A Randomized, Placebo Controlled, Investigator and Participant-blinded Study Investigating Safety, Tolerability, and Efficacy of RHH646 in Participants With Knee Osteoarthritis
Phase: PHASE2
Conditions: Osteoarthritis, Knee
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development 
Clinical Trial Protocol Title: 
A randomized, placebo controlled, investigator and 
participant-blinded study investigating safety, tolerability, 
and efficacy of RHH646 in participants with knee 
osteoarthritis 
Clinical Trial Protocol Number: CRHH646A12201 / NCT05816395
Version Number: v02 (Clean) 
Compound: RHH646 
Brief Title: Safety and efficacy of RHH646 for knee osteoarthritis 
Study Phase: IIa 
Sponsor Name: Novartis Pharma AG (or its affiliates outside the EEA), Lichtstrasse 
35, Basel Stadt, 4056 Basel, Switzerland 
Regulatory Agency Identifier Number(s):  
EU CT number 2022-502821-16-00, IND number 154142 
Content final Date: 28-Nov-2023 
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 5.0 dated 14-Jan-2022 

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Protocol No. CRHH646A12201 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 6 
Amendment 02 (28-Nov-2023) ........................................................................................... 7 
Amendment 01 (06-Jan-2023) ........................................................................................... 12 
1 
Protocol summary .............................................................................................................. 13 
1.1 
Summary ................................................................................................................ 13 
1.2 
Schema ................................................................................................................... 16 
1.3 
Schedule of activities (SoA) .................................................................................. 16 
2 
Introduction ....................................................................................................................... 22 
2.1 
Study rationale ....................................................................................................... 22 
2.2 
Background ............................................................................................................ 22 
2.3 
Benefit/Risk assessment ........................................................................................ 24 
2.3.1 
Blood sample volume ............................................................................ 27 
3 
Objectives, endpoints, and estimands ................................................................................ 27 
3.1 
Primary estimands ................................................................................................. 29 
3.2 
Secondary estimands ............................................................................................. 29 
4 
Study design ...................................................................................................................... 29 
4.1 
Overall design ........................................................................................................ 29 
4.2 
Scientific rationale for study design ...................................................................... 31 
4.3 
Justification for dose .............................................................................................. 31 
4.4 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 33 
4.5 
Rationale for public health emergency mitigation procedures .............................. 33 
4.6 
Purpose and timing of interim analyses/design adaptations .................................. 33 
4.7 
End of study definition .......................................................................................... 33 
5 
Study population ................................................................................................................ 34 
5.1 
Inclusion criteria .................................................................................................... 34 
5.2 
Exclusion criteria ................................................................................................... 34 
5.3 
Lifestyle considerations ......................................................................................... 38 
5.3.1 
Meals and dietary restrictions ............................................................... 38 
5.3.2 
Caffeine, alcohol, and tobacco .............................................................. 38 
5.3.3 
Activity .................................................................................................. 38 
5.4 
Screen failures ....................................................................................................... 38 
5.4.1 
Replacement policy ............................................................................... 39 
5.4.2 
Participant numbering ........................................................................... 39 

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6 
Study treatment(s) and concomitant therapy ..................................................................... 40 
6.1 
Study treatment(s) .................................................................................................. 40 
6.1.1 
Additional study treatments .................................................................. 40 
6.1.2 
Treatment arms/group ........................................................................... 40 
6.2 
Preparation, handling, storage, and accountability ................................................ 40 
6.2.1 
Handling of study treatment .................................................................. 41 
6.2.2 
Handling of other treatment .................................................................. 42 
6.2.3 
Instruction for prescribing and taking study treatment ......................... 42 
6.3 
Measures to minimize bias: randomization and blinding ...................................... 42 
6.3.1 
Treatment assignment, randomization .................................................. 42 
6.3.2 
Treatment blinding ................................................................................ 43 
6.3.3 
Emergency breaking of assigned treatment code .................................. 44 
6.4 
Study treatment compliance .................................................................................. 45 
6.4.1 
Recommended treatment of adverse events .......................................... 45 
6.5 
Dose modification .................................................................................................. 46 
6.6 
Continued access to study treatment after the end of the study ............................. 46 
6.6.1 
Post trial access ..................................................................................... 46 
6.7 
Treatment of overdose ........................................................................................... 47 
6.7.1 
Reporting of study treatment errors including misuse/abuse ................ 47 
6.8 
Concomitant and other therapy .............................................................................. 47 
6.8.1 
Concomitant therapy ............................................................................. 47 
6.8.2 
Prohibited medication ........................................................................... 48 
6.8.3 
Rescue medicine.................................................................................... 49 
7 
Discontinuation of study treatment and participant discontinuation/withdrawal .............. 49 
7.1 
Discontinuation of study treatment ........................................................................ 49 
7.2 
Participant discontinuation from the study ............................................................ 50 
7.3 
Withdrawal of informed consent and exercise of participants’ data privacy 
rights ...................................................................................................................... 51 
7.4 
Lost to follow-up ................................................................................................... 51 
7.5 
Study stopping rules .............................................................................................. 52 
7.6 
Early study termination by the Sponsor................................................................. 52 
8 
Study Assessments and Procedures ................................................................................... 52 
8.1 
Screening ............................................................................................................... 53 
8.1.1 
Eligibility screening .............................................................................. 53 
8.2 
Participant demographics/other baseline characteristics ....................................... 54 
8.3 
Efficacy assessments ............................................................................................. 54 

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8.3.1 
Knee MRI .............................................................................................. 54 
8.3.2 
Knee X-ray ............................................................................................ 56 
8.3.3 
Appropriateness of efficacy assessments .............................................. 57 
8.4 
Safety assessments ................................................................................................. 57 
8.4.1 
Physical examinations ........................................................................... 57 
8.4.2 
Vital signs.............................................................................................. 58 
8.4.3 
Electrocardiograms ............................................................................... 58 
8.4.4 
Clinical safety laboratory tests .............................................................. 59 
8.4.5 
Pregnancy testing .................................................................................. 61 
8.4.6 
Other safety evaluations ........................................................................ 62 
8.4.7 
Appropriateness of safety measurements .............................................. 62 
8.5 
Additional assessments .......................................................................................... 62 
8.5.1 
Clinical Outcome Assessments (COAs) ............................................... 62 
8.5.2 
Other assessments ................................................................................. 64 
8.6 
Adverse events (AEs), serious adverse events (SAEs), and other safety 
reporting ................................................................................................................. 64 
8.6.1 
Adverse events ...................................................................................... 65 
8.6.2 
Serious adverse events .......................................................................... 66 
8.6.3 
SAE reporting........................................................................................ 68 
8.6.4 
Pregnancy .............................................................................................. 69 
8.6.5 
Disease-related events and/or disease-related outcomes not 
qualifying as AEs or SAEs .................................................................... 69 
8.6.6 
Adverse events of special interest ......................................................... 69 
8.7 
Pharmacokinetics ................................................................................................... 70 
8.8 
Biomarkers ............................................................................................................. 70 
8.9 
Immunogenicity assessments................................................................................. 72 
8.10 
Medical resource utilization and health economics ............................................... 72 
9 
Statistical considerations ................................................................................................... 72 
9.1 
Analysis sets .......................................................................................................... 72 
9.2 
Statistical analyses ................................................................................................. 73 
9.2.1 
General considerations .......................................................................... 73 
9.2.2 
Participant demographics and other baseline characteristics ................ 74 
9.2.3 
Treatments ............................................................................................. 74 
9.3 
Primary endpoint(s)/estimand(s) analysis.............................................................. 74 
9.3.1 
Definition of primary endpoint(s) ......................................................... 74 
9.3.2 
Statistical model, hypothesis, and method of analysis .......................... 75 
9.3.3 
Handling of intercurrent events of primary estimand ........................... 75 

N o v arti s  
C o nfi d e nti al  
P a g e 5 of 1 0 3  
A m e n d e d  Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
9. 3. 4 
Ha n dli n g of missi n g val ues n ot relate d t o i nterc urre nt e ve nt  ............... 7 5  
9. 3. 5 
Se nsiti vit y a nal yses  ............................................................................... 7 5  
9. 3. 6  
S u p ple me ntar y a nal ysis ......................................................................... 7 5  
9. 3. 7 
Safet y a nal ysis  ....................................................................................... 7 6  
9. 4  
Sec o n dar y e n d p oi nt(s)/esti ma n d(s) a nal ysis.......................................................... 7 6  
9. 4. 1 
P har mac o ki netics  .................................................................................. 7 6  
9. 5 
E x pl orat or y e n d p oi nt(s) a nal ysis  ........................................................................... 7 7  
9. 5. 1 
 7 7  
9. 5. 2 
 7 7  
9. 5. 3 
 7 7  
9. 6 
Ot her Safet y a nal yses  ............................................................................................ 7 8  
9. 7  
Ot her a nal yses ........................................................................................................ 7 8  
9. 8 
I nteri m a nal ysis ...................................................................................................... 7 8  
9. 9 
Sa m ple size deter mi nati o n  ..................................................................................... 7 8  
9. 9. 1 
Pri mar y e n d p oi nt(s)  ............................................................................... 7 8  
1 0  S u p p orti n g d oc u me ntati o n a n d o perati o nal c o nsi derati o ns ............................................... 8 0  
1 0. 1  
A p pe n di x 1: Re g ulat or y, et hical, a n d st u d y o versi g ht c o nsi derati o ns................... 8 0  
1 0. 1. 1  
Re g ulat or y a n d et hical c o nsi derati o ns .................................................. 8 0  
1 0. 1. 2  
I nf or me d c o nse nt pr ocess ...................................................................... 8 1  
1 0. 1. 3 
Data pr otecti o n  ...................................................................................... 8 2  
1 0. 1. 4 
C o m mittees str uct ure  ............................................................................ 8 3  
1 0. 1. 5 
Data q ualit y ass ura nce  ........................................................................... 8 3  
1 0. 1. 6  
S o urce d oc u me nts ................................................................................. 8 4  
1 0. 1. 7 
P u blicati o n p olic y .................................................................................. 8 5  
1 0. 1. 8 
Pr ot oc ol a d here nce a n d pr ot oc ol a me n d me nts  ...................................... 8 5  
1 0. 2  
A p pe n di x 2: A b bre viati o ns a n d defi niti o ns ........................................................... 8 7  
1 0. 2. 1 
List of a b bre viati o ns  .............................................................................. 8 7  
1 0. 2. 2 
Defi niti o ns  ............................................................................................. 9 0  
1 0. 3 
A p pe n di x 3: Cli nical la b orat or y tests  .................................................................... 9 4  
1 0. 3. 1 
Cli nicall y n ota ble la b orat or y val ues a n d vital si g ns  ............................. 9 4  
1 0. 4  
A p pe n di x 4: Partici pa nt E n ga ge me nt .................................................................... 9 5  
1 0. 5  
A p pe n di x 5: Li ver safet y m o nit ori n g .................................................................... 9 6  
1 0. 5. 1 
Li ver e ve nt a n d la b orat or y tri g ger defi niti o ns & f oll o w - u p 
re q uire me nts .......................................................................................... 9 7  
1 0. 6  
A p pe n di x 6: Re nal safet y m o nit ori n g .................................................................. 1 0 0  
1 0. 6. 1 
S pecific Re nal Alert Criteria a n d Acti o ns a n d E ve nt F oll o w - u p ........ 1 0 0  
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11 References ....................................................................................................................... 102 
List of tables 
Table 1-1 
Assessment Schedule ............................................................................ 18 
Table 3-1 
Objectives and related endpoints .......................................................... 27 
Table 4-1 
Steady-state exposure multiples by RHH646 dose ............................... 32 
Table 6-1 
Investigational and control drug ............................................................ 40 
Table 6-2 
Dose and treatment schedule ................................................................. 42 
Table 6-3 
Blinding and unblinding plan ................................................................ 44 
Table 6-4 
Prohibited medication ........................................................................... 48 
Table 8-1 
Laboratory evaluations .......................................................................... 60 
Table 10-1 
Liver event and laboratory trigger definitions ...................................... 97 
Table 10-2 
Follow up requirements for liver laboratory triggers - ALT, AST, 
TBL ....................................................................................................... 98 
Table 10-3 
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia ............................................................................... 99 
Table 10-4 
Specific renal alert criteria and actions ............................................... 100 
Table 10-5 
Renal Event Follow Up ....................................................................... 101 
List of figures 
Figure 1-1 
Study design .......................................................................................... 16 
Figure 8-1 
Timing of study procedures .................................................................. 58 

N o v arti s  
C o nfi d e nti al  
P a g e 7 of 1 0 3  
A m e n d e d  Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
A m e n d m e nt 0 2  ( 28- N o v -2 0 2 3)   
A m e n d m e nt r ati o n al e  
T he pr ot oc ol was a me n de d t o c o m bi ne u p dates t hat were ma de base d o n re q uests recei ve d fr o m 
t he U. S. F o o d a n d Dr u g A d mi nistrati o n as well as re q uests f or i nf or mati o n recei ve d fr o m t he 
partici pati n g E ur o pea n me m ber states pre vi o usl y d oc u me nte d i n l ocal pr ot o c ol a me n d me nts 
v 0 1- U S. 0 1 a n d v 0 1 -E E A. 0 1, res pecti vel y. T he o p p ort u nit y was als o ta ke n t o re vise i ncl usi o n 
criteri o n  7  fr o m  j oi nt  s pace  wi dt h  t o  j oi nt  s pace  narr o wi n g  a n d  t o  clarif y  a n d  c orrect  
discre pa ncies a n d i nc o nsiste ncies wit hi n t he pr ot oc ol.  
C h a n g e s t o t h e pr ot o c ol  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 8 of 1 0 3  
A m e n d e d  Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 9 of 1 0 3  
A m e n d e d  Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 0  of 1 0 3  
A m e n d e d  Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 1  of 1 0 3  
A m e n d e d  Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
I R B s/I E C s 
A  c o p y  of  t his  a me n de d  pr ot oc ol  will  be  se nt  t o  t he  I nstit uti o nal  Re vie w  B oar d  
(I R Bs)/I n de pe n de nt Et hics C o m mittee (I E Cs) a n d Healt h A ut h orities. 
T he  c ha n ges  descri be d  i n  t his  a me n de d  pr ot oc ol  re q uire  I R B/I E C  a p pr o val  pri or  t o  
i m ple me ntati o n.  
T he c ha n ges herei n  affect t he I nf or me d C o nse nt. Sites are re q uire d t o u p date a n d s u b mit f or 
a p pr o val a re vise d I nf or me d C o nse nt t hat ta kes i nt o acc o u nt t he c ha n ges descri be d i n t his 
pr ot oc ol a me n d me nt. 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 1 2  of 1 0 3  
A m e n d e d  Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
A m e n d m e nt 0 1  ( 0 6-J a n -2 0 2 3)  
A m e n d m e nt r ati o n al e  
T he pri mar y p ur p ose of t his gl o bal pr ot oc ol a me n d me nt is t o u p date t he n u m ber of a d verse 
e ve nts re p orte d i n st u d y C R H H 6 4 6 A 0 2 1 0 1.  T he o p p ort u nit y was als o ta ke n t o clarif y a n d 
c orrect discre pa ncies a n d i nc o nsiste ncies wit hi n t he pr ot oc ol . 
P r ot oc ol  A me n d me nt v 0 1  has  bee n  iss ue d  bef ore  a n y  re g ulat or y  s u b missi o n.  
T he  i nc o nsiste ncies i n Ori gi nal P r ot oc ol v 0 0 were n ote d bef ore t he pr ot oc ol was s u b mitte d t o 
a n y Instit uti o nal Re vie w B oar ds (I R Bs)/I n de pe n de nt Et hic C o m mittees (I E Cs) a n d Healt h 
A ut h orities . 
C h a n g e s t o t h e pr ot o c ol  
C CI

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Protocol No. CRHH646A12201 
 
1 
Protocol summary 
1.1 
Summary 
Protocol Title: 
A randomized, placebo controlled, investigator and participant-blinded study investigating 
safety, tolerability, and efficacy of RHH646 in participants with knee osteoarthritis 
Brief Title: 
Safety and efficacy of RHH646 for knee osteoarthritis 
Purpose 
Study CRHH646A12201 is a phase 2a proof-of-concept (POC) study to evaluate the articular 
cartilage-regenerating capacity of RHH646 in the knee as well as to assess safety and 
tolerability in patients with knee osteoarthritis (OA) following 1 year of treatment. While 
the benefits of RHH646 on cartilage regeneration have been demonstrated in pre-clinical 
studies, this will be the first clinical test of the potential therapeutic effect of RHH646 in patients 
with knee OA. 
Study Indication /Medical Condition: 
Knee osteoarthritis 
Treatment type 
Drug 
Study type 
Interventional 
Objectives and Endpoints: 
Objectives 
Endpoints 
Primary 
 
To evaluate the articular cartilage-regenerating 
capacity of RHH646 in the knee following 1 year 
of treatment 
Change from baseline in cartilage volume in 
the index region of the target knee by MRI at 
Week 52 
To evaluate the safety and tolerability of 
RHH646 following 1 year of treatment 
Adverse Events (AEs) 
Electrocardiograms (ECGs) 
Vital signs 
Hematology, blood chemistry, urinalysis 
Secondary 
 
To evaluate the pharmacokinetics of RHH646 in 
patients with knee OA 
RHH646 plasma concentrations, Cmin,ss at 
Week 4, and any other PK parameter as 
appropriate 

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Protocol No. CRHH646A12201 
 
Trial Design: 
This is a non-confirmatory, randomized, investigator and participant blinded, two-arm, 
placebo-controlled, phase 2a study to assess safety, tolerability, and efficacy of orally 
administered RHH646 in male and female adult patients with symptomatic, mild to moderate 
radiographic knee OA (Kellgren and Lawrence (K&L) grade 2 to 3) in the target knee and with 
pain requiring analgesic therapy (e.g., n-acetyl-para-aminophenol (APAP) or non-steroidal 
anti-inflammatory drugs (NSAIDs)). Approximately 78 participants will be enrolled and 
randomized in the trial and treated for 52 weeks. 
Brief Summary: 
The purpose of this study is to evaluate the articular cartilage-regenerating capacity of RHH646 
in the knee as well as to assess safety and tolerability in participants with knee OA. 
• The total study duration for an individual participant will be up to 62 weeks. 
• The treatment duration will be up to 52 weeks. 
• The on-site visit frequency will be approximately monthly until Week 26 and then 
quarterly thereafter until Week 52 (End of treatment (EOT)). Phone visits will be 
scheduled monthly between the quarterly on-site visits. 
Treatment of interest 
Participants will be treated with either the orally administered RHH646 or the matching placebo 
treatment for 52 weeks. 
Number of Participants: 
Approximately 78 male and female participants 35 to 75 years old will be enrolled and 
randomized in the trial and treated for 52 weeks. 
Key Inclusion criteria 
• Participant is ≥35 and ≤75 years old, at time of screening 
• Participants must weigh at least 50 kg to participate in the study and must have a body 
mass index (BMI) ≤35 kg/m2. BMI = Body weight (kg) / [Height (m)]2 
• Diagnosis of tibiofemoral OA in at least one knee by standard American College of 
Rheumatology clinical and radiographic criteria (Altman et al 1986) at screening 
• K&L grade 2 to 3 OA in the target knee evaluated with X-Ray by the Central Reader at 
screening. 
• Predominantly medial tibiofemoral compartment involvement defined as medial Joint 
Space Narrowing (medJSN) 1-2 (Altman et al 1995; Altman, Gold 2007) and 
medJSN > lateral Joint Space Narrowing (latJSN)  in the target knee evaluated with X-
Ray by the Central Reader at screening 
• Symptomatic disease, defined as having pain in the target knee at least 3 days per week 
during the last 3 months from screening that is relieved by analgesic therapy (e.g., APAP 

N o v arti s  
C o nfi d e nti al  
P a g e 1 5  of 1 0 3  
A m e n d e d  Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
or N S AI Ds), acc or di n g t o t he i n vesti gat or’s e val uati o n a n d j u d g me nt of t he patie nt’s 
hist or y  
K e y E x cl u si o n crit eri a  
•  W o me n of c hil d - beari n g p ote ntial, defi ne d as all w o me n p h ysi ol o gicall y ca pa ble of 
bec o mi n g pre g na nt, u nless t he y are usi n g hi g hl y effecti ve met h o ds of c o ntrace pti o n w hile 
ta ki n g st u d y treat me nt a n d f or at least 
 after st o p pi n g st u d y treat me nt. I n E E A c o u ntries, w o me n of c hil d-
beari n g p ote ntial will be e xcl u de d fr o m partici pati o n i n t his trial, irres pecti ve of t he use of 
hi g hl y effecti ve met h o ds of c o ntrace pti o n 
•  Art hr osc o p y of t he tar get k nee wit hi n t he 6 m o nt hs pri or t o scree ni n g or pla n ne d 
art hr osc o p y d uri n g t he st u d y 
•  Pre vi o us s ur gical treat me nt of t he tar get k nee usi n g m osaic plast y, micr ofract ure, 
me niscect o m y > 5 0 % or oste ot o m y; pla n ne d s ur ger y f or eit her k nee d uri n g t he st u d y 
•  U nsta ble tar get k nee j oi nt (i ncl u di n g, b ut n ot li mite d t o, p ost- tra u matic or c o n ge nital 
la xit y) or i ns ufficie ntl y rec o nstr ucte d li ga me nts base d o n me dical hist or y a n d/ or p h ysical 
e xa mi nati o n b y t he i n vesti gat or 
•  Partici pa nt has se vere malali g n me nt ( val g us or var us def or mit y) i n t he tar get k nee  > 7. 5° 
base d o n X-ra y e val uati o n b y t he Ce ntral Rea der at scree ni n g. 
•  K & L gra de 4 O A i n eit her k nee 
•  Prese nce of se vere hi p O A t hat eit her (i) alters l o wer li m b f u ncti o n t o a de gree t hat 
i ncreases or a b n or mall y c ha n ges t he mec ha nical f orces i n t he k nee w hile wal ki n g, 
acc or di n g t o i n vesti gat or's e val uati o n, or (ii) c urre ntl y re q uires or is li kel y t o re q uir e 
s pecific me dical or s ur gical ma na ge me nt d uri n g t he st u d y peri o d 
•  Ot her pat h ol o gies affecti n g t he k nee, i ncl u di n g s u bc h o n dral i ns ufficie nc y fract ures, b o ne 
fract ure (ac ute or s u bac ute wit hi n t he 6 m o nt hs pri or t o scree ni n g) or b o ne br uise, 
oste o necr osis, mali g na nt b o ne marr o w i nfiltrati o n, s oli d t u m ors, a n d/ or patell ofe m oral 
d ys plasia base d o n cli nical assess me nt, or i ma gi n g  
•  K n o w n a ut oi m m u ne disease wit h i nfla m mat or y art hritis (i ncl u di n g b ut n ot li mite d t o 
r he u mat oi d art hritis, ps oriatic art hritis, a n k yl osi n g s p o n d ylitis, s yste mic l u p us 
er yt he mat os us), cr ystal -i n d uce d art hriti des ( g o ut or pse u d o g o ut art hritis), acti ve ac ute or 
c hr o nic i nfecti o n of t he k nee j oi nt, L y me disease i n v ol vi n g t he k nee, reacti ve art hritis, 
s yste mic cartila ge dis or ders, m o derate t o se vere fi br o m yal gia, a k n o w n s yste mic 
c o n necti ve tiss ue disease or a wi des prea d pai n i n de x > 4.  
•  I na bilit y t o u n der g o M RI (e. g., cla ustr o p h o bia, b o d y size, le g n ot fitti n g i n t he c oil) or 
c o ntrai n dicati o ns t o M RI (e. g., n o n M RI- c o m pati ble metallic i m pla nts, metallic f orei g n 
b o dies, pace ma ker, defi brillat or)  
Tr e at m e nt Gr o u p s:  
T he st u d y c o m prises a scree ni n g peri o d ( u p t o 6 wee ks), a treat me nt peri o d ( 
) a n d a 
f oll o w u p peri o d ( 
) p ost last a d mi nistrati o n of st u d y treat me nt bef ore t he E n d of St u d y 
( E O S) visit. T he t otal d urati o n f or eac h partici pa nt will be u p t o 6 2 wee ks.  
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N o v arti s  
C o nfi d e nti al  
P a g e 1 6  of 1 0 3  
A m e n d e d  Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
Partici pa nts will be assi g ne d t o o ne of t he f oll o wi n g 2 treat me nt ar ms i n a 1: 1 rati o:  
•  R H H 6 4 6   m g  
 
•  Matc hi n g place b o  
I n t he  e ve nt  t hat  a n y  st u d y  partici pa nt  a p pears  t o  be  n ot  t olerati n g  t he  st u d y  treat me nt,  
t he i n vesti gat or will ha ve t he discreti o n t o re d uce t he d ose t o gi ve t he st u d y partici pa nt a c ha nce 
t o re mai n o n st u d y treat me nt. 
D at a M o nit ori n g/ Ot h er C o m mitt e e:  
A Data M o nit ori n g C o m mittee ( D M C) is n ot pla n ne d f or t his st u d y  
K e y w or d s  
Ti bi ofe m oral O A, K & L gra de 2 t o 3 O A i n t he tar get k nee, Oral R H H 6 4 6 treat me nt  
1. 2  
S c h e m a  
Fi g ur e 1- 1 
St u d y d e si g n  
 
1. 3  
S c h e d ul e of a cti viti e s ( S o A)  
T he  S o A  lists  all  of  t he  assess me nts  w he n  t he y  are  perf or me d.  All  data  o btai ne d  fr o m  
t hese assess me nts m ust be s u p p orte d i n t he partici pa nt’s s o urce d oc u me ntati o n. T he “ X” i n 
t he ta ble  de n otes  t he  assess me nts  t o  be  rec or de d  i n  t he  cli nical  data base  or  recei ve d 
electr o nicall y fr o m a ve n d or. T he “ S” i n t he ta ble de n otes t he assess me nts t hat are o nl y i n 
t he partici pa nt’s s o urce d oc u me ntati o n a n d d o n ot nee d t o be rec or de d i n t he cli nical data base. 
Partici pa nts s h o ul d be see n f or all visits/assess me nts as o utli ne d i n t he S o A or as cl ose t o 
t he desi g nate d da y/ti me as p ossi ble. Misse d or resc he d ule d visits s h o ul d n ot lea d t o a ut o matic 
disc o nti n uati o n. 
Partici pa nts w h o disc o nti n ue fr o m st u d y treat me nt are t o c o m plete t he E O T visit as s o o n as 
p ossi ble a n d atte n d t he f oll o w - u p visits as i n dicate d i n t he S o A. 
Partici pa nts w h o disc o nti n ue fr o m st u d y s h o ul d als o be sc he d ule d f or a fi nal e val uati o n visit if 
t he y a gree, as s o o n as p ossi ble, at w hic h ti me all of t he assess me nts liste d f or t he E O S visit will 
be perf or me d. At t his fi nal visit, all dis pe nse d i n vesti gat i o nal pr o d uct s h o ul d be rec o ncile d, a n d 
t he A Es a n d c o nc o mita nt me dicati o ns n ot pre vi o usl y re p orte d m ust be rec or de d o n t he Case 
Re p ort F or m ( C R F).  
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Novartis 
Confidential 
Page 17 of 103 
Amended Protocol Version v02 (Clean) 
 
Protocol No. CRHH646A12201 
 
Patient reported outcome (PRO) measure(s) must be completed before any assessments are 
performed at any given visit. 
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e., pandemic, epidemic or natural disaster that limits or prevents on-site study visits, alternative 
methods of providing continuing care may be implemented by the investigator as the situation 
dictates. If allowable by a local health authority, national and local regulations and depending 
on operational capabilities, phone calls, virtual contacts (e.g., tele consultation) or visits by site 
staff/ off-site healthcare professional(s) staff to the participant´s home, can replace certain 
protocol assessments, for the duration of the disruption until it is safe for the participant to visit 
the site again. If the investigator delegates tasks to an off-site healthcare professional, 
the investigator must ensure the individual(s) is/are qualified and appropriately trained to 
perform assigned duties. The investigator must oversee their conduct and remain responsible 
for the evaluation of the data collected. 

