and preferred term for each 
treatment. A patient with multiple adverse events within a body system is only counted 
once towards the total of that body system.  If the same AE (preferred term) is reported 
several times for the same patient, it will only appear once for that specified treatment in 
the summary tables. 
 
For patients with multiple adverse events of the same preferred term and of different 
severities, the AE with the highest assessment of severity will be used in the summaries 
presented by severity.   
Presentations of AEs (tables and listings) will be by treatment defined by the dose level 
of MIV-711 and placebo. 
A general summary of all treatment-emergent adverse events will show the number and 
percentage of patients, as well as the number of events, according to the following 
categories: 
 All treatment emergent adverse events  
 ‘Related’ treatment emergent adverse events 
 Mild treatment emergent adverse events 
 Moderate treatment emergent adverse events 
 Severe treatment emergent adverse events 


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 Serious treatment emergent adverse events 
 Treatment emergent adverse events leading to early termination 
 Deaths 
 
Other summary tables for adverse events will include: 
 Number and Percentage of Patients with Treatment Emergent Adverse Events by 
System Organ Class, Preferred Term, and Treatment 
 Number and Percentage of Patients with Treatment Emergent Adverse Events 
‘Related to IMP’ by System Organ Class, Preferred Term, Severity, and Treatment. 
 Number and Percentage of Patients with Treatment Emergent Adverse Events ‘Not 
Related to IMP’ by System Organ Class, Preferred Term, Severity, and Treatment. 
 Number and Percentage of Patients with Serious Treatment Emergent Adverse Events 
by System Organ Class, Preferred Term, and Treatment 
 Number and Percentage of Patients with Treatment Emergent Adverse Events 
Leading to Discontinuation by System Organ Class, Preferred Term, and Treatment 
8.2 
Clinical Safety Laboratory Tests (Hematology, Chemistry, Urinalysis) 
8.2.1 Hematology and Chemistry 
A by-patient listing of all observed chemistry and hematology laboratory data will be 
provided.  Laboratory results outside the normal range will be flagged.  The abnormal 
values will be flagged with ‘L’ (low) for values below the lower limit of the laboratory’s 
normal range or ‘H’ (high) for values above the upper limit of the laboratory’s normal 
range. Abnormal values will be graded as not clinically significant (NCS) or clinically 
significant (CS). Clinically significant laboratory results will be included in the AE 
listings.   
 
The observed values of all safety laboratory assessments for clinical chemistry and 
hematology will be summarized using descriptive statistics showing the number of 
observations (n), mean, median, SD, minimum, and maximum value. Table summaries 
will be presented by treatment and time point. 
 
Baseline values for all clinical chemistry and hematology parameters will be categorized 
as being below the normal range (Low), within the normal range (Normal), and above the 
normal range (High).  Shift from baseline tables will present the frequency and 
percentage of patients who have observations that are Normal, Low, or High. Shift tables 
will be presented by treatment group for values shifting from Day -1 to the maximum and 
the minimum post-dose value. 
 


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All hematology, chemistry, and coagulation, laboratory parameters noted in Section 4.2.2 
of this SAP will be tabulated.   
 
8.2.2 Urinalysis 
 
Urinalysis test results will be listed. All positive findings in the microscopic examination 
will be listed.  
 
Observations outside the normal range will be flagged.  The abnormal quantitative values 
will be flagged with ‘L’ for values below the lower limit of the laboratory’s normal range, 
‘H’ for values above the upper limit of the laboratory’s normal range, or ‘Ab’ for 
abnormal qualitative test results.  All original and unscheduled assessments will be listed. 
8.3 
Other Blood and Urine Samples  
 
Details of the other blood and urine sample collections collected for pharmacogenomics, 
proteomics, genomics, metabolomics and lipidomics will be listed for each patient. 
8.4 
Vital Signs 
 
The observed data for blood pressure (systolic and diastolic), heart rate (pulse), pulse 
oximetry, and body temperature will be listed by patient, and time point. Change from 
baseline values for blood pressure (systolic and diastolic), and heart rate (pulse) will be 
derived and listed. The baseline value to be used to derive change from baseline will be 
last assessment prior to first dose on Visit 2. The overall qualitative assessment for vital 
signs will be listed. 
 
For systolic and diastolic blood pressure and heart rate, the observed values and change 
from baseline data will be summarized by treatment and time point. Table summaries will 
include descriptive statistics showing the number of observations (n), mean, SD, median, 
minimum, and maximum value. 
8.5 
12-Lead Safety ECG 
 
Observed quantitative results for RR, PR, QRS, QT, QTcB (corrected QT according to 
Bazett), QTcF (corrected QT according to Fridericia) and heart rate will be listed for each 
patient.  Change from baseline for QT, QTcB, QTcF will be derived and listed. 
 
In the calculation of change from baseline, the baseline value for each period will be the 
last assessment prior to first dose on Visit 2.  
 


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The overall qualitative ECG assessment Abnormal NCS, Abnormal CS, and any 
comments will be listed for each patient. 
 
For QT, QTcB, QTcF the observed and change from baseline data will be summarized by 
treatment and time point. Summaries will include tables of descriptive statistics showing 
the number of observations (n), mean, SD, median, minimum, and maximum value.  
 
The number and percentage of patients having observed QT, QTcB, QTcF values that 
satisfy the following conditions will be summarized by treatment and time point: 
 
 ≤ 450 msec 
 450 < to ≤ 480 msec 
 480 < to ≤ 500 msec 
 > 500 msec 
 
The number and percentage of patients having change from baseline QT, QTcB, QTcF 
values that satisfy the following conditions will be presented by treatment and time point: 
 
 ≤ 0 msec 
 > 0 to ≤ 30 msec 
 > 30 to ≤ 60 msec 
 > 60 msec 
8.6 
Physical Examination and Weight 
 
All abnormal physical exam findings (pre and post-dose assessments) will be listed. 
Patient weight collected pre and post dose will be listed. 
 
8.7 
Phone Call to Assess Safety  
 
Results of this assessment will be listed for each patient and each visit. 


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9. 
Reporting Output 
 
The following details the requirements and specifications for the presentation of the 
tables, figures and listings (TFLs) as set out in the TFL shells. 
 
The tables, listings, figures and any non-descriptive statistical analysis will be produced 
using Unix SAS Software (Version 9.2 or higher).  The REPORT procedure will be 
used to produce all tables and listings; SAS/GRAPH will be used to produce all figures.   
 
Tables, listings, and figures will be produced in the order that they appear in the textual 
sections of the plan.  
 
All tables, listings, and graphs will be produced to landscape orientation using Courier 
New 8pt font and will be incorporated into a MS Word document as a (RTF) rich text file 
(margins: top, left, right, and bottom: 1 inch).  Details are provided below. 
 
 
A separate RTF document will be created for each table, figure and listing 
individually. 
 
All TFLs will be produced in a landscape format, as far as is feasible. 
 
The standard font size and font type are "8 point", "Courier New" for all TFLs. 
 
Every page of each output will contain a footer indicating the date and time when 
the output was produced. 
 
Page numbering of tables and listings will use the format "Page X of Y". Page 
numbering for figures will be consecutive integers.  
 
The ordering of visits will be chronological  
 
Footnotes are left justified. 
 
 
 
 


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10. 
References 
 
1. Murphy, L. B., et al. (2010). "Estimating medical costs attributable to osteoarthritis in 
the US population: comment on the article by Kotlarz et al." Arthritis and Rheumatism 
62(8): 2566-2567; author reply 25672568.  
 
 


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11. 
Summary Tables 
TLF Number 
Title 
Topine 
Item 
Table 14.1.1 
Patient Disposition – All Enrolled Patients 
Yes 
Table 14.1.2.1 
Demographics - Continuous Variables, PPS Population  
 
Table 14.1.2.2 
Demographics – Continuous Variables, mITT Population 
 
Table 14.1.3.1 
Demographics - Categorical Variables, PPS Population  
 
Table 14.1.3.2 
Demographics - Categorical Variables, mITT Population  
 
Table 14.1.4.1 
Prior Medications, PPS Population  
 
Table 14.1.4.2 
Prior Medications, mITT Population 
 
Table 14.1.5.1 
Concomitant Medications, PPS Population  
 
Table 14.1.5.2 
Concomitant, mITT Population  
 
Table 14.1.6 
Dose Administration - Number and Percentage of Patients Who 
Received IMP by Visit, SAF Population 
Yes 
Table 14.1.7 
Dose Administration – Summary of Dosing Compliance, SAF 
Population  
Yes 
Pharmacoodynamics 
 
Table 14.2.1 
NRS Scores Observed and Change from Baseline Summary, mITT 
Population 
 
Table 14.2.2 
Number and Percentage of Patients by Category for Duration and 
Onset of Knee Pain at Baseline, mITT Population 
 
Table 14.2.3.1 
Statistical Analysis Primary Hypothesis - MIV-711 will Reduce Pain in 
Patients with Moderate Osteoarthritis - Assessments Using NRS Scores 
as Primary Endpoint, mITT Population 
Yes 
Table 14.2.3.2 
Statistical Analysis Primary Hypothesis - MIV-711 will Reduce Pain in 
Patients with Moderate Osteoarthritis - Assessments Using NRS Scores 
as Secondary Endpoints, mITT Population 
 
Table 14.2.3.3 
Statistical Analysis Primary Hypothesis - MIV-711 will Reduce Pain in 
Patients with Moderate Osteoarthritis - Assessments Using NRS Scores 
as Primary Endpoint, PPS Population 
Yes 
Table 14.2.3.4 
Statistical Analysis Primary Hypothesis - MIV-711 will Reduce Pain in 
Patients with Moderate Osteoarthritis - Assessments Using NRS Scores 
as Secondary Endpoints, PPS Population 
 
Table 14.2.4.1 
Imaging variables - MRI of Bone Area for the Target Knee Observed 
and Change from Baseline Summary, mITT Population  
 
Table 14.2.4.2 
Statistical Analysis - MRI of Bone Area for the Target Knee in Patients 
with Moderate Osteoarthritis, mITT Population 
 
Table 14.2.4.3 
Imaging variables - MRI of Cartilage Thickness for the Target Knee 
Observed and Change from Baseline Summary, mITT Population  
 
Table 14.2.4.4 
Statistical Analysis - MRI of Cartilage Thickness for the Target Knee 
in Patients with Moderate Osteoarthritis, mITT Population 
 
Table 14.2.4.5 
Imaging variables - MRI of Total BML Volume for the Target Knee 
 


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Observed and Change from Baseline Summary, mITT Population  
Table 14.2.4.6 
Statistical Analysis - MRI of Total BML Volume for the Target Knee 
in Patients with Moderate Osteoarthritis, mITT Population 
 
Table 14.2.4.7 
Other Imaging Variables MOAKS - Number and Percentage of 
Subjects by Category and Treatment, mITT Population 
 
Table 14.2.4.8 
Other Imaging variables MOAKS - Observed and Change from 
Baseline Summary, mITT Population 
 
Table 14.2.5 
Transformed ICOAP Scores Observed and Change from Baseline 
Summary, mITT Population 
 
Table 14.2.6.1 
WOMAC Scores Observed and Change from Baseline Summary - Pain 
Questions, mITT Population 
 
Table 14.2.6.2 
WOMAC Scores Observed and Change from Baseline Summary - 
Stiffness Questions, mITT Population 
 
Table 14.2.6.3 
WOMAC Scores Observed and Change from Baseline Summary - 
Difficulty Questions, mITT Population 
 
Table 14.2.7 
Number and Percentage of  Patients with a Positive OARSI-
OMERACT Response, mITT Population 
 
Table 14.2.8 
Number and Percentage of  Patients with Each Global Improvement 
Score Response, mITT Population 
 
Table 14.2.9 
EQ-5D-5L Health Rating Score Response Observed and Change from  
Baseline Summary, mITT Population 
 
Table 14.2.10.1 
E-Diary NRS Scores Observed and Change from Baseline Summary, 
mITT Population, AM Response, mITT Population 
 
Table 14.2.10.2 
E-Diary NRS Scores Observed and Change from Baseline Summary, 
mITT Population, PM Response, mITT Population 
 
