A Multicenter, Single Arm, Open-label Trial to Evaluate Efficacy and Safety of Oral, Twice Daily Iptacopan in Adult PNH Patients Who Have Hb≥10 g/dL in Response to Anti-C5 Antibody and Switch to Iptacopan
Phase: PHASE3
Conditions: Paroxysmal Nocturnal Hemoglobinuria
Sponsor: Novartis Pharmaceuticals

Novartis Research and Development
Clinical Trial Protocol Title:
A multicenter, single arm, open-label trial to evaluate 
efficacy and safety of oral, twice daily iptacopan in adult 
PNH patients who have Hb≥10 g/dL in response to anti-C5 
antibody and switch to iptacopan 
Clinical Trial Protocol Number: CLNP023C12303 / NCT05630001
Version Number: 02 (Clean)
Compound: LNP023
Brief Title: A multicenter, single arm, open-label trial to evaluate efficacy and safety 
of oral, twice daily iptacopan in adult PNH patients who have Hb≥10 g/dL in response 
to anti-C5 antibody and switch to iptacopan 
Study Phase: IIIb
Acronym: APPULSE
Sponsor Name: Novartis
Regulatory Agency Identifier Number(s): EU CT number: 2022-502148-10-00
Approval Date: 12-Dec-2023 (content final)
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. CLNP023C12303
Table of contents
Table of contents..................................................................................................................2
List of tables.........................................................................................................................6
List of figures.......................................................................................................................6
Amendment 02 (12-December-2023)..................................................................................7
Amendment 01 (23 February 2023).....................................................................................9
1
Protocol summary..............................................................................................................11
1.1
Summary................................................................................................................11
1.2
Schema...................................................................................................................13
1.3
Schedule of activities (SoA) ..................................................................................13
2
Introduction........................................................................................................................19
2.1
Study rationale .......................................................................................................19
2.2
Background............................................................................................................19
2.3
Benefit/Risk assessment.........................................................................................21
3
Objectives, endpoints, and estimands................................................................................24
3.1
Primary estimands..................................................................................................25
3.2
Secondary estimands..............................................................................................25
4
Study design.......................................................................................................................26
4.1
Overall design ........................................................................................................26
4.2
Scientific rationale for study design.......................................................................28
4.2.1
Participant input into design..................................................................29
4.3
Justification for dose..............................................................................................29
4.3.1
Rationale for choice of background therapy .........................................32
4.4
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs.......................................................................................................................32
4.5
Rationale for public health emergency mitigation procedures ..............................32
4.6
Purpose and timing of interim analyses/design adaptations ..................................32
4.7
End of study definition...........................................................................................32
4.8
Rationale for planned off-site procedures..............................................................33
5
Study population................................................................................................................33
5.1
Inclusion criteria ....................................................................................................33
5.2
Exclusion criteria ...................................................................................................34
5.3
Screen failures........................................................................................................36
5.3.1
Replacement policy ...............................................................................36
5.3.2
Participant numbering ...........................................................................36
6
Study treatment(s) and concomitant therapy .....................................................................37
6.1
Study treatment(s)..................................................................................................37

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6.1.1
Additional study treatments...................................................................37
6.1.2
Treatment arms/group ...........................................................................38
6.1.3
Treatment duration ................................................................................38
6.2
Preparation, handling, storage, and accountability ................................................38
6.2.1
Handling of study treatment..................................................................38
6.2.2
Handling of other treatment...................................................................39
6.2.3
Instruction for prescribing and taking study treatment..........................39
6.3
Measures to minimize bias: randomization and blinding ......................................40
6.3.1
Treatment assignment, randomization...................................................40
6.3.2
Treatment blinding ................................................................................40
6.3.3
Emergency breaking of assigned treatment code ..................................40
6.4
Study treatment compliance...................................................................................40
6.4.1
Recommended treatment of adverse events ..........................................40
6.5
Dose modification..................................................................................................41
6.5.1
Definitions of dose limiting toxicities (DLTs)......................................41
6.5.2
Follow-up for toxicities.........................................................................41
6.6
Continued access to study treatment after the end of the study.............................41
6.6.1
Post trial access......................................................................................41
6.7
Treatment of overdose ...........................................................................................41
6.7.1
Reporting of study treatment errors including misuse/abuse ................42
6.8
Concomitant and other therapy..............................................................................42
6.8.1
RBC transfusions and recommendations for breakthrough 
hemolysis (BTH) ...................................................................................42
6.8.2
Concomitant therapy .............................................................................43
6.8.3
Prohibited medication............................................................................44
6.8.4
Rescue medicine....................................................................................44
7
Discontinuation of study treatment and participant discontinuation/withdrawal ..............44
7.1
Discontinuation of study treatment........................................................................44
7.2
Participant discontinuation from the study ............................................................46
7.3
Withdrawal of informed consent and exercise of participants’ data privacy 
rights.......................................................................................................................46
7.4
Lost to follow-up....................................................................................................47
7.5
Early study termination by the Sponsor.................................................................47
8
Study Assessments and Procedures ...................................................................................47
8.1
Screening................................................................................................................48
8.1.1
Hemoglobin assessments during Screening ..........................................48
8.1.2
Absolute Reticulocytes Count during Screening...................................48

N o v arti s
C o nfi d e nti al
P a g e 4 of 9 2
A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
8. 2 
Partici pa nt de m o gra p hics/ ot her baseli ne c haracteristics........................................ 4 8
8. 3 
Efficac y assess me nts.............................................................................................. 4 9
8. 3. 1  
He m o gl o bi n, retic ul oc ytes, L D H a n d ot her P N H-relate d la b orat or y 
para meters.............................................................................................. 4 9
8. 3. 2 
Brea kt hr o u g h he m ol ysis........................................................................ 4 9
8. 3. 3 
P N H-relate d si g ns a n d s y m pt o ms ......................................................... 5 0
8. 3. 4  
Maj or A d verse Vasc ular E ve nts ( M A V Es)........................................... 5 0
8. 3. 5  
A p pr o priate ness of efficac y assess me nts .............................................. 5 1
8. 4 
Safet y assess me nts................................................................................................. 5 2
8. 4. 1 
P h ysical e xa mi nati o ns........................................................................... 5 2
8. 4. 2  
Vital si g ns.............................................................................................. 5 2
8. 4. 3 
Electr ocar di o gra ms................................................................................ 5 2
8. 4. 4 
Cli nical safet y la b orat or y tests .............................................................. 5 3
8. 4. 5 
Pre g na nc y testi n g................................................................................... 5 4
8. 4. 6  
A p pr o priate ness of safet y meas ure me nts.............................................. 5 5
8. 5  
A d diti o nal assess me nts.......................................................................................... 5 5
8. 5. 1 
Cli nical O utc o me Assess me nts ( C O As)................................................ 5 5
8. 6  
A d verse e ve nts ( A Es), seri o us a d verse e ve nts ( S A Es), a n d ot her safet y 
re p orti n g.................................................................................................................5 7
8. 6. 1  
A d verse e ve nts....................................................................................... 5 7
8. 6. 2 
Seri o us a d verse e ve nts........................................................................... 6 0
8. 6. 3 
S A E re p orti n g........................................................................................ 6 0
8. 6. 4 
Pre g na nc y.............................................................................................. 6 2
8. 6. 5  
Disease-relate d e ve nts a n d/ or disease-relate d o utc o mes n ot 
q ualif yi n g as A Es or S A Es.................................................................... 6 2
8. 6. 6  
A d verse e ve nts of s pecial i nterest ......................................................... 6 3
8. 7
...................................................................................................6 3
8. 8
.............................................................................................................6 3
8. 9 
I m m u n o ge nicit y assess me nts................................................................................. 6 4
8. 1 0  
Me dical res o urce utilizati o n a n d healt h ec o n o mics............................................... 6 5
8. 1 1  
Off-site Pr oce d ures ................................................................................................ 6 5
8. 1 1. 1 
Res p o nsi bilit y of i n vesti gat or o versi g ht of off-site acti vities................ 6 5
8. 1 1. 2 
Res p o nsi bilit y of O H Ps......................................................................... 6 6
9 
Statistical c o nsi derati o ns.................................................................................................... 6 6
9. 1  
A nal ysis sets........................................................................................................... 6 6
9. 2 
Statistical a nal yses................................................................................................. 6 6
9. 2. 1  
Ge neral c o nsi derati o ns .......................................................................... 6 6
C CI
C CI