N o v arti s  
 
C o nfi d e nti al  
 
P a g e 1 8  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
T a bl e 1- 1 
A s s e s s m e nt S c h e d ul e  
P eri o d  
S cr e e ni n g  
Tr e at m e nt  
F oll o w -U p  
Vi sit N a m e
Vi sit N u m b er s 1
D a y s
Ti m e ( p o st -d o s e)
I nf or m e d c o n s e nt 
X  
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
G e n eti c c o n s e nt 2  
X  
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
I n cl u si o n / 
E x cl u si o n crit eri a  
X 
X 
  
  
  
  
  
  
  
 
 
  
 
 
  
  
D e m o gr a p h y  
X  
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
M e di c al 
hi st or y/ c urr e nt 
m e di c al 
c o n diti o n s  
X 
X 
  
  
  
  
  
  
  
 
 
  
 
 
  
  
S m o ki n g/ ni c oti n e 
u s e hi st or y  
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
C o n c o mit a nt 
m e di c ati o n s  
X 
A s s e s s m e nt s of 
f ertilit y 
S 
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
S er u m pr e g n a n c y 
t e st 
X 
X 
  
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
Uri n e pr e g n a n c y 
t e st kit 
di s p e n s ati o n t o 
w o m e n of 
c hil d b e ari n g 
p ot e nti al f or h o m e 
t e sti n g 
  
  
  
  
  
  
  
  
S 
 
 
S 
 
 
  
  
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N o v arti s  
 
C o nfi d e nti al  
 
P a g e 1 9  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
P eri o d  
S cr e e ni n g  
Tr e at m e nt  
F oll o w -U p  
Vi sit N a m e
Vi sit N u m b er s 1
D a y s
Ti m e ( p o st -d o s e)
R e p orti n g of uri n e 
pr e g n a n c y t e st 
p erf or m e d at 
h o m e  
 
 
 
 
 
 
 
 
 
S 
S 
 
S 
S 
 
 
Al c o h ol T e st a n d 
Dr u g S cr e e n  
S 
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
HI V s cr e e n  
S  
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
H e p atiti s s cr e e n  
S  
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
C o m pl et e 
p h y si c al 
e x a mi n ati o n  
S 
  
  
  
  
S 
  
  
S 
 
 
S 
 
 
S 
S 
S h ort p h y si c al 
e x a mi n ati o n  
  
S 
  
S 
S 
  
S 
S 
  
 
 
  
 
 
  
  
T e sti c ul ar 
ultr a s o u n d 3  
  
X 
  
  
  
  
  
  
  
 
 
  
 
 
X 
  
W PI  
X  
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
B o d y H ei g ht  
X  
  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
B o d y W ei g ht  
X  
X  
  
  
  
X  
  
  
X  
 
 
X  
 
 
X  
X  
B o d y 
T e m p er at ur e  
X 
X 
  
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
Vit al Si g n s  
X  
X  
X  
X  
X  
X  
X  
X  
X  
 
 
X  
 
 
X  
X  
El e ctr o c ar di o gr a m 
( E C G) 
X 
X 
  
X 
  
  
  
  
X 
 
 
  
 
 
X 
X 
H e m at ol o g y  
X  
X  
  
X  
  
X  
  
  
X  
 
 
X  
 
 
X  
X  
Cli ni c al C h e mi str y  
X  
X 4  
  
X  
  
X  
  
  
X 4  
 
 
X  
 
 
X  
X 4  
Uri n al y si s  
X  
X  
  
X  
  
X  
  
  
X  
 
 
X  
 
 
X  
X  
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N o v arti s  
 
C o nfi d e nti al  
 
P a g e 2 0  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
P eri o d  
S cr e e ni n g  
Tr e at m e nt  
F oll o w -U p  
Vi sit N a m e
Vi sit N u m b er s 1
D a y s
Ti m e ( p o st -d o s e)
C o a g ul ati o n 
P a n el  
X 
X 
  
X 
  
X 
  
  
X 
 
 
X 
 
 
X 
X 
T h yr oi d  
X  
X  
  
  
  
X  
  
  
X  
 
 
X  
 
 
X  
X  
X -r a y 
X  
  
  
  
  
  
  
  
  
 
 
  
 
 
X  
  
3 T M RI 3  
  
X  
  
  
  
  
  
  
X  
 
 
  
 
 
X  
  
R a n d o mi z ati o n  
  
X  
  
  
  
  
  
  
  
 
 
  
 
 
  
  
Dr u g di s p e n s ati o n  
  
  
X  
X  
X  
X  
X  
X  
X  
 
 
X  
 
 
  
  
St u d y dr u g 
a d mi ni str ati o n at 
st u d y sit e  
  
X 
  
X 
  
  
  
  
  
 
 
  
 
 
  
  
P arti ci p a nt di ar y 
( st u d y tr e at m e nt)5  
 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
 
P K bl o o d 
c oll e cti o n 9  
  
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
 
 
X 
X 
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N o v arti s  
C o nfi d e nti al  
P a g e 2 1  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
P eri o d  
S cr e e ni n g  
Tr e at m e nt  
F oll o w -U p  
Vi sit N a m e
Vi sit N u m b er s 1
D a y s
Ti m e ( p o st -d o s e)
A d v er s e E v e nt s  
X  
St u d y c o m pl eti o n 
i nf or m ati o n 
X 
X  A s s e s s m e nt t o b e r e c or d e d i n t h e cli ni c al d at a b a s e or r e c ei v e d el e ctr o ni c all y fr o m a v e n d or  
S  A s s e s s m e nt t o b e r e c or d e d i n t h e s o ur c e d o c u m e nt ati o n o nl y  
1  Vi sit str u ct ur e gi v e n f or i nt er n al pr o gr a m mi n g p ur p o s e o nl y  
2  
  
3  T h e b a s eli n e a s s e s s m e nt c a n b e p erf or m e d u p t o t w o w e e k s b ef or e D a y 1, d uri n g t h e s cr e e ni n g p eri o d, aft er c o nfir m ati o n of cli ni c al, l a b or at or y a n d X -r a y eli gi bilit y 
crit eri a ar e m et. A s s e s s m e nt s f or W e e k 2 6 a n d W e e k 5 2 m a y b e p erf or m e d u p t o 2 w e e k s b ef or e D a y 2 8 3 a n d u p t o 2 w e e k s b ef or e D a y 3 6 5 , r e s p e cti v el y. 
4  A s s e s s m e nt of f a sti n g gl u c o s e r e q uir e d  
5  D at e a n d ti m e of t h e  
 d o s e s of st u d y m e di c ati o n pri or t o e a c h vi sit w h er e P K s a m pl e s ar e c oll e ct e d will b e c a pt ur e d b y t h e p arti ci p a nt i n a di ar y.  
6
 
 
7  
  
8  
 
9  At t h e B a s eli n e vi sit s a m pl e s will b e c oll e ct e d pr e -d o s e a n d 4 h o ur s p o st d o s e. At t h e W e e k 4 vi sit, a pr e -d o s e P K s a m pl e will b e c oll e ct e d t o d et er mi n e C mi n, s s. At 
s u b s e q u e nt vi sit s, P K s a m pl e s will b e c oll e ct e d at a n y ti m e p oi nt i n r el ati o n t o a d mi ni str ati o n of st u d y d r u g.  
1 0  P h o n e vi sit s  
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N o v arti s  
C o nfi d e nti al  
P a g e 2 2  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
2 
I ntr o d u cti o n 
Oste oart hritis ( O A) is t he m ost pre vale nt f or m of art hritis a n d a lea di n g ca use of pai n a n d 
disa bilit y.  S y m pt o matic  O A  affects  o ver  5 0 0  milli o n  pe o ple  gl o ball y,  affecti n g  1  i n  
5 pe o ple > 4 5 years of a ge wit h a n i nci de nce t hat i ncreases wit h a ge (L o n g et al 2 0 2 2). D ue t o 
i ncreases i n life e x pecta nc y a n d t he pre vale nce of o besit y, k nee O A is n o w t he t hir d m ost 
ra pi dl y risi n g c o n diti o n ass ociate d wit h disa bilit y. 
C urre nt  p har mac ol o gic  treat me nts  (e. g.,  a nti -i nfla m mat ories,  a nal gesics)  offer  o nl y  
s y m pt o matic relief a n d d o n ot m o dif y or ot her wise i m pact t he c o urse of t he disease. T he o nl y 
disease -m o dif yi n g t hera p y a vaila ble f or O A is art hr o plast y (j oi nt re place me nt),  w hic h is use d 
f or  e n d-sta ge  disease  a n d  is  n ot  a n  o pti o n  f or  all  t y pes  of  O A.  T heref ore,  t he  nee d  f or  
disease -m o dif yi n g me dical treat me nt o pti o ns is u n met.  
R H H 6 4 6  is  a n  orall y  bi oa vaila ble  s mall  m olec ule  bei n g  de vel o pe d  as  a  n o vel  cartila ge  
re ge nerati n g  t hera p y  wit h  p ossi ble  s yste mic  a nti-i nfla m mat or y  a n d  meta b olic  be nefits.  
Its e x pecte d  pri mar y  effect  o n  re pairi n g  a n d  re ge nerati n g  da ma ge d  a n d  l ost  cartila ge  has 
t he p ote ntial t o re verse t he c o urse of disease a n d effecti vel y c ure it i n s o me patie nts. S yste mic 
a d mi nistrati o n  of  R H H 6 4 6  ma y  pr o vi de  br oa der  cli nical  utilit y  f or  t he  treat me nt  of  O A,  
i ncl u di n g patie nts wit h m ulti ple j oi nt i n v ol ve me nt or t h ose wit h disease i n j oi nts n ot a me na ble 
t o l ocal, i njecta ble t hera pies. 
R H H 6 4 6 has bee n safel y a d mi nistere d 
 
 N o d ose -li miti n g or d ose-de pe n de n t a d verse effects or differe nces 
fr o m place b o were a p pare nt. T he c urre nt st u d y ( St u d y C R H H 6 4 6 A 1 2 2 0 1) ai ms t o e val uate 
R H H 6 4 6 treat me nt i n patie nts wit h a dia g n osis of ti bi ofe m oral O A.  
A m ore detaile d  re vie w of t he a vaila ble pre-cli nical a n d cli nical i nf or mati o n o n R H H 6 4 6 ca n 
be f o u n d i n t he I n vesti gat or's Br oc h ure (I B). 
2. 1  
St u d y r ati o n al e  
St u d y  C R H H 6 4 6 A 1 2 2 0 1  is  a  p hase  2a  P O C  st u d y  t o  e val uate  t he  artic ular  
cartila ge -re ge nerati n g  ca pacit y  of  R H H 6 4 6  i n  t he  k nee  as  well  as  t o  assess  safet y  a n d  
t olera bilit y i n patie nts wit h k nee O A f oll o wi n g 1 year of treat me nt. W hile t he be nefits of 
R H H 6 4 6 o n cartila ge re ge nerati o n ha ve bee n de m o nstrate d i n pre- cli nical st u dies, t his st u d y is 
t he first cli nical test of t he p ote ntial t hera pe utic effect of R H H 6 4 6 i n patie nts wit h k nee O A. 
2. 2  
B a c k gr o u n d  
O A  affects  m ore  t ha n  5 0 0  milli o n  patie nts  gl o ball y  wit h  i ncreasi n g  i nci de nce  a n d  
pre vale nce  (L o n g et al 2 0 2 2). T he pre vale nce of O A has i ncrease d a p pr o xi matel y 1 1 3 % si nce 
1 9 9 0 ( L o n g et al 2 0 2 2). T he k nees, ha n ds, hi ps, feet, a n d s pi ne are m ost c o m m o nl y affecte d. 
T he  pre vale nce of O A is pr o gressi vel y risi n g i n part d ue t o a n i ncrease i n life e x pecta nc y, al o n g 
wit h m ore pre vale nt pre dis p osi n g ris k fact ors s uc h as o besit y a n d relate d meta b olic dis ease. 
Pai n a n d l oss of f u ncti o n d ue t o O A are acc o m pa nie d b y a n i ncrease d ris k of a d diti o nal 
c o m or bi dities s uc h as t y pe 2 dia betes a n d car di o vasc ular disease  (Fer na n des, Val des  2 0 1 5). 
T he  hall mar k of O A is j oi nt pai n a n d pr o gressi ve de gra dati o n of artic ular cartila ge, s y n o vitis, 
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N o v arti s  
C o nfi d e nti al  
P a g e 2 3  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
a n d alterati o ns i n s u bc h o n dral b o ne a n d periartic ular tiss ues w hic h ulti matel y lea d t o l oss of 
f u ncti o n (G ol dri n g, Oter o  2 0 1 1).  O ver  o ne  milli o n  t otal  k nee  re place me nts  are  perf or me d  
a n n uall y i n t he U S al o ne a n d are e x pecte d t o d o u ble e ver y deca de ( Si n g h et al 2 0 1 9). 
T he  mai nsta y  of  treat me nt  f or  patie nts  wit h  O A  i ncl u des  n o n -p har mac ol o gical  a n d  
p har mac ol o gical  meas ures  t o  re d uce  pai n  (a nal gesic  me dicati o n)  a n d  i m pr o ve  k nee  a n d  
l o wer-e xtre mit y
 f u ncti o n
 ( p h ysi ot hera p y,
 lifest yle
 c ha n ges,
 a n d
 wei g ht
 l oss)
 
(K olasi ns ki  et al 2 0 2 0). C urre nt p har mac ol o gical treat me nts are directe d o nl y at s y m pt o ms wit h 
n o i m pact o n str uct ure or ot her m o dificati o n of disease pr o gressi o n. T heref ore, t he  me dical nee d 
f or n o n-s ur gical disease m o dificati o n of O A re mai ns u n met. Des pite maj or eff orts s pa n n i n g 
se veral deca des, t here are n o a p pr o ve d disease-m o dif yi n g p har mac ot hera pies f or O A.  
Cli nical de m o nstrati o n t hat c h o n dr o pr otecti o n (i.e., a n effect s h ort of cartila ge re ge nerati o n) 
ca n relie ve pai n ma y n ot  be p ossi ble ( Bac o n  et al 2 0 2 0). T he lac k of c orrelati o n bet wee n  
t he s y m pt o ms  a n d  str uct ural  si g ns  of  O A  ma kes  t he  cli nical  de vel o p me nt  of  n o vel  
disease -m o dif yi n g  t hera pies  f or  O A  partic ularl y  c halle n gi n g.  A  rece nt  a p pr oac h  is  
t he re ge nerati o n of h yali ne cartila ge w hic h i n v ol ves n o vel mec ha nis ms a n d b ot h i ntra-artic ular 
a n d s yste mic t hera p y. T he c halle n ge of li n ki n g cartila ge re ge nerati o n t o i m pr o ve me nts i n h o w 
t he patie nt feels a n d f u ncti o ns is si milar t o t hat f or c h o n dr o pr otecti ve t hera pies. W hile pr o of of 
c o nce pt  f or  t hera pe utic  cart ila ge  re ge nerati o n  has  bee n  s h o w n  (Ec kstei n  et al 2 0 2 1; 
Ger wi n  et al 2 0 2 2), t he cli nical fi n di n gs s u g gest t hat s y m pt o matic i m pr o ve me nts relate d t o 
cartila ge  re ge nerati o n  (i.e.,  t he  patie nt  feeli n g  a n d  f u ncti o ni n g  better)  ma y  ta ke  ti me  
(Ec kstei n  et al 2 0 2 1). 
C h o n dr o ge nic pr o ge nit or cells ha ve bee n i de ntifie d i n h u ma n a d ult cartila ge. T hese cells e x hi bit 
ste m cell c haracteristics s uc h as cl o n o ge nicit y, m ulti p ote nc y, a n d mi grat or y acti vit y s u g gesti n g 
t hat,  u n der  t he  pr o per  c o n diti o ns,  cartila ge  ma y  ha ve  i ntri nsic  re ge nerati ve  ca pacit y  
(Alsale me h  et al 2 0 0 4; K oelli n g  et al 2 0 0 9).  M olec ules  acti vati n g  t he  tiss ue  re ge nerati ve  
p ote ntial  o f  c h o n dr oc yte  pr o ge nit ors  t h us  ha ve t he  p ote ntial  t o  n ot  o nl y  pre ve nt  cartila ge  
destr ucti o n b ut als o sti m ulate re pair of da ma ge d cartila ge. R H H 6 4 6 pr o m otes h yali ne cartila ge 
re pair i n precli nical mo dels of O A. 
 
 
 
 
 
R H H 6 4 6 i s n ot ge n ot o xic or p h ot ot o xic. It has s h o w n n o ac ute car di o vasc ular, res pirat or y, or 
ce ntral ner v o us s yste m effects i n i n vi v o safet y p har mac ol o g y st u dies. T he l o n ger ter m safet y 
of R H H 6 4 6 has als o bee n i n vesti gate d i n re peat d ose i n vi v o st u dies of u p t o 2 6 wee ks d urati o n 
i n rats a n d 3 9 wee ks d urati o n i n d o gs. 
 
 
 
 
 
T he m ost c o m m o nl y re p orte d a d verse e ve nts ( A Es) i n healt h y a d ults were hea dac he 
( n = 5) a n d C O VI D-1 9/ S A R S -C o V -2 i nfecti o n ( n = 3), b ot h of w hic h occ urre d i n t he R H H 6 4 6 
a n d place b o gr o u ps. T here were n o treat me nt -relate d c ha n ges i n vital si g ns, la b orat or y tests, or 
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N o v arti s  
C o nfi d e nti al  
P a g e 2 4  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
electr ocar di o gra ms after t w o wee ks of d osi n g. O verall, t he a vaila ble n o n -cli nical a n d cli nical 
safet y  data  al o n g  wit h  t he  u ni q ue  c o m bi nati o n  of  p ote ntial  cartila ge-re ge nerati n g  a n d  
a nti-i nfla m mat or y effects of R H H 6 4 6 s u p p ort cli nical i n vesti gati o n of R H H 6 46 i n patie nts wit h 
O A.  
2. 3  
B e n efit/ Ri s k a s s e s s m e nt  
T his st u d y is t he first ti me t hat R H H 6 4 6 will be a d mi nistere d t o patie nts wit h k nee O A. 
T heref ore, t his st u d y is t he first test of t he efficac y of R H H 6 4 6 i n h u ma ns.  
 
 
 
 
 
 A n orall y a d mi niste re d t herap y als o br oa de ns 
t he p ote ntial cli nical utilit y of R H H 6 4 6 t o i ncl u de patie nts wit h m ulti ple j oi nt i n v ol ve me nt or 
t h ose wit h disease i n j oi nts n ot a me na ble t o l ocal/i njecta ble t hera pies. If R H H 6 4 6 pr o ves t o be 
effecti ve,  it  ma y  rest ore  f u ncti o n,  re d uce  relia nce  o n  ot her  s y m pt o matic  t hera pies,  a v oi d  
t he nee d f or art hr o plast y, a n d miti gate t he i m pact of sec o n dar y c o m plicati o ns of i m paire d 
f u ncti o n a n d m o bilit y (f or l o wer e xtre mit y O A). N o c urre nt t hera p y offers t hese be nefits. 
T he  R H H 6 4 6  d oses/e x p os ures  at  w hic h  t o xicities  ha ve  bee n  f o u n d  relati ve  t o  
t he d oses/e x p os ures at w hic h efficac y has bee n s h o w n i n a ni mal m o dels s u g gest a t hera pe utic 
i n de x acce pta ble f or t he treat me nt of O A. T he lac k of a n y a p pare nt d ose-li miti n g or d ose-
de pe n de nt a d verse effects 
 
als o  su p p orts  c o nti n ue d  cli nical  i n vesti gati o n  of  R H H 6 4 6.  
T he  m ost c o m m o n A E re p orte d i n healt h y a d ults was hea dac he, w hic h occ urre d i n  a t otal of 
5 st u d y partici pa nts: 4 w h o recei ve d R H H 6 4 6 
 
 a n d o ne w h o recei ve d place b o. T he sec o n d m ost c o m m o n A E re p orte d i n healt h y a d ults 
was C O VI D -1 9, w hic h was dia g n ose d i n t w o st u d y partici pa nts a fter recei vi n g 
 
 of R H H 6 4 6. A n as y m pt o matic S A R S-C o V -2 i nfecti o n occ urre d i n o ne partici pa nt w h o 
recei ve d place b o. Asi de fr o m t he gra de 2 s y m pt o mat ol o g y i n t he partici pa nts w h o ha d C O VI D-
1 9, all A Es were gra de 1. T here were n o e vi de nt R H H 6 4 6- relate d c ha n ges i n la b orat or y tests, 
vital si g ns, or E C Gs. T heref ore, t he o verall be nefit/ris k bala nce f or c o n d ucti n g t his  st u d y is 
fa v ora ble. 
T he p ote nti al ris ks of partici pati o n i n t he st u d y i ncl u de ris ks ass ociate d wit h t he a d mi nistrati o n 
of  st u d y  dr u g  a n d  pr oce d ural  ris ks  (e. g.,  ris ks  ass ociate d  wit h  i ma gi n g  pr oce d ures,  
ve ni p u nct ure,  ot her  assess me nts).  T he  ris k  t o  partici pa nts  i n  t his  trial  are  mi ni mize d  b y  
c o m plia nce wit h t he eli gi bilit y criteria a n d st u d y pr oce d ures, as well as cl ose cli nical m o nit ori n g 
a n d st o p pi n g r ules. 
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N o v arti s  
C o nfi d e nti al  
P a g e 2 5  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
Ri s k s a s s o ci at e d wit h a d mi ni str ati o n of R H H 6 4 6  
 
 
 
 T he re ma y be ris ks of R H H 6 4 6 t hat are u n k n o w n a n d 
p ote ntiall y seri o us. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 If t here is a n R H H 6 4 6-
ass ociate d r is k of ac ute e pi di d y mitis i n males, it is e x pecte d t o prese nt i n a wa y t hat is si milar 
t o t he wa y ac ute e pi di d y mitis t y picall y prese nts. T his w o ul d i ncl u de ne w o nset scr otal pai n, 
scr otal s welli n g, scr otal te n der ness, uri nar y or ejac ulat or y c o m plai nts. St u d y partici pa nts wit h 
a n y s uc h c o m plai nts s h o ul d be referre d t o a ur ol o g ist f or dia g n osis a n d ma na ge me nt. S pecific 
m o nit ori n g  of  male  partici pa nts  i ncl u di n g  e xter nal  ge nitalia  e xa mi nati o ns  a n d  ur ol o g y  
c o ns ultati o ns has bee n i ncl u de d i n t he st u d y pr ot oc ol t o e ns ure safet y (see Secti o n 8. 4. 6  for 
details).  
 
 
 
 
 
 
Re g ular m o nit ori n g of t he cell c o u nts i n circ ulati o n is pla n ne d. 
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N o v arti s  
C o nfi d e nti al  
P a g e 2 6  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
Ot her  p ote ntial  ris ks  i n  t his  st u d y  i ncl u de  c ha n ges  i n  la b orat or y  test  res ults  (e. g.,  t otal  
c h olester ol,  fi bri n o ge n,  retic ul oc yte  c o u nts)  a n d  c ha n ges  i n  b o d y  wei g ht.  
 