Table 14.2.10.3 
E-Diary NRS Scores Observed and Change from Baseline Summary, 
mITT Population, Overall Response, mITT Population 
 
Table 14.2.10.4 
Number and Percentage of Patients with E-Diary Pain Medication 
Usage (Yes/No) Over Last 12 Hours, AM Response, mITT Population 
 
Table 14.2.10.5 
Number and Percentage of Patients with E-Diary Pain Medication 
Usage (Yes/No) Over Last 12 Hours, PM Response, mITT Population 
 
Table 14.2.10.6 
Number and Percentage of Patients with E-Diary Pain Medication 
Usage (Yes/No) Over Last 12 Hours, Overall Response, mITT 
Population 
 
Table 14.2.10.7 
E-Diary Pain Medication Usage Number and Percentage of  Patients 
with each Reported Category, AM Response, mITT Population 
 
Table 14.2.10.8 
E-Diary Pain Medication Usage Number and Percentage of  Patients 
with each Reported Category, PM Response, mITT Population 
 
 
 
 
Safety  
 
Table 14.3.1.1 
Summary of Treatment Emergent Adverse Events , SAF Population  
Yes 
Table 14.3.1.2 
Number and Percentage of  Patients with Treatment Emergent Adverse 
Events by System Organ Class, Preferred Term, and Treatment, SAF 
Population  
Yes 
Table 14.3.1.3 
Number and Percentage of Patients with Treatment Emergent  
Adverse Events ‘Related to IMP’ by System Organ Class,  
Yes 


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Preferred Term, Severity, and Treatment, SAF Population 
Table 14.3.1.4 
Number and Percentage of Patients with Treatment Emergent  
Adverse Events ‘Not Related to IMP’ by System Organ Class,  
Preferred Term, Severity, and Treatment, SAF Population 
 
Table 14.3.1.5 
Number and Percentage of  Patients with Serious Treatment Emergent  
Adverse Events by System Organ Class, Preferred Term, and  
Treatment, SAF Population 
 
Table 14.3.1.6 
Number and Percentage of Patients with Treatment Emergent Adverse 
Events Leading to Discontinuation by System Organ Class, Preferred 
Term, and Treatment, SAF Population 
 
Table 14.3.2.1 
Clinical Laboratory Chemistry Summary of Observed Values, SAF 
Population 
 
Table 14.3.2.2 
Clinical Laboratory Hematology Summary of Observed Values, SAF 
Population 
 
Table 14.3.2.3 
Clinical Laboratory Chemistry – Shift From Baseline to Maximum 
Post-dose Value, SAF Population  
 
Table 14.3.2.4 
Clinical Laboratory Chemistry – Shift From Baseline to Minimum 
Post-dose Value, SAF Population 
 
Table 14.3.2.5 
Clinical Laboratory Hematology – Shift From Baseline to Maximum 
Post-dose Value, SAF Population 
 
Table 14.3.2.6 
Clinical Laboratory Hematology – Shift From Baseline to Minimum 
Post-dose Value, SAF Population 
 
Table 14.3.3 
Vital Signs Blood Pressure and Heart Rate Summary of Observed and 
Change from Baseline Values, SAF Population 
 
Table 14.3.4.1 
12 Lead ECG – Summary of Observed and Change from Baseline 
Values SAF Population 
 
Table 14.3.4.2 
12-Lead ECG – Categorical Summary of Observed Values, SAF 
Population  
 
Table 14.3.4.3 
12-Lead ECG – Categorical Summary of Change From Baseline, SAF 
Population  
 


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12. 
Figures 
TLF Number 
Title 
Topline 
Item 
Figure 14.2.1 
Mean ± 95% CI Profiles of Observed NRS Scores 
by Treatment, mITT Population 
 
Figure 14.2.2 
Mean ± 95% CI Profiles of Change From Baseline 
NRS Scores by Treatment, mITT Population 
 
Figure 14.2.3.1 
NRS Change From Baseline Scores (LSMean ± 
95% CI) by Treatment and Time Point, mITT 
Population 
 
Figure 14.2.3.2 
NRS Change From Baseline Scores (LSMean ± 
95% CI) by Treatment and Time Point, PPS 
Population 
 
Figure 14.2.3.3 
NRS Change From Baseline (LSMean Difference ± 
95% CI) Difference from Placebo by Treatment and 
Time Point, mITT Population 
Yes 
Figure 14.2.3.4 
NRS Change From Baseline (LSMean Difference ± 
95% CI) Difference from Placebo by Treatment and 
Time Point, PPS Population 
Yes 
Figure 14.2.4.1 
MRI of Bone Area for the Target Knee - Mean 
(SD) Change From Baseline Response over Time, 
mITT Population  
 
Figure 14.2.4.2 
MRI of Bone Area for the Target Knee Change 
From Baseline (LSMean Difference ± 95% CI) 
Difference from Placebo by Treatment and Time 
Point, mITT Population 
 
Figure 14.2.4.3 
MRI of Cartilage Thickness Change From Baseline 
(LSMean Difference ± 95% CI) Difference from 
Placebo by Treatment and Time Point, mITT 
Population 
 
Figure 14.2.4.4 
MRI of Total BML Volume Change From Baseline 
(LSMean Difference ± 95% CI) Difference from 
Placebo by Treatment and Time Point, mITT 
Population 
 
Figure 14.2.5 
ICOAP Mean Change From Baseline by Treatment 
and Time Point, mITT Population 
 
Figure 14.2.6.1 
WOMAC Pain Score Mean Change From Baseline 
by Treatment and Time Point, mITT Population 
 
Figure 14.2.6.2 
WOMAC Stiffness Score Mean Change From 
Baseline by Treatment and Time Point, mITT 
Population 
 
Figure 14.2.6.3 
WOMAC Difficulty Score Mean Change From 
Baseline by Treatment and Time Point, mITT 
Population 
 


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Figure 14.2.7 
Quality of Life PRO – EQ-5D-5L Oberved Mean 
Scores (95% CI) by Treatment and Time 
 
Figure 14.2.8 
Mean ± SD Profiles of Observed NRS E-Diary 
Scores by Treatment, mITT Population 
 
Figure 14.2.9 
Mean ± SD Profiles of Change from Baseline NRS 
E-Diary Scores by Treatment, mITT Population 
 
Figure 14.2.10 
Figures of Mean Response (95% CI) Over Time of 
Efficacy Biomarkers Serum CTX-I and Urinary 
CTX-II  
 
 
 


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13. 
Listings 
 
TLF Number 
Title 
Topline 
Item 
Listing 16.2.1.1 
Patient Disposition 
Yes 
Listing 16.2.1.2 
Patients Excluded from Analysis Populations 
Yes 
 Listing 16.2.1.3 
 Enrolled Patients Who Did Not Meet All Eligibility Criteria 
Yes 
Listing 16.2.1.4 
Exclusion Tests  
Yes 
 Listing 16.2.2.1 
 Protocol Deviations  
Yes 
Listing 16.2.4.1 
Demographics 
Yes 
Listing 16.2.4.2 
Medical History  
 
Listing 16.2.5.1 
Prior and Concomitant Medications 
Yes 
Listing 16.2.5.2 
Dose Administration  
Yes 
Listing 16.2.5.3 
Dose Administration Compliance 
 
Listing 16.2.6.1 
Numerical Rating Scale of Knee Pain 
 
Listing 16.2.6.2 
Numerical Rating Scale of Knee Pain Change From Baseline 
Yes 
Listing 16.2.6.3 
Numerical Rating Scale of Knee Pain – Duration and Onset 
Yes 
Listing 16.2.6.4 
Imaging Results - MRI of Bone Area for the Target Knee 
 
Listing 16.2.6.5 
Imaging Results - MRI of Cartilage Thickness for the Target Knee 
 
Listing 16.2.6.6 
Other Secondary Imaging Variables – MOAKS  
 
Listing 16.2.6.7 
Other Secondary Imaging Variables Change From Baseline – 
MOAKS  
 
Listing 16.2.6.8 
Other Secondary Imaging Variables – Imorphics  
 
Listing 16.2.6.9 
Other Secondary Imaging Variables Change From Baseline – 
Imorphics  
 
Listing 16.2.6.10 
Observed Raw ICOAP Scores 
 
Listing 16.2.6.11 
Transformed ICOAP Scores 
 
Listing 16.2.6.12 
Western Ontario and McMaster Index (WOMAC)  - Pain Questions   
Listing 16.2.6.13 
Western Ontario and McMaster Index (WOMAC) -  Stiffness 
Questions 
 
Listing 16.2.6.14 
Western Ontario and McMaster Index (WOMAC) - Difficulty 
Questions 
 
Listing 16.2.6.15 
Western Ontario and McMaster Index (WOMAC) Change From 
Baseline - Pain Questions  
 
Listing 16.2.6.16 
Western Ontario and McMaster Index (WOMAC) Change From 
Baseline -  Stiffness Questions 
 
Listing 16.2.6.17 
Western Ontario and McMaster Index (WOMAC) Change From 
Baseline - Difficulty Questions 
 
Listing 16.2.6.18 
OARSI-OMERACT Responder Index Derived Scores out of 100 
 
Listing 16.2.6.19 
OARSI-OMERACT Responder Index  
Change from Baseline and Percentage Change from Baseline 
Scores 
 
Listing 16.2.6.20 
Global Improvements 
 
Listing 16.2.6.21 
Quality of Life Patient Reported Outcomes - EQ-5D-5L  
 


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Listing 16.2.6.22 
Quality of Life Patient Reported Outcomes Change from Baseline 
Scores - EQ-5D-5L  
 
Listing 16.2.6.23 
Brief Medication Questionnaire 
 
Listing 16.2.6.24 
E-Diary 
 
Listing 16.2.6.25 
Efficacy Biomarkers from Serum and Urine Samples 
 
Listing 16.2.6.26 
Time-Integrated Concentrations (TIC) and Their Z-scores  
for Efficacy Biomarkers from Serum and Urine Samples 
 
Listing 16.2.7.1 
Adverse Events 
 
Listing 16.2.7.2 
Serious Adverse Events 
 
Listing 16.2.7.3 
Adverse Events Leading to Discontinuation 
 
Listing 16.2.8.1 
Clinical Laboratory Chemistry – Observed Values 
 
Listing 16.2.8.2 
Clinical Laboratory Hematology – Observed Values 
 
Listing 16.2.8.3 
Clinical Laboratory Urinalysis – Observed Values 
 
Listing 16.2.8.4 
Clinical Laboratory Urinalysis – Positive Microscopic Findings 
 
Listing 16.2.8.5 
Vital Signs Observed Values 
 
Listing 16.2.8.6 
Vital Signs Change from Baseline 
 
Listing 16.2.8.7 
Vital Signs Overall Qualitative Results Abnormal Assessments 
 
Listing 16.2.8.8 
12 Lead ECG Quantitative Findings 
 
Listing 16.2.8.9 
12 Lead ECG Change From Baseline 
 
Listing 16.2.8.10 
12 Lead ECG Overall Qualitative Assessment 
 
Listing 16.2.8.11 
Physical Examination Abnormal Findings 
 
Listing 16.2.8.12 
Patient Weight 
 
Listing 16.2.8.13 
Phone Call to Assess Safety 
 
 


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                                                                                                                                                                                                             Page 52 of 155 
 
 
 
14. 
Table Shells 


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Protocol Number: MIV-711-201 
Table 14.1.1 
Patient Disposition  
All Enrolled Patients 
 
 
Treatment 
 
 
 
 
Overall 
N = x 
 
 
Placebo 
N = x 
 
100 mg 
MIV-711 
N = x 
 
200 mg 
MIV-711 
N = x 
Number Patients Enrolled 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Completed Study 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Discontinued from Study 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Number Patients in ITT Population 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Number Patients in mITT Population 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Number Patients in PPS Population 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Number Patients in SAF Population 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
Reason for Discontinuation 
 
 
 
 
Adverse Event  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Protocol Deviation 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Consent Withdrawn  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Lost to Follow-Up 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Death 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Other 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 
 


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Protocol Number: MIV-711-201 
 