N o v arti s
C o nfi d e nti al
P a g e 5 of 9 2
A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
9. 2. 2 
Partici pa nt de m o gra p hics a n d ot her baseli ne c haracteristics ................ 6 7
9. 2. 3 
Treat me nts............................................................................................. 6 7
9. 3 
Pri mar y e n d p oi nt(s)/esti ma n d(s) a nal ysis.............................................................. 6 7
9. 3. 1  
Defi niti o n of pri mar y e n d p oi nt(s) ......................................................... 6 7
9. 3. 2 
Statistical m o del, h y p ot hesis, a n d met h o d of a nal ysis.......................... 6 7
9. 3. 3  
Ha n dli n g of i nterc urre nt e ve nts of pri mar y esti ma n d (if a p plica ble).... 6 8
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................ 6 8
9. 3. 5  
M ulti plicit y a dj ust me nt (if a p plica ble).................................................. 6 8
9. 3. 6 
Se nsiti vit y a nal yses ............................................................................... 6 9
9. 3. 7 
S u p ple me ntar y a nal ysis......................................................................... 6 9
9. 4 
Sec o n dar y e n d p oi nt(s)/esti ma n d(s) a nal ysis.......................................................... 6 9
9. 4. 1 
Efficac y a n d/ or p har mac o d y na mic e n d p oi nt(s)..................................... 6 9
9. 4. 2 
Safet y e n d p oi nts .................................................................................... 7 1
9. 4. 3 
Patie nt re p orte d o utc o mes ..................................................................... 7 2
9. 5 
E x pl orat or y e n d p oi nt(s)/esti ma n d(s) a nal ysis........................................................ 7 2
9. 5. 1 
P har mac o ki netics................................................................................... 7 3
9. 5. 2 
Bi o mar kers ............................................................................................ 7 3
9. 5. 3 
...................................................................................................... 7 4
9. 5. 4
..............................................................................7 4
9. 6 
( Ot her) Safet y a nal yses.......................................................................................... 7 4
9. 7  
Ot her a nal yses........................................................................................................ 7 4
9. 8 
I nteri m a nal ysis...................................................................................................... 7 4
9. 9 
Sa m ple size deter mi nati o n..................................................................................... 7 4
9. 9. 1 
Pri mar y e n d p oi nt(s)............................................................................... 7 4
9. 9. 2 
Sec o n dar y e n d p oi nt(s)........................................................................... 7 5
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............................................... 7 5
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................... 7 5
1 0. 1. 1 
Re g ulat or y a n d et hical c o nsi derati o ns................................................... 7 5
1 0. 1. 2 
I nf or me d c o nse nt pr ocess...................................................................... 7 6
1 0. 1. 3  
Data pr otecti o n ...................................................................................... 7 8
1 0. 1. 4 
C o m mittees str uct ure............................................................................. 7 8
1 0. 1. 5  
Data q ualit y ass ura nce........................................................................... 7 9
1 0. 1. 6 
S o urce d oc u me nts.................................................................................. 8 0
1 0. 1. 7 
P u blicati o n p olic y.................................................................................. 8 0
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 1
1 0. 2  
A p pe n di x 2: A b bre viati o ns a n d defi niti o ns........................................................... 8 2
C CI
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10.2.1
List of abbreviations..............................................................................82
10.2.2
Definitions.............................................................................................84
10.3
Appendix 3: Clinical laboratory tests.....................................................................86
10.3.1
Clinically notable laboratory values and vital signs..............................86
10.4
Appendix 4: Participant Engagement ....................................................................86
10.5
Appendix 5: Liver safety monitoring.....................................................................86
10.5.1
Liver event and laboratory trigger definitions & follow-up 
requirements ..........................................................................................87
10.6
Appendix 6: Renal safety monitoring....................................................................89
11 References..........................................................................................................................90
List of tables
Table 1-1
Assessment Schedule.............................................................................15
Table 3-1
Objectives and related endpoints...........................................................24
Table 6-1
Investigational and control drug............................................................37
Table 6-2
Guidance for capturing the study treatment errors including 
misuse/abuse..........................................................................................42
Table 8-1
Breakthrough definition.........................................................................50
Table 8-2
Laboratory tests .....................................................................................53
Table 9-1
Power for non-inferiority test based on different assumptions .............75
Table 9-2
Power for superiority test based on different assumptions....................75
Table 10-1
Definitions of Triggers, Actions and Follow-up requirements for 
liver events.............................................................................................87
List of figures
Figure 1-1
Study design ..........................................................................................13
Figure 8-1
Timing of study procedures...................................................................53
Figure 9-1
Hierarchy of testing non-inferiority and superiority of iptacopan.........69

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Amendment 02 (12-December-2023)
Amendment Rationale
This amendment aims to revise the protocol based on new information in line with the annual 
Investigator’s Brochure update and to include updates related to the Auxiliary Medicinal 
Products (AxMPs) and their safety reporting in line with the changes required under EU Clinical 
Trial Regulation (EU-CTR) No 536/2014. 
Main changes in this amendment:
Section 2.2, Section 2.3, Section 4.1, Section 4.3: Updated risks as per IB v10 and updated 
status of phase 2 and 3 studies in PNH. Added results from completed hepatic impairment and 
results from CLNP023X2201, CLNP023X2204 and QTc study.
Section 4.1 and Section 6.4.1: Based on updates in IB v10, added requirement of sample 
collection for bacterial cultures in suspicion/confirmation of infection, added guidance to treat 
infections and recommendations for treatment interruptions and recommencement as per 
investigator’s clinical assessment of benefit and risk.
Section 5.1: Updated inclusion criteria 3 to 3a: clarified stable regimen of previous anti-C5 
antibody treatment should be as per the locally approved label.
Section 6.8.2.1: Removed the OATP1B1/1B3 and P-gp inhibitors as prohibited medications and 
permitted concomitant medications requiring caution and/or action based on results from 
completed drug-drug interaction (DDI) study.
Section 8.6, Section 8.6.1 to Section 8.6.3: Causality assessment and reporting of AE and SAEs 
related to AxMPs added. 
Section 8.6.3 and Table 10-1: Expedited reporting of potential Hy’s Law cases added.
Other changes to the protocol:
Table 1-1: 
•
Updated footnote 1: Guidance for conducting ETD visit, footnote 4: Urinalysis dipstick 
assessment results will be recorded in eCRF and footnote 13: for collection of cultures in 
case of bacterial infection. 
•
Added footnote 14: Defined time window for patient interview.
Section 7.1: Removed discontinuation of study treatment in case of use of prohibited medication.
Section 8.2: Clarified data collection of “eligible” participants
Section 8.4.4: Changed “WBC/leukocytes” to “leukocyte esterase” as a test name and aligned 
with Table 1-1.
Section 8.6.6: Removed sentence about infections caused by encapsulated bacteria as an AESIs
Section 10.1.2: Added new abbreviations.
Section 11: Added references

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Other changes to align with latest Novartis protocol template were performed 
to:
Table 6-1: Updated formatting
Section 6.2.1: Added storage conditions of study treatment can be found on the IMP bottle label.
Section 6.3.2: Added clarification that treatment blinding is not applicable as this is an open 
label study.
Section 6.7.1: Updated language for study treatment errors
Section 7.5: Added indication (PNH) to reasons of early termination.
Section 8.6.4: Updated language for pregnancy follow-up and reporting.
Section 10.2.2: Definitions of AxMP added and definition for Investigational medicinal product 
is updated.
Other relevant sections in the protocol are updated for consistency and clarity in relation to 
updates made in above mentioned sections. Also, observed typos and formatting errors were 
corrected.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs) 
/Independent Ethics Committee (IECs) and Health Authorities, if applicable.
The changes herein are also reflected in the Informed Consent.