 
 
 
 
La b orat or y tests a n d b o d y wei g ht will 
be m o nit ore d d ur i n g t he st u d y. 
T he re pr o d uct i ve t o xicit y of R H H 6 4 6 has n ot bee n i n vesti gate d. T heref ore, t here ma y be a ris k 
t o  a  de vel o pi n g  fet us.  I n  E E A,  wo me n  of  c hil d -beari n g  p ote ntial  will  be  e xcl u de d  fr o m  
partici pati o n i n t his trial . W o me n of c hil d-beari n g p ote ntial i n ot her re gi o ns a n d se x uall y acti ve 
males i n all re gi o ns m ust be i nf or me d t hat ta ki n g t he st u d y treat me nt ma y i n v ol ve u n k n o w n 
ris ks t o t he fet us if pre g na nc y were t o occ ur d uri n g t he st u d y a n d a gree t hat i n or der t o 
part ici pate i n t he st u d y, t he y m ust a d here t o t he c o ntrace pti o n re q uire me nts o utli ne d i n t he 
e xcl usi o n criteria. If t here is a n y q uesti o n t hat t he partici pa nt will n ot relia bl y c o m pl y, t he y 
s h o ul d n ot be e ntere d or c o nti n ue i n t he st u d y. 
Ri s k s a s s o ci at e d wit h i m a gi n g pr o c e d ur e s  
X- ra y  vie ws  will  be  re q uire d  f or  scree ni n g  p ur p oses  a n d  k nee  O A  assess me nt  at  
t he Wee k  5 2/ E O T visit. T hese are ofte n perf or me d d uri n g t he r o uti ne e val uati o n of patie nts 
wit h k nee pai n, b ut n ot al wa ys. C o nse q ue ntl y, f or t he scree ni n g assess me nt of s o me pati e nts, 
t he y will be o btai ne d as descri be d i n t he I ma gi n g Ma n ual o nl y f or researc h p ur p oses. T he t otal 
a m o u nt of ra diati o n e x p os ure per partici pa nt fr o m t hese X -ra ys will be a b o ut u p t o 4 0 0 µ S v. 
T his  a m o u nt  of  ra diati o n  is  e q ui vale nt  t o  a p pr o xi matel y  5 6  da ys  of  bac k gr o u n d  e x p os ure 
(a p pr o x. 0. 3 µ S v per h o ur at sea le vel). F or effecti ve ra diati o n d oses u n der 3 m S v ( 3 0 0 mre m), 
t he ris k is c o nsi dere d " mi ni mal". T heref ore, t he ra diati o n e x p os ure i n t his st u d y i n v ol ves 
mi ni mal ris k a n d is necessar y t o e ns ure eli gi b ilit y of patie nts. 
Ma g netic res o na nce i ma gi n g ( M RI) will be use d i n t his st u d y t o m o nit or t he effects of R H H 6 4 6 
o n cartila ge str uct ure a n d c o m p ositi o n. M RI is a n o n -i n vasi ve i ma gi n g tec h ni q ue t hat has n o 
ra diati o n e x p os ure. T he M RI sca n ni n g e q ui p me nt ma y ca use a feeli n g of cla ustr o p h o bia i n 
s usce pti ble pers o ns. T he prese nce of metal i n t he b o d y ma y als o be a safet y hazar d or affect 
t he M RI i ma ge q ualit y. F or m ore i nf or mati o n, see  Secti o n  5. 2 E xcl usi o n criteria.  
Ot h er pr o c e d ur al ri s k s  
T he ris ks of ve ni p u nct ure i ncl u de pai n/ disc o mf ort, br uisi n g, a n d i nfecti o n. T hese ris ks are 
mi ni mize d b y e m pl o yi n g sterile tec h ni q ues a n d usi n g t he s mallest ga u ge nee dles s uita ble f or 
t he st u d y  p ur p ose.  Lea ds  place d  f or  electr ocar di o gra p hic  m o nit ori n g  a n d  ta pes  (e. g.,  f or  
sec uri n g c ott o n, ga uze, or i ntra ve n o us ca n n ulas, if use d) ma y ca use s ki n irritati o n. 
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N o v arti s  
C o nfi d e nti al  
P a g e 2 7  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
2. 3. 1  
Bl o o d s a m pl e v ol u m e  
A v ol u me s maller t ha n a t y pical bl o o d d o nati o n is pla n ne d t o be c ollecte d o ver a peri o d of 
1 4 m o nt hs, fr o m eac h partici pa nt as part of t he st u d y. T he a p pr o xi mate v ol u mes are me nti o ne d 
i n  t he I nf or me d  C o nse nt  F or m  (I C F).  A d diti o nal  sa m ples  ma y  be  re q uire d  for  safet y  
m o nit ori n g.  
Ti mi n gs of bl o o d sa m ple c ollecti o n are o utli ne d i n Secti o n  1. 3 . 
3 
O bj e cti v e s, e n d p oi nt s, a n d e sti m a n d s  
T a bl e 3- 1 
O bj e cti v e s a n d r el at e d e n d p oi nt s  
O bj e cti v e( s)  
E n d p oi nt( s)  
Pri m ar y o bj e cti v e( s)  
E n d p oi nt( s) f or pri m ar y o bj e cti v e( s)  
•  
T o e v al u at e t h e arti c ul ar c artil a g e -
r e g e n er ati n g c a p a cit y of R H H 6 4 6 i n t h e 
k n e e f oll o wi n g 1 y e ar of tr e at m e nt  
•  
C h a n g e fr o m b a s eli n e i n c artil a g e v ol u m e i n 
t h e i n d e x r e gi o n of t h e t ar g et k n e e b y M RI at 
W e e k 5 2  
•  
T o e v al u at e t h e s af et y a n d t ol er a bilit y of 
R H H 6 4 6 f oll o wi n g 1 y e ar of tr e at m e nt  
•  
A E s  
El e ctr o c ar di o gr a m s ( E C G s)  
Vit al si g n s  
H e m at ol o g y, bl o o d c h e mi str y, uri n al y si s  
S e c o n d ar y o bj e cti v e( s)  
E n d p oi nt( s) f or s e c o n d ar y o bj e cti v e( s)  
•  
T o e v al u at e t h e p h ar m a c o ki n eti c s of 
R H H 6 4 6 i n p ati e nt s wit h k n e e O A  
•  
R H H 6 4 6 pl a s m a c o n c e ntr ati o n s, C mi n, s s at 
W e e k 4, a n d a n y ot h er P K p ar a m et er a s 
a p pr o pri at e  
E x pl or at or y o bj e cti v e( s)  
E n d p oi nt( s) f or e x pl or at or y o bj e cti v e( s)  
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C o nfi d e nti al  
P a g e 2 8  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
O bj e cti v e( s)  
E n d p oi nt( s)  
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N o v arti s  
C o nfi d e nti al  
P a g e 2 9  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
3. 1  
Pri m ar y e sti m a n d s  
T he esti ma n d is t he precise descri pti o n of t he treat me nt effect a n d reflects strate gies t o a d dress 
e ve nts occ urri n g d uri n g trial c o n d uct w hic h c o ul d i m pact t he i nter pretati o n of t he trial res ults. 
T he pri mar y cli nical q uesti o n of i nterest is:  
W hat is t he effect of  
, orall y a d mi nistere d R H H 6 4 6, wit h acce pta ble c o m plia nce, o n 
k nee  cartila ge  v ol u me  after  5 2 wee ks  of treat me nt i n patie nts wit h s y m pt o matic, mil d  t o 
m o derate k nee O A? T he pri mar y esti ma n d is descri be d b y t he f oll o wi n g attri b utes:  
1.  P o p ul ati o n:  Patie nts wit h s y m pt o matic, mil d t o m o derate ra di o gra p hic k nee O A ( K & L 
gra de 2 t o 3) i n t he tar get k nee a n d wit h pai n re q uiri n g a nal gesic t hera p y. F urt her details 
a b o ut t he p o p ulati o n are pr o vi de d i n Secti o n  5. 
2.  Pri m ar y v ari a ble:  c ha n ge fr o m baseli ne t o Wee k 5 2 i n cartila ge v ol u me i n t he i n de x 
re gi o n of t he k nee. 
3.  Tre at me nt of i nterest: t he ra n d o mize d treat me nt ( R H H 6 4 6 or place b o) as   m g 
 as all o we d per pr ot oc ol 
(Secti o n  6. 5). 
H a n dli n g of re m ai ni n g i nterc urre nt e ve nts (I C Es)  
U nacce pta ble n o n -c o m plia nce wit h treat me nt: H y p ot hetical strate g y (see  Secti o n  9. 3. 3). 
T he s u m m ar y me as ure  
T he differe nce bet wee n treat me nts i n t he mea n c ha n ges fr o m baseli ne t o Wee k 5 2 i n cartila ge 
v ol u me i n t he i n de x re gi o n of t he k nee. 
3. 2  
S e c o n d ar y e sti m a n d s  
N ot a p plica ble. 
4 
St u d y d e si g n  
4. 1  
O v er all d e si g n  
Refer t o  Secti o n  1. 2 Sc he ma f or st u d y desi g n Fi g ure 1 - 1. 
T his  is  a  n o n -c o nfir mat or y,  ra n d o mize d,  i n vesti gat or  a n d  partici pa nt -bli n de d,  t w o -ar m, 
place b o -c o ntr olle d, p hase 2a st u d y t o assess safet y, t olera bilit y, a n d efficac y of R H H 6 4 6 i n 
male a n d fe male a d ult patie nts wit h s y m pt o matic, mil d t o m o derate ra di o gra p h ic k nee O A 
( K & L gra de 2 t o 3) i n t he tar get k nee a n d wit h pai n re q uiri n g a nal gesic t hera p y (e. g., A P A P or 
N S AI Ds). A p pr o xi matel y 7 8 partici pa nts will be e nr olle d a n d ra n d o mize d i n t he trial a n d 
treate d f or 5 2 wee ks.  
T he st u d y c o m prises a scree ni n g peri o d ( u p t o 6 wee ks), a treat me nt peri o d (
) a nd 
a f oll o w u p peri o d (
) p os t last a d mi nistrati o n of st u d y treat me nt bef ore t he E O S visit. 
T he  t otal d urati o n f or eac h partici pa nt will be u p t o 6 2 wee ks ( u nless f oll o w u p of a d verse 
e ve nts re q uires t he d urati o n t o be l o n ger). 
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N o v arti s  
C o nfi d e nti al  
P a g e 3 0  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
S cr e e ni n g p eri o d  
Pri or  t o  scree ni n g,  o pti o nal  st u d y  s pecific  pre -scree ni n g  assess me nts  ma y  be  carrie d  o ut,  
i ncl u di n g  b ut  n ot  li mite d  t o  X-ra y  a n d  k nee  p h ysical  e xa mi nati o n,  t o  assess  partici pa nt  
eli gi bilit y  f or  i ncl usi o n.  Pri or  t o  a n y  st u d y  s pecific  assess me nts  bei n g  carri e d  o ut,  
t he pre-scree ni n g I C F m ust be si g ne d b y t he partici pa nt. If X-ra y is ta ke n d uri n g pre-scree ni n g 
acc or di n g t o t he pr ot oc ol i ma gi n g criteria, it will n ot nee d t o be re peate d d uri n g scree ni n g.  
After si g ni n g i nf or me d c o nse nt, scree ni n g e val uati o ns will ta ke place fr o m Da y -4 2 t o Da y  -1. 
D ur i n g t his peri o d safet y a n d ot her assess me nts m ust be perf or me d t o e val uate eli gi bilit y. T he 
tar get k nee f or t he st u d y s h o ul d be selecte d b y t he i n vesti gat or base d o n partici pa nt  c o m plai nts, 
me dical hist or y, caref ul k nee e xa mi nati o n al o n g wit h a l ocal re vie w of t he X -ra y. T he  X-ra y 
will re q uire assess me nt b y a ce ntral rea der. T he re q uire d assess me nts ma y be c o n d ucte d o ver 
se veral da ys if it is i n t he best i nterest of t he partici pa nt, or f or l o gistical reas o ns. D uri n g t he 
scree ni n g  peri o d,  a n y  pr o hi bite d  me dicati o n  will  be  was he d-o ut.  
 
 
 
as descri be d i n Secti o n 6. 8. 2  Pr o hi bite d me dicati o n . 
Tr e at m e nt p eri o d  
T he treat me nt peri o d is 5 2 wee ks ( 1 year). St u d y visits are pla n ne d a p pr o xi matel y m o nt hl y 
d uri n g t he first 6 m o nt hs a n d e ver y 3 m o nt hs t hereafter.  I n a d diti o n, partici pa nts will ha ve p h o ne 
visits  at Wee ks 3 0, 3 4, 4 3 a n d 4 7 w here t he  well bei n g of t he partici pa nt will be assesse d 
re m otel y.  Partici pa nts ma y  be  i n vite d  f or  u nsc he d ule d  assess me nts  at  t he  site  if  dee me d  
necessar y .  
Eli gi ble partici pa nts will be ra n d o mize d o n Da y 1 t o recei ve R H H 6 4 6 or place b o. M RIs f or t he 
pri mar y e n d p oi nt are perf or me d at baseli ne ( ma y be perf or me d u p t o 2 wee ks pri or t o Da y 1 
d uri n g t he scree ni n g peri o d), at 6 m o nt hs, a n d 1 2 m o nt hs. 
At sc he d ule d o nsite visits, partici pa nts will u n der g o safet y, efficac y a n d f u ncti o nal assess me nts, 
vari o us  P K,  
 
 as i ndicate d i n  Secti o n  1. 3. At Wee k 4 t he part ici pa nts 
will  ta ke t heir  
 d ose  of st u d y treat me nt d uri n g  t he  visit t o all o w f or  a  c ollecti o n  of 
a pre- d ose sa m ple.
 
 
 Date  a n d ti me of i nta ke of t he 
 d oses of  st u d y me dicati o n pri or t o eac h visit w here P K sa m ples are c ollecte d will als o be 
ca pt ure d i n a diar y.
 
 
as i n dicate d i n Secti o n  1. 3. 
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N o v arti s  
C o nfi d e nti al  
P a g e 3 1  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
F oll o w -u p p eri o d  
After recei pt of last d ose a n d after all safet y a n d efficac y assess me nts are c o m plete d, all 
partici pa nts  will  be gi n  a  4 -wee k  f oll o w -u p  peri o d  t o  e ns ure  c o m plete  was h o ut  of  
t he i n vesti gati o nal treat me nt bef ore t he E O S visit. At t his visit, partici pa nts will u n der g o fi nal 
assess me nts as i n dicate d i n  Secti o n  1. 3. U p o n c o m pleti o n of t his visit, partici pa nts will be 
disc har ge d fr o m t he st u d y. 
4. 2  
S ci e ntifi c r ati o n al e f or st u d y d e si g n  
T he ra n d o mize d, bli n de d, t w o -ar m, place b o-c o ntr olle d desi g n all o ws a n i nitial assess me nt of 
efficac y (i.e., re ge nerati o n of h yali ne cartila ge meas ure d as cartila ge v ol u me b y M RI) a n d safet y 
i n patie nts wit h k nee O A usi n g t he m ost efficie nt desi g n ( o pti mal p o wer) f or t he pri mar y 
e n d p oi nt.  T he  bli n de d  1: 1  ra n d o mizati o n  tar gets  bala nce  acr oss  t he  treat me nt  gr o u ps  a n d  
mi ni mizes p ote ntial bias f or t he e val uati o n of safet y f or t he first cli nical i n vesti gati o n of 
R H H 6 4 6 i n t his patie nt p o p ulati o n wit h a relati vel y  s mall sa m ple size a n d a 5 2-wee k d urati o n 
of treat me nt. T he bala nce d ra n d o mizati o n als o e ns ures a c o m para bl y r o b ust assess me nt of t he  
pri mar y e n d p oi nt (cartila ge v ol u me b y M RI) i n b ot h treat me nt gr o u ps, w hic h res pects t he  
heter o ge neit y of O A pr o gressi o n a m o n g patie nts, a v oi ds relia nce o n n o n -c o nc urre nt c o ntr ol or 
nat ural hist or y data, a n d mi ni mizes t he ris k of a false ne gati ve res ult.  
 
 
T he p o p ulati o n of patie nts wit h s y m pt o matic, K & L gra de 2 t o 3 k nee O A has a sta ge of disease 
e x pecte d  t o  be  res p o nsi ve  t o  p ote ntial  disease -m o dif yi n g  t hera pies  a n d  is  c o nsiste nt  wit h  
t he p o p ulati o n e nr olle d i n rece nt st u dies of ot her p ote ntiall y disease -m o dif yi n g t hera pies t hat 
use d M RI t o e val uate j oi nt str uct ures. T he pri mar y e n d p oi nt of cartila ge v ol u me b y M RI all o ws 
t he earliest a n d m ost precise assess me nt of a n y c h o n dr oa na b olic effect of t he treat me nt.  
4. 3  
J u stifi c ati o n f or d o s e  
T he   m g  
 d ose is t he hi g hest d ose c o nsi dere d safe t o a d mi nister i n t his P O C st u d y. 
T his  d ose will ma xi mize t he c ha nce f or efficac y a n d mi ni mize t he ris k of a false ne gati ve res ult 
(i.e., d ue t o i ns ufficie nt e x p os ure) beca use t his is t he first test of t he cli nical efficac y of R H H 6 4 6 
i n h u ma ns. 
 ma y n ot f ull y 
reca pit ulate h u ma n O A a n d si m ple scali n g of P K (s yste mic e x p os ures) bet wee n s pecies ma y 
n ot tra nslate t o cli nical efficac y d ue t o differe nces i n disease pat h o ge nesis/ pat h o p h ys i ol o g y, 
j oi nt  size,  s y n o vial  fl ui d  v ol u me  a n d  fl o w  d y na mics,  cartila ge  v ol u me,  l oa d- beari n g 
c haracteristics, a n d ot her rele va nt differe nces bet wee n rats a n d h u ma ns, t h us ma ki n g d oses i n 
t he l o wer e n d of t he pre dicte d t hera pe utic ra n ge har der t o j ustif y i n a n i nitial pr o of-of -c o nce pt 
st u d y wit h o ne acti ve treat me nt ar m. T he cli nical e x perie nce i ncl u des R H H 6 4 6 
 
 t hat  were  safe  a n d  well  t olerate d  i n  healt h y  a d ults  wit h o ut  
d ose- li miti n g or d ose- de pe n de nt A Es or differe nces fr o m place b o. 
T he P K of R H H 6 4 6 i n h u ma ns s u p p ort  
 d osi n g.
 
 
 
 
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N o v arti s  
C o nfi d e nti al  
P a g e 3 2  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
 
 
H u ma n P K at vari o us d ose le vels was si m ulate d base d o n h u ma n P K i n healt h y a d ults after p. o. 
a d mi nistrati o n ( D M P K R 2 2 7 0 3 4 4). 
T a bl e 4- 1 
St e a d y -st at e e x p o s ur e m ulti pl e s b y R H H 6 4 6 d o s e  
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N o v arti s  
C o nfi d e nti al  
P a g e 3 3  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
I n t h ose partici pa nts f or w h o m a d ose m o dificati o n ma y be necessar y (Secti o n  6. 5), a 
 
d ose le vel a dj ust me nt (i.e., fr o m  
 m g i n t h ose patie nts recei vi n g acti ve treat me nt) ca n 
be re gar de d as s ufficie ntl y differe nt fr o m a safet y or t olera bilit y p oi nt of vie w, w hile still 
preser vi n g a c ha nce f or efficac y.  
4. 4  
R ati o n al e f or c h oi c e of c o ntr ol dr u g s ( c o m p ar at or/ pl a c e b o) or 
c o m bi n ati o n dr u g s  
Si nce t here are n o a p pr o ve d disease -m o dif yi n g dr u gs f or O A a n d t his is t he first cli nical test of 
t he safet y of R H H 6 4 6 i n patie nts wit h O A, place b o will be use d as a c o ntr ol. Sta n dar d of care 
treat me nts  f or  k nee  O A  (e. g.,  a nal gesics)  are  all o we d  t hr o u g h o ut t he  st u d y  wit h  li mite d  
restricti o ns, as descri be d i n Secti o n  6. 8. 1. 
4. 5  
R ati o n al e f or p u bli c h e alt h e m er g e n c y miti g ati o n pr o c e d ur e s  
D uri n g a p u blic healt h e mer ge nc y as declare d b y l ocal or re gi o nal a ut h orities e. g.,  pa n de mic, 
e pi de mic, nat ural disaster, or war, miti gati o n pr oce d ures t o e ns ure partici pa nt safet y a n d trial 
i nte grit y ma y be i m ple me nte d. N otificati o n of t he p u blic healt h emer ge nc y as declare d b y l ocal 
or re gi o nal a ut h orities s h o ul d be disc usse d a m o n g i n vesti gat ors a n d N o vartis. All pr oce d ures 
a da pte d t o t he sit uati o n m ust be s u b mitte d, if re q uire d as per l ocal re g ulati o ns, t hr o u g h a 
pr ot oc ol  a me n d me nt  f or  a p pr o val  b y  l ocal  or  re gi o nal  Healt h  A ut h orities  a n d  Et hics  
C o m mittees pri or t o i m ple me ntati o n of miti gati o n pr oce d ures . 
4. 6  
P ur p o s e a n d ti mi n g of i nt eri m a n al y s e s/ d e si g n a d a pt ati o n s  
A n i nteri m a nal ysis is pla n ne d t o be carrie d o ut after eit her a mi ni m u m of 4 6 partici pa nts ha ve 
c o m plete d Wee k 5 2, or a mi ni m u m of 6 6 % ( 2/ 3) of t he t otal n u m ber of assess me nts ( Wee k  2 6 
a n d/ or  Wee k  5 2)  f or  t he  cartila ge  v ol u me  are  c ollecte d.
 
 
 If  a n y  a dj ust me nts  are  dee me d  
necessar y, s uc h as a dj usti n g t he n u m ber of partici pa nts, t he p r ot oc ol will be a me n de d. 
A d diti o nal  i nt eri m  a nal yses  ma y  be  c o n d ucte d  t o  s u p p ort  decisi o n  ma ki n g  c o ncer ni n g  
t he c urre nt cli nical st u d y, t he S p o ns or’s cli nical de vel o p me nt pr ojects i n ge neral, or i n case of 
a n y safet y c o ncer ns. 
A d diti o nal i nf or mati o n is prese nte d i n t he i nteri m a nal ysis secti o n ( Secti o n  9. 8). 
4. 7  
E n d of st u d y d efi niti o n  
T he E O S is defi ne d as t he date of t he last visit of t he last partici pa nt ( L P L V) i n t he st u d y or last 
sc he d ule d pr oce d ure or f oll o w-u p s h o w n i n  Secti o n  1. 3 f or t he last partici pa nt i n t he st u d y 
gl o ball y. 
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5 
Study population 
The study population will include males and females 35 to 75 years old with symptomatic, mild 
to moderate radiographic knee OA (K&L grade 2 to 3) in the target knee and with pain requiring 
analgesic therapy (e.g., APAP or NSAIDs). Approximately 78 participants will be randomized 
for an expected 70 participants evaluable for the primary analysis. 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Signed informed consent must be obtained prior to participation in the study 
2. Able to communicate well with the investigator, to understand and comply with 
the requirements of the study 
3. Participant is ≥35 and ≤75 years old, at time of screening 
4. Participants must weigh at least 50 kg to participate in the study and must have a body 
mass index (BMI) ≤35 kg/m2. BMI = Body weight (kg) / [Height (m)]2 
5. Diagnosis of tibiofemoral OA in at least one knee by standard American College of 
Rheumatology clinical and radiographic criteria (Altman et al 1986) at screening 
6. K&L grade 2 to 3 OA in the target knee evaluated with X-Ray by the Central Reader at 
screening 
7a. Predominantly medial tibiofemoral compartment involvement defined as medial Joint 
Space Narrowing (medJSN) 1-2 (Altman and Gold 2007) and medJSN > lateral Joint 
Space Narrowing (latJSN) in the target knee evaluated with X-Ray by the Central Reader 
at screening 
8. Symptomatic disease, defined as having pain in the target knee at least 3 days per week 
during the last 3 months from screening that is relieved by analgesic therapy (e.g. APAP 
or NSAIDs), according to the investigator’s evaluation and judgment of the patient’s 
history 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
General Note: In the case where a safety laboratory assessment at screening is outside of 
the range specified below, the assessment may be repeated once prior to randomization. 
If the repeat value remains outside of the specified ranges, the participant is excluded from 
the study. Also the X-ray performed to confirm participant eligibility may be repeated once if 
the image quality does not allow determination of eligibility. If the repeated X-ray confirms 
ineligibility, a third X-ray is not allowed, and the participant will be excluded from the study. 
1. Use of other investigational drugs within 5 half-lives of enrollment/initiation of study 
treatment (select as appropriate) within 30 days (e.g., small molecules) / or until 
the expected pharmacodynamic effect has returned to baseline (e.g., biologics), whichever 
is longer; or longer if required by local regulations 
2. History of hypersensitivity to any of the excipients in the study treatment 

N o v arti s  
C o nfi d e nti al  
P a g e 3 5  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
3.  Hist or y of Ste ve ns-J o h ns o n S y n dr o me ( SJ S), t o xic e pi der mal necr ol ysis ( T E N), dr u g ras h 
wit h e osi n o p hilia a n d s yste mic s y m pt o ms ( D R E S S), or a dr u g -relate d a na p h yla xis 
4a. W o me n of c hil d - beari n g p ote ntial, defi ne d as all w o me n p h ysi ol o gicall y ca pa ble of 
bec o mi n g pre g na nt, u nless t he y are usi n g hi g hl y effecti ve met h o ds of c o ntrace pti o n w hile 
ta ki n g st u d y treat me nt a n d f or 
 