Table 14.1.2.1 
Demographics – Continuous Variables 
PPS Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: table will be created for mITT population: Table 14.1.2.2 Demographics – Continuous Variables, mITT Population 
 
 
 
 
 
 
 
Statistic 
 
Treatment 
 
 
 
 
 
 
Overall 
N = x 
 
 
 
Placebo 
N = x 
 
 
100 mg 
MIV-711 
N = x 
 
 
200 mg 
MIV-711 
N = x 
Age 
(years) 
n 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Height 
(cm) 
n 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Weight 
(kg) 
n 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
BMI 
(kg/m^2) 
n 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 


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Protocol Number: MIV-711-201 
Table 14.1.3.1 
Demographics – Categorical Variables 
PPS Population 
 
 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
Overall 
N = x 
 
Placebo 
N = x 
 
100 mg 
MIV-711 
N = x 
 
200 mg 
MIV-711 
N = x 
Ethnicity 
 
 
 
 
Hispanic/Latino 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
   Non-Hispanic/Latino 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
Race 
 
 
 
 
White  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
American Indian/Alaska Native 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Asian 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Native Hawaiian or other Pacific Islander 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Black/African American 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Other 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
Gender 
 
 
 
 
Female 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Male 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
Programming note: table will be created for mITT population: Table 14.1.3.2 Demographics – Categorical Variables, mITT Population 


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                                                        22 June 2017 
 
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Protocol Number: MIV-711-201 
Table 14.1.4.1 
Prior Medications  
PPS Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
ATC Classification 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
Overall 
N = x 
 
Placebo 
N = x 
 
100 mg 
MIV-711 
N = x 
 
200 mg 
MIV-711 
N = x 
 
 
 
 
 
 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: table will be created for mITT population: Table 14.1.4.2 Prior Medications, mITT Population 


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Protocol Number: MIV-711-201 
Table 14.1.5.1 
Concomitant Medications  
PPS Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
ATC Classification 
 
 
 
 
 
 
Treatment 
 
 
 
 
 
 
 
 
 
Overall 
N = x 
 
Placebo 
N = x 
 
100 mg 
MIV-711 
N = x 
 
200 mg 
MIV-711 
N = x 
 
 
 
 
 
 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: table will be created for mITT population: Table 14.1.5.2 Concomitant Medications, mITT Population 


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Protocol Number: MIV-711-201 
 
 
Table 14.1.6 
Dose Administration - Number and Percentage of Patients Who Received IMP by Visit 
SAF Population 
 
 
 
 
Visit 
Treatment 
 
 
Overall 
 
N = x 
 
Placebo 
N = x 
 
100 mg 
MIV-711 
N = x 
 
200 mg 
MIV-711 
N = x 
 
 
 
 
 
VISIT 2 BASELINE DAY 1 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
VISIT 5 WEEK 8 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
VISIT 6 WEEK 14 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
      
 
 
 
 
Etc… 
 
 
 
 
 
 
 
 


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Page X of Y 
Protocol Number: MIV-711-201 
 
Table 14.1.7 
Summary of Dosing Compliance  
SAF Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The ‘actual number of capsules used’ was derived as the ‘number of capsules dispensed’ minus the ‘number of capsules returned’.  
‘Planned number of capsules’ is the number of days of per protocol dosing from V2 (first dose) to V8 (last dose), since each patient is to 
receive 1 capsule of dosing per day of dose administration.  
IMP compliance: (actual number of capsules used / planned number of capsules administered) x 100% 
 
 
 
 
 
 
 
 
 
 
Statistic 
 
Treatment 
 
 
 
 
 
 
Overall 
N = x 
 
 
 
Placebo 
N = x 
 
 
100 mg 
MIV-711 
N = x 
 
 
200 mg 
MIV-711 
N = x 
Planned 
Number of 
Days IMP 
exposure 
n 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Actual 
Number of 
Capsules  
used 
n 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
n 
nn 
nn 
nn 
nn 
 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
IMP  
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Compliance Median 
xx.x 
xx.x 
xx.x 
xx.x 
(%) 
Min 
xx 
xx 
xx 
xx 
 
Max 
xx 
xx 
xx 
xx 
 
 
 
 
 
 


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                                                        22 June 2017 
 
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Protocol Number: MIV-711-201 
Table 14.2.1 
NRS Scores Observed and Change from Baseline Summary 
mITT Population 
 
Parameter = How Active the target knee arthritis has been 
 
Visit 
Statistic 
 
Treatment 
 
Placebo 
100 mg 
MIV-711 
 
200 mg 
MIV-711 
 
 
Observed 
 
N = x 
 
Change 
 
N = x 
 
Observed 
 
N = x 
 
Change 
 
N = x 
 
Observed 
 
N = x 
 
Change 
 
N = x 
VISIT 2 
Baseline 
n 
nn 
 
nn 
 
nn 
 
Mean 
xx.x 
 
xx.x 
 
xx.x 
 
SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
Median 
xx.x 
 
xx.x 
 
xx.x 
 
Min 
xx 
 
xx 
 
xx 
 
Max 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
VISIT 5 
WEEK 8 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
VISIT 6 
WEEK 14 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
Etc… 
 
 
 
 
 
 
 
Programming note: table will include summaries for following other NRS scores: 
 
Primary endpoint: Amount of pain severity in the target knee last week (SDTM: Overall pain severity in target knee 
 
Global Assessment Score: How active has the target knee arthritis has been in the past week (SDTM: How active was target knee arthritis) 
 
Satisfaction with target knee function (SDTM:How satisfied are you with target knee function) 
 
Worst pain severity in target knee (SDTM: Worst pain severity in target knee) 
 
Overall pain severity in other knee (SDTM: Overall pain severity in other knee) 


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Protocol Number: MIV-711-201 
 
 
Table 14.2.2 
Number and Percentage of Patients by Category for Duration and Onset of Knee Pain at Baseline 
mITT Population 
 
  
 
 
 
 
  Parameter = Duration of Knee Pain Past 12 Months 
  
 
 
 
 
Category 
Treatment 
 
Placebo 
N = x 
 
100 mg 
MIV-711 
N = x 
 
200 mg 
MIV-711 
N = x 
 
 
 
 
 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
Etc… 
 
 
 
 
 
 
Programming note: table will include summaries for: 
 
Duration of Knee Pain Past 12 Months 
 
Onset of Knee Pain 


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Protocol Number: MIV-711-201 
Table 14.2.3.1 
Statistical Analysis Primary Hypothesis - MIV-711 will Reduce Pain in Patients with Moderate Osteoarthritis 
Assessments Using NRS Scores as Primary Endpoint 
 mITT Population 
 
 
 
Question 
 
 
Treatment 
 
 
Week 
 
N 
Change From Baseline NRS 
Difference From 
Placebo 
LS  
Mean 
 
95% CI 
LS Mean 
Difference 
 
95% CI 
 
 
 
 
 
NRS question 
1: Pain 
severity in 
target knee 
[last week] 
Placebo 
8 
nn  
xx.xx 
(x.xx, x.xx) 
 
 
 
14 
nn  
xx.xx 
(x.xx, x.xx) 
 
 
 
26 
nn  
xx.xx 
(xx.x, xx.x) 
 
 
 
30 
nn  
xx.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
 
 
 
100 mg MIV-711 
8 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
14 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
26 
nn  
xx.xx 
(xx.x, xx.x) 
xx.xx 
(x.xx, x.xx) 
 
30 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
200 mg MIV-711 
8 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
14 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
26 
nn  
xx.xx 
(xx.x, xx.x) 
xx.xx 
(x.xx, x.xx) 
 
30 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(xx.x, xx.x) 
 
  
LS Mean = least squares mean, N denotes the number of Patients for each level of treatment used to estimate the LS means. 
Programming notes: 
Low pain scores are associated with a positive outcome (effect of drug).  
For positive study expect large (negative changes from week 26) decreases from baseline by the time treatment reaches week 26.    
 
 


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Table 14.2.3.2 
Statistical Analysis Primary Hypothesis - MIV-711 will Reduce Pain in Patients with Moderate Osteoarthritis 
Assessments Using NRS Scores as Secondary Endpoints 
 mITT Population 
 
 
 
Question 
 
 
Treatment 
 
 
Week 
 
N 
Change From Baseline NRS 
Difference From 
Placebo 
LS  
Mean 
 
95% CI 
LS Mean 
Difference 
 
95% CI 
 
 
 
 
 
Global 
Assessment 
Score: How 
active was 
target knee 
arthritis 
Placebo 
8 
nn  
xx.xx 
(x.xx, x.xx) 
 
 
 
14 
nn  
xx.xx 
(x.xx, x.xx) 
 
 
 
26 
nn  
xx.xx 
(xx.x, xx.x) 
 
 
 
30 
nn  
xx.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
 
 
 
100 mg MIV-711 
8 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
14 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
26 
nn  
xx.xx 
(xx.x, xx.x) 
xx.xx 
(x.xx, x.xx) 
 
30 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
200 mg MIV-711 
8 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
14 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
26 
nn  
xx.xx 
(xx.x, xx.x) 
xx.xx 
(x.xx, x.xx) 
 
30 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(xx.x, xx.x) 
 
  
LS Mean = least squares mean, N denotes the number of Patients for each level of treatment used to estimate the LS means. 
Programming notes: 
Low pain scores are associated with a positive outcome (effect of drug).  
For positive study expect large (negative changes from week 26) decreases from baseline by the time treatment reaches week 26.    
 
Table will be expanded to include the analysis of the following NRS scores:  
 
Global Assessment Score: How active has the target knee arthritis has been in the past week (SDTM: How active was target knee arthritis) 
 
Satisfaction with target knee function (SDTM:How satisfied are you with target knee function) 
 
Worst pain severity in target knee (SDTM: Worst pain severity in target knee) 
 
Overall pain severity in other knee (SDTM: Overall pain severity in other knee) 
 
 


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Protocol Number: MIV-711-201 
Table 14.2.3.3 
Statistical Analysis Primary Hypothesis - MIV-711 will Reduce Pain in Patients with Moderate Osteoarthritis 
Assessments Using NRS Scores as Primary Endpoint 
PPS Population 
 
 
 
Question 
 
 
Treatment 
 
 
Week 
 
N 
Change From Baseline NRS 
Difference From 
Placebo 
LS  
Mean 
 
95% CI 
LS Mean 
Difference 
 
95% CI 
 
 
 
 
 
NRS question 
1: Pain 
severity in 
target knee 
[last week] 
Placebo 
8 
nn  
xx.xx 
(x.xx, x.xx) 
 
 
 
14 
nn  
xx.xx 
(x.xx, x.xx) 
 
 
 
26 
nn  
xx.xx 
(xx.x, xx.x) 
 
 
 
30 
nn  
xx.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
 
 
 
100 mg MIV-711 
8 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
14 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
26 
nn  
xx.xx 
(xx.x, xx.x) 
xx.xx 
(x.xx, x.xx) 
 
30 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
200 mg MIV-711 
8 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
14 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
26 
nn  
xx.xx 
(xx.x, xx.x) 
xx.xx 
(x.xx, x.xx) 
 
30 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(xx.x, xx.x) 
 
  
LS Mean = least squares mean, N denotes the number of Patients for each level of treatment used to estimate the LS means. 
Programming notes: 
Low pain scores are associated with a positive outcome (effect of drug).  
For positive study expect large (negative changes from week 26) decreases from baseline by the time treatment reaches week 26.    
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 65 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.3.4 
Statistical Analysis Primary Hypothesis - MIV-711 will Reduce Pain in Patients with Moderate Osteoarthritis 
Assessments Using NRS Scores as Secondary Endpoints 
PPS Population 
 
 
 
Question 
 
 
Treatment 
 
 
Week 
 
N 
Change From Baseline NRS 
Difference From 
Placebo 
LS  
Mean 
 
95% CI 
LS Mean 
Difference 
 
95% CI 
 
 
 
 
 
Global 
Assessment 
Score: How 
active was 
target knee 
arthritis 
Placebo 
8 
nn  
xx.xx 
(x.xx, x.xx) 
 
 
 
14 
nn  
xx.xx 
(x.xx, x.xx) 
 
 
 
26 
nn  
xx.xx 
(xx.x, xx.x) 
 
 
 
30 
nn  
xx.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
 
 
 
100 mg MIV-711 
8 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
14 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
26 
nn  
xx.xx 
(xx.x, xx.x) 
xx.xx 
(x.xx, x.xx) 
 
30 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(xx.x, xx.x) 
 
 
 
 
 
 
 
 
200 mg MIV-711 
8 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
14 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
26 
nn  
xx.xx 
(xx.x, xx.x) 
xx.xx 
(x.xx, x.xx) 
 
30 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(xx.x, xx.x) 
 
  
LS Mean = least squares mean, N denotes the number of Patients for each level of treatment used to estimate the LS means. 
Programming notes: 
Low pain scores are associated with a positive outcome (effect of drug).  
For positive study expect large (negative changes from week 26) decreases from baseline by the time treatment reaches week 26.    
 