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Protocol No. CLNP023C12303
Amendment 01 (23 February 2023)
Amendment Rationale
The main rationale of this amendment is to define the time limit for the historical PNH clone 
size results for eligibility, without which patients with a PNH clone size of below 10% could 
be included. The limit of 12 months before screening to get this data is reasonably sufficient to 
have a PNH clone size of similar amount at time of screening. Additionally, the optional interim 
analyses are removed. 
Major revisions are made to:
Section 3: Added a secondary objective to assess the effect of iptacopan on transfusion 
avoidance defined as the proportion of participants who remain free from transfusions and 
added a corresponding endpoint evaluating absence of administration of packed RBC 
transfusions between Day 1 and Day 168 (no change in data collection strategy).
Section 4.6 and Section 9.8: Optional Interim Analyses are removed.
Section 5.1: Inclusion criterion #2: Updated to define a limit of 12 months prior to Screening 
visit 1 for use of the PNH clone size test results from historical data to determine eligibility. 
Other changes to the protocol are:
Section 2.2: Updated based on available results of APPLY-PNH study.
Section 4.3.1: Auxiliary Medicinal Product (AxMP) defined as per EU CTR.
Section 6.2.3: Updated instructions for dosing of iptacopan in the event of vomiting.  
Section 6.7: Clarified that in case of missed iptacopan dose or vomiting within 4 hours of 
previous dose, a single dose of iptacopan taken will not be considered as an overdose to reduce 
the risk to participants of hemolysis.
Section 8.6.4: Aligned with standard template language
Section 7.1: Clarified that permanent treatment discontinuation is when study treatment is 
discontinued before EoS visit/Day 168 visit.
Section 9.3.3 and Section 9.3.4: Clarified imputation strategies.
Section 9.4.1: Added back-up methods for secondary endpoints in case of non-convergence of 
regression models.
Table 1-1: 
•
Added a Urinalysis assessment timepoint at D168
•
Added vaping as an option in smoking history. 
•
Updated Surgical procedures to Surgical and medical procedures, added a timepoint at 
screening visit 2

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Other relevant sections in the protocol are updated for consistency and clarity in relation to 
updates made in above mentioned sections. Also, observed typos and formatting errors were 
corrected.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs) 
/Independent Ethics Committee (IECs) and Health Authorities, if applicable.
The changes herein are also reflected in the Informed Consent.

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1
Protocol summary
1.1
Summary
This is a multicenter, single-arm, open label trial, with iptacopan treatment for 24 weeks in adult 
PNH patients. Eligible participants must have a mean Hb ≥10 g/dL in response to a stable 
regimen with anti-C5 for at least 6 months and must be transfusion free for the same period. 
This study is comprised of two periods:
•
A Screening period lasting up to 8 weeks.
Baseline for primary and key secondary objectives is defined as the mean of three Hb 
assessments conducted at central laboratory: two during screening and the third on Day 1 before 
starting treatment.
Baseline for all other objectives is defined as Day 1 or, in case of missing data on Day 1, any 
previous assessment done during Screening.
•
A 24-week open-label, iptacopan Treatment period.
A total of approximately 50 participants will be enrolled in the trial. All participants must 
provide written informed consent prior to start of any study-related activities.
The study design is shown in the schematic in Section 1.2.
Screening
Screening period starts at the time of Informed Consent Form (ICF) signing and lasts until the 
day preceding Day 1 of the Treatment period.
Participants will be asked to review and sign the ICF prior to starting the screening assessments. 
After signing the ICF, inclusion and exclusion criteria will be assessed to verify participants’ 
eligibility for enrollment into the study at screening visit 1. If patient meets eligibility criteria 
during screening visit 1, screening visit 2 will be performed to confirm hemoglobin as per 
inclusion criterion 4 and vaccination status as per inclusion criteria 5 and 6. This will be 
followed by the visit’s assessment as outlined in Table 1-1, as applicable.
By signing the ICFs, the participants will provide access to the following medical records for 
the last 6 to 12 months prior to Screening:
•
Date and result of PNH WBC clone size performed in the 12 months prior to screening.
•
Hb levels, MAVEs and anti-C5 antibody regimen reported in the past 6 months
•
the number of transfusions and unit numbers of packed-RBC received in the past 12 
months.
Participants must be vaccinated as outlined in Section 5.1 Inclusion criteria. Vaccines should 
cover as many serotypes as possible (including meningococcal serotypes A, C, Y, W-135 and 
B). To minimize participant burden, the use of multivalent vaccines is recommended as locally 
available and per local guidelines and regulations (e.g. quadrivalent vaccine for N. meningitidis 
which covers serotypes A, C, Y and W-135 and Pneumovax-23 which covers 23 S. pneumoniae 
serotypes). For the vaccination type and booster requirements use local guidelines, and locally 
available vaccines (and refer to the package insert of those, or local guidelines).

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If eligibility criteria are not met due to any assessment, the participant should be considered as 
having failed the screening and does not proceed to treatment period. In the case where a safety 
laboratory value at screening is outside of the range specified in the exclusion criteria, the 
assessment may be repeated once, before participant is considered to have failed screening. The 
participant can be rescreened as described in detail in Section 5.3.
Treatment period
Participants who meet all the eligibility criteria will proceed to the treatment period. Treatment 
with iptacopan at a dose of 200 mg b.i.d. will start on the first day (Day 1) and continue for 24 
weeks with study visits and corresponding assessments according to schedule described in 
Table 1-1.
Refer to Section 6.8.1 which provides details about the protocol-specific guidelines for 
participants who need to receive a packed-RBC transfusion during the treatment period.
Because of the known increased risk of infections with encapsulated bacteria, all participants 
will be provided with a Participant Safety Card. Participants will be instructed to be vigilant for 
any clinical sign of bacterial infections and to contact the Investigator or local physician 
immediately in case of suspicion of infection and start antibiotic treatment as soon as possible.
For participants who permanently discontinue iptacopan administration, close monitoring and 
treatment proposals are indicated in Section 7.1. Every effort must be made to keep participants 
in the study to complete all visits and assessments up to Day 168 visit. The treatment period 
will end with the completion of the Day 168 visit assessments.
After completion of the treatment period, participants who complete this trial while still 
receiving iptacopan and who continue to derive clinical benefit from the treatment based on the 
Investigator’s evaluation will be able to join the Roll-over extension program (REP; 
CLNP023C12001B), which will provide access to iptacopan and enable long-term safety 
monitoring.
For participants not agreeing to continue in the REP after completing Day 168 visit, they may 
follow the recommended procedures defined in Section 7.1.