 after st o p pi n g st u d y treat me nt. 
I n E E A, w o me n of c hil d-beari n g p ote ntial will be e xcl u de d fr o m partici pati o n i n t his trial, 
irres pecti ve of t he use of hi g hl y effecti ve met h o ds of c o ntrace pti o n. 
Hi g hl y effecti ve c o ntrace pti o n met h o ds i ncl u de:  
•  T otal a bsti ne nce ( w he n t his is i n li ne wit h t he preferre d a n d us ual lifest yle of 
t he partici pa nt). Peri o dic a bsti ne nce (e. g., cale n dar, o v ulati o n, s y m pt ot her mal, p ost-
o v ulati o n met h o ds) a n d wit h dra wal are n ot acce pta ble met h o ds of c o ntrace pti o n. 
•  Fe male bilateral t u bal li gati o n, fe male sterilizati o n (s ur gical bilateral o o p h orect o m y, 
t otal h ysterect o m y or sal pi n gect o m y) at least si x wee ks pri or t o e nr oll me nt o n st u d y. 
I n case of o o p h orect o m y al o ne, o nl y w he n t he re pr o d ucti ve stat us of t he w o ma n has 
bee n c o nfir me d b y f oll o w u p h or m o ne le vel assess me nt. 
•  Male sterilizati o n (at least 6 m o nt hs pri or t o scree ni n g). F or fe male partici pa nts o n 
t he st u d y, t he vasect o mize d male part ner s h o ul d be t he s ole part ner f or t hat 
partici pa nt.  
•  Use of oral (estr o ge n a n d pr o gester o ne), i njecte d, or i m pla nte d h or m o nal met h o ds of 
c o ntrace pti o n or place me nt of a n i ntra uteri ne de vice (I U D) or i ntra uteri ne s yste m 
(I U S), or ot her f or ms of h or m o nal c o ntrace pti o n t hat ha ve c o m para ble efficac y 
(fail ure rate < 1 %), f or e xa m ple h or m o ne va gi nal ri n g or tra ns der mal h or m o ne 
c o ntrace pti o n. I n case of use of oral c o ntrace pti o n w o me n s h o ul d ha ve bee n sta ble o n 
t he sa me pill f or a mi ni m u m of 3 m o nt hs bef ore ta ki n g st u d y treat me nt. 
If l ocal re g ulati o ns are m ore stri n ge nt t ha n t he c o ntrace pti o n met h o ds liste d a b o ve t o 
pre ve nt pre g na nc y, l ocal re g ulati o ns a p pl y a n d will be descri be d i n t he I C F. 
W o me n are c o nsi dere d p ost - me n o pa usal if t he y ha ve ha d 1 2 m o nt hs of nat ural 
(s p o nta ne o us) a me n orr hea wit h a n a p pr o priate cli nical pr ofile (e. g. a ge-a p pr o priate hist or y 
of vas o m ot or s y m pt o ms). W o me n are c o nsi dere d n ot of c hil d- beari n g p ote ntial if t he y are 
p ost- me n o pa usal or ha ve ha d s ur gical bilateral o o p h orect o m y ( wit h or wit h o ut 
h ysterect o m y), t otal h ysterect o m y or bilateral sal pi n gect o m y at least si x wee ks pri or t o 
e nr oll me nt o n st u d y. I n t he case of o o p h orect o m y al o ne, o nl y w he n t he re pr o d ucti ve stat us 
of t he w o ma n has bee n c o nfir me d b y f oll o w- u p h or m o ne le vel assess me nt is s he 
c o nsi dere d t o be n ot of c hil d- beari n g p ote ntial. 
5.  W o me n w h o are pre g na nt, n ursi n g (lactati n g), or pla n ni n g t o bec o me pre g na nt d uri n g 
t he st u d y 
6.  Se x uall y acti ve males u n willi n g t o use a c o n d o m d uri n g i nterc o urse w hile ta ki n g st u d y 
treat me nt a nd f or 
 after 
st o p pi n g st u d y treat me nt. A c o n d o m is re q uire d f or all se x uall y acti ve male partici pa nts t o 
pre ve nt t he m fr o m fat heri n g a c hil d A N D t o pre ve nt deli ver y of st u d y treat me nt via 
se mi nal fl ui d t o t heir part ner. I n a d diti o n, male partici pa nts m ust n ot d o nate s per m f or 
t he ti me peri o d s pecifie d a b o ve. 
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7. Arthroscopy of the target knee within the 6 months prior to screening or planned 
arthroscopy during the study 
8. Previous surgical treatment of the target knee using mosaicplasty, microfracture, 
meniscectomy >50% or osteotomy; planned surgery for either knee during the study 
9. Unstable target knee joint (including, but not limited to, posttraumatic or congenital 
laxity) or insufficiently reconstructed ligaments based on medical history and/or physical 
examination by the investigator 
10. Participant has severe malalignment (valgus- or varus-deformity) in the target knee >7.5° 
based on X-ray evaluation by the Central Reader at screening 
11. K&L grade 4 OA in either knee 
12. Presence of severe hip OA that either (i) alters lower limb function to a degree that 
increases or abnormally changes the mechanical forces in the knee while walking, 
according to investigator’s evaluation or (ii) currently requires or is likely to require 
specific medical or surgical management during the study period 
13. Other pathologies affecting the knee, including subchondral insufficiency fractures, bone 
fracture (acute or subacute within the 6 months prior to screening) or bone bruise, 
osteonecrosis, malignant bone marrow infiltration, solid tumors, and/or patellofemoral 
dysplasia based on clinical assessment, or imaging 
14. Known autoimmune disease with inflammatory arthritis (including but not limited to 
rheumatoid arthritis, psoriatic arthritis, ankylosing spondylitis, systemic lupus 
erythematosus), crystal-induced arthritides (gout or pseudogout arthritis), active acute or 
chronic infection of the knee joint, Lyme disease involving the knee, reactive arthritis, 
systemic cartilage disorders, moderate to severe fibromyalgia, a known systemic 
connective tissue disease or a widespread pain index (WPI) >4. 
15. Inability to undergo MRI (e.g., claustrophobia, body size, leg not fitting in the coil) or 
contraindications to MRI (e.g., non MRI-compatible metallic implants, metallic foreign 
bodies, pacemaker, defibrillator) 
16. History of testicular disease (males) or ovarian disease (females) unless status post 
bilateral orchiectomy (males) or bilateral oophorectomy (females). Males who have 
undergone sub-epididymal orchiectomy are not eligible for participation. 
17. History of unstable or untreated mood or anxiety disorders 
18. History or evidence of clinically significant or unstable ECG abnormalities including but 
not necessarily limited to: 
• sustained ventricular tachycardia 
• clinically significant second or third degree AV block without a pacemaker 
• familial long QT syndrome or family history of Torsades de Pointes 
• resting QTcF >450 msec (male) or >470 msec (female) at screening or baseline 
• chronic use of medications with known pro-arrhythmic risks 
19. History of malignancy of any organ system (other than localized basal cell carcinoma of 
the skin or in-situ cervical cancer), treated or untreated, within the past 5 years, regardless 
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20. Any surgical or medical condition which might significantly alter the absorption, 
distribution, metabolism, or excretion of drugs, or which may jeopardize the participant in 
case of participation in the study. The investigator should make this determination in 
consideration of the participant’s medical history and/or clinical or laboratory evidence of 
any of the following: 
• Major gastrointestinal tract surgery such as gastrectomy, gastroenterostomy, or bowel 
resection 
• Pancreatic injury or pancreatitis 
21. History of or current clinically significant liver disease or liver injury as indicated by 
abnormal liver function tests such as AST (Aspartate Aminotransferase), ALT (Alanine 
Aminotransferase), alkaline phosphatase (ALP), or serum bilirubin at screening. 
The investigator should be guided by the following criteria: 
• Any single parameter may not exceed 2× upper limit of normal (ULN) 
• A single parameter elevated up to and including 2× ULN should be re-checked once 
more as soon as possible, and in all cases, at least prior to enrollment/randomization, 
to rule out lab error 
22. Estimated GFR < 50 mL/min/1.73 m2 by the CKD-EPI creatinine equation (2021) at 
screening 
23. History or evidence of immunodeficiency, including a positive HIV (ELISA and Western 
blot) test result regardless of immune status 
24. Chronic infection with Hepatitis B (HBV) or Hepatitis C (HCV). A positive HBV surface 
antigen (HBsAg) test, or if standard local practice, a positive HBV core antigen (HbcAg) 
test, excludes a participant. Participants with a positive HCV antibody test should have 
HCV RNA levels measured. Participants with positive (detectable) HCV RNA should be 
excluded. 
25. Any significant chronic condition that has not been well-controlled for a minimum of 
3 months prior to screening (e.g., uncontrolled hypertension, diabetes or chronic heart 
failure (e.g., patients with New York Heart Association class III or IV)), or poor 
functional status unable to perform self-care 
26. Regular users of nicotine (e.g., smoked tobacco, smokeless tobacco, vaporizers) defined 
as >10 cigarettes or equivalent use of other forms of tobacco/nicotine per day or former 
users currently reliant on daily nicotine replacement therapy 
27. History of drug abuse or unhealthy alcohol use within the 12 months prior to dosing, or 
evidence of such abuse as indicated by the laboratory assays conducted during screening. 
Unhealthy alcohol use is defined as a history of, or current alcohol misuse/abuse, defined 
as “Five or more drinks on the same occasion on each of 5 or more days in the past 
30 days.” 
28. Taking medications prohibited by the protocol (see Section 6.8.2) 
29. Any surgical, medical, psychiatric, or additional physical or social condition that 
the investigator feels may jeopardize the safety of the participant or may interfere with 
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5.3 
Lifestyle considerations 
For the duration of the study, participants should be informed and reminded of the restrictions 
outlined in this section. 
5.3.1 
Meals and dietary restrictions 
After signing the informed consent, the study participants should be instructed to refrain from 
consuming citrus-containing fruits or beverages, and tonic water in the 4 hours prior to the ECG 
collection. 
At Baseline, Week 26, and EOS visits, where fasting glucose will be assessed (Table 1-1), 
participants will fast (i.e. no food and liquid except water) for at least 8 hours prior to 
the assessment. 
5.3.2 
Caffeine, alcohol, and tobacco 
From Screening to EOS, the participant should not smoke >10 cigarettes per day or use other 
tobacco products in amounts corresponding to >10 cigarettes per day. Use of nicotine 
replacement therapy is not allowed. 
From Screening to EOS, the participant should not consume five or more drinks on the same 
occasion on each of 5 or more days in a 30-day period. 
From Screening to EOS, the participant should not use recreational drugs, even if legal in 
their location. 
After signing the informed consent, the study participants should be instructed to refrain from 
smoking, consuming alcohol and methylxanthine-containing beverages (i.e., coffee, tea, soda, 
chocolate) in the 4 hours prior to the ECG collection. 
5.3.3 
Activity 
From Screening to EOS, study participants should refrain from substantial changes in 
their regular activity or exercise habits. Participation in contact or high impact sports or other 
activities involving heavy loading, rotation, or pivoting should not begin anew during the study. 
5.4 
Screen failures 
Participants who sign a pre-screening ICF and are subsequently found to be ineligible prior to 
signing the main ICF will be considered pre-screen failures. Only data related to serious adverse 
event (SAE) causally related to pre-screening study procedures (e.g., X-ray, knee examination) 
will be collected (see Section 8.6.3). All other data related to pre-screening will only be 
recorded in source documentation. 
Participants who sign the main ICF and are subsequently found to be ineligible prior to 
randomization will be considered as screen failures. The reason for screen failure should be 
recorded on the appropriate CRF. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screen failure participants. No other data 
will be entered into the clinical database for participants who are screen failures, unless 
the participant experienced a SAE during the screening period (see Section 8.6.3). Data and 
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If the participant fails to be randomized, the Interactive Response Technology (IRT) must be 
notified within 2 days of the screen fail that the participant was not randomized. 
Participants who are randomized and fail to start treatment, e.g., participants randomized in 
error, will be considered an early terminator. The reason should be recorded on the appropriate 
CRF. 
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened. Each case must be discussed and agreed with Novartis on a case-by-case basis. 
In the case where a safety laboratory assessment at screening is outside of the range specified 
in the eligibility criteria, the assessment may be repeated once prior to randomization. 
If the repeat value remains outside of the specified range, the participant must be excluded from 
the study. 
5.4.1 
Replacement policy 
Discontinued participants will not be replaced. 
5.4.2 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. A new Participant No. will be assigned at every 
subsequent enrollment if the participant is rescreened. The Participant No. consists of the Site 
Number (Site No.) (as assigned by Novartis to the investigative site) with a sequential 
participant number suffixed to it, so that each participant’s participation is numbered uniquely 
across the entire database. Upon signing the ICF, the participant is assigned to the next 
sequential Participant No. available. 
A new ICF will need to be signed if the investigator chooses to rescreen the participant after 
a participant has screen failed, and the participant will be assigned a new Participant No. 

N o v arti s  
C o nfi d e nti al  
P a g e 4 0  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
6 
St u d y tr e at m e nt( s) a n d c o n c o mit a nt t h er a p y  
Details o n t he re q uire me nts f or st ora ge a n d ma na ge me nt of st u d y treat me nt, a n d i nstr ucti o ns t o 
be f oll o we d f or partici pa nt n u m beri n g, prescri bi n g/ dis pe nsi n g, a n d ta ki n g st u d y treat me nt are 
o utli ne d i n t he pr ot oc ol. 
6. 1  
St u d y tr e at m e nt( s)  
T a bl e 6- 1 
I n v e sti g ati o n al a n d c o ntr ol dr u g 
Tr e at m e nt Titl e  
R H H 6 4 6  
Pl a c e b o  
Tr e at m e nt D e s cri pti o n  
R H H 6 4 6 or al c a p s ul e  
R H H 6 4 6 pl a c e b o or al c a p s ul e  
T y p e  
Dr u g  
Dr u g  
D o s e F or m ul ati o n  
C a p s ul e  
C a p s ul e  
U nit D o s e Str e n gt h( s)  
 m g 
0 m g  
D o s a g e L e v el( s)  
 m g, 
 
0 m g, 
 
R o ut e of A d mi ni str ati o n  
Or al  
Or al  
U s e  
E x p eri m e nt al  
Pl a c e b o  
I M P 
Y e s  
Y e s  
S o ur ci n g 
Pr o vi d e d c e ntr all y b y t h e 
s p o n s or  
Pr o vi d e d c e ntr all y b y t h e 
s p o n s or  
P a c k a gi n g a n d L a b eli n g  
St u d y tr e at m e nt will b e 
pr o vi d e d i n b ottl e s . E a c h b ottl e  
will b e l a b el e d a s r e q uir e d p er 
c o u ntr y r e q uir e m e nt.  
St u d y tr e at m e nt will b e 
pr o vi d e d i n b ottl e s . E a c h b ottl e  
will b e l a b el e d a s r e q uir e d p er 
c o u ntr y r e q uir e m e nt.  
6. 1. 1  
A d diti o n al st u d y tr e at m e nt s  
N o ot her treat me nt be y o n d i n vesti gati o nal dr u g a n d c o ntr ol dr u g are i ncl u de d i n t his trial.  
6. 1. 2  
Tr e at m e nt ar m s/ gr o u p  
Partici pa nts will be assi g ne d t o o ne of t he f oll o wi n g 2 treat me nt ar ms i n a 1: 1 rati o:  
•  R H H 6 4 6   m g  
 
•  Place b o  
 
I n t he e ve nt a n y st u d y partici pa nt a p pears t o be n ot t olerati n g t he st u d y treat me nt a n d t he o nl y 
alter nati ve w o ul d be t o disc o nti n ue t he st u d y treat me nt, t he i n vesti gat or will ha ve t he o pti o n t o 
re d uce  t he  d ose  t o  gi ve  t he  st u d y  partici pa nt  a  c ha nce  t o  re mai n  o n  st u d y  treat me nt,  
see Secti o n  6. 5. 
6. 2  
Pr e p ar ati o n, h a n dli n g, st or a g e, a n d a c c o u nt a bilit y  
Eac h  st u d y  site  will  be  s u p plie d  wit h  st u d y  treat me nt  i n  pac ka gi n g  as  descri be d  
u n der Ta ble  6- 1 I n vesti gati o nal a n d c o ntr ol dr u gs secti o n. 
A u ni q ue me dicati o n n u m ber is pri nte d o n t he st u d y me dicati o n la bel. 
I n vesti gat or staff will i de ntif y t he st u d y me dicati o n kits t o dis pe nse t o t he partici pa nt b y 
c o ntacti n g t he I R T a n d o btai ni n g t he me dicati o n n u m ber(s). T he st u d y me dicati o n has a 2- part 
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label (base plus tear-off label), immediately before dispensing the medication kit to 
the participant, site personnel will detach the outer part of the label from the packaging and 
affix it to the source document. 
As per Section 4.5, during a public health emergency as declared by local or regional authorities 
i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, delivery 
of Investigational Medicinal Product (IMP) directly to a participant's home may be permitted 
(if allowed by local or regional health authorities and ethics committees, as appropriate) in 
the event the investigator has decided that an on-site visit by the participant is no longer 
appropriate or possible, and that it is in the interest of the participant's health to administer 
the study treatment even without performing an on-site visit. The dispatch of IMP from the site 
to the participant’s home remains under the accountability of the investigator. 
Each shipment/provisioning will be for a maximum of 1-month supply. In this case, regular 
phone calls or virtual contacts (every 4 weeks or more frequently if needed) will occur between 
the site and the participant for instructional purposes, safety monitoring, investigation of any 
AEs, ensuring participants continue to benefit from treatment, and discussion of 
the participant's health status until the participants can resume visits at the study site. 
6.2.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, the designated person at the site should verify that all 
study treatment sent per the shipping documentation is received and should verify the condition 
of the study treatment (e.g., not damaged and no issues, including temperature deviations, 
during shipment). Once received at site, all study treatment must be stored according to 
the instructions specified on the labels. 
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis Country Organization Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The investigator or designated site staff must maintain an accurate record of the shipment and 
dispensing of study treatment in a drug accountability log. Monitoring of drug accountability 
will be performed by field monitors during site or remote monitoring visits, and at 
the completion of the trial. 
If study treatment is administered at home, participants will be asked to return all unused study 
treatment and packaging at each visit or at the time of discontinuation of study treatment. 
The site may destroy and document destruction of unused study treatment, drug labels and 
packaging, as appropriate in compliance with site processes, monitoring processes, and per local 
regulation/guidelines. Otherwise, the investigator will return all unused study treatment, 
packaging, drug labels, and a copy of the completed drug accountability log to 
the Novartis monitor or to the Novartis address provided in the investigator folder at each site. 

N o v arti s  
C o nfi d e nti al  
P a g e 4 2  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
6. 2. 2  
H a n dli n g of ot h er tr e at m e nt  
N o ot her treat me nt will be pr o vi de d.  
6. 2. 3  
I n str u cti o n f or pr e s cri bi n g a n d t a ki n g st u d y tr e at m e nt 
T a bl e 6- 2 
D o s e a n d tr e at m e nt s c h e d ul e   
I n v e sti g ati o n al / C o ntr ol 
Dr u g ( N a m e a n d Str e n gt h)  
D o s e  
Fr e q u e n c y a n d/ or R e gi m e n  
R H H 6 4 6  
 m g  
 m g ( 
 m g c a p s ul e s) 
 
R H H 6 4 6 Pl a c e b o  
pl a c e b o ( 
 pl a c e b o c a p s ul e s)  
 
All kits of st u d y treat me nt assi g ne d b y t he I R T will be rec or de d i n t he I R T s yste m.  
T he first d ose will be a d mi nistere d at t he site o n Da y 1. T hereafter, partici pa nts s h o ul d ta ke 
t he st u d y  treat me nt  
 wit h  
t he e xce pti o n of t he d ose o n visit Wee k 4 w hic h will be a d mi nistere d i n t he cli nic t o all o w f or 
a pre- d ose sa m ple t o be c ollecte d. Partici pa nts will be pr o vi de d wit h i n di vi d ual diar y car ds t o 
rec or d t he date a n d ti me of t he  
 d oses pri or t o eac h visit wit h P K sa m pli n g. T hese will be 
c hec ke d at eac h visit b y site staff.  
Partici pa nts s h o ul d ta ke t he st u d y treat me nt wit h o ut re gar d t o f o o d. Eac h d ose ma y be ta ke n 
wit h a glass of water a n d partici pa nts s h o ul d be i nstr ucte d t o s wall o w w h ole ca ps ules a n d n ot 
t o c he w or o pe n t he m. 
If  v o miti n g  occ urs  d uri n g  t he  c o urse  of  treat me nt,  partici pa nts  s h o ul d  n ot  ta ke  t he  st u d y 
treat me nt a gai n bef ore t he ne xt sc he d ule d d ose. 
Partici pa nts s h o ul d be i nstr ucte d n ot t o ma ke u p misse d d oses.
 
 
 a n d t he partici pa nt s ho ul d c o nti n ue treat me nt 
wit h t he ne xt sc he d ule d d ose. 
6. 3  
M e a s ur e s t o mi ni mi z e bi a s: r a n d o mi z ati o n a n d bli n di n g  
6. 3. 1  
Tr e at m e nt a s si g n m e nt, r a n d o mi z ati o n  
At t he Baseli ne visit, all eli gi ble partici pa nts will be ra n d o mize d via I R T t o o ne of t he treat me nt 
ar ms.  T he  i n vesti gat or  or  his/ her  dele gate  will  c o ntact  t he  I R T  after  c o nfir mi n g  t hat  
t he partici pa nt f ulfills all t he i ncl usi o n a n d n o ne of t he e xcl usi o n c riteria. T he I R T will assi g n a 
ra n d o mizati o n n u m ber t o t he partici pa nt, w hic h will be use d t o li n k t he partici pa nt t o a treat me nt 
ar m a n d will s pecif y a u ni q ue me dicati o n n u m ber f or t he first pac ka ge of st u d y treat me nt t o be 
dis pe nse d t o t he partici pa nt. 
T he ra n d o mizati o n n u m bers will be ge nerate d usi n g t he f oll o wi n g pr oce d ure t o e ns ure t hat 
treat me nt  assi g n me nt  is  u n biase d  a n d  c o nceale d  fr o m  partici pa nts  a n d  i n vesti gat or  staff.  
A partici pa nt ra n d o mizati o n list will be pr o d uce d b y t he I R T pr o vi der usi n g a vali date d s yste m 
t hat  a ut o mates  t he  ra n d o m  assi g n me nt  of  partici pa nt  n u m bers  t o  ra n d o mizati o n  n u m bers.  
T hese  ra n d o mizati o n n u m bers are li n ke d t o t he differe nt treat me nt ar ms, w hic h i n t ur n are 
li n ke d  t o  me dicati o n  n u m bers.  A  se parate  me dicati o n  list  will  be  pr o d uce d  b y  or  u n der  
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the responsibility of Novartis GCS using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment. 
The randomization scheme for participants will be reviewed and approved by a member of 
the Randomization Office. 
6.3.2 
Treatment blinding 
Participants, investigator staff and persons performing the assessments will remain blinded to 
study treatment from the time of randomization until database lock, except where indicated 
below. The identity of the treatments will be concealed by the use of study drugs that are all 
identical in packaging, labeling, schedule of administration, appearance, and odor. 
Site staff 
All site staff (including investigator and study nurse) will be blinded to study treatment 
throughout the study. 
Unblinding a single participant at site for safety reasons (necessary for participant management) 
will occur via an emergency system in place at the site. As a result, the participant should be 
discontinued from the study treatment. 
Interim results may be used to prepare abstracts to scientific meetings. This would typically 
require investigator input to abstract preparation. Every attempt will be made to assure that 
the investigator will not have access to individual participants' data, but rather will review 
aggregate, summary data. 
Sponsor staff 
Unblinding of a single participant for evaluation of a study stopping rule (Section 7.5) will 
occur via an emergency system. As a result, the participant should be discontinued from the 
study treatment. 
The following unblinded sponsor roles are required for the duration of the study: 
• Unblinded clinical staff managing drug re-supply to site 
• Unblinded sample analyst(s) (PK-Bioanalyst) 
• Unblinded sample analyst(s) (biomarker) 
All unblinded personnel will keep randomization lists and data or information that could 
unblind other study team members confidential and secure except as described below. 
The sample analysts will receive a copy of the randomization schedule (via request to the 
Randomization Office), to facilitate analysis of the samples. The sample analysts will provide 
the sample data to the study team under blinded conditions unless otherwise allowed. 
In addition, the following unblinded sponsor roles are required for interim analysis: 
• Study statistician 
• Study programmers and personnel involved in the study data analysis 
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• Other sponsor staff 
The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unblinded information with the rest of the clinical team as appropriate for 
internal decision purposes. For example, unblinded summaries and unblinded individual data 
can be shared with the clinical team for interim analyses. 
Study programmers and other personnel involved in study data analysis (e.g., biomarker expert) 
are allowed to access treatment assignment information for the purpose of conducting interim 
analyses. 
The clinical trial team is allowed to share unblinded results with other sponsor staff 
(e.g., decision boards) as required for internal decision making on the study or the project at 
the time of interim analyses while the study is ongoing. 
Following final database lock all roles may be considered unblinded. 
Table 6-3 
Blinding and unblinding plan 
Role 
Time or Event 
Randomization 
list generated 
Treatment 
allocation & 
dosing 
Safety event 
(single 
subject 
unblinded) 
Interim 
Analysis/ 
dose 
escalation/ 
safety review 
Participants 
B 
B 
UI 
B 
Site Staff 
B 
B 
UI 
B 
Global Clinical Supply 
UI 
UI 
UI 
UI 
Randomization Office 
UI 
UI 
UI 
UI 
Statistician/statistical 
programmer/ data analysts 
(e.g. biomarker, PK) 
B 
UI 
UI 
UI 
Unblinded Sponsor staff, e.g. 
for study treatment re-supply, 
unblinded monitor(s), sample 
analyst(s) 
B 
UI 
UI 
UI 
All other Sponsor staff not 
identified above (i.e. project 
team, management & 
decision boards, support 
functions) 
B 
B 
UI 
UI 
B Complete blinded 
UI Unblinded to individual participant treatment codes 
6.3.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required to in order to treat 
the participant safely. 
Most often, discontinuation from study treatment and knowledge of the possible treatment 
assignments are sufficient to treat a study participant who presents with an emergency 

N o v arti s  
C o nfi d e nti al  
P a g e 4 5  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
c o n diti o n.  E mer ge nc y  treat me nt  c o de  brea ks  are  perf or me d  usi n g  t he  I R T.  W he n  
t he i n vesti gat or c o ntacts t he s yste m t o brea k a treat me nt c o de f or a partici pa nt, he/s he m ust 
pr o vi de t he re q ueste d partici pa nt i de ntif yi n g i nf or mati o n a n d c o nfir m t he necessit y t o brea k 
t he treat me nt  c o de  f or  t he  partici pa nt.  T he  i n vesti gat or  will  t he n  recei ve  details  of  
t he i n vesti gati o nal dr u g treat me nt f or t he s pecifie d partici pa nt a n d a fa x or e mail c o nfir mi n g 
t his i nf or mati o n. T he s yste m will a ut o maticall y i nf or m t he N o vartis  m o nit or f or t he site a n d 
t he st u d y tea m t hat t he c o de has bee n br o ke n. 
It is t he i n vesti gat or’s res p o nsi bilit y t o e ns ure t hat t here is a de pe n da ble pr oce d ure i n place t o 
all o w access t o t he I R T at a n y ti me i n case of e mer ge nc y. T he i n vesti gat or will pr o vi de:  
•  pr ot oc ol n u m ber 
•  partici pa nt n u m ber  
I n a d diti o n, oral a n d writte n i nf or mati o n t o t he partici pa nt m ust be pr o vi de d o n h o w t o c o ntact 
his/ her bac k u p i n cases of e mer ge nc y, or w he n he/s he is u na vaila ble, t o e ns ure t hat u n - bli n di n g 
ca n be perf or me d at a n y ti me.  
As a res ult  of t he e mer ge nc y u n bli n di n g, t he partici pa nt s h o ul d be disc o nti n ue d fr o m t he st u d y 
treat me nt. 
6. 4  
St u d y tr e at m e nt c o m pli a n c e  
T he i n vesti gat or m ust pr o m ote c o m plia nce b y i nstr ucti n g t he partici pa nt t o ta ke t he st u d y 
treat me nt e xactl y as prescri be d a n d b y stati n g t hat c o m plia nce is necessar y f or t he partici pa nt’s 
safet y  a n d  t he  vali dit y  of  t he  st u d y.  T he  partici pa nt  m ust  als o  be  instr ucte d  t o  c o ntact  
t he i n vesti gat or if he/s he is u na ble f or a n y reas o n t o ta ke t he st u d y treat me nt as prescri be d. 
C o m plia nce will be assesse d b y t he i n vesti gat or a n d/ or st u d y pers o n nel at eac h visit usi n g pill 
c o u nts (if a p plica ble) a n d i nf or mati o n pr o vi de d b y t he partici pa nt. T his i nf or mati o n s h o ul d be 
ca pt ure d i n t he s o urce d oc u me nt at eac h visit. All st u d y treat me nt dis pe nse d a n d ret ur ne d m ust 
be rec or de d i n t he Dr u g Acc o u nta bilit y L o g. 
6. 4. 1  
R e c o m m e n d e d tr e at m e nt of a d v er s e e v e nt s  
A Es  re q uiri n g treat me nt  s h o ul d be treate d acc or di n g t o c urre nt sta n dar ds of  care. D ue t o 
t he li mite d cli nical  e x perie nce  wit h  R H H 6 4 6,  t here  is  i ns ufficie nt  i nf or mati o n  t o  pr o vi de  
s pecific rec o m me n dati o ns re gar di n g treat me nt of A Es. A Es i n i n di vi d ual partici pa nts ma y be 
ma na ge d at t he discreti o n of t he i n vesti gat or a n d/ or s u b -i n vesti gat or(s) pr o vi di n g me dical 
o versi g ht. T he  ris k of a c o nse q ue ntial dr u g-dr u g i nteracti o n bet wee n R H H 6 4 6 a n d ot her dr u gs 
use d t o treat a n A E is c o nsi dere d l o w a n d o ut wei g he d b y t he  be nefits of treati n g t he A E. 
 