Table will be expanded to include the analysis of the following NRS scores:  
 
Global Assessment Score: How active has the target knee arthritis has been in the past week (SDTM: How active was target knee arthritis) 
 
Satisfaction with target knee function (SDTM:How satisfied are you with target knee function) 
 
Worst pain severity in target knee (SDTM: Worst pain severity in target knee) 
 
Overall pain severity in other knee (SDTM: Overall pain severity in other knee) 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 66 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.4.1 
Imaging variables - MRI of Bone Area for the Target Knee Observed and Change from Baseline Summary  
mITT Population 
 
 
Visit 
Statistic 
 
Treatment 
 
Placebo 
100 mg 
MIV-711 
 
200 mg 
MIV-711 
 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
VISIT 2  
Baseline 
n 
nn 
 
nn 
 
nn 
 
Mean 
xx.x 
 
xx.x 
 
xx.x 
 
SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
Median 
xx.x 
 
xx.x 
 
xx.x 
 
Min 
xx 
 
xx 
 
xx 
 
Max 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VISIT 8 
WEEK 26 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
Programming note: source data obtained from MF_TAB: Area of bone in the medial femur region, MF 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 67 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.4.2 
Statistical Analysis - MRI of Bone Area for the Target Knee in Patients with Moderate Osteoarthritis 
mITT Population 
 
 
 
Question 
 
 
Treatment 
 
N 
Change From Baseline NRS 
(Visit 8 Week 26) 
Difference From 
Placebo 
LS  
Mean 
 
95% CI 
LS Mean 
Difference 
 
95% CI 
 
MRI of Bone 
Area 
Placebo 
nn  
xx.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
 
 
100 mg MIV-711 nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
200 mg MIV-711 nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
  
LS Mean = least squares mean, N denotes the number of Patients for each level of treatment used to estimate the LS means. 
Programming notes: 
 
 
 
Programming note: source data obtained from MF_TAB: Area of bone in the medial femur region, MF 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 68 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.4.3 
Imaging variables – MRI of Cartilage Thickness for the Target Knee Observed and Change from Baseline Summary  
mITT Population 
 
Parameter = Femur Region 
 
Visit 
Statistic 
 
Treatment 
 
Placebo 
100 mg 
MIV-711 
 
200 mg 
MIV-711 
 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
VISIT 2  
Baseline 
n 
nn 
 
nn 
 
nn 
 
Mean 
xx.x 
 
xx.x 
 
xx.x 
 
SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
Median 
xx.x 
 
xx.x 
 
xx.x 
 
Min 
xx 
 
xx 
 
xx 
 
Max 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VISIT 8 
WEEK 26 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
Programming note: source data obtained from: 
 
CM_FEMUR_THCTAB: Average thickness of cartilage in the central medial femur region 
 
CM_TIBIA_THCTAB: Average thickness of cartilage in the central medial tibia region 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 69 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.4.4 
Statistical Analysis - MRI of Cartilage Thickness for the Target Knee in Patients with Moderate Osteoarthritis 
mITT Population 
 
 
 
Parameter 
 
 
Treatment 
 
N 
Change From Baseline NRS 
(Visit 8 Week 26) 
Difference From 
Placebo 
LS  
Mean 
 
95% CI 
LS Mean 
Difference 
 
95% CI 
 
Femur Region 
Placebo 
nn  
xx.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
 
 
100 mg MIV-711 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
200 mg MIV-711 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LS Mean = least squares mean, N denotes the number of Patients for each level of treatment used to estimate the LS means. 
Programming notes: 
 
 
 
Programming note: source data obtained from: 
 
CM_FEMUR_THCTAB: Average thickness of cartilage in the central medial femur region 
 
CM_TIBIA_THCTAB: Average thickness of cartilage in the central medial tibia region 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 70 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.4.5 
Imaging variables – MRI of Total BML Volume for the Target Knee Observed and Change from Baseline Summary  
mITT Population 
 
Parameter = Femur Region 
 
Visit 
Statistic 
 
Treatment 
 
Placebo 
100 mg 
MIV-711 
 
200 mg 
MIV-711 
 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
VISIT 2  
Baseline 
n 
nn 
 
nn 
 
nn 
 
Mean 
xx.x 
 
xx.x 
 
xx.x 
 
SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
Median 
xx.x 
 
xx.x 
 
xx.x 
 
Min 
xx 
 
xx 
 
xx 
 
Max 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VISIT 8 
WEEK 26 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
Programming note: source data obtained from: TOTAL_BML_VOLUME 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 71 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.4.6 
Statistical Analysis - MRI of Total BML Volume for the Target Knee in Patients with Moderate Osteoarthritis 
mITT Population 
 
 
 
Parameter 
 
 
Treatment 
 
N 
Change From Baseline NRS 
(Visit 8 Week 26) 
Difference From 
Placebo 
LS  
Mean 
 
95% CI 
LS Mean 
Difference 
 
95% CI 
 
Femur Region 
Placebo 
nn  
xx.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
 
 
100 mg MIV-711 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
200 mg MIV-711 
nn  
xx.xx 
(x.xx, x.xx) 
xx.xx 
(x.xx, x.xx) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc.. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
LS Mean = least squares mean, N denotes the number of Patients for each level of treatment used to estimate the LS means. 
Programming notes: 
 
Programming note: source data obtained from: TOTAL_BML_VOLUME 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 72 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.4.7 
Other Imaging variables MOAKS and Imorphics  
Number and Percentage of Subjects by Category and Treatment 
mITT Population 
 
 
 
 
 
 
 
 
Catgeory 
Treatment 
 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
Size of BML 
None 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
<33% 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
33-66% 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
>66% 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
Not Evaluable 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
Percentage that is BML 
None 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
<33% 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
33-66% 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
>66% 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
Not Evaluable 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc… 
Etc… 
 
 
 
 
 
 
 
 
                  
 
 
 
 
 
 
 
Programming note: table will include summaries for the MOAKS and Imorphics imaging variables collected using a categorical response 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 73 of 155 
 
 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.4.8 
Other Imaging variables MOAKS and Imorphics  
Observed and Change from Baseline Summary  
mITT Population 
 
Parameter = Number of Bone Marrow Lesions 
 
Visit 
Statistic 
 
Treatment 
 
Placebo 
100 mg 
MIV-711 
 
200 mg 
MIV-711 
 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
VISIT 2  
Baseline 
n 
nn 
 
nn 
 
nn 
 
Mean 
xx.x 
 
xx.x 
 
xx.x 
 
SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
Median 
xx.x 
 
xx.x 
 
xx.x 
 
Min 
xx 
 
xx 
 
xx 
 
Max 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
VISIT 8 
WEEK 26 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
Programming note: table will include summaries for the other MOAKS and Imorphics variables collected using a quantitative response 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 74 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.5 
Transformed ICOAP Scores Observed and Change from Baseline Summary  
mITT Population 
 
Parameter = Constant Pain 
 
 
Visit 
Statistic 
 
Treatment 
 
Placebo 
100 mg 
MIV-711 
 
200 mg 
MIV-711 
 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
VISIT 2  
Baseline 
n 
nn 
 
nn 
 
nn 
 
Mean 
xx.x 
 
xx.x 
 
xx.x 
 
SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
Median 
xx.x 
 
xx.x 
 
xx.x 
 
Min 
xx 
 
xx 
 
xx 
 
Max 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
VISIT 5 
WEEK 8 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
VISIT 6 
WEEK 14 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
Etc… 
 
 
 
 
 
 
 
 
Programming note: table will include summaries for following transformed ICOAP scores: 
Constant Pain, Intermittent Pain, and Total Pain.


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 75 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.6.1 
WOMAC Scores Observed and Change from Baseline Summary - Pain Questions 
mITT Population 
 
Parameter = Walking on flat surface 
 
Visit 
Statistic 
 
Treatment 
 
Placebo 
100 mg 
MIV-711 
 
200 mg 
MIV-711 
 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
VISIT 2  
Baseline 
n 
nn 
 
nn 
 
nn 
 
Mean 
xx.x 
 
xx.x 
 
xx.x 
 
SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
Median 
xx.x 
 
xx.x 
 
xx.x 
 
Min 
xx 
 
xx 
 
xx 
 
Max 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
VISIT 5 
WEEK 8 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
VISIT 6 
WEEK 14 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
Etc… 
 
 
 
 
 
 
 
 
Programming note: table will be expanded to include all WOMAC Pain questions  


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 76 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.6.2 
WOMAC Scores Observed and Change from Baseline Summary - Stiffness Questions 
mITT Population 
 
Parameter = Stiffness after First Woke Up in Morning 
 
Visit 
Statistic 
 
Treatment 
 
Placebo 
100 mg 
MIV-711 
 
200 mg 
MIV-711 
 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
VISIT 2  
Baseline 
n 
nn 
 
nn 
 
nn 
 
Mean 
xx.x 
 
xx.x 
 
xx.x 
 
SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
Median 
xx.x 
 
xx.x 
 
xx.x 
 
Min 
xx 
 
xx 
 
xx 
 
Max 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
VISIT 5 
WEEK 8 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
VISIT 6 
WEEK 14 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
Etc… 
 
 
 
 
 
 
 
 
Programming note: table will be expanded to include all WOMAC stiffness questions  


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 77 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.6.3 
WOMAC Scores Observed and Change from Baseline Summary - Difficulty Questions 
mITT Population 
 
Parameter = Stiffness after First Woke Up in Morning 
 
Visit 
Statistic 
 
Treatment 
 
Placebo 
100 mg 
MIV-711 
 
200 mg 
MIV-711 
 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
VISIT 2  
Baseline 
n 
nn 
 
nn 
 
nn 
 
Mean 
xx.x 
 
xx.x 
 
xx.x 
 
SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
Median 
xx.x 
 
xx.x 
 
xx.x 
 
Min 
xx 
 
xx 
 
xx 
 
Max 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
VISIT 5 
WEEK 8 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
VISIT 6 
WEEK 14 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
Etc… 
 
 
 
 
 
 
 
 
 
Programming note: table will be expanded to include all WOMAC Difficulty questions  


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 78 of 155 
 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.7 
Number and Percentage of Patients with a Positive OARSI-OMERACT Response 
mITT Population 
 
Parameter = Completely Better 
 
 
 
 
 
 
 
Response 
Treatment 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
Yes 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
No 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 79 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.8 
Number and Percentage of Patients with Each Global Improvement Score Response 
mITT Population 
 
Parameter = Knee Problem 
 
 
Visit 
 
 
 
 
 
Score 
Treatment 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
VISIT 5 WEEK 8 
Completely better 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Much better  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Better 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
No change 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Worse 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Much worse 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
VISIT 6 WEEK 14 
Completely better 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Much better  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Better 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
No change 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Worse 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Much worse 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
VISIT 8 WEEK 26 
Completely better 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Much better  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Better 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
No change 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Worse 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Much worse 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 
Programming note: table will be expanded to include all Global improvement questions:  
Knee Problem, Knee Pain, Ability to use knee. 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 80 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.9 
EQ-5D-5L Health Rating Score Response Observed and Change from Baseline Summary 
mITT Population 
 
Parameter = Mobility 
 
Visit 
Statistic 
 
Treatment 
 
Placebo 
100 mg 
MIV-711 
 
200 mg 
MIV-711 
 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
VISIT 2, 
Day 1  
n 
nn 
 
nn 
 
nn 
 
Mean 
xx.x 
 
xx.x 
 
xx.x 
 
SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
Median 
xx.x 
 
xx.x 
 
xx.x 
 
Min 
xx 
 
xx 
 
xx 
 
Max 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
VISIT 8 
WEEK 26 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
Programming note: table will be expanded to include all QOL variables:  
Mobility, self-care, usual activity, pain or discomfort, and anxiety or depression, health rating score. 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 81 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.10.1 
E-Diary NRS Scores Observed and Change from Baseline Summary, AM Reponse 
mITT Population 
 
Parameter = How would you rate overall pain severity over last 12 Hours? 
 