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1.2
Schema
Figure 1-1
Study design 
1.3
Schedule of activities (SoA)
The SoA lists all of the assessments when they are performed. All data obtained from these 
assessments must be supported in the participant’s source documentation. The “X” in the table 
denotes the assessments to be recorded in the clinical database or received electronically from 
a vendor. The “S” in the table denotes the assessments that are only in the participant’s source 
documentation and do not need to be recorded in the clinical database.
Participants should be seen for all visits/assessments as outlined in the SoA or as close to the 
designated day/time as possible. If one visit is postponed or brought forward, it should not result 
in the next visit being postponed or brought forward. Missed or rescheduled visits should not 
lead to automatic discontinuation.
Participants, that the Investigator identifies as suitable for off-site visits, must provide informed 
consent (i.e., signature on the optional consent for activities that may be done outside of the 
study site, in the study informed consent form). The participants are under no obligation to 
participate in off-site visits, as they can decide to continue with on-site visits at the study site. 
Participants may have Off-Site Healthcare Professional (OHP) available to them for the second 
screening visit, Day 14/21, Day 28, Day 56, Day 112, Day 126, Day 140 and Day 154. The 
off‑site visits will be carried out by a third-party vendor centrally sourced by the Sponsor that 
can provide qualified research nurses who will perform study assessments under the oversight 
of the Investigator, as per Section 8.11. The qualified nurses will be under the delegation of the 
Investigator. The Investigator will retain accountability for participant’s oversight and all 
medical decisions (i.e. protocol specified medical procedures, AE/SAE assessment and 
reporting, changes in medication, etc.).
Participants who discontinue from study treatment are to complete the early treatment 
discontinuation (ETD) visit as soon as possible and attend the follow-up visits as indicated in 
the SoA.
Participants who discontinue from study should be scheduled for a final evaluation visit if they 
agree, as soon as possible, at which time all the assessments listed for the final visit will be 
performed. At this final visit, all dispensed investigational product must be reconciled, and the 

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adverse events and concomitant medications not previously reported must be recorded on the 
CRF.
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.

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Table 1-1
Assessment Schedule
Period
Screening
Treatment Period
Follow-up
Visit Name
Visit 1
Visit 2
Visit 
101
Visit 
102
Visit 103
Visit 
104
Visit 
105
Visit 
106
Visit 
107
Visit 
108
Visit 
109
Visit 
110
ETD/EoS1
Follow-up 1
Follow-up 2
Days
-56 to -8 -49 to -2
1
7
±1
14±3 or 21±3
28
±3
56
±3
84
±3
112
±3
126
±3
140
±3
154
±3
168
±3
ETD + 7 days ETD + 14 days
Weeks
-8 to -2
-7 to -1
1
1
2 or 3
4
8
12
16
18
20
22
24
-
-
Informed consent
X
Inclusion / 
Exclusion criteria
X
X2
X2
Demography
X
Medical 
history/current 
medical conditions
X
Vaccination
X
X
Smoking/vaping 
history
X
Alcohol history
X
Hepatitis screen
X
HIV screen
X
Physical 
Examination
S
S
S
S
Body Height
X
Body Weight
X
X
X
Blood Pressure and 
Pulse Rate
X
X
X
X
X
X
X
X
X
X
X
X
Body Temperature
X
X
X
X
X
X
X
X
X
X
X
X
X
Electrocardiogram 
(ECG)
X
X

N o v arti s
C o nfi d e nti al
P a g e 1 6 of 9 2
A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
P eri o d
S cr e e ni n g
Tr e at m e nt P eri o d
F oll o w- u p
Vi sit N a m e
Vi sit 1
Vi sit 2
Vi sit 
1 0 1
Vi sit 
1 0 2
Vi sit 1 0 3
Vi sit 
1 0 4
Vi sit 
1 0 5
Vi sit 
1 0 6
Vi sit 
1 0 7
Vi sit 
1 0 8
Vi sit 
1 0 9
Vi sit 
1 1 0
E T D/ E o S 1
F oll o w- u p 1
F oll o w- u p 2
D a y s
- 5 6 t o - 8 - 4 9 t o - 2
1
7
± 1
1 4 ± 3 or 2 1 ± 3
2 8
± 3
5 6
± 3
8 4
± 3
1 1 2
± 3
1 2 6
± 3
1 4 0
± 3
1 5 4
± 3
1 6 8
± 3
E T D + 7 d a y s
E T D + 1 4 d a y s
Pr e g n a n c y a n d 
a s s e s s m e nt s of 
f ertilit y3
S
S
Uri n al y si s 4
X
X
X
X
X
X
X
X
X
X
X
X
Cli ni c al C h e mi str y 
(f ull)
X
X
X
X
Cli ni c al C h e mi str y 
( a b br e vi at e d) 5
X
X
X
X
X
X
X
X
X
X
H e m at ol o g y
X
X 6
X
X
X
X
X
X
X
X
X
X
X
X
X
C o a g ul ati o n
X
X
X
X
X
X
X
X
X
X
X
X
X
X
 
 
 
X
F A CI T- F ati g u e
X
X
X
X
T S Q M 
X
X
X
 
 
 
P N H si g n s a n d 
s y m pt o m s
 
 
X
X
X
X
X
X
X
X
X
X
X
X
X
Br e a kt hr o u g h 
h e m ol y si s 1 2
X
X
X
X
X
X
X
X
X
X
X
C CI
C CI

N o v arti s
C o nfi d e nti al
P a g e 1 7 of 9 2
A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
P eri o d
S cr e e ni n g
Tr e at m e nt P eri o d
F oll o w- u p
Vi sit N a m e
Vi sit 1
Vi sit 2
Vi sit 
1 0 1
Vi sit 
1 0 2
Vi sit 1 0 3
Vi sit 
1 0 4
Vi sit 
1 0 5
Vi sit 
1 0 6
Vi sit 
1 0 7
Vi sit 
1 0 8
Vi sit 
1 0 9
Vi sit 
1 1 0
E T D/ E o S 1
F oll o w- u p 1
F oll o w- u p 2
D a y s
- 5 6 t o - 8 - 4 9 t o - 2
1
7
± 1
1 4 ± 3 or 2 1 ± 3
2 8
± 3
5 6
± 3
8 4
± 3
1 1 2
± 3
1 2 6
± 3
1 4 0
± 3
1 5 4
± 3
1 6 8
± 3
E T D + 7 d a y s
E T D + 1 4 d a y s
M A V E s
X
X
X
X
X
X
X
X
X
X
X
R B C tr a n sf u si o n
X
X
X
X
X
X
X
X
X
X
X
A d v er s e E v e nt s 1 3
X
X
X
Pri or m e di c ati o n s
X
X
C o n c o mit a nt 
m e di c ati o n s
X
X
X
X
X
X
X
X
X
X
X
S ur gi c al a n d 
m e di c al Pr o c e d ur e s 
X
X
X
X
X
X
X
X
X
X
X
X
X
I pt a c o p a n 
b.i. d.
I pt a c o p a n kit 
di s p e n si n g
X
X
X
X
X
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  I n c a s e of p er m a n e nt tr e at m e nt di s c o nti n u ati o n, E T D ( E arl y Tr e at m e nt Di s c o nti n u ati o n) a s s e s s m e nt s a n d f oll o w- u p vi sit s m u st b e p erf or m e d, r ef er t o S e cti o n 7. 1 . 
P ati e nt s h o ul d al s o c o nti n u e wit h st u d y vi sit s a s ori gi n all y pl a n n e d a n d c o m pl et e E o S at D a y 1 6 8. If F oll o w- u p vi sit s c orr e s p o n d t o st a n d ar d vi sit s i n t h e Tr e at m e nt 
p eri o d, a n y a d diti o n al a s s e s s m e nt d efi n e d f or t h o s e st a n d ar d vi sit s ( e. g. P R O s) s h o ul d al s o b e c o m pl et e d. E T D vi sit s h o ul d b e p erf or m e d a s s o o n a s p o s si bl e aft er t h e 
p er m a n e nt tr e at m e nt di s c o nti n u ati o n.
2  I n cl u si o n crit eri a 4, 5 a n d 6, e x cl u si o n crit eri a 2, 7, 8 will b e c h e c k e d at t hi s vi sit.
3  S er u m t e st at s cr e e ni n g; uri n e t e st at E T D
4  Di p sti c k m e a s ur e m e nt s f or pr ot ei n, bilir u bi n, bl o o d, gl u c o s e, k et o n e s, nitrit e s, p H, s p e cifi c gr a vit y, ur o bili n o g e n, a n d l e u k o c yt e e st er a s e will b e p erf or m e d at t h e sit e’ s 
l o c al l a b or at or y.  R e s ult s fr o m  di p sti c k m e a s ur e m e nt  will b e c a pt ur e d i n t h e e C R F. Mi cr o s c o p y m u st b e a s s e s s e d l o c all y f oll o wi n g a n a b n or m al di p sti c k t e st a n d r e s ult s 
c a pt ur e d i n t h e e C R F.
5  L D H, A L T, A S T, A L P, G G T, e G F R, h s- C R P, S er u m cr e ati ni n e, T ot al bilir u bi n a n d fr a cti o n s, C K, T ot al c h ol e st er ol, L D L, H D L, Tri gl y c eri d e s 
6  O nl y h e m o gl o bi n will b e a s s e s s e d at S cr e e ni n g vi sit 2
 