 
 
 
 If n ecessar y, st u d y treat me nt ma y be te m p oraril y wit h hel d t o ma na ge 
certai n A Es ( Secti o n  6. 5). 
Detail s of me dicati o n(s) a n d/ or ot her i nter ve nti o n(s) use d t o treat A Es m ust be rec or de d i n 
t he s o urce d oc u me nts a n d t he C R F. 
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6. 5  
D o s e m o difi c ati o n  
D o w n war d d ose a dj ust me nt fr o m 
 a n d/ or te m p orar y 
i nterr u pti o ns are per missi ble i n i n di vi d ual partici pa nts if t he partici pa nt is n ot t olerati n g st u d y 
treat me nt or me dicall y re q uires a te m p orar y i nterr u pti o n i n or der to gi ve t he partici pa nt a c ha nce 
t o re mai n i n t he st u d y. A  
 d ose le vel a dj ust me nt (i.e., fr o m  
 m g i n t h ose patie nts 
recei vi n g acti ve treat me nt) ca n be re gar de d as s ufficie ntl y differe nt fr o m a safet y or t olera bilit y 
p oi nt of vie w w hile still p reser vi n g a c ha nce f or efficac y. 
A dj ust me nts or te m p orar y i nterr u pti o ns ma y occ ur at t he discreti o n of t he i n vesti gat or i n 
c o ns ultati o n wit h t he me dical m o nit or w he n t he o nl y alter nati ve w o ul d be disc o nti n uati o n of 
st u d y treat me nt. E xa m ples of e ve nts or sit uati o ns t hat ma y warra nt d ose a dj ust me nt i ncl u de b ut 
are  n ot  li mite d  t o  persiste nt  gastr oi ntesti nal  c o m plai nts  (e. g.,  na usea,  diarr hea),  persiste nt  
la b orat or y a b n or malities, persiste nt ras h, or persiste nt i ncreases i n bl o o d press ure. E xa m ples of 
e ve nts or sit uati o ns t hat ma y warra nt a te m p orar y i nterr u pti o n of st u d y treat me nt i ncl u de b ut 
are  n ot  li mite d  t o  me dical/s ur gical  pr oce d ures  t hat  are  eit her  u ne x pecte d  or  ca n n ot  be  
p ost p o ne d. D ose a dj ust me nts or te m p orar y i nterr u pti o ns are n ot per missi ble f or circ u msta nces 
t hat  w o ul d  n ot  ot her wise warra nt  c o nsi derati o n  of  st u d y  treat me nt  disc o nti n uati o n  
(e. g., relati vel y l o w i nte nsit y, tra nsie nt, ma na gea ble A Es) or e ve nts t hat f ulfil t he criteria f or 
disc o nti n uati o n of st u d y treat me nt ( Secti o n  7. 1). 
A d o w n war d d ose a dj ust me nt s hall persist f or t he re mai n der of t he st u d y (i.e., t he partici pa nt 
s h o ul d n ot res u me t he hi g her d ose). A te m p orar y i nterr u pti o n of st u d y treat me nt ma y be f or n o 
m ore  t ha n  
 of  R H H 6 4 6.  
If t he i nterr u pti o n of st u d y treat me nt is re q uire d f or circ u msta nces u nrelate d t o t he st u d y or 
st u d y treat me nt, t he partici pa nt s h o ul d res u me t he d ose of st u d y treat me nt t hat was bei n g ta ke n 
pri or  t o  t he  i nterr u pti o n.  If  t he  i nterr u pti o n  of  st u d y  treat me nt  is  re q uire d  f or  safet y  or  
t olera bilit y reas o ns p ossi bl y relate d t o t he st u d y treat me nt, t he n t he partici pa nt s h o ul d res u me 
st u d y treat me nt at t he l o wer d ose. 
T he  date  of  t he  d o w n war d  d ose  a dj ust me nt  a n d/ or  t he  dates  of  t he  te m p orar y  treat me nt  
i nterr u pti o n, al o n g wit h t he reas o ns, i ncl u di n g A Es, ot her treat me nts, a n d ot her circ u msta nces 
t hat were rele va nt t o t he decisi o n t o re d uce t he d ose or te m p oraril y i nterr upt st u d y treat me nt 
s h o ul d be d oc u me nte d b y t he site i n t he s o urce d oc u me nts a n d as a p plica ble i n t he electr o nic 
case re p ort f or m (e C R F).  
6. 6  
C o nti n u e d a c c e s s t o st u d y tr e at m e nt aft er t h e e n d of t h e st u d y  
Si nce  t his  is  a n  e x pl orat or y  st u d y,  n o  f urt her  st u d y  treat me nt  will  be  ma de  a vaila ble  t o  
t he partici pa nts after st u d y c o m pleti o n.  
6. 6. 1  
P o st tri al a c c e s s  
N ot a p plica ble. 
C CI
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 4 7  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
6. 7  
Tr e at m e nt of o v er d o s e  
I n t he e ve nt of a c o nfir me d or s us pecte d o ver d ose, t he i n vesti gat or s h o ul d: 
•  C o ntact t he me dical m o nit or i m me diatel y.  
•  E val uate t he partici pa nt t o deter mi ne, i n c o ns ultati o n wit h t he me dical m o nit or, w het her 
st u d y treat me nt s h o ul d be i nterr u pte d or w het her t he d ose s h o ul d be re d uce d. 
•  Cl osel y m o nit or t he partici pa nt f or a n y A E/ S A E a n d la b orat or y a b n or malities at least u ntil 
R H H 6 4 6 ca n n o l o n ger be detecte d s yste micall y (at least  
). Si milar t o a n y ot her 
A E or S A E, o ver d ose- relate d A Es m ust be f oll o we d u ntil its res ol uti o n or u ntil it is j u d ge d 
t o be n ot rec o vere d/ n ot res ol ve d (Secti o n  8. 6). 
•  O btai n a plas ma sa m ple f or P K a nal ysis wit hi n t hree da ys fr o m t he date of t he last d ose of 
st u d y treat me nt if re q ueste d b y t he me dical m o nit or ( deter mi ne d o n a case- b y-case basis). 
•  D oc u me nt t he q ua ntit y of t he e xcess d ose as well as t he d urati o n of t he o ver d ose. 
6. 7. 1  
R e p orti n g of st u d y tr e at m e nt err or s i n cl u di n g mi s u s e/ a b u s e  
St u d y treat me nt err ors are u ni nte nti o nal err ors i n t he prescri bi n g, dis pe nsi n g, a n d a d mi nistrati o n 
of st u d y treat me nt.  
St u d y treat me nt mis use refers t o sit uati o ns w here t he st u d y treat me nt is i nte nti o nall y a n d 
i na p pr o priatel y use d n ot i n acc or da nce wit h t he pr ot oc ol. 
St u d y treat me nt a b use c orres p o n ds t o t he persiste nt or s p ora dic, i nte nti o nal e xcessi ve use of 
st u d y treat me nt, w hic h is acc o m pa nie d b y har mf ul p h ysical or ps yc h ol o gical effects. 
St u d y treat me nt err ors a n d uses o utsi de of w hat is f oresee n i n t he pr ot oc ol, i ncl u di n g mis use or 
a b use, m ust be re p orte d o n t he A E ( or S A E, if t he e ve nt meets t he defi niti o n of a n S A E) C R F. 
6. 8  
C o n c o mit a nt a n d ot h er t h er a p y  
6. 8. 1  
C o n c o mit a nt t h er a p y  
All me dicati o ns, pr oce d ures, a n d si g nifica nt n o n -dr u g t hera pies (i ncl u di n g b ut n ot li mite d t o 
p h ysical t hera p y, diet f or wei g ht l oss, i ns ole we d ges a n d bl o o d tra nsf usi o ns) a d mi nistere d after 
t he partici pa nt was e nr olle d i nt o t he st u d y m ust be rec or de d o n the a p pr o priate e C R Fs.  
Eac h  c o nc o mita nt  dr u g  m ust  be  i n di vi d uall y  assesse d  a gai nst  all  e xcl usi o n  criteria  a n d  
pr o hi bite d me dicati o n. If i n d o u bt, t he i n vesti gat or s h o ul d c o ntact t he N o vartis me dical m o nit or 
bef ore ra n d o mizi n g a partici pa nt or all o wi n g a ne w me dicati o n t o be starte d. If t he partici pa nt 
is alrea d y e nr olle d, c o ntact N o vartis t o deter mi ne if t he partici pa nt s h o ul d c o nti n ue partici pati o n 
i n t he st u d y. 
6. 8. 1. 1  
P er mitt e d c o n c o mit a nt t h er a p y r e q uiri n g c a uti o n a n d/ or a cti o n  
Partici pa nts u n der g oi n g p h ysical or occ u pati o nal t hera p y (e. g., diet f or wei g ht l oss, i ns ole 
we d ges) a n d/ or ta ki n g N S AI Ds, C O X -2 i n hi bit ors, l o w p ote nc y o pi oi ds or A P A P ca n c o nti n ue 
t o d o s o i n t he st u d y as l o n g as t he y are o n a sta ble re gi me n i n t he o pi ni o n of t he i n vesti gat or 
f or at least 4 wee ks pri or t o scree ni n g. Partici pa nts ca n c o nti n ue ta ki n g t hese me dicati o ns d uri n g 
t he trial b ut will nee d t o 
 as 
C CI
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N o v arti s  
C o nfi d e nti al  
P a g e 4 8  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
descri be d i n  Secti o n  6. 8. 2 Pr o hi bite d me dicati o n. I n vesti gat ors are e nc o ura ge d t o mi ni mize 
c ha n ges t o c o nc o mita nt t hera pies i ncl u di n g p h ysical a n d occ u pati o nal t hera pies d uri n g t he 
st u d y u nless c ha n ges are ot her wise s pecificall y i n dicate d f or a n i n di vi d ual partici pa nt. 
I n a d diti o n t o t he a b o ve a n d wit h s pecific res pect t o per mitte d c o nc o mita nt dr u g t hera pies f or 
t he s y m pt o ms of O A, i n vesti gat ors s h o ul d c o nsi der: 
•  T he p ote ntial gastr oi ntesti nal, li ver a n d car di o -re nal t o xicities of N S AI Ds i ncl u di n g 
C O X - 2 i n hi bit ors, w he n a dj u dicati n g A Es or c o nte m plati n g ne w t hera p y. It is 
rec o m me n de d t o i nitiate oral N S AI Ds/ C O X-2 i n hi bit ors at t he l o west effecti ve d ose f or 
t he s h ortest peri o d of ti me wit h a d diti o nal pr otecti ve me dicati o n (e. g. mis o pr ost ol, pr ot o n 
p u m p i n hi bit ors), if j u d ge d necessar y b y t he treati n g p h ysicia n. It is als o a d vise d t hat 
a nee d f or ne w a nal gesic t hera p y i n patie nts w h o re q uire l o w - d ose as piri n or ot her 
a ntic oa g ula nt t hera p y be a d dresse d b y n o n- N S AI D treat me nts or t o pical N S AI Ds, if 
p ossi ble. 
•  T he p ossi ble r ole of aceta mi n o p he n ( paraceta m ol, A P A P) as a ca use or c o ntri b ut or t o 
la b orat or y e vi de nce of p ote ntial he pat ot o xicit y, es peciall y i n patie nts w h o re g ularl y rel y 
o n t otal dail y d oses bet wee n 3 a n d 4 gra ms. 
•  T he p ote ntial i m pact of pai n i n ot her j oi nts or else w here a n d its ma na ge me nt o n t he 
assess me nt of pai n i n t he tar get k nee f or t his st u d y. Cli nical hist ories s h o ul d be ta ke n 
caref ull y w he n t he  pr ot oc ol -s pecifie d assess me nts of pai n i n t he tar get k nee are 
pe rf or me d. 
 
 
(see Secti o n  6. 8. 2 Pr o hi bite d me dicati o n).  
6. 8. 2  
Pr o hi bit e d m e di c ati o n  
Use  of  t he  treat me nts  dis pla ye d  i n  Ta ble  6- 4 are  n ot  all o we d  f or  t he  d urati o n  i n dicate d.  
A n y  acti o ns ta ke n i n i n di vi d ual cases if a pr o hi bite d me dicati o n is ta ke n will be disc usse d a n d 
a gree d bet wee n t he i n vesti gat or a n d s p o ns or. 
T a bl e 6- 4 
Pr o hi bit e d m e di c ati o n  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 4 9  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
6. 8. 3  
R e s c u e m e di ci n e  
N ot a p plica ble. 
7 
Di s c o nti n u ati o n of st u d y tr e at m e nt a n d p arti ci p a nt 
di s c o nti n u ati o n/ wit h dr a w al  
7. 1  
Di s c o nti n u ati o n of st u d y tr e at m e nt  
Disc o nti n uati o n of st u d y treat me nt f or a partici pa nt occ urs w he n st u d y treat me nt is per ma ne ntl y 
st o p pe d f or a n y reas o n ( pri or t o t he pla n ne d c o m pleti o n of st u d y treat me nt a d mi nistrati o n, if 
a n y) a n d ca n be i nitiate d b y eit her t he partici pa nt or t he i n vesti gat or.  
T he i n vesti gat or m ust disc o nti n ue st u d y treat me nt f or a gi ve n partici pa nt if, he/s he belie ves t hat 
c o nti n uati o n w o ul d ne gati vel y i m pact t he partici pa nt's well - bei n g. 
C CI

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Discontinuation from study treatment is required under the following circumstances: 
• Participant decision 
• Pregnancy 
• Following emergency unblinding 
• Diagnosis of non-infectious epididymitis or development of a new scrotal mass (in male 
participants) 
• Hypersensitivity reaction occurs, corresponding to CTCAE grade 2 or higher, including 
any of the following: anaphylaxis, fever, chills, urticaria, dyspnea, headache, myalgia, 
hypotension 
• An AE of severe intensity (corresponding to CTCAE grade 3 or higher) considered 
possibly related to RHH646 treatment  
• Any laboratory abnormalities or other situation, that in the judgment of the investigator, 
taking into consideration the participant’s overall status, might result in a safety risk or 
otherwise prevents the participant from continuing participation in the study 
If a liver or renal event occurs, follow guidelines outlined in Section 10.5 and Section 10.6 
regarding discontinuation of study treatment. If discontinuation from study treatment occurs, 
the investigator should make a reasonable effort to understand the primary reason for 
the participant’s discontinuation from study treatment and record this information. 
Participants who discontinue from study treatment or who decide they do not wish to participate 
in the study further should NOT be considered withdrawn from the study UNLESS 
they withdraw consent (see Section 7.3). Where possible, participants should be asked if 
they agree to return for the EOT and EOS visits indicated in Section 1.3. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by 
the participant. This telephone contact should preferably be done according to the study visit 
schedule. 
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• AEs / SAEs 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
7.2 
Participant discontinuation from the study 
Discontinuation from study is when the participant permanently stops receiving the study 
treatment, and further protocol-required assessments or follow-up, for any reason. 
If the participant agrees, a final evaluation at the time of the participant’s study discontinuation 
should be performed as detailed in Section 1.3. 

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7.3 
Withdrawal of informed consent and exercise of participants’ 
data privacy rights 
Withdrawal of consent/opposition to use of data and/or biological samples occurs in countries 
where the legal justification to collect and process the data is consent and when a participant: 
• Explicitly requests to stop use of their data 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be as per local regulations (e.g., in writing) and recorded in the source 
documentation. 
Withdrawal of consent impacts ability to further contact the participant, collect follow-up data 
(e.g., to respond to data queries) and potentially other country-specific restrictions. It is 
therefore very important to ensure accurate recording of withdrawal vs. discontinuation based 
on the protocol definitions of these terms. 
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw 
their consent/exercise data privacy rights and record this information. The investigator shall 
clearly document if the participant has withdrawn his/her consent for the use of data in addition 
to a study discontinuation. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 
If the participant agrees, a final evaluation should be made at the time of the participant's 
withdrawal of consent/exercise of data privacy rights, as detailed in Section 1.3. 
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding ICF. 
7.4 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits or fail to 
respond to any site attempts to contact them without stating an intention to discontinue from 
study treatment or discontinue from study or withdraw consent (or exercise other participants’ 
data privacy rights), the investigator must show "due diligence" by documenting in the source 
documents steps taken to contact the participant, e.g. dates of telephone calls, registered letters, 
etc. A participant should not be considered as lost to follow-up until due diligence has been 
completed or until EOS. 

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7.5 
Study stopping rules 
The study will be stopped and no further dosing and/or new recruitment will occur pending full 
safety review, if any of the following criteria are met: 
• Any death or life-threatening event (CTCAE Grade 4 or higher) considered possibly 
related to RHH646 treatment; 
• Two or more participants experience a similar SAE (other than death or life-threatening 
events) considered possibly related to the study treatment; 
• Two or more participants are diagnosed with non-infectious epididymitis or develop a new 
scrotal mass (detected by palpation or ultrasound) while receiving RHH646; 
• Two or more participants experience a similar AE which was assessed as CTCAE grade 3 
or higher in intensity and are considered as possibly related to the study treatment; 
• Novartis considers that the number and/or severity of AEs, abnormal safety monitoring 
tests, or abnormal laboratory findings justify putting the study on hold. 
The study may resume following the safety review if the investigator and Novartis agree it is 
safe to proceed. Dependent on regional guidance, any restart following a temporary hold due to 
stopping rules being met will require prior submission and approval of a substantial CTA 
amendment to the competent authorities. 
7.6 
Early study termination by the Sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination (but not limited to): 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study treatment development 
In taking the decision to terminate, Novartis will always consider participant welfare and safety. 
Should early termination be necessary, participants must be seen as soon as possible and treated 
as a participant who discontinued from study treatment. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the participant’s interests. The investigator or Novartis depending on local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
8 
Study Assessments and Procedures 
Study procedures and their timing are summarized in Section 1.3. Protocol waivers or 
exemptions are not allowed. Adherence to the study design requirements, including those 
specified in Section 1.3, is essential and required for study conduct. 
Immediate safety concerns should be discussed with Novartis upon occurrence or awareness to 
determine if the participant should continue or discontinue study treatment. 

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Results that could unblind the study will not be reported to investigative sites or other blinded 
personnel until the study has been unblinded. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues with 
the samples. 
8.1 
Screening 
8.1.1 
Eligibility screening 
This section describes assessments which are performed at screening in order to evaluate 
a participant's eligibility. Eligibility assessments which are performed at screening to describe 
the population or also later during the study to evaluate efficacy, safety, or other outcomes, are 
described in separate sections. 
The screening assessments should be completed as per Section 1.3, starting with informed 
consents. Assessments should be performed from the less invasive/burdensome to the more 
invasive/burdensome assessments for the participant. 
In the case where a safety laboratory assessment at screening meets any of the exclusion criteria 
but where the condition is expected to be transient and resolved prior to first dose, or if 
a laboratory error is suspected, the assessment may be repeated once prior to randomization. 
If the repeat value still meets the exclusion criterion, the patient does not qualify for the study. 
8.1.1.1 
Pre-screening 
Prior to the Screening visit, optional study specific pre-screening assessments may be carried 
out, including but not limited to collection of medical history, concomitant medication, height 
and weight, X-ray (Section 8.1.1.4) and knee physical examination (e.g., assessment of knee 
OA laterality) (Section 8.4.1), to assess participant eligibility for inclusion. Prior to any study 
specific assessments being carried out, the pre-screening ICF must be signed by the participant. 
Data from the pre-screening will not be entered into the clinical database, unless the participant 
either experiences an SAE causally related to pre-screening study procedures (X-ray, knee 
examination), in which case the SAE will be collected (see Section 8.6.3), or the participant 
signs the main consent and is screened within 3 months, in which case the pre-screening X-ray 
can replace the screening X-ray. All other data related to pre-screening will only be recorded in 
source documentation. 
8.1.1.2 
Widespread Pain Index (WPI) 
WPI will be assessed at Screening only, to exclude participants with substantial pain due to 
unknown illness (Wolfe et al 2016). 
8.1.1.3 
Hepatitis screen, HIV screen 
All participants will be screened for HBsAg or HBcAg (per standard local practice). Screening 
for Hepatitis C will be based in HCV antibodies and if positive, HCV RNA levels should be 
determined. 

N o v arti s  
C o nfi d e nti al  
P a g e 5 4  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
E val uati o n f or HI V ser o p ositi vit y will be perf or me d, a n d, if p ositi ve, c o nfir mati o n b y a  sec o n d 
tec h ni q ue a vaila ble at t he la b orat or y site, e. g., E LI S A, Wester n bl ot. A p pr o priate c o u nseli n g 
will  be  ma de  a vaila ble  b y  t he  i n vesti gat or  i n  t he  e ve nt  of  a  p ositi ve  c o nfir mat or y  test.  
N otificati o n of state a n d fe deral a ut h orities, as re q uire d b y la w, will be t he res p o nsi bilit y of 
t he i n vesti gat or. Res ults will be rec or de d i n s o urce data o nl y. 
8. 1. 1. 4  
Al c o h ol t e st, dr u g s cr e e n, uri n e c oti ni n e  
Partici pa nts will be teste d f or s u bsta nces of a b use (e. g., alc o h ol, a m p heta mi nes, bar bit urates, 
be nz o diaze pi nes,  ca n na bi n oi ds,  c ocai ne,  a n d  o piates).  A  p ositi ve  res ult  f or  alc o h ol  a n d/ or  
ca n na bi n oi ds  use  ma y  n ot  be  e xcl usi o nar y.  H o we ver,  c o ns u m pti o n  ha bits  f or  partici pa nts  
s h o ul d be clarifie d b y t he i n vesti gat or. C oti ni ne i n uri ne will n ot be a nal yze d at scree ni n g. 
H o we ver, t he i n vesti gat or s h o ul d clarif y t o bacc o use ha bits f or partici pa nts w h o use t o bacc o as 
per Secti o n  5. 2. Res ults will be rec or de d i n s o urce data o nl y. 
8. 2  
P arti ci p a nt d e m o gr a p hi c s/ ot h er b a s eli n e c h ar a ct eri sti c s  
Partici pa nt de m o gra p hics: f ull date ( o nl y if re q uire d a n d per mitte d) or year of birt h or a ge, 
bi ol o gic  se x,  race/ pre d o mi na nt  et h nicit y  (if  per mitte d  per  l ocal  re g ulati o ns)  a n d  rele va nt  
me dical hist or y/c urre nt me dical c o n diti o ns ( u ntil date of si g nat ure of mai n i nf or me d c o nse nt) 
will be rec or de d i n t he e C R F. Partici pa nt race/et h nicit y data are c ollecte d a n d a nal yze d t o 
i de ntif y a n y differe nces i n t he safet y a n d/ or efficac y pr ofile of t he treat me nt d ue t o t hese 
c haracteristics.  I n  a d diti o n,  t hese  data  are  necessar y  t o  assess  t he  di versit y  of  t he  st u d y  
p o p ulati o n as re q uire d b y healt h a ut h orities. 
All prescri pti o n me dicati o ns, o ver -t he-c o u nter dr u gs a n d si g nifica nt n o n -dr u g t hera pies pri or t o 
t he start of t he st u d y m ust be d oc u me nte d. See t he pr ot oc ol Secti o n  6. 8. 1 C o nc o mita nt T hera p y 
f or f urt her details o n w hat i nf or mati o n m ust be rec or de d o n t he a p pr o priate pa ge of t he e C R F. 
S m o ki n g a n d/ or nic oti ne use hist ories (e. g., f or mer user, c urre nt user, ne ver use d) a n d esti mates 
of c urre nt or past use, if a p plica ble, will als o be c ollecte d.  
8. 3  
Effi c a c y a s s e s s m e nt s  
Pla n ne d ti me p oi nts f or all efficac y assess me nts are pr o vi de d i n  Secti o n  1. 3 . 
8. 3. 1  
K n e e M RI  
M RI will be o btai ne d fr o m t he tar get k nee. S pecific M RI p ulse se q ue nces will be use d t o 
q ua ntif y  c ha n ges i n v ol u me a n d t hic k ness of cartila ge; 
 
 
 
 
T he  i n dex re gi o n is defi ne d as t he u ni o n of t he fe m oral me dial a nteri or ( F M A), ce ntral ( F M C) 
a n d p ost eri or ( F M P) cartila ge s u b -re gi o ns i n t he k nee. 
 
 
 
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 5  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
 
 
 
 
 
 
 
I m a g e c ol l e cti o n 
M RI ac q uisiti o n will be perf or me d b y a trai ne d M RI pr ofessi o nal at t he i ma gi n g facilit y. 
I ma gi n g facilities f or t he st u d y s h o ul d be trai ne d a n d q ualifie d b y t he ce ntral i ma gi n g la b orat or y 
pri or t o t he first i ma ge is ta ke n f or t he st u d y assess me nt. T he M RI ra di ol o gist will be bli n de d 
t o t he treat me nt recei ve d b y t he partici pa nt. All partici pa nts will be i ma ge d usi n g a cli nical M RI 
3 T sca n ner a n d a m ulti -c ha n nel k nee c oil. F or eac h M RI sessi o n, i ma ges will be ac q uire d as 
descri be d  i n  t he  M RI  Partici pa nt  Sca n n i n g  G ui de  t o  assess  o ver  t he  c o urse  of  t he st u d y 
t he e xte nt of cartila ge l oss or re ge nerati o n i n t he i n de x re gi o n as well as ot her p ote ntiall y 
rele va nt k nee O A str uct ures as me nti o ne d a b o ve. 
M R i ma ges will be ac q uire d at t he i ma gi n g site(s) a n d se nt f or i n de pe n de nt ce ntral re vie w b y 
t he i ma gi n g c ore la b orat ories. T he re vie wers will be bli n de d t o t he treat me nt recei ve d b y 
t he partici pa nt. M RI a nal ysis res ults will n ot be s hare d wit h t he i n vesti gat ors t o mai ntai n 
t he bli n d. 
If t he M RI q ualit y d oes n ot all o w ce ntral rea der a nal ysis, t he M RI ac q uisiti o n m ust be re peate d 
as s o o n as p ossi ble.  
I m a g e pr o c e s si n g 
T he i ma ge a nal ysis will be perf or me d ce ntrall y, as defi ne d i n t he I n de pe n de nt Re vie w C harter 
f or M RI, t o assess c ha n ges i n cartila ge v ol u me, t hic k ness, T 2 a n d te xt ure b ot h i n t he i n de x 
re gi o n a n d t he rest of t he j oi nt as well as c ha n ges i n ot her k nee str uct ures as descri be d a b o ve. 
Se g me ntati o n of k nee artic ular cartila ge will be perf or me d f or t he meas ure me nt of cartila ge 
v ol u me a n d t hic k ness b y usi n g a C E mar ke d a n d F D A a p pr o ve d ( 5 1 0 ( k) n u m ber K 2 3 1 3 5 1) 
a ut o mate d  se g me ntati o n  s oft ware  ( C h o n dral  Q ua nt,  Sie me ns,  Erla n ge n,  Ger ma n y).  T he  
s oft ware all o ws r o b ust a ut o mate d se g me ntati o n of t he fe m oral, ti bial, a n d patellar cartila ge as 
well as t he Re gi o n - of-I nterest a nal ysis. It uses 3 D acti ve s ha pe m o dels, t he e xtracti o n of t he 
e x pecte d b o ne – cartila ge i nterface, a n d cartila ge se g me ntati o n us i n g a gra p h-base d met h o d. As 
a res ult, t he c o m plete set of para meters is pr o vi de d ( v ol u metr y a n d descri pti ve statistics of 
q ua ntitati ve M R para meters). T hese i ncl u de v ol u mes (i n milliliters) a n d cartila ge t hic k ness (i n 
milli meters) se paratel y  f or  2 1  re gi o n s  (fe m ur:  me dial  p osteri or F M P,  me dial  ce ntral-F M C, 
me dial a nteri or -F M A, tr oc hlea me dial -F T M, tr oc hlea ce ntral F T C, tr oc hlea lateral -F T C, lateral 
p osteri or- F L P,  lateral  ce ntral -F L C  a n d  lateral  a nteri or -F L A;  lateral  p osteri or T L P,  lateral  
ce ntral -T L C,  lateral  a nteri or -T L A,  me dial  p osteri or -T P M,  me dial  a nteri or T M A;  lateral  
i nferi or-P LI, lateral ce ntral -P L C, lateral s u peri or -P L S, me dial i nferi or P MI, me dial ce ntral -
P M C, me dial s u peri or -P M S). T his defi niti o n of t he s u bfiel ds is base d o n a m o difie d I C R S sc ore 
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 6  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
as p u blis he d bef ore  (S ur o wiec  et al 2 0 1 4). T his s u b di visi o n of t he k nee j oi nt is m ore acc urate 
t ha n t he s u b di visi o n pr o vi de d b y t he M O A K S classificati o n. T he a ut o mate d s oft ware will 
calc ulate cartila ge v ol u me a n d cartila ge t hic k ness wit hi n eac h of t hese s u bfiel ds.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
I nci de ntal  fi n di n gs  are  be y o n d  t he  sc o pe  of  ce ntral  i ma gi n g  ve n d or.  If  a n  
i n vesti gat or/ra di ol o gist rec o g nizes a n y i nci de ntal fi n di n g i n t he i ma ges d uri n g t he c o urse of 
c o n d ucti n g t he cli nical trial, t he i n vesti gat or s h o ul d f oll o w u p as part of his/ her d ut y  of care t o 
e ns ure t he safet y a n d well -bei n g of t he partici pa nt, as well as c o m plia nce wit h l ocal et hical 
re g ulati o ns. 
T he c o de d me dical i ma ges will be use d pri maril y f or a nal ysis as descri be d i n t his  pr ot oc ol; 
h o we ver, t he i ma ges ma y als o be use d f or t he de vel o p me nt a n d e val uati o n of ne w a nal ysis 
met h o ds relate d t o t he area of researc h t hat t his st u d y c o vers.  
8. 3. 2  
K n e e X -r a y 
A bilateral p osteri or -a nteri or ( P A) fi xe d fle xi o n k nee X -ra y will be perf or me d t o c o nfir m 
partici pa nt eli gi bilit y 
 t o e val uate t he K & L gra de a n d me dial 
J S N usi n g a n o nf l u or o, sta n dar dize d a n d q ualit y-c o ntr olle d met h o d, as descri be d i n t he I ma gi n g 
Ma n ual.  I n  a d diti o n,  a  bilateral  wei g ht  beari n g  a nteri or -p osteri or  ( A P)  f ull  le n gt h  l o wer  
e xtre mit y X-ra y will be ac q uire d f or t he malali g n me nt eli gi bilit y criteri o n. If a site d oes n ot 
ha ve a l o n g cassette, a bilateral A P k nees wit h c olli mati o n t o i ncl u de as m uc h of t he fe m urs a n d 
ti bias as p ossi ble ma y be ac q uire d i nstea d. T he l ocal ra di ol o gist a n d/ or i n vesti gat or s h o ul d 
re vie w t he i ma ges f or deter mi nati o n of t he tar get k nee a n d i nci de ntal fi n di n gs rele va nt t o t he 
partici pa nt's safet y. T hereafter, a ce ntral rea der will a nal yze t he i ma ges as descri be d i n t he 
I n de pe n de nt Re vie w C harter f or X-ra y. 
If  a  partici pa nt  has  bee n  scree ne d  f or  a  si milar  trial  wit h  t he  sa me  c o n ve nti o nal  X-ra y 
pr ojecti o ns, t he i ma ges ac q uire d d uri n g scree ni n g ca n be use d wit hi n 6 m o nt hs of t he X -ra y 
date.  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 5 7  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
T he X -ra y perf or me d t o c o nfir m partici pa nt eli gi bilit y ma y be re peate d o nce, if t he i ma ge 
q ualit y d oes n ot all o w deter mi nati o n of eli gi bilit y b y t he ce ntral rea der. If t he re peat X -ra y 
c o nfir ms i neli gi bilit y, a t hir d X -ra y is n ot all o we d, a n d t he partici pant will be e xcl u de d fr o m 
t he st u d y. 
8. 3. 3  
A p pr o pri at e n e s s of effi c a c y a s s e s s m e nt s  
I ma gi n g tec h ni q ues i ncl u di n g X-ra ys a n d M RI are sta n dar d meas ures use d f or assessi n g j oi nt 
str uct ure i n partici pa nts wit h O A (Ha yas hi  et al 2 0 1 9). 
T he use of a n a ut o mate d se g me ntati o n s oft ware will ma ke it p ossi ble t o o verc o me t he i n here nt 
li mitati o ns in t he ma n ual se g me ntati o n of M R i ma ges, i.e., a ti me -c o ns u mi n g pr ocess, p ossi ble 
meas ure me nt i nacc uracies relate d t o t he s u bjecti vit y of t he ra di ol o gi st a n d i nc o m plete k nee 
c o vera ge.
 