Visit 
Statistic 
 
Treatment 
 
Placebo 
100 mg 
MIV-711 
 
200 mg 
MIV-711 
 
 
Observed 
 
N = x 
 
Change 
 
N = x 
 
Observed 
 
N = x 
 
Change 
 
N = x 
 
Observed 
 
N = x 
 
Change 
 
N = x 
VISIT 2 
Baseline 
n 
nn 
 
nn 
 
nn 
 
Mean 
xx.x 
 
xx.x 
 
xx.x 
 
SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
Median 
xx.x 
 
xx.x 
 
xx.x 
 
Min 
xx 
 
xx 
 
xx 
 
Max 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
VISIT 6 
WEEK 14 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
VISIT 8  
WEEK 26 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 82 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.10.2 
E-Diary NRS Scores Observed and Change from Baseline Summary, PM Reponse 
mITT Population 
 
Parameter = How would you rate overall pain severity over last 12 Hours? 
 
Visit 
Statistic 
 
Treatment 
 
Placebo 
100 mg 
MIV-711 
 
200 mg 
MIV-711 
 
 
Observed 
 
N = x 
 
Change 
 
N = x 
 
Observed 
 
N = x 
 
Change 
 
N = x 
 
Observed 
 
N = x 
 
Change 
 
N = x 
VISIT 2 
Baseline 
n 
nn 
 
nn 
 
nn 
 
Mean 
xx.x 
 
xx.x 
 
xx.x 
 
SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
Median 
xx.x 
 
xx.x 
 
xx.x 
 
Min 
xx 
 
xx 
 
xx 
 
Max 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
VISIT 6 
WEEK 14 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
VISIT 8  
WEEK 26 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 83 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.10.3 
E-Diary NRS Scores Observed and Change from Baseline Summary, Overall Response  
mITT Population 
 
Parameter = How would you rate overall pain severity over last 12 Hours? 
 
Visit 
Statistic 
 
Treatment 
 
Placebo 
100 mg 
MIV-711 
 
200 mg 
MIV-711 
 
 
Observed 
 
N = x 
 
Change 
 
N = x 
 
Observed 
 
N = x 
 
Change 
 
N = x 
 
Observed 
 
N = x 
 
Change 
 
N = x 
VISIT 2 
Baseline 
n 
nn 
 
nn 
 
nn 
 
Mean 
xx.x 
 
xx.x 
 
xx.x 
 
SD 
xx.xx 
 
xx.xx 
 
xx.xx 
 
Median 
xx.x 
 
xx.x 
 
xx.x 
 
Min 
xx 
 
xx 
 
xx 
 
Max 
xx 
 
xx 
 
xx 
 
 
 
 
 
 
 
 
 
VISIT 6 
WEEK 14 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
VISIT 8  
WEEK 26 
n 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
Programming note: The mean of the AM, PM NRS scores will be used to obtain 1 record at each visit prior to computing descriptive statistics 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 84 of 155 
 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.10.4 
Number and Percentage of Patients with E-Diary Pain Medication Usage (Yes/No) Over Last 12 Hours, AM Response 
mITT Population 
 
Question = Have you taken any pain medication over the last 12 hours since you last answered your OA Daily Diary?  
 
 
Visit 
 
 
 
 
 
Score 
Treatment 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
VISIT 2 Baseline 
Yes 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
No 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
VISIT 6 WEEK 14 
Yes 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
No  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
VISIT 8 WEEK 26 
Yes 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
No  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 85 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.10.5 
Number and Percentage of Patients with E-Diary Pain Medication Usage (Yes/No) Over Last 12 Hours, PM Response 
mITT Population 
 
Question = Have you taken any pain medication over the last 12 hours since you last answered your OA Daily Diary?  
 
 
 
 
Visit 
 
 
 
 
 
Score 
Treatment 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
VISIT 2 Baseline 
Yes 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
No 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
VISIT 6 WEEK 14 
Yes 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
No  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
VISIT 8 WEEK 26 
Yes 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
No  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 86 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.2.10.6 
Number and Percentage of Patients with E-Diary Pain Medication Usage (Yes/No) Over Last 12 Hours, Overall Response 
mITT Population 
 
Question = Have you taken any pain medication over the last 12 hours since you last answered your OA Daily Diary?  
 
 
 
 
Visit 
 
 
 
 
 
Score 
Treatment 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
VISIT 2 Baseline 
Yes 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
No 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
VISIT 6 WEEK 14 
Yes 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
No  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
VISIT 8 WEEK 26 
Yes 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
No  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
Programming note: at least one ‘Yes’ response for AM or PM will be interpreted as a ‘Yes’ response 24 hours overall. 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 87 of 155 
 
Table 14.2.10.7 
E-Diary Pain Medication Usage Over Last 12 Hours  
Number and Percentage of Patients with each Reported Category, AM Response 
mITT Population 
 
 
 
Visit 
 
 
 
 
 
Category 
Treatment 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
VISIT 2, Baseline  
Less than Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
More than Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
VISIT 6 WEEK 14 
Less than Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
More than Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
VISIT 8 WEEK 26 
Less than Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
More than Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 88 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
Table 14.2.10.8 
E-Diary Pain Medication Usage Over Last 12 Hours  
Number and Percentage of Patients with each Reported Category, PM Response 
mITT Population 
 
 
 
Visit 
 
 
 
 
 
Category 
Treatment 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
VISIT 2, Baseline  
Less than Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
More than Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
VISIT 6 WEEK 14 
Less than Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
More than Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
VISIT 8 WEEK 26 
Less than Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
More than Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 89 of 155 
 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
Table 14.3.1.1 
Summary of Treatment Emergent Adverse Events   
SAF Population 
 
 
Treatment 
 
 
 
Overall 
N = x 
nn (%) E 
 
Placebo 
N = x 
 
nn (%) E 
 
100 mg 
MIV-711 
N = x 
nn (%) E 
 
200 mg 
MIV-711 
N = x 
nn (%) E 
All AEs 
nn (nn.n%) E 
nn (nn.n%) E 
nn (nn.n%) E 
nn (nn.n%) E 
‘Related’ AEs 
nn (nn.n%) E 
nn (nn.n%) E 
nn (nn.n%) E 
nn (nn.n%) E 
Mild AEs 
nn (nn.n%) E 
nn (nn.n%) E 
nn (nn.n%) E 
nn (nn.n%) E 
Moderate AEs 
nn (nn.n%) E 
nn (nn.n%) E 
nn (nn.n%) E 
nn (nn.n%) E 
Severe AEs 
nn (nn.n%) E 
nn (nn.n%) E 
nn (nn.n%) E 
nn (nn.n%) E 
Deaths 
nn (nn.n%) E 
nn (nn.n%) E 
nn (nn.n%) E 
nn (nn.n%) E 
Serious AEs 
nn (nn.n%) E 
nn (nn.n%) E 
nn (nn.n%) E 
nn (nn.n%) E 
AEs Leading to early discontinuation 
from study 
nn (nn.n%) E 
nn (nn.n%) E 
nn (nn.n%) E 
nn (nn.n%) E 
 
 
 
TEAE = Treatment Emergent Adverse Event  
nn = Number of Patientswith TEAEs 
N  = Number of PatientsExposed  
(nn.n%) = nn/N x 100 
E = Number of AEs 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 90 of 155 
 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
 
Table 14.3.1.2 
Number and Percentage of Patients with Treatment Emergent Adverse Events 
by System Organ Class, Preferred Term, and Treatment  
SAF Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 
   Preferred Term 
Treatment 
 
 
Overall 
 
 
N = x 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
 
 
 
 
 
System Organ Class 1 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 1 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 2 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 3 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term xx 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
System Organ Class 2 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 1 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 2 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 3 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term xx 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 91 of 155 
 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
 
Table 14.3.1.3 
Number and Percentage of Patients with Treatment Emergent Adverse Events ‘Related to IMP’ 
by System Organ Class, Preferred Term, Severity, and Treatment  
SAF Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For patients with multiple adverse events of the same preferred term and different severities, the AE with the highest assessment of severity was 
used in the summary table. 
 
 
 
 
 
 
 
System Organ Class 
   Preferred Term 
 
 
 
 
 
Severity 
Treatment 
 
 
Overall 
 
 
N = x 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
System Organ Class 1 
Mild 
Moderate 
Severe 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 1 
Mild 
Moderate 
Severe 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term xx 
Mild 
Moderate 
Severe 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 
System Organ Class 2 
Mild 
Moderate 
Severe 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 1 
Mild 
Moderate 
Severe 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term xx 
Mild 
Moderate 
Severe 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Etc.. 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 92 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
 
Table 14.3.1.4 
Number and Percentage of Patients with Treatment Emergent Adverse Events ‘Not Related to IMP’ 
by System Organ Class, Preferred Term, Severity, and Treatment  
SAF Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
For patients with multiple adverse events of the same preferred term and different severities, the AE with the highest assessment of severity was 
used in the summary table. 
 
 
 
 
 
System Organ Class 
   Preferred Term 
 
 
 
 
 
Severity 
Treatment 
 
 
Overall 
 
 
N = x 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
System Organ Class 1 
Mild 
Moderate 
Severe 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 1 
Mild 
Moderate 
Severe 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term xx 
Mild 
Moderate 
Severe 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 
System Organ Class 2 
Mild 
Moderate 
Severe 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 1 
Mild 
Moderate 
Severe 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term xx 
Mild 
Moderate 
Severe 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Etc.. 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 93 of 155 
 
 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
 
Table 14.3.1.5 
Number and Percentage of Patients with Serious Treatment Emergent Adverse Events 
by System Organ Class, Preferred Term, and Treatment  
SAF Population 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
System Organ Class 
   Preferred Term 
Treatment 
 
 
Overall 
 
 
N = x 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
 
 
 
 
 
System Organ Class 1 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 1 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 2 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 3 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term xx 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
System Organ Class 2 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 1 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 2 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 3 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term xx 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 94 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
 
Table 14.3.1.6 
Number and Percentage of Patients with Treatment Emergent Adverse Events Leading to Discontinuation 
by System Organ Class, Preferred Term, and Treatment  
SAF Population 
 
 
 
 
System Organ Class 
   Preferred Term 
Treatment 
 
 
Overall 
 
 
N = x 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
 
 
 
 
 
System Organ Class 1 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 1 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 2 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 3 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term xx 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
System Organ Class 2 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 1 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 2 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term 3 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
  Preferred Term xx 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 95 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.3.2.1 
Clinical Laboratory Chemistry - Summary of Observed Values  
SAF Population 
 
Lab Parameter = Lab Parameter (unit) 
 
Visit 
Statistic 
Treatment 
 
 
 
Overall 
 
N = x 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
Screening 
 
n 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Visit 2 
Baseline 
Day 1 
n 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Visit 3 
Week 2 
n 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Visit 4 
Week 4 
 
n 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
Etc… 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 96 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.3.2.2 
Clinical Laboratory Hematology - Summary of Observed Values  
SAF Population 
 
Lab Parameter = Lab Parameter (unit) 
 
Visit 
Statistic 
Treatment 
 
 
 
Overall 
 
N = x 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
Screening 
 
n 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Visit 2 
Baseline 
Day 1 
n 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Visit 3 
Week 2 
n 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
Visit 4 
Week 4 
 
n 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
Etc… 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 97 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.3.2.3 
Clinical Laboratory Chemistry – Shift From Baseline to Maximum Post-dose Value 
SAF Population 
 