 
 
 
 
 
C CI

N o v arti s
C o nfi d e nti al
P a g e 1 8 of 9 2
A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
P eri o d
S cr e e ni n g
Tr e at m e nt P eri o d
F oll o w- u p
Vi sit N a m e
Vi sit 1
Vi sit 2
Vi sit 
1 0 1
Vi sit 
1 0 2
Vi sit 1 0 3
Vi sit 
1 0 4
Vi sit 
1 0 5
Vi sit 
1 0 6
Vi sit 
1 0 7
Vi sit 
1 0 8
Vi sit 
1 0 9
Vi sit 
1 1 0
E T D/ E o S 1
F oll o w- u p 1
F oll o w- u p 2
D a y s
- 5 6 t o - 8 - 4 9 t o - 2
1
7
± 1
1 4 ± 3 or 2 1 ± 3
2 8
± 3
5 6
± 3
8 4
± 3
1 1 2
± 3
1 2 6
± 3
1 4 0
± 3
1 5 4
± 3
1 6 8
± 3
E T D + 7 d a y s
E T D + 1 4 d a y s
1 2  i n c a s e of a s u s p e ct e d e v e nt of B T H b et w e e n s c h e d ul e d vi sit s, a n u n pl a n n e d vi sit s h o ul d b e c o n d u ct e d. T h e I n v e sti g at or s h o ul d al s o c oll e ct a s a m pl e f or t h e c e ntr al 
l a b or at or y a s s e s s m e nt of H b, L D H a n d Bilir u bi n (t ot al a n d fr a cti o n s), bi o m ar k er s (i n cl u di n g 
) a n d P K, w h e n e v er p o s si bl e.
1 3  B T H a n d M A V E s d uri n g s cr e e ni n g a n d f oll o w- u p p eri o d ar e t o b e c oll e ct e d i n t h e A E p a g e. I n p ati e nt s wit h a s u s pi ci o n of or c o nfir m e d b a ct eri al i nf e cti o n, c ult ur e s 
s h o ul d b e t a k e n a n d tr e at m e nt, i n cl u di n g a p pr o pri at e a nti bi oti c s, s h o ul d b e c o n si d er e d a s p er i n v e sti g at or’ s cli ni c al j u d g e m e nt.
C CI
C CI
C CI

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2
Introduction
2.1
Study rationale
The purpose of this trial is to assess efficacy and safety of iptacopan in a population of PNH 
patients who have Hb ≥10 g/dL in response to anti-C5 standard of care treatment (SoC, 
eculizumab or ravulizumab) and switch to iptacopan. It will provide data in a population of 
PNH patients who were excluded from the iptacopan studies APPLY-PNH and APPOINT-PNH, 
but still represent a large component of PNH patients.
This trial intends to demonstrate non-inferiority to SoC treatment in patients who have achieved 
a good/major/complete hematological response to SoC, applying hematologic response 
categories reported by Risitano et al (2019) and to assess the effect on the change from baseline 
in Hb levels after 24 weeks of treatment with iptacopan 200 mg twice daily.
It also intends to demonstrate, as key secondary objective, superiority to SoC treatment.
The data generated will provide scientific evidence to switch from the SoC intra-venous (iv) 
infusion with anti-C5 antibody treatment (eculizumab/ravulizumab) to oral iptacopan treatment 
in these patients, while also providing information on patient's preference on administration 
route.
2.2
Background
Paroxysmal nocturnal hemoglobinuria (PNH) is a rare acquired hemolytic disorder 
characterized by complement-mediated intravascular hemolysis (IVH), bone marrow failure 
(BMF) and severe thrombophilia (Risitano 2012). It begins with the clonal expansion of a 
hematopoietic stem cell that has acquired a somatic mutation in the phosphatidylinositol N 
acetylglucosaminyltransferase subunit A (PIGA) gene. Consequently, PNH blood cells lack the 
glycophosphatidylinositol anchor protein and are deficient in the membrane-bound complement 
inhibitory proteins CD55 and CD59. As a result, PNH type red blood cells (RBCs) are attacked 
by complement leading to complement mediated lysis (Brodsky 2014).
The clinical spectrum of PNH varies, and signs and symptoms include anemia, thrombosis, 
smooth muscle dystonia, fatigue, hemoglobinuria, chronic kidney disease and pulmonary 
hypertension. The clinical presentation is driven by uncontrolled complement activation on 
CD55 and CD59 deficient PNH type RBCs culminating with hemolysis and the release of free 
hemoglobin, and platelet activation (Hill et al 2013). Hemolysis results in release of 
intracellular hemoglobin and lactate hydrogenase (LDH) into the circulation. Irreversible 
binding to and inactivation of nitric oxide (NO) by hemoglobin and inhibition of NO synthesis 
with consequent vasoconstriction and tissues ischemia, result in abdominal pain, dysphagia, 
erectile dysfunction, platelet activation and a prothrombotic status (Hill et al 2013, 
Brodsky 2014). Thromboembolism is the leading cause of morbidity and mortality in patients 
with PNH and can occur at any site; although venous is more common (80–85%), it can also be 
arterial (15–20%) (Brodsky 2014).
Eculizumab and ravulizumab (engineered from eculizumab with prolonged dosing interval) are 
approved anti-C5 antibody therapies for the treatment of PNH and the current SoC where 
available. The introduction of eculizumab has significantly reduced the thromboembolic risk of 