 
 
8. 4  
S af et y a s s e s s m e nt s  
Safet y assess me nts are s pecifie d bel o w wit h  Secti o n  1. 3 detaili n g w he n eac h assess me nt is t o 
be perf or me d.  
F or details o n A E c ollecti o n a n d re p orti n g, refer t o Secti o n  8. 6 . 
As per  Secti o n  4. 5, d uri n g a p u blic healt h e mer ge nc y as declare d b y l ocal or re gi o nal a ut h orities 
i.e., pa n de mic, e pi de mic or nat ural disaster, t hat li mits or pre ve nts o n-site st u d y visits, re g ular 
p h o ne or virt ual calls ca n occ ur (e ver y 4 wee ks or m ore fre q ue ntl y if nee de d ) f or safet y 
m o nit ori n g a n d disc ussi o n of t he partici pa nt´s healt h stat us u ntil it is safe f or t he partici pa nt t o 
visit t he site a gai n.  
8. 4. 1  
P h y si c al e x a mi n ati o n s  
A c o m plete or a s h ort p h ysical e xa mi nati o n will be perf or me d at eac h visit.  
A c o m plete p h ysical e xa mi nati o n will i ncl u de t he e xa mi nati o n of ge neral a p peara nce, s ki n, 
nec k (i ncl u di n g t h yr oi d), e yes, ears, n ose, t hr oat, l u n gs, heart, a b d o me n, bac k, l y m p h n o des, 
e xtre mities,  vasc ular,  ne ur ol o gical  a n d  testic ular/e xter nal  ge nitalia  e x a ms  (Secti o n  8. 4. 6). 
If i n dicate d base d o n me dical hist or y a n d/ or s y m pt o ms, rectal, breast, a n d pel vic e xa ms will be 
perf or me d. I n a d diti o n, a caref ul e xa mi nati o n of t he tar get k nee will be perf or me d b y assessi n g 
re d ness, war mt h, s welli n g, pai n, ra n ge of m oti o n, sta bilit y, a n d b ul ge si g n, cre pit us, fle xi o n 
c o ntract ure, var us/ val g us la xit y, a nter o -p ost la xit y, ma xi m u m e xte nsi o n, a n d ma xi m u m fle xi o n 
s h o ul d be rec or de d. 
A s h ort p h ysical e xa m will i ncl u de t he e xa mi nati o n of ge neral a p peara nce as well as tar get k nee 
a n d s y m pt o m- orie nte d e xa mi nati o n. 
Hei g ht i n ce nti meters (c m) a n d b o d y wei g ht (t o t he nearest 0. 1 kil o gra m ( k g) wit h o ut s h oes) 
will be meas ure d as s pecifie d i n t he  Secti o n  1. 3. B o d y wei g ht s hall be meas ure d i n t he sa me 
c o n diti o n (e. g., cl ot he d or u ncl ot he d weari n g a cli nic g o w n) t hr o u g h o ut t he st u d y. 
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BMI will be calculated using the following formula (rounding to the nearest tenth): 
BMI = Body weight (kg) / [Height (m)]2 
The Screening visit height measurement will be used for BMI calculations throughout the study. 
Investigators should pay special attention to clinical signs related to previous serious illnesses. 
Information for all physical examinations must be included in the source documentation at 
the study site. Clinically relevant findings that are present prior to signing informed consent 
must be recorded on the appropriate CRF that captures medical history. Significant findings 
made after signing informed consent which meet the definition of an AE must be recorded as 
an AE. 
8.4.2 
Vital signs 
Vital signs will include the collection of body temperature (recorded in °C), blood pressure (BP) 
and pulse measurements. The method of measurement of body temperature (e.g., oral, otic, 
transdermal) shall be recorded in the source documents and the eCRF. The method of 
measurement shall remain the same throughout the study if possible. 
After the participant has been sitting for 3 minutes, with back supported and both feet placed 
on the floor, systolic and diastolic BP will be measured using an automated validated device, 
e.g., OMRON with an appropriately sized cuff. In case the cuff sizes available are not large 
enough for the participant's arm circumference, a sphygmomanometer with an appropriately 
sized cuff may be used. 
8.4.3 
Electrocardiograms 
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable baseline. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, blood sampling, and any remaining assessments for that visit 
(Figure 8-1). 
Figure 8-1 
Timing of study procedures 
 
The Fridericia QT correction formula (QTcF) must be used for clinical decisions, e.g., at 
the Screening and Baseline visits to assess eligibility. The investigator must calculate QTcF if 
it is not auto-calculated by the ECG machine. 
Single 12 lead ECGs will be locally collected and evaluated. Interpretation of the tracing must 
be made by a qualified physician and documented on the appropriate CRF. Each ECG tracing 
should be labeled with the study number, participant initials (where regulations permit), 
participant number, date, and kept in the source documents at the study site. 

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Clinically significant abnormalities present at screening should be reported on the appropriate 
CRF. Clinically significant findings must be discussed with Novartis prior to enrolling the 
participant in the study. New or worsened clinically significant findings occurring after 
informed consent must be recorded as AEs. 
The original ECGs on non-heat-sensitive paper or a certified copy on non-heat sensitive paper, 
appropriately signed, must be archived at the study site. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. For any ECGs with participant safety concerns, 
two additional ECGs must be performed to confirm the safety finding. ECG safety monitoring, 
or a review process, should be in place for clinically significant ECG findings at baseline before 
administration of study treatment and during the study. 
If an ECG abnormality is suspected to being related to potential ECG-altering 
activities/beverages, ECG should be repeated under conditions that exclude potentially 
interfering factors (such as smoking, consuming alcohol and methylxanthine-containing 
beverages [i.e., coffee, tea, soda, chocolate] citrus-containing fruits or beverages, and tonic 
water). 
Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or AEs as appropriate. 
8.4.4 
Clinical safety laboratory tests 
A central laboratory will be used for analysis of all safety specimens collected. Details on 
the collection, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the central Laboratory Manual. 
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or AEs as appropriate. All abnormal lab results must be evaluated for criteria 
defining an AE and reported as such if the criteria are met. For those lab AEs, repeated 
evaluations are mandatory until normalization of the result(s) or until the result is no longer 
considered to be clinically significant. 
In all cases, the investigator must document in the source documents, the clinical considerations 
(i.e., result was/was not clinically significant and/or medically relevant) in allowing or 
disallowing the participant to continue in the study. 
As per Section 4.5, during a public health emergency as declared by local or regional 
authorities' i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, if participants cannot visit the site for protocol-specified safety lab assessments, 
an alternative lab (local) collection site may be used. 
Urinalysis 
A midstream urine sample (approx. 30 mL) will be obtained, in order to avoid contamination 
with epithelial cells and sediments and to allow proper assessments. 

N o v arti s  
C o nfi d e nti al  
P a g e 6 0  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
T a bl e 8- 1 
L a b or at or y e v al u ati o n s  
T e st C at e g or y  
T e st N a m e  
H e m at ol o g y  
Er yt hr o c yt e M e a n C or p u s c ul ar H e m o gl o bi n, Er yt hr o c yt e M e a n C or p u s c ul ar 
H G B C o n c e ntr ati o n, Er yt hr o c yt e M e a n C or p u s c ul ar V ol u m e, Er yt hr o c yt e 
C ell M or p h ol o g y, Er yt hr o c yt e s, H e m at o crit, H e m o gl o bi n, L e u k o c yt e s, 
Pl at el et s, Diff er e nti al B a s o p hil s, E o si n o p hil s, L y m p h o c yt e s, M o n o c yt e s, 
N e utr o p hil s, B a n d s, Ot h er ( a b s ol ut e v al u e pr ef err e d, % s ar e a c c e pt a bl e)  
C h e mi str y  
Al b u mi n, Al k ali n e p h o s p h at a s e ( A L P), A L T, A m yl a s e, A S T, Bi c ar b o n at e, 
C al ci u m, C hl ori d e, Cr e ati n e ki n a s e ( C K), Cr e ati ni n e, Dir e ct Bilir u bi n, 
G a m m a -gl ut a m yl -tr a n sf er a s e ( G G T), N o n-f a sti n g a n d F a sti n g Gl u c o s e1 , 
H D L C h ol e st er ol, I n dir e ct Bilir u bi n, L a ct at e d e h y dr o g e n a s e ( L D H), L D L 
C h ol e st er ol, Li p a s e, M a g n e si u m, P h o s p h at e, P ot a s si u m, S o di u m, T ot al 
Bilir u bi n, T ot al C h ol e st er ol, T ot al Pr ot ei n, Tri gl y c eri d e s, Ur e a Nitr o g e n or 
Ur e a, Uri c A ci d  
T h e c e ntr al l a b will u s e t h e C K D -E PI Cr e ati ni n e E q u ati o n ( 2 0 2 1) t o e sti m at e 
G F R.  
Uri n al y si s  
Mi cr o s c o pi c P a n el ( Er yt hr o c yt e s, L e u k o c yt e s, C a st s, Cr y st al s, B a ct eri a, 
E pit h eli al c ell s)  
M a cr o s c o pi c P a n el ( Di p sti c k) ( C ol or, Bilir u bi n, O c c ult Bl o o d, M a cr o s c o pi c 
Bl o o d, Gl u c o s e, K et o n e s, L e u k o c yt e s e st er a s e, Nitrit e, p H, Pr ot ei n, S p e cifi c 
Gr a vit y, Ur o bil i n o g e n) 
C o a g ul ati o n  
Pr ot hr o m bi n ti m e ( P T), I nt er n ati o n al n or m ali z e d r ati o (I N R), A cti v at e d p arti al 
t hr o m b o pl a sti n ti m e ( A P T T) 
T h yr oi d  
T h yr otr o pi n, T h yr o xi n e, Fr e e  
H e p atiti s m ar k er s  
H B s A g ( or H B c A g), H C V A nti b o d y, H e p atiti s C Vir u s R N A  
Li v er E v e nt T e sti n g 
a n d Li v er F oll o w -U p 
T e sti n g  
Al b u mi n, A L P, A L T, A S T, C K, G G T, G L D H, I N R, P T, a n d T ot al Bilir u bi n 
( T BI L). T e st f or h e m ol y si s ( h a pt o gl o bi n, r eti c ul o c yt e s, u n c o nj u g at e d 
[i n dir e ct] bilir u bi n). 
T h e s e t e st s ar e i n a d diti o n t o r o uti n e t e sti n g, t o b e p erf or m e d o nl y i n f oll o w -
u p t o s af et y e v e nt s w h e n i n di c at e d i n S e cti o n 1 0. 5  Li v er s af et y m o nit ori n g  
R e n al f oll o w -u p  
Uri n e Al b u mi n a n d Al b u mi n (f or Al b u mi n: cr e ati ni n e r ati o ( A C R)), S er u m 
Cr e ati ni n e. R e p e at st a n d ar d c h e mi str y t e sti n g a n d st a n d ar d uri n al y si s 
( Mi cr o s c o pi c P a n el ( C a st s, Cr y st al s, B a ct eri a, E pit h eli al c ell s, Er yt hr o c yt e s, 
L e u k o c yt e s.) a n d M a cr o s c o pi c p a n el ( Di p sti c k) ( C ol or, Bilir u bi n, Gl u c o s e, 
K et o n e s, L e u k o c yt e s e st er a s e, M a cr o s c o pi c Bl o o d, Nitrit e O c c ult Bl o o d, p H, 
Pr ot ei n, S p e cifi c Gr a vit y, Ur o bili n o g e n))  
T h e s e t e st s ar e i n a d diti o n t o r o uti n e t e sti n g, t o b e p erf or m e d o nl y i n f oll o w -
u p t o s af et y e v e nt s w h e n i n di c at e d i n S e cti o n 1 0. 6 , R e n al s af et y m o nit ori n g 
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Test Category 
Test Name 
Pregnancy Test and 
Assessments of 
Fertility 
Serum pregnancy test 
Urine pregnancy test 
Confirmatory serum pregnancy required in case of positive urine pregnancy 
test 
Follicle Stimulating Hormone, Luteinizing Hormone 
Refer to Section 8.4.5 Pregnancy testing. 
Inclusion/Exclusion 
For inclusion or exclusion criteria testing not already included above, please 
refer to Section 5.1 and Section 5.2. 
1 Fasting glucose is required at Baseline, Week 26 and EoS visits only. Non-fasting glucose will be 
collected at all other visits, see Table 1-1. 
8.4.5 
Pregnancy testing 
Pregnancy testing 
All women of child-bearing potential will have pregnancy testing. Additional pregnancy testing 
might be performed if requested by local requirements. In EEA women of child-bearing 
potential are excluded from the study. 
A central laboratory will be used for analysis of the serum pregnancy tests collected. Details on 
the collection, shipment of samples and reporting of results by the central laboratory are 
provided to investigators in the central Laboratory Manual. In addition, participants will be 
provided with urine pregnancy test kits at Week 26 and 38 to use at home at Weeks 30, 34, 43, 
and 47. The participant will be instructed to report the results to the site during the scheduled 
safety follow-up phone visits. The date and the result of the home testing will be captured in 
source documents only. Any positive urine pregnancy test should be confirmed with a serum 
pregnancy test. 
As per Section 4.5, during a public health emergency as declared by local or regional 
authorities' i.e., pandemic, epidemic or natural disaster, that limits or prevents on-site study 
visits, if participants cannot visit the site to have serum pregnancy tests, urine pregnancy test 
kits may be used. Relevant participants can perform the urine pregnancy test at home and report 
the result to the site. It is important that participants are instructed to perform the urine 
pregnancy test first and only if the test result is negative proceed with the administration of 
the study treatment. A communication process should be established with the participant so that 
the site is informed and can verify the pregnancy test results (e.g., following country specific 
measures). 
Assessments of fertility 
A woman is considered of childbearing potential from menarche and until becoming post 
menopausal unless permanently sterile. Permanent sterilization methods include hysterectomy, 
bilateral salpingectomy and bilateral oophorectomy. Medical documentation of permanent 
method of sterilization must be retained as source documents. In the case of oophorectomy 
alone, only when the reproductive status of the woman has been confirmed by follow-up 
hormone level assessment is she considered to be not of child-bearing potential. 

N o v arti s  
C o nfi d e nti al  
P a g e 6 2  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
A p ost me n o pa usal state is defi ne d as n o me nses f or 1 2 m o nt hs wit h o ut a n alter nati ve me dical 
ca use a n d a n a p pr o priate cli nical pr ofile.  
I n  a bse nce  of  t he  me dical  d oc u me ntati o n  c o nfir mi n g  per ma ne nt  sterilizati o n,  or  if  
t he p ost-me n o pa usal stat us is n ot clear, t he i n vesti gat or s h o ul d use his me dical j u d g me nt t o 
a p pr o priatel y e val uate t he fertilit y state of t he w o ma n a n d d oc u me nt it i n t he s o urce d oc u me nt.  
8. 4. 6  
Ot h er s af et y e v al u ati o n s  
Testic ular ultras o u n ds will be perf or me d at scree ni n g a n d at t he e n d -of -treat me nt e val uati o n. 
I nf or mati o n f or t he testic ular ultras o u n ds m ust be i ncl u de d i n t he s o urce d oc u me ntati o n at 
t he st u d y site a n d i n t he e C R F. Cli nicall y rele va nt fi n di n gs t hat are prese nt pri or t o si g ni n g 
i nf or me d c o nse nt m ust be rec or de d o n t he a p pr o priate C R F t hat ca pt ures me dical hist or y. 
Si g nifica nt fi n di n gs ma de after si g ni n g i nf or me d c o nse nt w hic h meet t he defi niti o n of a n  A E 
m ust be rec or de d as a n A E.  
E xter nal ge nitalia e xa mi nati o ns of male partici pa nts will be perf or me d a p pr o xi matel y e ver y 
t hree  m o nt hs  d uri n g  st u d y  treat me nt  (Secti o n  8. 4. 1).  If  t here  are  fi n di n gs  o n  t he e xter nal 
ge nitalia e xa mi nati o ns of male partici pa nts or ne w c o m plai nts of testic ular pai n, te n der ness, 
re d ness, i nfla m mati o n, pai nf ul uri nati o n or ejac ulati o n, uri nar y fre q ue nc y, a b n or mal disc har ge 
fr o m t he pe nis, bl o o d i n t he se me n, or l o wer a b d o mi nal pai n or disc o mf ort, t he st u d y partici pa nt 
s h o ul d be referre d t o a ur ol o gist t o c o nfir m t he dia g n osis a n d treat me nt pla n i n c o ns ultati o n 
wit h t he pri nci pal i n vesti gat or a n d t he me dical m o nit or.  
If t here are ne w, n o n-s pecific c o m plai nts fr o m fe male partici pa nts of l o wer a b d o mi nal pai n or 
disc o mf ort, pel vic  pai n or  f ull ness, pai n d uri n g va gi nal  i nterc o urse, uri nar y fre q ue nc y, or  
c ha n ge i n b o wel ha bits, t he st u d y partici pa nt ma y be referre d t o a g y nec ol o gist t o c o nfir m 
t he dia g n osis a n d treat me nt pla n i n c o ns ultati o n wit h t he pri nci pal i n vesti gat or a n d t he me dical 
m o nit or.  
All A Es ( dia g n oses), treat me nts a n d ot her c o urses of acti o n, a n d o utc o mes s hall be d oc u me nte d.  
8. 4. 7  
A p pr o pri at e n e s s of s af et y m e a s ur e m e nt s  
T he safet y assess me nts a n d m o nit ori n g pla n are a p pr o priate f or t he patie nt p o p ulati o n a n d 
t he p ote ntial ris ks of t he st u d y treat me nt as i nf or me d b y t he n o n -cli nical safet y st u dies a n d 
t he li mite d cli nical e x perie nce wit h t he st u d y treat me nt t o date. 
8. 5  
A d diti o n al a s s e s s m e nt s  
8. 5. 1  
 
C CI
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N o v arti s  
C o nfi d e nti al  
P a g e 6 3  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
8. 5. 1. 1  
 
8. 5. 1. 1. 1  
 
8. 5. 1. 1. 2  
 
8. 5. 1. 2  
 
C CI
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C CI
C CI
C CI
C CI
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N o v arti s  
C o nfi d e nti al  
P a g e 6 4  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
8. 5. 1. 2. 1   
 
8. 5. 1. 2. 2  
 
8. 5. 2  
Ot h er a s s e s s m e nt s  
8. 5. 2. 1  
 
8. 6  
A d v er s e e v e nt s ( A E s), s eri o u s a d v er s e e v e nt s ( S A E s), a n d ot h er 
s af et y r e p orti n g  
T he defi niti o ns of A Es a n d S A Es ca n be f o u n d i n Secti o n  8. 6 . 
A Es will be re p orte d b y t he partici pa nt ( or, w he n a p pr o priate, b y a care gi ver, s urr o gate, or 
t he partici pa nt’s le gall y a ut h orize d re prese ntati ve).  
T he i n vesti gat or a n d a n y q ualifie d desi g nees are res p o nsi ble f or detecti n g, d oc u me nti n g, a n d 
rec or di n g e ve nts t hat meet t he defi niti o n of a n A E or S A E a n d re mai n res p o nsi ble f or f oll o wi n g 
u p all A Es. 
C CI
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The method of recording, evaluating, and assessing causality of AEs and SAEs and 
the procedures for completing and transmitting SAE reports are provided in Section 8.6.3. 
8.6.1 
Adverse events 
An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a clinical investigation 
participant after providing written informed consent for participation in the study. Therefore, an 
AE may or may not be temporally or causally associated with the use of a medicinal 
(investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying AEs. 
Novartis qualified medical personnel will be readily available to advise on trial-related medical 
questions or problems. 
For participants who sign the pre-screening ICF, AEs which occur after signature of this consent 
will only be captured if they meet the definition of serious as outlined in Section 8.6.2 and are 
reported to be causally related with study procedures (e.g. the X-ray). Once the main study ICF 
is signed, all AEs per the descriptions below will be captured as adverse events. 
The occurrence of AEs must be sought by non-directive questioning of the participant at each 
visit during the study. AEs also may be detected when they are volunteered by the participant 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments (PROs are considered as other assessments to detect AEs, See Section 8.5.1). 
AEs must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer 
to Section 8.6.2): 
1. The Common Toxicity Criteria (CTC) AE grade (version 5 or higher). AEs will be 
assessed and graded according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version. 
2. The causality. The investigator is obligated to assess the relationship between the study 
treatment and each occurrence of each AE. The investigator will use clinical judgment to 
determine the relationship. A reasonable possibility of a relationship conveys that there are 
facts, evidence, and/or arguments to suggest a causal relationship, rather than that a 
relationship cannot be ruled out. Alternative causes, such as underlying disease(s), 
concomitant therapy, and other risk factors, as well as the temporal relationship of the 
event to study intervention administration, will be considered and investigated. For 
causality assessment, the investigator will also consult the IB. The causality assessment is 
one of the criteria used when determining regulatory reporting requirements. If the event 
is due to lack of efficacy or progression of underlying illness (i.e., progression of the study 
indication) the assessment of causality will usually be ‘Not suspected.’ The rationale for 
this guidance is that the symptoms of a lack of efficacy or progression of underlying 
illness are not caused by the trial drug, they happen in spite of its administration and/or 
both lack of efficacy and progression of underlying disease can only be evaluated 
meaningfully by an analysis of cohorts, not on a single participant. 

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3. Its duration (start and end dates or ongoing) and the outcome must be reported. 
4. Whether it constitutes a SAE (see Section 8.6.2 for definition of SAE) and which 
seriousness criteria have been met. 
5. Action taken regarding with study treatment. All AEs must be treated appropriately. 
Treatment may include one or more of the following: 
• Dose not changed 
• Dose Reduced 
• Drug interrupted/permanently discontinued 
6. Its outcome (i.e., recovery status or whether it was fatal). 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. 
AE monitoring should be continued until the EOS visit. 
Once an AE is detected, it must be followed until its resolution or until it is judged to be not 
recovered/not resolved (e.g., continuing at the end of the study), and assessment must be made 
at each visit (or more frequently, if necessary) of any changes in severity, the suspected 
relationship to the interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the IB. 
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of 
the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
Clinically significant abnormal laboratory values or test results must be identified through 
a review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in participant 
with the underlying disease. Alert ranges for laboratory and other test abnormalities are included 
in Section 10.5 and Section 10.6. For a complete list of reference ranges, please refer to 
the Laboratory Manual. 
8.6.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 

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Life-threatening in the context of a SAE refers to a reaction in which the participant was at risk 
of death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect, fetal death or a congenital abnormality or 
birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g., defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life-threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All new malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
All reports of intentional misuse and abuse of the product are also considered SAEs irrespective 
of whether a clinical event has occurred. 
Any suspected transmission via a medicinal product of an infectious agent is also considered 
a serious adverse reaction. 
Treatment-emergent elevations in AST or ALT (>3x ULN) in combination with total 
bilirubin >2x ULN or jaundice in the absence of cholestasis (defined as ALP < 2 ULN) or other 
causes of hyperbilirubinemia can be an indicator of severe drug induced liver injury (Hy’s Law). 
For this reason, a potential Hy’s Law case requires expedited reporting, and will be handled as 
a serious unexpected adverse event (assessing it as medically significant in the absence of any 
other seriousness criteria). It must be reported as an SAE to the sponsor promptly (i.e., even 
before all other possible causes of liver injury have been excluded). Reporting should include 
all available information, especially that needed for evaluating the diagnosis, severity and 
likelihood that the study treatment caused the reaction. For patient monitoring and to better 

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understand potential etiologies, the investigator must initiate a close follow-up until complete 
resolution of the problem and completion of all attempts to obtain supplementary data. 
8.6.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until the EOS visit must be reported to Novartis safety 
immediately, without undue delay, but under no circumstances later than within 24 hours of 
obtaining knowledge of the events. Note: If more stringent, local regulations regarding 
reporting timelines prevail. Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site. Information about 
all SAEs is collected and recorded on the electronic SAE Report Form (with paper backup, if 
needed); all applicable sections of the form must be completed in order to provide a clinically 
thorough report. 
Screen Failures: SAEs occurring after the participant has provided informed consent until 
the time the participant is deemed a Screen Failure must be reported to Novartis. 
Randomized Participants: SAEs collected between time participant signs ICF until 30 days 
after the participant has discontinued from study treatment (or longer, depending on 
the elimination half-life of the specific compound). 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
immediately, without undue delay, but under no circumstances later than within 24 hours of 
the investigator receiving the follow-up information (Note: If more stringent, local regulations 
regarding reporting timelines prevail). An SAE occurring at a different time interval or 
otherwise considered completely unrelated to a previously reported one must be reported 
separately as a new event. 
If the SAE is not previously documented in the IB or Package Insert (new occurrence) and is 
thought to be related to the study treatment, a Chief Medical Office and Patient Safety 
(CMO&PS) Department associate may urgently require further information from 
the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with EU Clinical Trial 
Regulation 536/2014 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the EOS visit should only be reported to Novartis Safety if 
the investigator suspects a causal relationship to study treatment, unless otherwise specified by 
local law/regulations. 