Lab Parameter = Lab Parameter (unit) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Note: Similar table will be created for hematology parameters: Tables 14.3.2.4 
 
 
Treatment 
 
Maximum 
Post-dose 
Value 
Baseline (Visit 2) 
Low 
Normal 
High 
 
 Placebo 
Low 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
High 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 
100 mg 
MIV-711 
 
Low 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
High 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 
200 mg 
MIV-711 
 
Low 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
High 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 98 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.3.2.5 
Clinical Laboratory Chemistry – Shift From Baseline to Minimum Post-dose Value 
SAF Population 
 
Lab Parameter = Lab Parameter (unit) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming Note: Similar table will be created for hematology parameters: Tables 14.3.2.6 
 
 
Treatment 
 
Maximum 
Post-dose 
Value 
Baseline (Visit 2) 
Low 
Normal 
High 
 
 Placebo 
Low 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
High 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 
100 mg 
MIV-711 
 
Low 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
High 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 
200 mg 
MIV-711 
 
Low 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Normal 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
High 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 99 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.3.3 
Vital Signs Blood Pressure and Heart Rate Summary of Observed and Change from Baseline Values  
SAF Population 
 
Parameter = Systolic Blood Pressure (mmHg) 
 
Visit 
Statistic 
 
Treatment 
 
 
Overall 
 
N = x 
 
Placebo 
100 mg 
MIV-711 
 
200 mg 
MIV-711 
 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
Screening 
 
n 
nn 
nn 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
Visit 2 
Baseline 
Day 1 
 
n 
nn 
nn 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
Visit 3 
Week 2 
n 
nn 
nn 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Etc… 
 
 
 
 
 
 
 
 
 
 
 
Programming Notes: Table will be expanded to include diastolic blood pressure and heart rate, subject weight 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 100 of 155 
 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
Table 14.3.4.1 
12 Lead ECG – Summary of Observed and Change from Baseline Values 
SAF Population 
 
Parameter = QT Interval (unit) 
 
Visit 
Statistic 
 
Treatment 
 
 
Overall 
 
N = x 
 
Placebo 
100 mg 
MIV-711 
 
200 mg 
MIV-711 
 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
 
 
Observed 
 
N = x 
 
 
Change 
 
N = x 
Screening 
 
n 
nn 
nn 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
Visit 2 
Baseline 
Day 1 
 
n 
nn 
nn 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
 
 
 
 
 
 
 
 
 
 
Visit 3 
Week 2 
n 
nn 
nn 
nn 
nn 
nn 
nn 
nn 
nn 
Mean 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
SD 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
xx.xx 
Median 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
xx.x 
Min 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Max 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
xx 
Etc… 
 
 
 
 
 
 
 
 
 
 
 
QTcB = QT corrected according to Bazett, QTcF = QT corrected according to Fridericia. 
 
Programming note: Table will include: QTcB interval and QTcF interval


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 101 of 155 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
 
Table 14.3.4.2 
12 Lead ECG – Categorical Summary of Observed Values   
SAF Population 
 
Parameter = QT (msec) 
 
 
 
Visit 
 
 
 
 
Category (unit) 
Treatment 
 
 
Overall 
 
N = x 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
Screening 
≤ 450  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
450 < to ≤ 480 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
480 < to ≤ 500 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
>500 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 
Visit 2 Baseline Day 1 
≤ 450  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
450 < to ≤ 480 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
480 < to ≤ 500 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
>500 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 
Visit 3 Week 2 
≤ 450  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
450 < to ≤ 480 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
480 < to ≤ 500 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
>500 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Etc… 
Etc… 
 
 
 
 
 
 
QTcB = QT corrected according to Bazett, QTcF = QT corrected according to Fridericia. 
 
Programming note: Table will include: QTcB interval and QTcF interval


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 102 of 155 
 
Medivir Page X of Y 
Protocol Number: MIV-711-201 
 
Table 14.3.4.3 
12 Lead ECG – Categorical Summary of Change from Baseline   
SAF Population 
 
 Parameter = QT (msec) 
 
 
Visit 
 
 
 
Category (unit) 
Treatment 
 
 
 
Overall 
  
N = x 
 
Placebo 
 
 
N = x 
 
100 mg 
MIV-711 
 
N = x 
 
200 mg 
MIV-711 
 
N = x 
Visit 3 Week 2 
<= 0 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
>0 to ≤ 30  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
>30 to ≤ 60 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
>60 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
 
 
 
 
 
 
Visit 4 Week 4 
 
<= 0 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
>0 to ≤ 30  
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
>30 to ≤ 60 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
>60 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
nn (nn.n%) 
Etc… 
 
 
 
 
 
 
 
 
QTcB = QT corrected according to Bazett, QTcF = QT corrected according to Fridericia. 
 
Programming note: Table will include: QTcB interval and QTcF interval 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 103 of 155 
 
  
 
 
15. 
Listing Shells 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 104 of 155 
 
 
Medivir 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.1.1 
Patient Disposition   
 
       Treatment = MIV-711 200 mg 
 
 
 
 
 
 
Patient 
 
Completion Status 
 
 
If Discontinued, 
Day of 
Withdrawal 
 
 
If Discontinued, 
Date of 
Withdrawal 
Reason For 
Discontinuation 
 
 
Finalization 
of Visit 9 
(Week 30) 
 
Roll-over to 
and 
finalization 
of Visit 2 of 
MIV-711-202 
 
Completed  
 
 
 
 
 
 
Discontinued  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 105 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.1.2 
Patients Excluded from the Analysis Populations 
 
 
                                           Treatment = MIV-711 200 mg 
 
Patient 
 
 
 
Population 
 
 
 
Reason for Exclusion 
 
ITT 
 
 
mITT 
 
 
PPS 
 
 
SAF 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 106 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.1.3 
Enrolled Patients Who Did Not Meet All Eligibility Criteria 
 
 
 
                                Treatment = MIV-711 200 mg 
 
Patient 
 
 
 
Criteria Category 
 
 
 
Criteria Description 
 
 
 
Response 
 
Inclusion 
 
No  
 
Exclusion 
 
Yes 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 107 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.1.4 
Exclusion Tests   
FSH test, Serology, Urine Drug Screen 
 
                 Treatment = MIV-711 200 mg 
 
 
 
 
 
 
Patient 
Visit 
 
Collection 
Date 
 Collection 
Time 
 
Exclusion Test 
 
Result 
 
 
 
 
 
Units 
 
 
 
 
 
 
 
 
 
 
 
FSH test 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc... 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 108 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
Listing 16.2.2.1 
Protocol Deviations  
 
 
Treatment = MIV-711 200 mg 
 
 
Patient 
Study 
Day 
Time Point 
Date Deviation 
Occurred 
 
Category 
Explanation 
 
Classification 
 
 
 
 
Time Window  
 
Minor  
 
 
 
 
Dosing  
 
Major 
 
 
 
 
Exclusion Tests 
 
Major 
 
 
 
 
Etc… 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 109 of 155 
 
  
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
Listing 16.2.4.1  
Demographics  
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
Patient 
Gender 
Ethnicity 
Race 
Age 
(yrs) 
Height 
(cm) 
Weight 
(kg) 
BMI 
(kg/m^2) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 110 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.4.2 
 Medical History   
 
Treatment = MIV-711 200 mg 
 
Patient 
Reported Term 
>MedDRA Preferred 
Term 
>>System Organ 
Class 
Onset 
Date 
 
 
 
 
 
Status 
Recovered 
Date 
Currently 
Treated with 
Medication? 
 
 
 
Ongoing 
 
Yes/No 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 111 of 155 
 
 
Medivir 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.5.1 
Prior and Concomitant Medications   
 
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
 
Patient 
 
Medication 
Name 
>WHO Drug Name 
>>ATC 
Classification 
 
 
 
 
 
Category 
Start 
Date 
Stop 
Date 
Ongoing? 
Dose/ 
Unit 
Frequency Route Indication 
Was 
There 
an AE 
 
 
 
 
Pain 
Medication 
 
 
Prior  
 
 
 
Yes/No 
 
 
 
 
Yes/No 
 
 
CM 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
Programming note: Pain Medication = ‘Yes’ if ATC = ‘ANALGESICS’ 


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Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 112 of 155 
 
Medivir 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.5.2 
Dose Administration 
 
 
 
                                   Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
Date of 
Dose 
Time of 
Dose 
 
 
 
 
Dose Form / 
Route 
 
 
 
 
Category of 
Treatment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 113 of 155 
 
Medivir 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.5.3 
Dose Administration Compliance 
 
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
Date 
of 
Dose 
Time 
of 
Dose 
 
 
 
 
 
 
 
 
 
Category 
of 
Treatment 
Dispensed 
Amount 
(Capsules) 
Returned 
Amount 
(Capsules) 
 
 
 
 
 
 
 
Actual 
Number 
of 
Capsules 
used 
 
 
 
 
 
 
 
 
Planned 
number 
of 
capsules 
 
 
 
 
 
 
 
Were all 
unused 
Capsules 
returned? 
 
 
 
 
 
 
Reason 
not all 
unused 
Capsules 
returned 
 
 
 
 
 
 
 
 
 
Medication 
error 
 
 
 
 
 
 
 
Number 
of Days 
exposed 
to IMP 
 
 
 
 
 
 
 
 
 
IMP  
Compliance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
The ‘actual number of capsules used’ was derived as the ‘number of capsules dispensed’ minus the ‘number of capsules returned’.  
‘Planned number of capsules’ is the number of days of per protocol dosing from V2 (first dose) to V8 (last dose), since each patient is to 
receive 1 capsule of dosing per day of dose administration.  
IMP compliance: (actual number of capsules used / planned number of capsules administered) x 100% 
 


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Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 114 of 155 
 
 
 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.1 
Numerical Rating Scale of Knee Pain 
 
 
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
Date of 
Assessment 
Target 
Knee 
Used 
for 
NRS 
Pain 
Severity 
in 
Target 
Knee 
(last 
week) 
Global 
Assessment 
NRS 
Satisfied 
with 
Target 
Knee 
Function 
Worst 
Pain 
Severity 
Target 
Knee 
Overall 
pain 
severity 
in other 
knee 
 
VISIT 2 BASELINE DAY 
VISIT 5 WEEK 8 
 
 
 
 
 
 
 
 
VISIT 6 WEEK 14 
 
 
 
 
 
 
 
 
Etc… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: listing will include: 
 
Primary endpoint: Amount of pain severity in the target knee last week (SDTM: Overall pain severity in target knee 
 
Global Assessment Score: How active has the target knee arthritis has been in the past week (SDTM: How active was target knee arthritis) 
 
Satisfaction with target knee function (SDTM:How satisfied are you with target knee function) 
 
Worst pain severity in target knee (SDTM: Worst pain severity in target knee) 
 
Overall pain severity in other knee (SDTM: Overall pain severity in other knee) 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 115 of 155 
 
  
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.2 
Numerical Rating Scale of Knee Pain Change From Baseline 
             
 
 
 
                    Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
Date of 
Assessment 
Pain 
Severity 
in 
Target 
Knee 
(last 
week) 
Global 
Assessment 
NRS 
Satisfied 
with 
Target 
Knee 
Function 
Worst 
Pain 
Severity 
Target 
Knee 
Overall 
pain 
severity 
in other 
knee 
 
VISIT 2 BASELINE DAY 
VISIT 5 WEEK 8 
 
 
 
 
 
 
 
VISIT 6 WEEK 14 
 
 
 
 
 
 
 
Etc… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: listing will include: 
 
Primary endpoint: Amount of pain severity in the target knee last week (SDTM: Overall pain severity in target knee 
 
Global Assessment Score: How active has the target knee arthritis has been in the past week (SDTM: How active was target knee arthritis) 
 
Satisfaction with target knee function (SDTM:How satisfied are you with target knee function) 
 
Worst pain severity in target knee (SDTM: Worst pain severity in target knee) 
 
Overall pain severity in other knee (SDTM: Overall pain severity in other knee) 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 116 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.3 
Numerical Rating Scale of Knee Pain – Duration and Onset 
       
 
 
                            Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
 
Patient 
Visit 
Date of 
Assessment 
Duration 
of 
Knee 
Pain 
Past 
12 
Months 
Onset of 
Knee Pain 
 