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PNH patients improving morbidity and mortality and largely improved the quality of life (QoL) 
of PNH patients. Although the anti-C5 antibody treatment is generally effective in treating IVH, 
there remains a high unmet medical need for PNH. In the study of Risitano and colleagues, only 
about one third of patients treated with eculizumab achieved normal or near normal Hb levels 
(Hb ≥11 g/dL) without requiring RBC transfusions (Risitano et al 2009).
A classification of hematological response categories to complement inhibitor therapy has been 
proposed by the Severe Aplastic Anemia (SAA) Working Party of the European group for Bone 
Marrow Transplantation (EBMT) (Risitano et al (2019)). The classification using six categories 
has been applied to a large cohort of 93 PNH patients retrospectively (Debureaux et al 2019) 
after the first six months of treatment with eculizumab (n=80). It was observed that only 13% 
of patients achieved a complete or major response i.e. no transfusion with normal Hb ≥12 g/dL 
without (complete response) or with residual significant IVH / increased erythropoietic 
response (major response). 34% of patients achieved a good response (no transfusion with mild 
anemia (Hb ≥10 to <12 g/dL) with or without residual significant IVH and BMF ruled out) 
while the rest were patients with Hb <10 g/dL.
A simplified classification using four categories was applied to a large cohort of 160 PNH 
patients retrospectively (Debureaux et al 2021) with a median treatment duration of 5.8 years 
with eculizumab. It was observed that nearly 60% of patients achieved transfusion independent 
good (Hb 10-12 g/dL) or complete (no anemia) response in the first year of therapy. However 
they still suffered from extravascular hemolysis (EVH; 43% and 17% in patients with good 
response and complete response respectively), BTH (8% and 11% in patients with good 
response and complete response respectively) and other PNH symptoms.
The heterogeneous response to eculizumab or other anti-C5 antibody treatment can, in part, be 
explained through its mechanism of action inhibiting only the terminal part of the complement 
cascade. Therefore, deposition of C3 fragments on the cell surface of PNH type erythrocytes 
lacking CD55 is not impacted, rendering the cells susceptible to EVH. This is inconspicuous in 
untreated PNH patients, because signs and symptoms of IVH dominate. However, EVH 
eventually emerges once the therapeutic inhibition with anti-C5 agents prevents IVH. In fact, it 
can become the main mechanism of hemolysis in patients treated with eculizumab 
(Risitano et al 2009) and C3 mediated EVH represents an unmet medical need.
The PEGASUS trial showed that patients with Hb <10.5 g/dL who switched from anti-C5 to 
pegcetacoplan (anti-C3) had an improvement in hemoglobin, clinical and hematologic 
outcomes; these results support the additional benefit of a broad control over the complement 
cascade, which translate into reduction of IVH and EVH (Hillmen et al 2021).
Iptacopan (LNP023) is a novel, oral, small molecule compound that inhibits factor B (FB). FB 
is a key protease of the complement alternative pathway (AP). Inhibition of FB with oral 
iptacopan has the potential to prevent both IVH and EVH, and therefore, offer therapeutic 
benefits over and above the current SoC. Additionally, the oral route of administration offers 
patients an advantage compared to the intravenous route of administration of current SoC.
Final results from the completed Phase 2 PNH studies show that PNH patients treated with 
iptacopan, both as add-on therapy to eculizumab (CLNP023X2201) for at least 6 months 
followed by iptacopan monotherapy and as monotherapy (CLNP023X2204), have clinically 
relevant benefits as shown by a reduction in LDH levels and improvements in hemoglobin in 

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the absence of RBC transfusions in majority of the patients. Two Phase 3 studies with iptacopan 
are also completed, confirming the evidence of iptacopan’s effect on inhibiting both IVH and 
EVH:
•
APPLY-PNH was a Phase 3 study in PNH patients presenting with residual anemia (Hb 
<10 g/dL) despite treatment with anti-C5 antibody; this was  a 24-week randomized, active 
comparator controlled, open-label study followed by a 24-week open-label treatment 
extension period. Results of the 24 Week randomized treatment period showed that both 
primary endpoints were achieved with iptacopan monotherapy, showing superiority vs. SoC; 
oral Iptacopan was significantly superior to anti-C5 in increasing Hb ≥2g/dL from baseline 
and a significant majority of patients achieved Hb ≥12 g/dL, via resolution of EVH and 
maintenance of IVH control. These hematological benefits were associated with transfusion 
independence in almost all patients and clinically meaningful improvements in patient-
reported fatigue. Iptacopan monotherapy was well tolerated with a favorable safety profile 
(Peffault de Latour et al 2022)
•
APPOINT-PNH was a single-arm, open label study to determine whether iptacopan is 
efficacious and safe for the treatment of PNH patients who are naive to complement 
inhibition therapy, including anti-C5 antibody. This study has a 24-week core treatment 
period followed by 24-week extension period. The study met the primary hematological 
response endpoint (increase in Hb ≥2g/dL from baseline). Results of the 24-week core 
treatment period showed that iptacopan monotherapy resulted in a clinically meaningful 
increase in Hb levels, with majority of patients achieving Hb levels of ≥ 12 g/dL, 
significantly reducing the need for RBC transfusions in nearly all patients. Iptacopan had a 
favorable safety profile and was well tolerated in PNH patients naïve to complement 
inhibitor therapy (Risitano et al 2023). 
2.3
Benefit/Risk assessment
The risks associated with the use of iptacopan are those inferred by its pharmacology and the 
results of preclinical and clinical safety studies. The most relevant risks are described below 
and a complete description of preclinical and clinical safety findings is available in the 
iptacopan Investigator Brochure (IB).
Appropriate eligibility criteria, as well as study procedures, close clinical monitoring with 
appropriate risk mitigation strategies which may include a periodic review of safety data by an 
independent Data Monitoring Committee (DMC), guidance in case of serious hemolysis, 
clinical BTH or need for RBC transfusion and in case of treatment discontinuation to ensure 
continued treatment of PNH, are included in this protocol and will minimize risks for 
participants.
This study does not involve any risks regarding study procedures (e.g. no invasive research 
procedures).
One potential risk which is specific to PNH patients is the risk of serious hemolysis following 
discontinuation of treatment with iptacopan. The importance of compliance with treatment will 
be emphasized to patients and the risk of hemolysis following missed doses mentioned in the 
ICF. In case of permanent discontinuation of iptacopan, specific discontinuation procedures are 
outlined in Section 7.1.