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8.6.4 
Pregnancy 
In EEA countries, female trial participants must be physiologically incapable of becoming 
pregnant. 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study treatment and until the EOS visit. 
While pregnancy itself is not considered to be an AE or SAE, any pregnancy complication or 
elective termination of a pregnancy for medical reasons will be reported as an AE or SAE. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAEs and will be reported as such. 
Any post study pregnancy-related SAE considered reasonably related to the study treatment by 
the investigator will be reported to Novartis as described in Section 8.6.3. While the investigator 
is not obligated to actively seek this information in former study participants/pregnant female 
partner, he or she may learn of an SAE through spontaneous reporting. 
If a female trial participant becomes pregnant, the study treatment should be stopped, and 
the pregnancy consent form should be presented to the trial participant. The participant must be 
given adequate time to read, review and sign the pregnancy consent form. This consent form is 
necessary to allow the Investigator to collect and report information regarding the pregnancy. 
To ensure participant safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported by the Investigator to the Novartis CMO&PS. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment for any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported. 
If a female partner of a male trial participant who took study treatment in this study becomes 
pregnant, pregnancy outcomes should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother. 
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. 
8.6.5 
Disease-related events and/or disease-related outcomes not qualifying 
as AEs or SAEs 
Not applicable. 
8.6.6 
Adverse events of special interest 
Not applicable. 

N o v arti s  
C o nfi d e nti al  
P a g e 7 0  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
8. 7  
P h ar m a c o ki n eti c s  
P K sa m ples will be c ollecte d at t he visits defi ne d i n  Secti o n  1. 3 . 
At t he Baseli ne visit, a pre -d ose a n d 4 -h o ur p ost d ose P K sa m ple will be c ollecte d. At t he Wee k 
4 visit, a pre -d ose P K sa m ple will be dra w n t o deter mi ne C mi n,ss. At s u bse q ue nt visits, P K 
sa m ples will be dra w n at a n y ti me p oi nt. Partici pa nts will rec or d t he date a n d ti me of t he  
 
d oses of st u d y treat me nt pri or t o eac h visit after t he Baseli ne visit i n a diar y as descri be d 
i n Secti o n  6. 2. 3. 
F oll o w i nstr ucti o ns o utli ne d i n t he  La b orat or y Ma n ual re gar di n g sa m ple c ollecti o n, n u m beri n g, 
pr ocessi n g a n d s hi p me nt. See  Secti o n  8. 8 f or t he p ote ntial use of resi d ual sa m ples f or m ore 
i nf or mati o n. P K sa m ples will be o btai ne d i n all partici pa nts a n d e val uate d i n all partici pa nts 
e xce pt t he place b o gr o u p. 
R H H 6 4 6 will be deter mi ne d b y a vali date d L C -M S/ M S met h o d; t he a ntici pate d L o wer Li mit 
of Q ua ntificati o n ( L L O Q) is 2 n g/ m L.  
C o nce ntrati o ns will be e x presse d i n mass per v ol u me u nits a n d will refer t o t he free base. 
C o nce ntrati o ns bel o w t he L L O Q will be re p orte d as “zer o” a n d missi n g data will be la bele d as 
s uc h i n t he Bi oa nal ytical Data Re p ort. 
C mi n,ss c ollecte d at Wee k  4 will be t he o nl y P K para meter deter mi ne d i n t his st u d y a n d will 
be deter mi ne d usi n g t he act ual rec or de d sa m pli n g ti mes wit h P h oe ni x Wi n N o nli n ( Versi o n 6. 4 
or hi g her). All P K data fr o m t his st u d y, i n c o m bi nati o n wit h ric h P K data fr o m t he FI H trial, 
will be use d t o de vel o p a p o p ulati o n P K m o del i n O A patie nts. Res ults fr o m t he p o p ulati o n P K 
m o del will be re p orte d se paratel y.  
F or  sta n dar d  p har mac o ki netic  a b bre viati o ns  a n d  defi niti o ns  see  t he  list  pr o vi de d  i n  
t he a p pe n dices of t his pr ot oc ol. 
8. 8  
Bi o m ar k er s  
C CI
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N o v arti s  
C o nfi d e nti al  
P a g e 7 1  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
 
 
 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 7 2  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
 
 
8. 9  
I m m u n o g e ni cit y a s s e s s m e nt s 
I m m u n o ge nicit y is n ot bei n g e val uate d i n t his st u d y. T here is n o a pri ori  reas o n t o belie ve t hat 
R H H 6 4 6 is i m m u n o ge nic. H o we ver, if a partici pa nt e x perie nces a n a p pare nt h y perse nsiti vit y 
reacti o n or ot her e ve nt s u g gesti n g i m m u n o ge nicit y of t he st u d y treat me nt, ma na ge me nt of 
t he e ve nt ma y i ncl u de c ollecti o n of bl o o d/ plas ma/ser u m  or ot her sa m ples t hat ma y ai d i n 
t he dia g n osis a n d u n dersta n di n g of t he e ve nt. 
8. 1 0   
 M e di c al r e s o ur c e utili z ati o n a n d h e alt h e c o n o mi c s  
Me dical res o urce utilizati o n a n d healt h ec o n o mics is n ot bei n g e val uate d i n t his st u d y. 
9 
St ati sti c al c o n si d er ati o n s  
T he a nal yses will be c o n d ucte d o n all partici pa nt data at t he ti me w he n i nteri m a nal ysis occ urs 
a n d w he n t he trial e n ds. A n y data a nal ysis carrie d o ut i n de pe n de ntl y b y t he i n vesti gat or s h o ul d 
be s u b mitte d t o N o vartis bef ore p u blicati o n or prese ntati o n. 
9. 1  
A n al y si s s et s  
Partici pa nts will be a nal yze d acc or di n g t o t he treat me nt assi g ne d.  
T he F ull A n al ysis Set ( F A S)  will i ncl u de all partici pa nts w h o recei ve d a n y st u d y treat me nt. 
T he S afet y A n al ysis Set  will i ncl u de all partici pa nts w h o recei ve d a n y st u d y treat me nt.  
F or t his st u d y, t he F A S a n d t he Safet y A nal ysis set are i de ntical.  
T he P K A n al ysis Set  will i ncl u de all partici pa nts wit h at least o ne a vaila ble vali d (i.e., n ot 
fla g ge d f or e xcl usi o n) P K c o nce ntrati o n meas ure me nt, w h o recei ve d a n y st u d y treat me nt a n d 
wit h n o pr ot oc ol de viati o ns t hat i m pact P K data. 
C CI
C CI
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9.2 
Statistical analyses 
9.2.1 
General considerations 
The term study drug or investigational treatment refers to RHH646 or placebo, while the term 
investigational drug refers exclusively to RHH646. 
Study day 
Study day 1 for all assessments is taken to be the start of investigational treatment. The study 
day for all assessments will be calculated as follows: 
1. If date of assessment occurred on or after the start of investigational treatment, then Study 
day = Date of assessment - Start of investigational treatment + 1. 
2. If date of assessment occurred before the start of investigational treatment, then Study day 
= Date of assessment - Start of investigational treatment. 
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative. 
Baseline 
For safety evaluations, the last available assessment on or before the date of start of 
investigational treatment is taken as 'baseline' assessment. In case time of assessment and time 
of treatment start is captured, the last available assessment before the treatment start date/time 
is used for baseline. 
For safety parameters, scheduled pre-dose collections as well as unscheduled collections on 
Day 1 for which no time is available will be considered as pre-dose. 
For ECG, study Day 1 scheduled pre-dose ECGs will be considered to have been obtained prior 
to start of investigational treatment if dosing time or ECG time is missing and used in 
the calculation of the baseline value. If a scheduled pre-dose measurement actually occurred 
post-dose, then the corresponding measurement will be treated and analyzed similar to an 
unscheduled post-dose measurement. 
Regarding MRI, baseline is defined as the scan performed between Day -14 and Day 1. 
On-treatment assessment/event 
The overall observation period will be divided into two mutually exclusive segments: 
1. pre-treatment period: from day of participant’s informed consent to before date of first 
administration of investigational treatment 
2. on-treatment period: from date of first administration of investigational treatment to 
28 days after date of last administration of investigational treatment (including start and 
stop date) 
Note: If dates are incomplete in a way that clear assignment to pre-, on-treatment period cannot 
be made, then the respective data will be assigned to the on-treatment period. 

N o v arti s  
C o nfi d e nti al  
P a g e 7 4  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
Safet y  s u m maries  (ta bles,  fi g ures)  i ncl u de  o nl y  data  fr o m  t he  o n -treat me nt  peri o d,  wit h  
t he e xce pti o n of baseli ne data w hic h will als o be s u m marize d w here a p pr o priate (e. g., c ha n ge 
fr o m  baseli ne  s u m maries).  I n  partic ular,  s u m mar y  ta bles  f or  A Es  will  s u m marize  o nl y  
o n- treat me nt e ve nts, wit h a start date d uri n g t he o n-treat me nt peri o d (treat me nt-e mer ge nt  A Es).  
9. 2. 2  
P arti ci p a nt d e m o gr a p hi c s a n d ot h er b a s eli n e c h ar a ct eri sti c s  
All data f or bac k gr o u n d a n d de m o gra p hic varia bles will be liste d b y treat me nt gr o u p a n d 
partici pa nt. S u m mar y statistics will be pr o vi de d b y treat me nt gr o u p f or t he F A S.  
Cate g orical data will be prese nte d as fre q ue ncies a n d perce nta ges. F or c o nti n u o us data, mea n, 
sta n dar d de viati o n, me dia n, mi ni m u m, a n d ma xi m u m will be prese nte d.  
Rele va nt me dical hist or y, c urre nt me dical c o n diti o ns, res ults of la b orat or y scree ns, dr u g tests 
a n d a n y ot her rele va nt i nf or mati o n will be liste d b y treat me nt gr o u p a n d partici pa nt.  
9. 2. 3  
Tr e at m e nt s  
T he Safet y A nal ysis Set will be use d f or t he a nal yses bel o w.  
Cate g orical data will be s u m marize d as fre q ue ncies a n d perce nta ges. F or c o nti n u o us data, 
mea n, sta n dar d de viati o n, me dia n, 2 5t h a n d 7 5t h perce ntiles, mi ni m u m, a n d ma xi m u m will be 
prese nte d.  
T he d urati o n of e x p os ure i n da ys t o R H H 6 4 6 will be s u m marize d b y mea ns of descri pti ve 
statistics usi n g t he safet y set. 
C o nc o mita nt me dicati o ns a n d si g nifica nt n o n -dr u g t hera pies pri or t o a n d after t he start of 
t he st u d y treat me nt will be s u m marize d acc or di n g t o t he A nat o mical T hera pe utic C he mical 
( A T C) classificati o n s yste m, b y treat me nt gr o u p. 
9. 3  
Pri m ar y e n d p oi nt( s)/ e sti m a n d( s) a n al y si s  
T he pri mar y ai m of t his st u d y is t o e val uate t he efficac y of R H H 6 4 6 a d mi nistere d  
 
. A statistical a nal ysis will be perf or me d t o c o m pare t he c ha n ge fr o m baseli ne i n 
cartila ge v ol u me i n t he i n de x re gi o n of t he k nee f or partici pa nts rece i vi n g R H H 6 4 6 vers us t h ose 
recei vi n g place b o. 
I n  a d diti o n,  t he  st u d y  ai ms  t o  e val uate  t he  safet y  a n d  t olera bilit y  of  R H H 6 4 6   
 
 of treat me nt. A Es, E C Gs, vital si g ns, a n d cli nical la b orat or y assess me nts s uc h as 
he mat ol o g y, bl o o d c he mistr y, uri nal ysis will be t he e n d p oi nts use d t o assess t his o bjecti ve. 
9. 3. 1  
D efi niti o n of pri m ar y e n d p oi nt( s)  
T he pri mar y efficac y e n d p oi nt of t he st u d y is c ha n ge fr o m baseli ne i n cartila ge v ol u me i n 
t he i n de x re gi o n of t he k nee. 
T he pri mar y safet y e n d p oi nt of t he st u d y is e val uati o n of A Es, E C Gs, vital si g ns, a n d cli nical 
la b orat or y assess me nts. 
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9.3.2 
Statistical model, hypothesis, and method of analysis 
The aim is to estimate the treatment effect of the RHH646 compared to placebo, for the target 
population, in the change from baseline in cartilage volume. The definition of the corresponding 
primary estimand is detailed in Section 3.1. 
The primary efficacy endpoint will be analyzed using a mixed effect model for repeated 
measures (MMRM). The model will include baseline, treatment, time-point, and treatment by 
time-points as fixed effects. An unstructured covariance will be assumed; if not possible, other 
appropriate covariance structures may be explored. A two-sided 90% confidence interval for 
the treatment effect (i.e., RHH646 minus placebo) at Week 52 will be reported. 
9.3.3 
Handling of intercurrent events of primary estimand 
Handling of the ICE will follow a hypothetical strategy. Assessments impacted by an ICE will 
be considered missing and implicitly imputed by the MMRM under the missing at random 
(MAR) assumption (i.e., assuming that participants with missing data would have efficacy 
outcomes like those of similar participants in their treatment group who continue their 
randomized treatment). 
The assumptions underlying the hypothetical strategy might be revised and/or the SAP may be 
amended prior to database lock if: 
• An unexpectedly high number of participants show poor compliance with study treatment, 
• Other events with potential impact on the interpretation of the treatment effect occur at a 
relevant frequency. 
The definition of "unacceptable non-compliance with treatment” and the impact on the 
interpretability of the subsequent MRI assessments will happen prior the database lock before 
unblinding. 
9.3.4 
Handling of missing values not related to intercurrent event 
Some intermittently missing data may be expected due to participants occasionally missing 
a study visit while continuing with the randomized treatment. Such data will be implicitly 
imputed by the MMRM under the MAR assumption. 
9.3.5 
Sensitivity analyses 
Upon the review of the ICEs, a sensitivity analysis may be specified in the SAP, to test the 
assumption that the ICEs render impacted assessments following a MAR mechanism. 
9.3.6 
Supplementary analysis 
To estimate the treatment effect under real-world conditions, the data might be analyzed 
according to treatment policy instead of hypothetical strategy. 

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9.3.7 
Safety analysis 
For all safety analyses, the Safety Analysis Set will be used. All listings and tables will be 
presented by treatment group. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for AEs will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent AEs). 
Adverse events 
All information obtained on AEs will be displayed by treatment group and participant. 
The number (and percentage) of participants with treatment-emergent AEs will be summarized 
by treatment, primary system organ class (SOC) and preferred term (PT), with a breakdown by 
treatment. 
A participant with multiple AEs within a primary SOC is only counted once towards the total 
of the primary SOC. 
Vital signs 
All vital signs data will be summarized by treatment and visit/time. 
12-lead ECG 
All ECG data will be summarized by treatment and visit/time. 
Clinical laboratory evaluations 
All laboratory data will be summarized by treatment group, and visit/time. Shift tables using 
the low/normal/high/ (low and high) classification will be used to compare baseline to the worst 
on-treatment value. 
9.4 
Secondary endpoint(s)/estimand(s) analysis 
9.4.1 
Pharmacokinetics 
Descriptive summary statistics of RHH646 Cmin,ss at Week 4 will be provided by treatment 
and visit/sampling time point, including the frequency of concentrations below the LLOQ, 
which will be reported as zero. 
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum, and maximum. 
Drug concentrations below LLOQ will be treated as missing for the calculation of the geometric 
means and geometric CV%, and as zero for all other calculations including calculation of PK 
parameters (Cmin,ss). 

N o v arti s  
C o nfi d e nti al  
P a g e 7 7  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
Descri pti ve s u m mar y statistics will i ncl u de mea n (arit h metic a n d ge o metric), S D, a n d C V 
(arit h metic a n d ge o metric), me dia n, mi ni m u m, a n d ma xi m u m. 
At t he later ti me p oi nts t ha n Wee k 4, i n di vi d ual partici pa nt c o nce ntrati o ns will be liste d.  
9. 5  
E x pl or at or y e n d p oi nt( s) a n al y si s  
T he statistical a nal ysis f or e x pl orat or y e n d p oi nts will be descri be d i n detail i n t he S A P or i n 
de dicate d sta n d -al o ne e x pl orat or y S A Ps. 
9. 5. 1  
 
9. 5. 2   
 
9. 5. 3  
 
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C o nfi d e nti al  
P a g e 7 8  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
9. 6  
Ot h er S af et y a n al y s e s  
N ot a p plica ble. 
9. 7  
Ot h er a n al y s e s  
N ot a p plica ble. 
9. 8  
I nt eri m a n al y si s 
A n i nteri m a nal ysis wit h efficac y e val uati o n (see  Secti o n  4. 6) is pla n ne d t o be c o n d ucte d. T he 
data will be e xa mi ne d as a preli mi nar y e val uati o n of t hera pe utic effect 
 
 
A d diti o nal  i nteri m  a nal yses  ma y  be  c o n d ucte d
 
 or i n case of a n y 
safet y c o ncer ns. 
I nteri m a nal ysis res ults will be re vie we d b y t he cli nical tea m. 
T he  cli nical  tea m  ma y  c o m m u nicate  i nteri m  res ults  (e. g.,  e val uati o n  of  P o C  criteria  or  
i nf or mati o n  nee de d  f or  pla n ni n g/ m o dif yi n g  a n ot her  st u d y)  t o  rele va nt  N o vartis  tea ms  f or  
i nf or mati o n, c o ns ulti n g a n d/ or decisi o n p ur p oses. 
I nteri m res ults ma y be use d t o pre pare a bstracts t o scie ntific meeti n gs. T his w o ul d t y picall y 
re q uire i n vesti gat or i n p ut t o a bstract pre parati o n. E ver y atte m pt will be ma de t o ass ure t hat 
t he i n vesti gat or will n ot ha ve access t o i n di vi d ual partici pa nts' data, b ut rat her will re vie w 
a g gre gate, s u m mar y data. 
9. 9  
S a m pl e si z e d et er mi n ati o n  
9. 9. 1  
Pri m ar y e n d p oi nt( s)  
 A p ositi ve treat me nt effect is i n dicate d b y a n i ncrease i n cartila ge v ol u me at Wee k 5 2. A 
sta n dar d de viati o n of a p pr o xi matel y 
 of c ha n ge fr o m baseli ne t o Wee k 5 2 was o bser ve d 
o n t he preli mi nar y data fr o m O A patie nts 
 
 U n der t his ass u m pti o n, a sa m ple size of 3 5 e val ua ble partici pa nts per ar m, 
i.e., 7 0 partici pa nts i n t otal (ra n d o mizati o n rati o 1: 1), will pr o vi de at least 8 0 % p o wer t hat t he 
pri mar y a nal ysis will be statisticall y si g nifica nt at o ne -si de d 5 % si g nifica nce le vel f or a tr ue 
effect size of 
 a n d at least 9 0 % p o wer f or a tr ue effect size greater t ha n 
 
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In absence of prior evidence of clinical benefit gained from structural improvements, this range 
of true effect sizes is considered reasonable in the context of this Proof-of-Concept study, with 
the goal to not miss out on relevant anabolic effects beyond the prevention of further cartilage 
degradation. In order to account for potential early discontinuations an approximate 10% 
dropout rate is assumed, thus the number of participants enrolled will be approximately 78. 

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10 
Supporting documentation and operational considerations 
10.1 
Appendix 1: Regulatory, ethical, and study oversight 
considerations 
10.1.1 
Regulatory and ethical considerations 
This study will be conducted in accordance with the protocol and with the following: 
• Consensus ethical principles derived from international guidelines including 
the Declaration of Helsinki and Council for International Organizations of Medical 
Sciences (CIOMS) international ethical guidelines 
• Applicable ICH Good Clinical Practice (GCP) guidelines 
• Applicable laws and regulations 
The protocol, protocol amendments, ICF, Investigator’s Brochure, and other relevant 
documents (e.g., advertisements) must be submitted to an IRB/IEC by the Investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
Protocols and any substantial amendments/modifications to the protocol will require health 
authority approval prior to initiation except for changes necessary to eliminate an immediate 
hazard to study participants. 
The investigator will be responsible for the following: 
• Signing a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in 
this protocol and to give access to all relevant data and records to Novartis monitors, 
auditors, Novartis Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required 
• Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
• Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
• Providing oversight of the conduct of the study at the site and adherence to requirements 
of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 for clinical 
studies (if applicable), and all other applicable local regulations 
• Inform Novartis immediately if an inspection of the clinical site is requested by 
a regulatory authority 
This clinical study was designed and shall be implemented, executed, and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Clinical Trial Regulation 536/2014, US CFR 
21), and with the ethical principles laid down in the Declaration of Helsinki. 

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10.1.2 
Informed consent process 
The investigator or his/her representative will explain the nature of the study, including the risks 
and benefits, to the participant and answer all questions regarding the study. 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representatives will be required to sign a statement of informed consent that meets 
the requirements of 21 CFR 50, local regulations, ICH guidelines, privacy and data protection 
requirements, where applicable, and the IRB/IEC or study center. 
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
be documented in the participant source documents. 
The medical record must include a statement that written informed consent was obtained before 
the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
A copy of the ICF(s) must be provided to the participant. 
Participants who are rescreened are required to sign a new ICF. 
The ICF will contain a separate section that addresses the use of remaining mandatory samples 
for optional additional research. The investigator or authorized designee will explain to each 
participant the objectives of the additional research. Participants will be told that they are free 
to refuse to participate and may withdraw their consent at any time and for any reason during 
the storage period. A separate signature will be required to document a participant’s agreement 
to allow any remaining specimens to be used for additional research. Participants who decline 
to participate in this optional additional research will document this. 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
Information about common side effects already known about the investigational treatment can 
be found in the IB. This information will be included in the participant informed consent and 
should be discussed with the participant upon obtaining consent and also during the study as 
needed. Any new information regarding the safety profile of the investigational drug that is 
identified between IB updates will be communicated as appropriate, for example, via an 
investigator notification or an aggregate safety finding. New information might require an 
update to the informed consent and then must be discussed with the participant. 
The following informed consents are included in this study: 
• Pre-screening ICF 
• Main study consent, which also included: 
• A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during 
this study 
• Optional consent for activities that may be done outside of the study site 
• As applicable, Pregnancy Outcomes Reporting Consent for female participants or 
the female partners of any male participants who took study treatment 

N o v arti s  
C o nfi d e nti al  
P a g e 8 2  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
•  Patie nt i nf or mati o n s heet f or fe male part ners of a n y male partici pa nts w h o t o o k st u d y 
treat me nt 
•  
 
As a p plica ble b y l ocal re g ulati o n: 
•  Site Trai ni n g C o nse nt f or Di gital Se ns ors f or v ol u nteers weari n g a di gital se ns or f or 
t he p ur p ose of c ollecti n g data use d t o c o nfir m t hat t his site meets t he q ualificati o n 
re q uire me nts f or usi n g t he di gital se ns or i n t his st u d y. 
•  Site Trai ni n g C o nse nt f or I ma gi n g De vices f or v ol u nteers u n der g oi n g M RI f or t he  p ur p ose 
of c ollecti n g data use d t o c o nfir m t hat t his site meets t he q ualificati o n re q uire me nts f or 
c ollecti o n of M RI i n t his st u d y.  
T he st u d y i ncl u des a n o pti o nal s u b st u dies/  
 c o m p o ne nt w hic h re q uires a se parate si g nat ure 
if t he partici pa nt a grees t o partici pate. It is re q uire d as part of t his pr ot oc ol t hat t he i n vesti gat or 
prese nts t his o pti o n t o t he partici pa nts, as per mitte d b y l ocal g o ver ni n g re g ulati o ns. T he  pr ocess 
f or o btai ni n g c o nse nt s h o ul d be e xactl y t he sa me as descri be d a b o ve f or t he mai n i nf or me d 
c o nse nt. 
Decli ni n g t o partici pate i n t hese o pti o nal assess me nts (
) will i n n o wa y affect 
t he partici pa nt’s a bilit y t o j oi n t he mai n researc h st u d y.  
A c o p y of t he a p pr o ve d versi o n of all c o nse nt f or ms m ust be pr o vi de d t o  N o vartis  after I R B/I E C 
a p pr o val. 
As per  Secti o n  4. 5, d uri n g a p u blic healt h e mer ge nc y as declare d b y l ocal or re gi o nal a ut h orities 
i.e. pa n de mic, e pi de mic or nat ural disaster, t hat ma y c halle n ge t he a bilit y t o o btai n a sta n dar d 
writte n i nf or me d c o nse nt d ue t o li mits t hat pre ve nt a n o n -site visit, i n vesti gat or ma y c o n d uct 
t he i nf or me d c o nse nt disc ussi o n re m otel y (e. g. tele p h o ne, vi de oc o nfere nce) if all o wa ble b y 
a l ocal healt h a ut h orit y. 
G ui da nce iss ue d b y l ocal re g ulat or y b o dies o n t his as pect pre vail a n d m ust be i m ple me nte d a n d 
a p pr o priatel y d oc u me nte d (e. g. t he prese nce of a n i m partial wit ness, si g n/ dati n g se parate I C Fs 
b y trial partici pa nt a n d pers o n o btai ni n g i nf or me d c o nse nt, etc.). 
1 0. 1. 3  
D at a pr ot e cti o n  
Partici pa nts will be assi g ne d a u ni q ue i de ntifier b y  N o vartis. A n y partici pa nt rec or ds or datasets 
t hat  are  tra nsferre d  t o N o vartis  will  c o ntai n  t he  i de ntifier  o nl y;  partici pa nt  na mes  or  a n y  
i nf or mati o n w hic h w o ul d ma ke t he partici pa nt i de ntifia ble will n ot be tra nsferre d. 
T he  partici pa nt  m ust  be  i nf or me d  t hat  his/ her  pers o nal  st u d y -relate d  data  will  be  use d  
b y N o vartis  i n acc or da nce wit h l ocal data pr otecti o n la w. T he le vel of discl os ure m ust als o be 
e x plai ne d t o t he partici pa nt w h o will be re q uire d t o gi ve c o nse nt f or t hei r data t o be use d as 
descri be d i n t he i nf or me d c o nse nt. 
T he partici pa nt m ust be i nf or me d t hat his/ her me dical rec or ds ma y be e xa mi ne d b y Cli nical 
Q ualit y Ass ura nce a u dit ors or ot her a ut h orize d pers o n nel a p p oi nte d b y  N o vartis, b y a p pr o priate 
I R B/I E C me m bers, a n d b y i ns pect ors fr o m re g ulat or y a ut h orities. 
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Novartis has appropriate processes and policies in place to handle personal data breaches 
according to applicable privacy laws. 
10.1.4 
Committees structure 
Not applicable. 
10.1.5 
Data quality assurance 
Monitoring details describing strategy, including definition of study critical data items and 
processes (e.g. risk-based initiatives in operations and quality such as risk management and 
mitigation strategies and analytical risk-based monitoring), methods, responsibilities, and 
requirements, including handling of noncompliance issues and monitoring techniques 
(central, remote, or on-site monitoring) are provided in the monitoring plan. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for a minimum of 15 years after study completion unless local 
regulations or institutional policies require a longer retention period. No records may be 
destroyed during the retention period without the written approval of Novartis. No records may 
be transferred to another location or party without written notification to Novartis. 
Efforts should be made to collect all data that are relevant to support a statistical analysis aligned 
with the estimands of interest. If the estimands that are required to support regulatory decision 
making do not require the collection of the variable after an intercurrent event, then the benefits 
of collecting such data for other estimands should be weighed against any complications and 
potential drawbacks of the collection. 
10.1.5.1 Data collection 
Designated investigator staff will enter the data required by the protocol into the eCRF. 
The eCRFs have been built using fully validated secure web-enabled software that conforms to 
21 CFR Part 11 requirements, investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies in 
the eCRFs, allow modification and/or verification of the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate. 
After final database lock, the Investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
10.1.5.2 Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to 

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the investigational site via the EDC system. Designated Investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using 
the World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
AEs will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment(s) dispensed to the participant and all 
dosage changes will be tracked using an IRT. The system will be supplied by a vendor, who 
will also manage the database. The data will be sent electronically to Novartis (or a designated 
CRO) at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request 
of Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked, and the treatment codes will be unblinded and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
or statistician. Any changes to the database after that time can only be made after written 
agreement by Novartis development management. 
10.1.6 
Source documents 
Source documents provide evidence for the existence of the participant and substantiate 
the integrity of the data collected. Source documents are filed at the investigator’s site. 
Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. 
The investigator may need to request previous medical records or transfer records, depending 
on the study. Also, current medical records must be available. 
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the data capture and/or data entry. The investigator must also keep 
the original ICF signed by the participant (a signed copy is given to the participant). Definition 
of what constitutes source data and its origin can be found in the source data acknowledgment 
form. 
The investigator must maintain accurate documentation (source data) that supports 
the information entered in the CRF. Study monitors will perform ongoing source data 
verification to confirm that data entered into the CRF by authorized site personnel are accurate, 
complete, and verifiable from source documents; that the safety and rights of participants are 
being protected; and that the study is being conducted in accordance with the currently approved 
protocol and any other study agreements, ICH GCP, and all applicable regulatory requirements. 
Key study personnel must be available to assist the field monitor during these visits. Continuous 
remote monitoring of each site’s data may be performed by a centralized Novartis organization. 
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site operational parameters and provide reports to Novartis clinical teams to assist with trial 
oversight. 
10.1.7 
Publication policy 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in CTIS public website. In addition, after study completion (defined as LPLV) and 
finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required health authority websites (e.g. Clinicaltrials.gov, CTIS public 
website etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to 
the Novartis publication policy training materials that were provided to you at the trial 
Investigator meetings. 
Any data analysis carried out independently by the Investigator should be submitted 
to Novartis before publication or presentation. 
Summary results of primary and secondary endpoints will be disclosed based upon the global 
LPLV date, since multinational studies are locked and reported based upon the global LPLV. 
10.1.8 
Protocol adherence and protocol amendments 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it 
to Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon 
by Novartis and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented. 