VISIT 2 BASELINE DAY 
VISIT 5 WEEK 8 
 
 
 
 
VISIT 6 WEEK 14 
 
 
 
 
Etc… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 117 of 155 
 
  
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.4 
Imaging Results - MRI of Bone Area for the Target Knee  
Observed and Change from Baseline 
 
 
                             Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
 
Patient 
Visit 
Date of 
Assessment 
 
 
 
 
 
Time of 
Assessment 
MRI 
Result 
- Bone 
area 
MRI – 
Result -
Change from 
baseline 
Bone Area 
 
VISIT 2 BASELINE DAY 
VISIT 8 WEEK 26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: source data obtained from MF_TAB: Area of bone in the medial femur region, MF 
 
 


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Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 118 of 155 
 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.5 
Imaging Results - MRI of Cartilage Thickness for the Target Knee  
Observed and Change from Baseline 
 
 
 
                        Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
Date of 
Assessment 
 
 
 
 
 
Time of 
Assessment 
 
 
 
 
 
 
Region 
MRI 
Result- 
Cartilage 
Thickness 
MRI Result 
- Change 
from 
baseline 
Cartilage 
Thickness  
 
VISIT 2 BASELINE DAY 
VISIT 8 WEEK 26 
 
 
 
 
 
 
 
Programming note: source data obtained from: 
 
CM_FEMUR_THCTAB: Average thickness of cartilage in the central medial femur region 
 
CM_TIBIA_THCTAB: Average thickness of cartilage in the central medial tibia region 


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Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 119 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
Listing 16.2.6.6 
Other Secondary Imaging Variables – MOAKS  
Treatment = MIV-711 200 mg 
                                                                  
 
Patient 
 
Visit 
Date of 
Assessment 
Time of 
Assessment 
Question 
Group Name 
Question 
Sub-Group 
Name 
Question Name 
Result 
Score 
Result 
Score 
Description 
 
 
Comments 
 
VISIT 2 
BASELINE DAY 
VISIT 8 WEEK 
26 
 
 
BML and 
Cyst 
Size of 
BML 
Medial Patella 
 
 
 
 
 
 
 
 
 
Lateral Patella 
 
 
 
 
 
 
 
 
 
Medical Femur 
Trochlea 
 
 
 
 
 
 
 
 
 
Etc… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of 
BMLs 
Medial Patella 
 
 
 
 
 
 
 
 
 
Lateral Patella 
 
 
 
 
 
 
 
 
 
Medical Femur 
Trochlea 
 
 
 
 
 
 
 
 
 
Etc… 
 
 
 
 
 
 
 
 
Percent 
that is 
BML 
Medial Patella 
 
 
 
 
 
 
 
 
 
Lateral Patella 
 
 
 
 
 
 
 
 
 
Medical Femur 
Trochlea 
 
 
 
 
 
 
 
 
 
Etc… 
 
 
 
 
 
 
 
Cartilage 
Assessment 
Size of 
Cartilage 
Loss 
Medial Patella 
 
 
 
 
 
 
 
 
 
Lateral Patella 
 
 
 
 
 
 
 
 
 
Medical Femur 
Trochlea 
 
 
 
 
 
 
 
Etc… 
Etc.. 
Etc… 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 120 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
Listing 16.2.6.7 
Other Secondary Imaging Variables Change from Baseline – MOAKS  
           Treatment = MIV-711 200 mg 
                                                                  
 
Patient 
 
Visit 
Date of 
Assessment 
Time of 
Assessment 
Question 
Group Name 
Question 
Sub-Group 
Name 
Question Name 
 
Change 
Score 
 
VISIT 2 BASELINE DAY  
VISIT 8 WEEK 26 
 
 
BML and 
Cyst 
Size of 
BML 
Medial Patella 
 
 
 
 
 
 
 
Lateral Patella 
 
 
 
 
 
 
 
Medical Femur 
Trochlea 
 
 
 
 
 
 
 
Etc… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Number of 
BMLs 
Medial Patella 
 
 
 
 
 
 
 
Lateral Patella 
 
 
 
 
 
 
 
Medical Femur 
Trochlea 
 
 
 
 
 
 
 
Etc… 
 
 
 
 
 
 
Percent 
that is 
BML 
Medial Patella 
 
 
 
 
 
 
 
Lateral Patella 
 
 
 
 
 
 
 
Medical Femur 
Trochlea 
 
 
 
 
 
 
 
Etc… 
 
 
 
 
 
Cartilage 
Assessment 
Size of 
Cartilage 
Loss 
Medial Patella 
 
 
 
 
 
 
 
Lateral Patella 
 
 
 
 
 
 
 
Medical Femur 
Trochlea 
 
 
 
 
 
Etc… 
Etc.. 
Etc… 
 
 
Programming note: only select variables will be considered for change from baseline calculation per sponsor request. Will be noted in final SAP 
text.


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 121 of 155 
 
  
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
Listing 16.2.6.8 
Other Secondary Imaging Variables – Imorphics 
         Treatment = MIV-711 200 mg 
 
                                                           
 
Patient 
 
Visit 
Date of 
Assessment 
Time of 
Assessment 
Question 
Group Name 
Question 
Sub-Group 
Name 
Question Name 
Result 
Score 
Result 
Score 
Description 
 
 
Comments 
 
VISIT 2 
BASELINE DAY 
VISIT 8 WEEK 
26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 122 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
Listing 16.2.6.9 
Other Secondary Imaging Variables Change from Baseline – Imorphics 
                Treatment = MIV-711 200 mg 
 
                                                                  
 
Patient 
 
Visit 
Date of 
Assessment 
Time of 
Assessment 
Question 
Group Name 
Question 
Sub-Group 
Name 
Question Name 
Change 
Score 
 
VISIT 2 
BASELINE DAY 
VISIT 8 WEEK 
26 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 123 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.10 
Observed Raw ICOAP Scores 
                                                                  
 
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
 
Patient 
Visit 
Date of 
Assessment 
 
 
 
 
 
 
 
 
Time of 
Assessment IP1 
IP2 
IP3 
IP4 
IP5 
IP6 
 
 
 
 
 
 
 
 
 
IP7 
 
 
 
 
 
 
 
 
 
IP8 
IP9 
 
 
 
 
 
 
 
 
 
IP10 
 
 
 
 
 
 
 
 
 
IP11 
 
VISIT 2 BASELINE DAY 
VISIT 5 WEEK 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
VISIT 6 WEEK 14 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Etc… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 124 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.11 
Transformed ICOAP Scores 
 
 
 
               Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
Date of 
Assessment 
 
 
 
 
 
 
 
 
Time of 
Assessment 
Constant Pain Subscale  
 
Intermittent pain 
subscale 
 
Total pain score 
 
Observed 
Change 
Observed 
Change Observed Change 
 
VISIT 2 BASELINE 
DAY  
 
 
 
 
 
 
 
 
 
VISIT 5 WEEK 8 
 
 
 
 
 
 
 
 
 
VISIT 6 WEEK 14 
 
 
 
 
 
 
 
 
 
Etc… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 125 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
 
Listing 16.2.6.12 
Western Ontario and McMaster Index (WOMAC) – Pain Questions 
 
 
 
                  Treatment = MIV-711 200 mg 
 
 
 
 
 
 
Patient 
Visit 
 
Date 
Of 
Assessment 
Walking 
on 
a Flat 
Surface 
Going 
Up or 
Down 
Stairs 
at Night 
While 
in Bed 
Sitting 
or 
Lying 
Down 
While 
Standing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 126 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
Listing 16.2.6.13 
Western Ontario and McMaster Index (WOMAC) – Stiffness Questions 
 
                                    Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
 
Date 
Of 
Assessment 
Stiffness 
after 
First 
Woke Up 
in 
Morning 
Stiffness 
Sitting 
or Lying 
Down 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 127 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.14 
Western Ontario and McMaster Index (WOMAC) – Difficulty Questions 
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
 
Patient 
Visit 
 
Date 
Of 
Assessment 
When 
going 
Down 
the 
Stairs 
When 
Going 
Up the 
Stairs 
Getting 
Up 
from a 
sitting 
While 
Standing 
When 
Bending 
to the 
Floor 
Walking 
on 
a Flat 
Surface 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: listing will be expanded to show all 17 difficulty questions  


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 128 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.15 
Western Ontario and McMaster Index (WOMAC) Change from Baseline – Pain Questions 
 
 
               Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
 
Date 
Of 
Assessment 
Walking 
on 
a Flat 
Surface 
Going 
Up or 
Down 
Stairs 
at Night 
While 
in Bed 
Sitting 
or 
Lying 
Down 
While 
Standing 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 129 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
Listing 16.2.6.16 
Western Ontario and McMaster Index (WOMAC) Change from Baseline – Stiffness Questions 
 
                                       Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
 
Date 
Of 
Assessment 
Stiffness 
after 
First 
Woke Up 
in 
Morning 
Stiffness 
Sitting 
or Lying 
Down 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 130 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.17 
Western Ontario and McMaster Index (WOMAC) Change from Baseline – Difficulty Questions 
 
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
 
Date 
Of 
Assessment 
When 
going 
Down 
the 
Stairs 
When 
Going 
Up the 
Stairs 
Getting 
Up 
from a 
sitting 
While 
Standing 
When 
Bending 
to the 
Floor 
Walking 
on 
a Flat 
Surface 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Programming note: listing will be expanded to show all 17 difficulty questions  


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 131 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.18 
OARSI-OMERACT Responder Index 
Derived Scores out of 100 
 
 
 
                        Treatment = MIV-711 200 mg 
 
 
 
 
 
 
Patient 
Visit 
Total 
WOMAC 
Pain 
Score 
[1] 
Total 
WOMAC 
Function 
Score 
[2] 
WOMAC Pain 
Score 
100 
WOMAC Function 
Score 
100 
 
 
 
Global 
Assessment 
NRS 
100 
 
Visit 2 
 
 
 
 
 
 
Visit 8 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Total WOMAC Pain Score (Total_WOMAC_Pain_50): sum of the 5 WOMAC pain responses 
[2] Total WOMAC Function Score (Total_WOMAC_Func_170): sum of the 17 WOMAC function responses 
Global Assessment NRS = “How Active Target Knee Arthritis Has Been”, from Listing 16.2.6.1 
 
WOMAC PAIN Score 100 = Total_WOMAC_Pain_50 x 2.  
WOMAC Function Score 100 = Total_WOMAC_Func_170 ÷ 1.7. 
Global Assessment NRS 100= (Global Assessment NRS) x 10. 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 132 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
Listing 16.2.6.19 
OARSI-OMERACT Responder Index 
Change from Baseline and Percentage Change from Baseline Scores 
Treatment = MIV-711 200 mg 
 
Patient 
 
Score 
Change 
From 
Baseline 
Percent 
Change From 
Baseline  
 
 
Criteria 
 
 
Response 
per Score 
 
 
 