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Iptacopan did not show any mutagenic, teratogenic or genotoxic potential in a completed 
standard battery of genotoxicity testing. In addition, iptacopan was tested in embryo-fetal 
development studies in rats and rabbits and no iptacopan-related adverse fetal findings were 
detected in any of the studies. However, iptacopan has not been used in pregnant women, 
therefore, women of child-bearing potential must be informed that taking the study treatment 
may involve unknown risks to the fetus if pregnancy were to occur during the study and agree 
that in order to participate in the study, they must adhere to the contraception requirements 
outlined in the exclusion criteria. If there is any question that the participant will not reliably 
comply, they should not be entered or continue in the study. No contraception requirements are 
needed for males participating in the trial. A negative pregnancy test is required to participate 
in this trial and pregnancy test will also be performed at the end of the study as described in 
Section 8.4.5. Refer to IB for complete information.
Infections caused by encapsulated bacteria are an important risk in patients treated with 
complement inhibitors. Refer to IB for updated information on infections with iptacopan.
Translational research has shown that the serological response to meningococcal infection is 
maintained during AP blockade but that it is markedly reduced after blockade of the classical 
pathway with C5-blockers like eculizumab. Serum bactericidal activity studies of serum from 
vaccinated patients against meningococci showed that C5 inhibitors block killing of 
meningococci, whereas AP inhibitors have less inhibitory effect on meningococcal killing 
(Konar, Granoff 2017). In addition, more recent studies have confirmed this effect in 
meningococci (Ispasanie et al 2021) and shown that, although C5 inhibitors have no effect on 
host defence (opsonophagocytosis) against pneumococci, C3 inhibitors have a greater effect 
than inhibitors of Factor D or Factor B (Muri et al 2021). Vaccination is therefore predicted to 
be an effective mitigation strategy to reduce the risk for individuals treated with iptacopan. 
Participants are to be vaccinated against meningococcal, pneumococcal and H. influenzae 
infections according to local guidelines and availabilities, since these are all encapsulated 
bacteria. Publications on patients who are deficient in Factor B, report that they experienced 
recurrent Streptococcus pneumoniae and Neisseria meningitidis infections (Slade et al 2013, 
Gauthier et al 2021).
Participants will also be closely monitored for signs and symptoms of serious  
bacterialinfections (listed on a “Participant Safety Card” for participant awareness) and will be 
instructed to contact the Investigator or a local physician if they experience these symptoms. In 
patients with a suspicion of or confirmed bacterial infection, cultures should be taken and 
treatment, including appropriate antibiotics, should be considered as per investigator’s clinical 
judgement. The Investigator will employ clinical judgement to determine an appropriate course 
of treatment. Antibiotic treatment should be started immediately for infections caused by 
encapsulated bacteria, with action taken with study medication considered on a case-by-case 
basis. Recommended guidelines for monitoring and management of infections are provided in 
Section 6.4.1. For immunocompromised participants with a higher risk of infections, 
precautionary actions (e.g. prophylactic antibiotics) should be considered by the Investigator.
Other safety risks are based on preclinical data, with no relevant findings in clinical studies 
performed to date. These are classified as non-important potential risks of testicular effects and 
thyroid changes. The preclinical findings are described in more detail in the IB.

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In the iptacopan clinical studies, there have been no clinically relevant testicular adverse events 
or trends in changes from baseline in reproductive hormones reported to date. Since the 
testicular effects seen in preclinical studies have been shown to be mild and reversible with no 
notable effect on sperm parameters in dogs, and with a reasonable safety margin when 
comparing unbound concentrations achieved in the dog at the lowest dose where an effect was 
seen (LOAEL) and the concentrations achieved in man at the 200 mg twice daily dose, the 
relevance of the findings to man is considered questionable.
Preclinical thyroid effects have been observed; however, they were minimal and reversible. 
There have been no clinically relevant thyroid adverse events or changes in thyroid hormone 
levels in clinical trials to date.
Results from a hepatic impairment (HI) study (CLNP023A2105) showed that mild, moderate, 
severe HI had no impact on total iptacopan PK. No safety or tolerability concerns emerged from 
this study. A specific QTcF exposure response analysis was performed in healthy volunteers 
receiving single doses of iptacopan from 5 mg to 1200 mg. The QTcF exposure response 
analysis, including data from the study CLNP023X2101 and study CLNP023A2107, showed 
no effect of iptacopan on duration of QTcF at supratherapeutic dose up to 1200 mg.
In addition, safety results from completed healthy volunteer studies, two Phase 2 studies in 
patients with PNH, and Phase 2 studies carried out in complement-driven renal disease (IgA 
nephropathy and C3 glomerulopathy) confirm that the safety profile is favorable and support 
continuation of development. Refer to IB for complete information.
Based on the results from the 24 week randomized treatment period of APPLY-PNH 
(CLNP023C12302) and 24-week core treatment period of APPOINT-PNH (CLNP023C12301) 
(Section 2.2), the final results from the CLNP023X2201 study as well as CLNP023X2204 study 
(Section 4.3 for details), PNH patients randomized to iptacopan may have clinical benefits over 
and above the SoC including:
•
Increase of Hb to normal/near normal values in the absence of RBC transfusions
•
Control of EVH
•
Reduction of LDH
It is expected that the improved hematological response upon iptacopan treatment will translate 
into improved quality of life, most importantly an improvement in fatigue. More details about 
the results of the Phase 2 studies (CLNP023X2201 and CLNP023X2204) and completed Phase 
3 studies (APPLY-PNH and APPOINT-PNH) can be found in the IB.
In summary, the benefit risk relationship for iptacopan is positive supporting the start of this 
study.

N o v arti s
C o nfi d e nti al
P a g e 2 4 of 9 2
A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 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 d e m o n str at e n o n-i nf eri orit y of i pt a c o p a n aft er 
s wit c hi n g fr o m S o C ( a nti- C 5) i n 
H b c h a n g e fr o m 
b a s eli n e.
● C h a n g e i n H b l e v el s a s m e a n of vi sit s b et w e e n D a y 
1 2 6 a n d D a y 1 6 8 c o m p ar e d t o b a s eli n e, d efi n e d a s 
m e a n of H b c oll e ct e d at s cr e e ni n g ( 2 s a m pl e s) a n d D a y 
1.
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 
d e m o n str at e 
s u p eri orit y 
of i pt a c o p a n 
aft er 
s wit c hi n g fr o m S o C ( a nti- C 5) i n 
H b c h a n g e fr o m 
b a s eli n e.
● C h a n g e i n H b l e v el s a s m e a n of vi sit s b et w e e n D a y 
1 2 6 a n d D a y 1 6 8 c o m p ar e d t o b a s eli n e, d efi n e d a s 
m e a n of H b c oll e ct e d at s cr e e ni n g ( 2 s a m pl e s) a n d D a y 
1.
●T o 
a s s e s s 
t h e 
p er c e nt a g e 
of 
h e m at ol o gi c al 
r e s p o n d er s t o i pt a c o p a n tr e at m e nt d efi n e d a s H b ≥1 2 
g/ d L i n t h e a b s e n c e of R B C tr a n sf u si o n s
● R e s p o n s e d efi n e d a s H b ≥1 2 g/ d L a s s e s s e d b et w e e n 
vi sit s D a y 1 2 6 a n d D a y 1 6 8 i n t h e a b s e n c e of R B C 
tr a n sf u si o n s, o n t hr e e o ut of f o ur m e a s ur e m e nt s t a k e n 
at t h e vi sit s o c c urri n g i n l a st si x w e e k s
•
T o a s s e s s t h e eff e ct of i pt a c o p a n o n tr a n sf u si o n 
a v oi d a n c e d efi n e d a s t h e pr o p orti o n of p arti ci p a nt s 
w h o r e m ai n fr e e fr o m tr a n sf u si o n s
•
A b s e n c e 
of 
a d mi ni str ati o n 
of 
p a c k e d 
R B C 
tr a n sf u si o n s b et w e e n D a y 1 a n d D a y 1 6 8
● T o a s s e s s t h e eff e ct of i pt a c o p a n o n m ar k er s of E V H 
a n d I V H.
● C h a n g e fr o m b a s eli n e i n A R C l e v el s a s m e a n of vi sit s 
b et w e e n  
D a y  
1 2 6  
a n d  
D a y  
1 6 8
● P er c e nt a g e c h a n g e fr o m b a s eli n e i n L D H l e v el s a s 
m e a n of vi sit s b et w e e n D a y 1 2 6 a n d D a y 1 6 8
● T o a s s e s s t h e p ati e nt s’ p er c ei v e d diff er e n c e s i n 
gl o b al s ati sf a cti o n, eff e cti v e n e s s a n d c o n v e ni e n c e 
b et w e e n b a s eli n e a n d D a y 8 4 a n d D a y 1 6 8 aft er 
s wit c hi n g fr o m S o C ( a nti- C 5) t o i pt a c o p a n
● 
Diff er e n c e i n s c or e s of t h e gl o b al s ati sf a cti o n, 
eff e cti v e n e s s, 
a n d 
c o n v e ni e n c e 
d o m ai n s 
of t h e 
Tr e at m e nt S ati sf a cti o n Q u e sti o n n air e f or M e di c ati o n 
( T S Q M- 9) b et w e e n b a s eli n e a n d D a y 8 4 a n d D a y 1 6 8 
a s s e s s e d 
aft er s wit c hi n g fr o m 
S o C ( a nti- C 5) t o 
i pt a c o p a n
● T o a s s e s s c h a n g e s i n p ati e nt-r e p ort e d f ati g u e fr o m 
b a s eli n e t o D a y 8 4 a n d D a y 1 6 8
● C h a n g e fr o m b a s eli n e i n p ati e nt-r e p ort e d s c or e s f or 
F A CI T- F c oll e ct e d at D a y 8 4 a n d D a y 1 6 8
● T o a s s e s s t h e fr e q u e n c y of B T H r at e t hr o u g h D a y 
1 6 8
● O c c urr e n c e s of B T H r e p ort e d b et w e e n D a y 1 a n d 
D a y 1 6 8
● T o a s s e s s t h e r at e s of 
M aj or A d v er s e V a s c ul ar 
E v e nt s ( M A V E s i n cl u di n g t hr o m b o si s) of i pt a c o p a n 
t hr o u g h D a y 1 6 8
● O c c urr e n c e s of M A V E s o c c urri n g b et w e e n D a y 1 a n d 
D a y 1 6 8
● T o a s s e s s t h e s af et y a n d t ol er a bilit y of i pt a c o p a n
●  
S af et y  
a s s e s s m e nt s  
(i n cl u di n g  
a d v er s e 
e v e nt s/ s eri o u s 
a d v er s e 
e v e nt s, 
s af et y l a b or at or y 
p ar a m et er s, vit al si g n s et c.) b et w e e n D a y 1 a n d D a y 
1 6 8
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)
●T o 
a s s e s s 
t h e 
p er c e nt a g e 
of 
h e m at ol o gi c al 
r e s p o n d er s d efi n e d a s H b ≥1 2 g/ d L i n a b s e n c e of R B C 
tr a n sf u si o n, 
● R e s p o n s e d efi n e d a s H b ≥1 2 g/ d L a s s e s s e d b et w e e n 
vi sit s D a y 1 2 6 a n d D a y 1 6 8 o n t hr e e o ut of f o ur 
m e a s ur e m e nt s t a k e n at t h e vi sit s o c c urri n g i n l a st si x 
w e e k s 
 