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10.1.8.1 Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and 
the reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 

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10.2 
Appendix 2: Abbreviations and definitions 
10.2.1 
List of abbreviations 
ACR 
Albumin:creatinine ratio 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
ALP 
Alkaline Phosphatase 
ALT 
Alanine Aminotransferase 
AP 
Anterior-posterior 
APAP 
n-Acetyl-Para-Aminophenol 
APTT 
Activated partial thromboplastin time 
AST 
Aspartate Aminotransferase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BML 
Bone Marrow Lesion 
BP 
Blood Pressure 
CIOMS 
Council for International Organizations of Medical Sciences 
CK 
Creatine Kinase 
CKD-EPI 
Chronic Kidney Disease Epidemiology Collaboration 
cm 
centimeter(s) 
Cmax 
Maximum concentration 
Cmin,ss 
Minimum (trough) concentration, steady state 
CMO&PS 
Chief Medical Office and Patient Safety 
COA 
Clinical Outcome Assessment 
CRF 
Case Report/Record Form (paper or electronic) 
CRO 
Contract Research Organization 
CSR 
Clinical study report 
CTA 
Clinical Trial Application 
CTC 
Common Terminology Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTIS 
Clinical Trials Information System 
CV 
Coefficient of variation 
DMC 
Data Monitoring Committee 
DRESS 
Drug Rash with Eosinophilia and Systemic Symptoms 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
ELISA 
Enzyme-linked immunosorbent assay 
EOS 
End of Study 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
FIH 
First in Human 

N o v arti s  
C o nfi d e nti al  
P a g e 8 8  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
F L A/ C/ P  
F e m ur L at er al A nt eri or/ C e ntr al/ P o st eri or  
F M A/ C/ P  
F e m ur M e di al A nt eri or/ C e ntr al/ P o st eri or  
F T M  
F e m ur Tr o c hl e a M e di al/ C e ntr al/ P o st eri or  
G C P  
G o o d Cli ni c al Pr a cti c e  
G C S  
Gl o b al Cli ni c al S u p pl y  
G G T  
G a m m a -gl ut a m yl tr a n sf er a s e  
G L C M  
Gr e y L e v el C o -o c c urr e n c e M atri x  
G L D H  
Gl ut a m at e D e h y dr o g e n a s e  
G L P  
G o o d L a b or at or y Pr a cti c e  
H B c A g  
H e p atiti s B vir u s c or e a nti g e n  
H B s A g  
H e p atiti s B vir u s s urf a c e a nti g e n  
H B V  
H e p atiti s B Vir u s  
H C V  
H e p atiti s C Vir u s  
H D L  
Hi g h -D e n sit y Li p o pr ot ei n  
H G B  
H e m o gl o bi n  
HI V  
H u m a n i m m u n o d efi ci e n c y vir u s  
H O -1  
H e m e O x y g e n a s e -1  
 
 
i. v. 
i ntr a v e n o u s 
I B 
I n v e sti g at or’ s Br o c h ur e 
I C E 
I nt er c urr e nt E v e nt s 
I C F 
I nf or m e d C o n s e nt F or m 
I C H 
I nt er n ati o n al C o u n cil f or H ar m o ni z ati o n of T e c h ni c al R e q uir e m e nt s f or 
P h ar m a c e uti c al s f or H u m a n U s e  
I E C 
I n d e p e n d e nt Et hi c s C o m mitt e e 
I M P 
I n v e sti g ati o n al M e di ci n al Pr o d u ct 
I N 
I n v e sti g at or N otifi c ati o n 
I N D 
I n v e sti g ati o n al N e w Dr u g 
I N R 
I nt er n ati o n al N or m ali z e d R ati o 
I R B 
I n stit uti o n al R e vi e w B o ar d 
I R T 
I nt er a cti v e R e s p o n s e T e c h n ol o g y 
I U D 
I ntr a ut eri n e D e vi c e 
I U S 
I ntr a ut eri n e S y st e m 
J S W  
J oi nt S p a c e Wi dt h  
K & L  
K ell gr e n a n d L a wr e n c e  
K DI G O  
Ki d n e y Di s e a s e I m pr o vi n g Gl o b al O ut c o m e s  
k g  
kil o gr a m  
 
 
l at J S N 
L at er al J oi nt S p a c e N arr o wi n g  
L D H  
L a ct at e d e h y dr o g e n a s e  
L D L  
L o w -D e n sit y Li p o pr ot ei n  
L F T  
Li v er f u n cti o n t e st  
C CI
C CI

N o v arti s  
C o nfi d e nti al  
P a g e 8 9  of 1 0 3  
A m e n d e d Pr ot o c ol V er si o n v 0 2 ( Cl e a n ) 
 
Pr ot o c ol N o. C R H H 6 4 6 A 1 2 2 0 1  
 
L L O Q  
L o w er li mit of q u a ntifi c ati o n  
M A R  
Mi s si n g at R a n d o m  
M e d D R A  
M e di c al di cti o n ar y f or r e g ul at or y a cti viti e s 
m e d J S N  
M e di al J oi nt S p a c e N arr o wi n g  
m g  
milli gr a m( s)  
m L  
millilit er( s)  
M M R M  
Mi x e d Eff e ct M o d el f or R e p e at e d M e a s ur e s  
M O A K S  
M RI O st e o art hriti s K n e e S c or e  
mr e m  
millir e m  
M RI  
M a g n eti c R e s o n a n c e I m a gi n g  
m S v  
milli si e v ert s  
N O A E L  
N o o b s er v e d a d v er s e eff e ct l e v el  
 
 
N S AI D  
N o n -st er oi d al a nti -i nfl a m m at or y dr u g s 
O A  
O st e o art hriti s  
O H P  
Off -sit e H e alt h c ar e Pr of e s si o n al  
P A  
P o st eri or -a nt eri or  
p. o.  
Or al(l y)  
P C R  
Pr ot ei n -cr e ati ni n e r ati o  
P D  
P h ar m a c o d y n a mi c( s)  
P K  
P h ar m a c o ki n eti c( s)  
P o C  
Pr o of of C o n c e pt  
P R O  
P ati e nt R e p ort e d O ut c o m e s  
P T  
Pr ot hr o m bi n ti m e  
P T O A  
P o st -Tr a u m ati c O A  
Q D  
O n c e a d a y  
Q o L  
Q u alit y of Lif e  
Q T c F  
Q T i nt er v al c orr e ct e d b y Fri d eri ci a’ s f or m ul a  
S A E  
S eri o u s A d v er s e E v e nt  
S A P  
St ati sti c al A n al y si s Pl a n  
s Cr  
S er u m cr e ati ni n e  
S D  
St a n d ar d d e vi ati o n  
S J S  
St e v e n s -J o h n s o n S y n dr o m e  
S M Q  
St a n d ar di z e d M e d D R A Q u er y  
S o A  
S c h e d ul e of A cti viti e s  
S U S A R  
S u s p e ct e d U n e x p e ct e d S eri o u s A d v er s e R e a cti o n  
T BI L  
T ot al Bilir u bi n  
T E A E  
Tr e at m e nt -E m er g e nt A d v er s e E v e nt  
T E N  
T o xi c E pi d er m al N e cr ol y si s  
T L P/ C/ A  
Tr o c hl e a L at er al P o st eri or/ C e ntr al/ A nt eri or  
T M A  
Tr o c hl e a M e di al A nt eri or  
T P M  
Tr o c hl e a M e di al P o st eri or  
C CI

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ULN 
Upper limit of normal 
ULOQ 
Upper limit of quantification 
UTI 
Urinary Tract Infection 
WHO 
World Health Organization 
WPI 
Widespread Pain Index 
µSv 
microsieverts 
10.2.2 
Definitions 
Additional 
treatment 
Medicinal products that may be used during the clinical trial as described in 
the protocol, but not as an investigational medicinal product (e.g. any 
background therapy) 
Assessment 
A procedure used to generate data required by the study 
Auxiliary medicinal 
product 
Medicinal product used for the needs of a clinical trial as described in the 
protocol, but not as an investigational medicinal product (e.g. rescue 
medication, challenge agents, background treatment or medicinal products 
used to assess end-points in the clinical trial). 
Concomitant therapy is not considered as AMP. 
Biologic Samples 
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study participant 
Clinical Outcome 
Assessment (COA) 
A measure that describes or reflects how a participant feels, functions, or 
survives 
Clinical Trial Team 
A group of people responsible for the planning, execution and reporting of all 
clinical trial activities. Examples of team members include the Study Lead, 
Medical Monitor, Trial Statistician etc. 
Coded Data 
Personal Data which has been de-identified by the investigative center team 
by replacing personal identifiers with a code. 
Cohort 
A group of individuals who share a common exposure, experience or 
characteristic, or a group of individuals followed-up or traced over time 
Control drug 
A study intervention (active or placebo) used as a comparator to reduce 
assessment bias, preserve blinding of investigational drug, assess internal 
study validity, and/or evaluate comparative effects of the investigational drug 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g. q28 days) 
Discontinuation 
from study 
Point/time when the participant permanently stops receiving the study 
treatment and further protocol required assessments or follow-up, for any 
reason. No specific request is made to stop the use of their samples or data. 
Discontinuation 
from study 
treatment 
Point/time when the participant permanently stops receiving the study 
treatment for any reason (prior to the planned completion of study intervention 
administration, if any). Participant agrees to the other protocol required 
assessments including follow-up. No specific request is made to stop the use 
of their samples or data. 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg 
once a day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used to 

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capture data transcribed from source data/documents used at the point of 
care 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last participant. 
Enrollment 
Point/time of participant entry into the study at which informed consent must 
be obtained. The action of enrolling one or more participants 
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, 
allowing for the real time collection of clinical trial information to Novartis and 
other oversight authorities, as appropriate 
Estimand 
As defined in the ICH E9(R1) addendum, estimand is a precise description of 
the treatment effect reflecting the clinical question posed by the trial objective. 
It summarizes at a population-level what the outcomes would be in the same 
participants under different treatment conditions being compared. Attributes of 
an estimand include the population, variable (or endpoint) and treatment of 
interest, as well as the specification of how the remaining intercurrent events 
are addressed and a population-level summary for the variable. 
Healthy volunteer 
A person with no known significant health problems who volunteers to be a 
study participant  
Intercurrent events 
Events occurring after treatment initiation that affect either the interpretation 
or the existence of the measurements associated with the clinical question of 
interest. 
Investigational 
drug/ treatment 
The drug whose properties are being tested in the study 
Investigational 
Product/ 
Investigational 
Medicinal product 
A pharmaceutical form of an active ingredient or placebo being tested or used 
as a reference (such as an active comparator) in a clinical trial, including a 
product with a marketing authorization when used or assembled (formulated 
or packaged) in a way different from the approved form, or when used for an 
unapproved indication, or when used to gain further information about an 
approved use. 
Investigational 
Medical Device 
Medical Device being assessed for safety or performance in a clinical 
investigation. This includes devices already on the market and being 
evaluated for new intended uses, new populations, new materials, or design 
changes 
Medication number 
A unique identifier on the label of medication kits 
Mis-randomized 
participants 
Mis-randomized participants are those who were not qualified for 
randomization and who did not take study treatment, but have been 
inadvertently randomized into the study or the participant allocated to an 
invalid stratification factor 
Off-site 
Describes trial activities that are performed at remote location by an off-site 
healthcare professional, such as procedures performed at the participant's 
home. 
Off-site healthcare 
Professional (OHP) 
A qualified healthcare professional, who performs certain protocol procedures 
for the participant in an off-site location such as a participant's home. 
Other treatment 
Treatment that may be needed/allowed during the conduct of the study 
(i.e. concomitant or rescue therapy) 
Part 
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose part 

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and a multiple dose part, or a part in participants with established disease and 
in those with newly-diagnosed disease 
Participant 
A trial participant (can be a healthy volunteer or a patient). "Participant" 
terminology is used in the protocol whereas term "Subject" is used in data 
collection 
Participant number 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc. 
Patient-Reported 
Outcome (PRO) 
A measurement based on a report that comes directly from the participant 
about the status of a participant's health condition without amendment or 
interpretation of the participant's report by a clinician or anyone else 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis 
Personal data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples. 
Randomization 
The process of assigning trial participants to investigational drug or 
control/comparator drug using an element of chance to determine the 
assignments in order to reduce bias. 
Randomization 
number 
A unique identifier assigned to each randomized participant 
Remote 
Describes any trial activities performed at a location that is not the 
investigative site. 
Rescreening 
If a participant fails the initial screening and is considered as a Screen Failure, 
he/she can be invited once for a new Screening visit after medical judgment 
and as specified by the protocol 
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study 
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource 
Start of the clinical 
trial 
The start of the clinical trial is defined as the signature of the informed 
consent by the first participant 
Study device 
Study device is a medical device (marketed or investigational) that is used in 
a circumstance that makes it part of the investigation. 
Study treatment 
Any drug or combination of drugs or intervention administered to the study 
participants as part of the required study procedures; includes investigational 
drug(s), control(s) or background therapy 
Target knee 
Participants left or right knee, selected by the investigator based on patient 
complaints, medical history, careful knee examination along with a local 
review of the X-ray. For example, if a similar stage of radiographic disease 
exists in both knees and the level of pain is similar in both knees, then either 
knee can be chosen as the target knee. If a similar stage of radiographic 
disease exists in both knees but the patient acknowledges that one of the 
knees gives him/her more trouble than the other, the more troublesome knee 
should be chosen as the target knee. 

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Tele-visit 
Procedures or communications conducted using technology such as 
telephone or video-conference, whereby the participant is not at the 
investigative site where the Investigator will conduct the trial. 
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and 
may consist of 1 or more cohorts. 
Treatment of 
interest 
The treatment of interest and, as appropriate, the alternative treatment to 
which comparison will be made. These might be individual interventions, 
combinations of interventions administered concurrently, e.g. as add-on to 
standard of care, or might consist of an overall regimen involving a complex 
sequence of interventions. This is the treatment of interest used in describing 
the related clinical question of interest, which might or might not be the same 
as the study treatment. 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event. 
Withdrawal of 
consent 
Withdrawal of consent from the study occurs when the participant explicitly 
requests to stop use of their data and/or biological samples AND no longer 
wishes to receive study treatment, AND does not agree to further protocol 
required assessments. This request should be in writing (depending on local 
regulations) and recorded in the source documentation. 
This request should be distinguished from a request to discontinue the study. 
Other study participant's privacy rights are described in the corresponding 
informed consent form. 

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10.3 
Appendix 3: Clinical laboratory tests 
10.3.1 
Clinically notable laboratory values and vital signs 
Please refer to the Laboratory Manual for details. 

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10.4 
Appendix 4: Participant Engagement 
The following participant engagement initiatives are included in this study and will be provided, 
as available, for distribution to study participants at the time points indicated. If compliance is 
impacted by cultural norms or local laws and regulations, sites may discuss modifications to 
these requirements with Novartis. 
• Thank You letter 
• Participant visit guide 
• Individual treatment information - after database lock 
• Plain language trial summary - after CSR publication 

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10.5 
Appendix 5: Liver safety monitoring 
To ensure participant safety and enhance reliability in determining the hepatotoxic potential of 
an investigational drug, a standardized process for identification, monitoring and evaluation of 
liver events has to be followed. 
Please refer to Table 10-1 for complete definitions of liver laboratory triggers. 
Once a participant is exposed to study treatment, every liver event defined in Table 10-1 should 
be followed up by the investigator or designated personnel at the trial site, as summarized 
below. Additional details on actions required in case of liver events are outlined in Table 10-2. 
Repeat liver chemistry tests (i.e. ALT, AST, TBL, PT/INR, ALP and G-GT) to confirm 
elevation. 
• These liver chemistry repeats will be performed using the central laboratory. If results will 
not be available from the central laboratory, then the repeats can also be performed at 
a local laboratory to monitor the safety of the participant. If a liver event is subsequently 
reported, any local liver chemistry tests previously conducted that are associated with 
this event should have results recorded on the appropriate CRF. 
• If the initial elevation is confirmed, close observation of the participant will be initiated, 
including consideration of treatment interruption if deemed appropriate. 
• Discontinuation of the investigational drug (refer to the Discontinuation of study treatment 
Section 7.1), if appropriate 
• Hospitalization of the participant if appropriate 
• Causality assessment of the liver event 
• Thorough follow-up of the liver event should include 
• These investigations can include based on investigator’s discretion: serology tests, 
imaging and pathology assessments, hepatologist’s consultancy; obtaining more 
detailed history of symptoms and prior or concurrent diseases, history of concomitant 
drug use, exclusion of underlying liver disease 
All follow-up information and procedures performed must be recorded as appropriate in 
the CRF. 

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10.5.1 
Liver event and laboratory trigger definitions & follow-up requirements 
Table 10-1 
Liver event and laboratory trigger definitions 
 
Definition/ threshold 
Liver laboratory triggers 
If ALT, AST and total bilirubin 
normal at baseline: 
• 
ALT or AST > 5 × ULN 
• 
ALP > 2 × ULN (in the absence of known bone pathology) 
• 
Total bilirubin > 3 × ULN (in the absence of known Gilbert 
syndrome) 
• 
ALT or AST > 3 × ULN and INR > 1.5 
• 
Potential Hy’s Law cases (defined as ALT or AST > 3 × 
ULN and Total bilirubin > 2 × ULN [mainly conjugated 
fraction] without notable increase in ALP to > 2 × ULN) 
• 
Any clinical event of jaundice (or equivalent term) 
• 
ALT or AST > 3 × ULN accompanied by (general) 
malaise, fatigue, abdominal pain, nausea, or vomiting, or 
rash with eosinophilia 
• 
Any adverse event potentially indicative of a liver toxicity* 
If ALT or AST abnormal at 
baseline: 
• 
ALT or AST > 3x baseline AND > 5x ULN 
*These events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-
related conditions; non-infectious hepatitis; benign, malignant and unspecified liver neoplasms ULN: 
upper limit of normal 

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Table 10-2 
Follow up requirements for liver laboratory triggers - ALT, AST, TBL 
 
ALT 
TBL 
Liver 
Symptoms 
Action 
ALT increase without bilirubin increase: 
 
 
If normal at baseline: 
ALT > 5 x ULN for more than 
two weeks OR 
ALT > 8 x ULN 
Normal 
For 
participants with 
Gilbert’s 
syndrome: No 
change in 
baseline TBL 
None 
• 
Interrupt study 
treatment 
• 
Measure ALT, 
AST, ALP, 
GGT, TBIL, 
INR, albumin, 
CK, and GLDH 
in 48-72 hours. 
• 
Follow-up for 
symptoms. 
• 
Initiate close 
monitoring and 
workup for 
competing 
etiologies. 
• 
Study treatment 
can be 
restarted if liver 
enzymes return 
to baseline.. 
If elevated at baseline: 
ALT > 3 x baseline 
 AND > 5x ULN for more than 
two weeks 
OR 
ALT ≥ 5x baseline 
AND ≥ 8x ULN 
ALT increase with bilirubin increase: 
 
If normal at baseline: 
ALT > 3 x ULN 
TBL > 2 x ULN 
(or INR > 1.5) 
For participants 
with Gilbert’s 
syndrome: 
Doubling of direct 
bilirubin 
None 
If elevated at baseline: 
ALT > 2 x baseline 
AND > 3x ULN  
 
If normal at baseline: 
ALT > 3 x ULN 
Normal or 
elevated* 
Severe fatigue, 
nausea, 
vomiting, right 
upper quadrant 
pain* 
If elevated at baseline: 
ALT > 2 x baseline 
AND > 3x ULN 
* This situation suggests liver injury based on (i) elevation of ALT, and (ii) the presence of symptoms of 
liver injury. Even if bilirubin is normal, the presence of liver symptoms indicates potentially severe liver 
injury. 

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Table 10-3 
Follow up requirements for liver laboratory triggers - Isolated 
Hyperbilirubinemia 
Criteria 
Actions required 
Follow-up monitoring 
Total Bilirubin 
(isolated) 
 
 
>1.5 – 3.0 ULN 
• 
Maintain treatment 
• 
Repeat LFTs within 48-72 hours 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline 
> 3 - 10 × ULN (in 
the absence of 
known Gilbert 
syndrome) 
• 
Interrupt treatment 
• 
Repeat LFT within 48-72 hours 
• 
Hospitalize if clinically appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g. conmeds, med hx, lab) 
in the appropriate CRF 
Monitor LFTs weekly until 
resolution to ≤ Grade 1 or to 
baseline (ALT, AST, total bilirubin, 
Alb, PT/INR, ALP and GGT) 
Test for hemolysis (e.g. 
reticulocytes, haptoglobin, 
unconjugated [indirect] bilirubin) 
> 10 x ULN 
• 
Discontinue the study treatment 
immediately 
• 
Hospitalize the participant 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g. conmeds, med hx, lab) 
in the appropriate CRF 
ALT, AST, total bilirubin, Alb, 
PT/INR, ALP and GGT until 
resolution (frequency at 
Investigator discretion) 
Any AE potentially 
indicative of a 
liver toxicity 
• 
Consider study treatment 
interruption or discontinuation 
• 
Hospitalization if clinically 
appropriate 
• 
Establish causality 
• 
Record the AE and contributing 
factors (e.g. conmeds, med hx, lab) 
in the appropriate CRF 
 
Based on investigator’s discretion, investigation(s) for contributing factors for the liver event 
can include: Serology tests, imaging and pathology assessments, hepatologist’s consultancy; 
obtaining more detailed history of symptoms and prior or concurrent diseases, history of 
concomitant drug use, exclusion of underlying liver disease. 

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10.6 
Appendix 6: Renal safety monitoring 
Once a participant is exposed to study treatment, the following two categories of abnormal renal 
laboratory alert values should be assessed during the study period: 
• Serum creatinine increase ≥ 25% compared to baseline during normal hydration status 
• Any one of the following: 
• Urine protein-creatinine ratio (PCR) ≥1g/g or ≥100 mg/mmol, OR 
• New onset dipstick proteinuria ≥ 3+, OR 
• New onset dipstick hematuria ≥ 3+ (after excluding menstruation, UTI, extreme 
exercise, or trauma) 
Abnormal renal event findings must be confirmed within 24-48 hours after the first assessment. 
Once a participant is exposed to study treatment, renal laboratory alerts or renal safety events, 
as defined in Table 10-4, should be monitored and followed up by the investigator or designated 
trial staff as summarized in Table 10-5. 
10.6.1 
Specific Renal Alert Criteria and Actions and Event Follow-up 
Table 10-4 
Specific renal alert criteria and actions 
Renal Event 
 Actions 
Confirmed serum creatinine (SCr) 
increase 25 – 49% 
• 
Consider causes and possible interventions 
• 
Follow up within 2-5 days 
(SCr) increase 50 %+ 
• 
Consider causes and possible interventions 
• 
Repeat assessment within 24-48h if possible 
• 
Consider drug interruption or discontinuation 
unless other causes are diagnosed and corrected 
• 
Consider participant hospitalization and 
specialized treatment 
New onset dipstick proteinuria ≥ 3+ 
OR 
Protein-creatinine ratio (PCR) ≥ 1g/g Cr (or 
mg/mmol equivalent as converted by the 
measuring laboratory) 
• 
Consider causes and possible interventions 
• 
Assess serum albumin & serum total protein 
• 
Repeat assessment to confirm 
• 
Consider drug interruption or discontinuation 
unless other causes are diagnosed and corrected 
New onset hematuria ≥ 3+ on urine dipstick 
• 
Repeat assessment to confirm 
• 
Distinguish hemoglobinuria from hematuria 
• 
Urine sediment microscopy 
• 
Assess sCr 
• 
Exclude infection, trauma, bleeding from the 
distal urinary tract/bladder, menstruation 
• 
Consider bleeding disorder 

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Renal Event 
 Actions 
New evidence of crystals on microscopy 
• 
Repeat assessment to confirm 
• 
Assess (SCr), urea and electrolytes 
• 
Consider causes and possible interventions 
• 
Consider drug interruption or discontinuation 
unless other causes are diagnosed and corrected 
+ Corresponds to Kidney Disease Improving Global Outcomes (KDIGO) criteria for Acute Kidney Injury 
Table 10-5 
Renal Event Follow Up 
• 
Urine dipstick and sediment microscopy evidence of DIN:  crystals, red blood cells 
(dysmorphic/glomerular vs. non-dysmorphic/non-glomerular), white blood cells, tubular epithelial 
cells 
• 
Blood pressure and body weight 
• 
(SCr), BUN, electrolytes (sodium, potassium, phosphate, calcium), bicarbonate and uric acid 
• 
Urine output 
Review and record possible contributing factors to the renal event (co-medications, other co-morbid 
conditions) and additional diagnostic procedures (MRI etc.) in the eCRF 
• 
Event resolution: (sCr within 10% of baseline or PCR < 1 g/g Cr, or ACR <300 mg/g Cr) or 
• 
Event stabilization: sCr level with ±10% variability over last 6 months or protein-creatinine ratio 
stabilization at a new level with ±50% variability over last 6 months. 
• 
Analysis of urine markers in samples collected over the course of the DIN event 

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