Responder 
101 
WOMAC Pain Score 100 
xx 
yy 
 
No 
No 
101 
WOMAC Function Score 100 
xx 
yy 
 
No 
 
101 
Global Assessment NRS 100 
xx 
yy 
5 
No 
 
102 
WOMAC Pain Score 100 
xx 
yy 
1 
Yes 
Yes 
102 
WOMAC Function Score 100 
xx 
yy 
2 
Yes 
 
102 
Global Assessment NRS 100 
xx 
yy 
 
No 
 
103 
WOMAC Pain Score 100 
xx 
yy 
3 
Yes 
Yes 
103 
WOMAC Function Score 100 
xx 
yy 
 
No 
 
103 
Global Assessment NRS 100 
xx 
yy 
5 
Yes 
 
104 
WOMAC Pain Score 100 
xx 
yy 
3 
Yes 
 
104 
WOMAC Function Score 100 
xx 
yy 
4 
Yes 
 
104 
Global Assessment NRS 100 
xx 
yy 
 
No 
 
105 
WOMAC Pain Score 100 
xx 
yy 
 
No 
 
105 
WOMAC Function Score 100 
xx 
yy 
4 
No 
 
105 
Global Assessment NRS 100 
xx 
yy 
 
No 
 
 
Percent Change from Baseline: ((Visit 8 Score – Visit 2 Score) ÷ Visit 2 Score) x 100 
Criteria 1: WOMAC Pain: decrease from baseline >=20 and Percentage Decrease from Baseline >=50% 
Criteria 2: WOMAC Function: decrease from baseline >=20 and Percentage Decrease from Baseline >=50% 
Criteria 3: WOMAC Pain: decrease from baseline >=10 and Percentage Decrease from Baseline >=20% 
Criteria 4: WOMAC Function: decrease from baseline >=10 and Percentage Decrease from Baseline >=20% 
Criteria 5: Global Assessment: decrease from baseline >=10 and Percentage Decrease from Baseline >=20% 
A subject is a ‘Yes’ responder if either of criteria 1 or 2 are satisfied. If neither criteria 1 or 2 are satisfied, criteria 3, 4 and 5 will be 
checked. A subject is a ‘Yes’ responder if at least 2 of these 3 criteria (3, 4, 5) are satisfied. 
Programming notes: Criteria column will be flagged with the number 1, 2, 3, 4, 5 only if the conditions for that criteria are satisfied. 
Criteria 3, 4, 5 will be shown only if Crteria 1 and 2 have been checked and neither of these intial two conditions are satisfied. 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 133 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.20 
Global Improvements 
 
 
 
 
                               Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
 
Date 
Of 
Assessment 
Knee 
problem 
Knee Pain 
 Knee 
Function  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 134 of 155 
 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.21 
Quality of Life Patient Reported Outcomes - EQ-5D-5L  
 
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
 
Date 
Of 
Assessment 
Mobility 
Self-care 
 
 
 
 
 
Usual 
activity 
 
 
 
Pain or 
Discomfort 
Anxiety or 
depression 
 
 
Health rating 
score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 135 of 155 
 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.22 
Quality of Life Patient Reported Outcomes Change from Baseline Scores - EQ-5D-5L  
 
 
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
Patient 
Visit 
 
Date 
Of 
Assessment 
Mobility 
Self-care 
 
 
 
 
 
Usual 
activity 
 
 
 
Pain or 
Discomfort 
Anxiety or 
depression 
 
 
Health rating 
score 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 136 of 155 
 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.23 
Brief Medication Questionnaire 
 
                   Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
 
Date 
Of 
Assessment 
Question 
Response 
 
 
 
How much did you take each time 
How many days did you take it 
The dosage times are inconvenient 
 
 
 
 
Etc… 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 137 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.24 
E-Diary Assessments over the Last 12 Hours 
 
                  Treatment = MIV-711 200 mg 
 
 
 
 
 
 
Patient 
Visit 
 
Date 
Of 
Assessment 
Pain 
medication 
use over 
last 12 
hours? 
Pain medication usage 
over last 12 hours 
 
 
 
 
 
NRS: Overall 
pain severity 
in target 
knee over 
last 12 hours 
 
 
 
 
 
 
 
 
 
IMP Intake 
 
 
 
 
 
 
 
 
 
 
YES 
NO 
Less than Normal 
Normal 
More than normal 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 138 of 155 
 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.25 
Efficacy Biomarkers from Serum and Urine Samples 
 
 
                                 Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
 
Date 
Of 
Assessment 
Serum 
CTX-I 
urine CTX-
II 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 139 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
Listing 16.2.6.26 
Time-Integrated Concentrations (TIC) and Their Z-scores  
for Efficacy Biomarkers from Serum and Urine Samples 
 
 
                                Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
Serum 
CTX-I 
urine CTX-
II 
 
 
 
 
Z-Score 
Serum  
CTX-I 
 
 
 
 
Z-Score 
Urine 
CTX-II 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 140 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
Listing 16.2.7.1 
Adverse Events 
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Adverse Event 
>MedDRA Preferred Term 
>>System Organ Class  
Start 
Date 
Time 
Stop 
Date 
Time 
Seri- 
ous 
Outcome 
Severity 
Action 
Taken 
Study 
Medica- 
tion 
[1] 
Relation- 
ship to 
Study 
Medica- 
tion 
 
 
AE 
Start 
Time 
from 
First 
Dose 
(day) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Action taken results that state ‘MEDICATION’ indicate a concomitant medication was administered. No action was taken with res pect to study 
medication unless specifically stated otherwise 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 141 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
Listing 16.2.7.2 
Serious Adverse Events 
 
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
Patient 
Adverse Event 
>MedDRA Preferred Term 
>>System Organ Class  
Start 
Date 
Time 
Stop 
Date 
Time 
Outcome 
Severity 
Action 
Taken 
Study 
Medica- 
tion 
[1] 
Relation- 
ship to 
Study 
Medica- 
tion 
 
 
AE 
Start 
Time 
from 
First 
Dose 
(day) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Action taken results that state ‘MEDICATION’ indicate a concomitant medication was administered. No action was taken with res pect to study 
medication unless specifically stated otherwise 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 142 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
           
Page X of Y 
Protocol Number: MIV-711-201 
 
Listing 16.2.7.3 
Adverse Events Leading To Discontinuation  
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Adverse Event 
>MedDRA Preferred Term 
>>System Organ Class  
Start 
Date 
Time 
Stop 
Date 
Time 
Seri- 
ous 
Outcome 
Severity 
Action 
Taken 
Study 
Medica- 
tion 
[1] 
Relation- 
ship to 
Study 
Medica- 
tion 
 
 
AE 
Start 
Time 
from 
First 
Dose 
(day) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
[1] Action taken results that state ‘MEDICATION’ indicate a concomitant medication was administered. No action was taken with res pect to study 
medication unless specifically stated otherwise 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 143 of 155 
 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
Listing 16.2.8.1 
Clinical Laboratory Chemistry - Observed Values  
 
 
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
Collection 
Date  
 
 
 
 
 
 
Collection 
Time 
 
 
Lab 
Parameter 1 
(unit) 
Lab  
parameter 2 
(unit) 
Lab 
parameter 3 
(unit) 
Lab 
parameter 4 
(unit) 
 
 
 
 
Result/Flag 
Result/Flag 
Result/Flag 
Result/Flag 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H=High, L=Low, CS=Clinically Significant, NCS=Not Clinically Significant 
 
Programming Note: If Flag is present (H or L), clinical significance will be identified by one of ‘NCS’ or ‘CS’. 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 144 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
Listing 16.2.8.2 
Clinical Laboratory Hematology - Observed Values  
 
 
                     Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
 
Patient 
Visit 
Collection 
Date  
 
 
 
 
 
 
Collection 
Time 
 
 
Lab 
Parameter 1 
(unit) 
Lab  
parameter 2 
(unit) 
Lab 
parameter 3 
(unit) 
Lab 
parameter 4 
(unit) 
 
 
 
 
Result/Flag 
Result/Flag 
Result/Flag 
Result/Flag 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H=High, L=Low, CS=Clinically Significant, NCS=Not Clinically Significant 
 
 
Programming Note: If Flag is present (H or L), clinical significance will be identified by one of ‘NCS’ or ‘CS’. 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 145 of 155 
 
  
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
Listing 16.2.8.3 
Clinical Laboratory Urinalysis - Observed Values  
 
 
         Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
Collection 
Date  
 
 
 
 
 
 
Collection 
Time 
 
 
Lab 
Parameter 1 
(unit) 
Lab  
parameter 2 
(unit) 
Lab 
parameter 3 
(unit) 
Lab 
parameter 4 
(unit) 
 
 
 
 
Result/Flag 
Result/Flag 
Result/Flag 
Result/Flag 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
H=High, L=Low, AB=Abnormal, CS=Clinically Significant, NCS=Not Clinically Significant 
 
 
Programming Note: If Flag is present (H, L, or AB), clinical significance will be identified by one of ‘NCS’ or ‘CS’. 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 146 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
Listing 16.2.8.4 
Clinical Laboratory Urinalysis – Positive Microscopic Findings  
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
Collection 
Date 
Collection 
Time 
Test Name 
Result 
Unit 
Flag 
Clinical 
Significance 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
*H=High, L=Low, AB=Abnormal, CS=Clinically Significant, NCS=Not Clinically Significant 
 
 
Programming Note: If Flag is present (H, L, or AB), clinical significance will be identified by one of ‘NCS’ or ‘CS’. 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 147 of 155 
 
  
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
 
Listing 16.2.8.5 
Vital Signs – Observed Values  
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
 
 
 
Collection 
Date 
Collection 
Time 
Supine 
Heart Rate 
(beats/min) 
Supine 
Systolic 
Blood 
Pressure 
(mmHg) 
Supine 
Diastolic 
Blood 
Pressure 
(mmHg) 
Pulse 
Oximetry 
(%) 
Body 
Temperature 
(°C) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 148 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
 
 
Listing 16.2.8.6 
Vital Signs Change from Baseline   
 
 
                         Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
 
 
 
Collection 
Date 
Collection 
Time 
Supine 
Heart Rate 
(beats/min) 
Supine 
Systolic 
Blood 
Pressure 
(mmHg) 
Supine 
Diastolic 
Blood 
Pressure 
(mmHg) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 149 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
Listing 16.2.8.7 
Vital Signs Overall Qualitative Results Abnormal Assessments  
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
 
 
 
Collection 
Date 
Collection 
Time 
Assessment 
Interpretation 
 
 
 
 
 
 
 
 
 
 
 
ABNORMAL, NCS 
 
 
 
 
 
ABNORMAL, CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCS = Not Clinically Significant, CS = Clinically Significant 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 150 of 155 
 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
Listing 16.2.8.8 
12 Lead ECG Quantitative Findings 
 
 
  
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
Timepoint 
Collect-
ion 
Date 
Collec- 
tion 
Time 
Heart 
Rate 
(beats 
/min) 
PR 
(msec) 
RR 
(msec) 
QRS 
(msec) 
QT 
(msec) 
QTcB 
(msec) 
QTcF 
(msec) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QTcB = QT corrected according to Bazett, QTcF = QT corrected according to Fridericia. 
 
 
  


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 151 of 155 
 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
Listing 16.2.8.9 
12 Lead ECG Change From Baseline  
 
  
 
 
      Treatment = MIV-711 200 mg 
 
 
 
 
 
 
Patient 
Visit 
 
 
 
 
 
 
 
Timepoint 
 
 
 
Collection 
Date 
Collection 
Time 
 
 
 
 
QT  
(msec) 
QTcB 
 (msec) 
 
 
 
 
 
 
QTcF 
 (msec) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
QTcB = QT corrected according to Bazett, QTcF = QT corrected according to Fridericia. 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 152 of 155 
 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
Listing 16.2.8.10 
12 Lead ECG Overall Qualitative Assessment  
 
 
 
Treatment = MIV-711 200 mg 
 
 
 
 
 
 
Patient 
Visit 
Timepoint 
Collection 
Date 
Collection 
Time 
Assess- 
ment 
Interpretation 
Comment 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCS = Not Clinically Significant, CS = Clinically Significant 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 153 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
Listing 16.2.8.11 
Physical Examination Abnormal Findings  
 
 
 
                  Treatment = MIV-711 200 mg 
 
 
 
 
 
 
Patient 
Visit 
Exam 
Date 
Exam 
Time 
Body System 
Abnormality 
Clinical 
Significance 
 
 
 
 
 
 
NCS 
 
 
 
 
 
 
CS 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
NCS = Not Clinically Significant, CS = Clinically Significant 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 154 of 155 
 
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
Listing 16.2.8.12 
Patient Weight 
 
 
                                 Treatment = MIV-711 200 mg 
 
 
 
 
 
 
 
Patient 
Visit 
 
Date 
Time 
Weight (kg) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


PAREXEL International 
SAP Shells 
Medivir 
Protocol: MIV-711-201 
Final 1.0  
    
                                                        22 June 2017 
 
                                                                                                                                                                                                                Page 155 of 155 
 
  
Medivir  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Page X of Y 
Protocol Number: MIV-711-201 
 
 
Listing 16.2.8.13 
Phone Call to Assess Safety  
 
 
 
                                                Treatment = MIV-711 200 mg 
 
 
 
 
 
 
Patient 
Visit 
Comments