●T o a s s e s s t h e eff e ct of i pt a c o p a n tr e at m e nt o n  
 
● 
 
c oll e ct e d b et w e e n D a y 1 a n d D a y 1 6 8
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 2 5 of 9 2
A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
O bj e cti v e( s)
E n d p oi nt( s)
● T o a s s e s s t h e eff e ct s of i pt a c o p a n tr e at m e nt i n 
 
● 
  
p ar a m et er s 
  
 
 
 
c oll e ct e d b et w e e n D a y 1 a n d D a y 1 6 8
● T o a s s e s s t h e eff e ct of i pt a c o p a n tr e at m e nt i n 
 
● C h a n g e fr o m b a s eli n e i n 
 
c oll e ct e d 
at 
D a y 
1 6 8. 
P arti ci p a nt r e s p o n s e s t o a 
 
 
● T o a s s e s s 
 t o i pt a c o p a n i n t h e st u d y 
p o p ul ati o n a n d 
 
●  
 
  
 
i pt a c o p a n  
 
● 
● T o a s s e s s t h e eff e ct of i pt a c o p a n tr e at m e nt i n t h e 
● O c c urr e n c e of 
 
 D a y 1 a n d D a y 
1 6 8
3. 1 
Pri m ar y e sti m a n d s
T he pri mar y cli nical q uesti o n is: w hat is t he treat me nt effect of i ptac o pa n after 2 4 wee ks 
c o m pare d t o baseli ne i n P N H patie nts w h o ha ve H b ≥1 0  g/ d L i n res p o nse t o sta ble re gi me n of 
a nti- C 5 a nti b o d y treat me nt, re gar dless of disc o nti n uati o n of i ptac o pa n a n d occ urre nce of B T H 
or M A V Es?
T he attri b utes of t he pri mar y esti ma n d are:
•
P o p ulati o n: P N H Patie nts ≥ 1 8 years o n sta ble re gi me n of a nti- C 5 treat me nt a n d wit h H b 
le vels sta ble ≥1 0 g/ d L, wit h o ut a n y R B C tra nsf usi o n i n t he past 6 m o nt hs.
•
Treat me nt of i nterest: t he i n vesti gati o nal treat me nt i ptac o pa n at a d ose of 2 0 0 m g b.i. d 
re gar dless of w het her t he patie nt disc o nti n ues treat me nt (treat me nt p olic y).
•
I nterc urre nt e ve nts: disc o nti n uati o ns of st u d y me dicati o n f or a n y reas o n, B T H e ve nts, a n d 
M A V Es will be ha n dle d wit h a treat me nt p olic y strate g y. R B Cs will be ha n dle d usi n g a n 
h y p ot hetical strate g y, as if patie nt w o ul d n ot ha ve recei ve d tra nsf usi o ns o n i ptac o pa n 
treat me nt.
•
T he s u m mar y meas ure: t he a vera ge c ha n ge fr o m baseli ne i n H b a n d 9 5 % CI
3. 2 
S e c o n d ar y e sti m a n d s
T he p o p ulati o n ass ociate d wit h t he sec o n dar y esti ma n ds is t he sa me as f or t he pri mar y 
esti ma n ds. F or t hese sec o n dar y esti ma n ds we c o nsi der t he sa me i nterc urre nt e ve nts as f or t he 
pri mar y esti ma n ds. T he pr o p ose d a p pr oac h i n t he case of tra nsf usi o n ha n dli n g will be descri be d 
i n t he esti ma n d defi niti o n, w hile disc o nti n uati o ns of st u d y me dicati o n, B T H e ve nts, a n d 
M A V Es will be ha n dle d wit h a treat me nt p olic y strate g y.
T he sec o n dar y esti ma n ds are defi ne d b y t he e val uati o n of treat me nt effect o n t he f oll o wi n g 
e n d p oi nts a n d s u m mar y meas ures:
•
C ha n ge fr o m baseli ne i n H b le vels as mea n of visits bet wee n Da y 1 2 6 a n d Da y 1 6 8. 
S u peri orit y will be c o ncl u de d a n d o bjecti ve will be c o nsi dere d met if t he l o wer b o u n d of 
t he esti mate d t w o-si de d 9 5 % CI is greater t ha n 0 g/ d L. R B C tra nsf usi o ns will be ha n dle d 
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

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Protocol No. CLNP023C12303
using a hypothetical strategy, as if patient would not have received transfusions on iptacopan 
treatment. The summary measure is the mean change from baseline in Hb.
•
Response defined as Hb ≥12 g/dL assessed between visits Day 126 and Day 168 in the 
absence of RBC transfusions, on three out of four measurements taken at the visits occurring 
in last six weeks. The summary measure is the probability of being a responder or the 
proportion of responders if a logistic regression analysis is unfeasible.
•
Absence of administration of packed-RBC transfusions between Day 1 and Day 168: 
proportion of participants not receiving any transfusions between Day 1 and Day 168 
(transfusion avoidance). The summary measure is the probability of being a responder or 
the proportion of responders if a logistic regression analysis is unfeasible.
•
Change from baseline in ARC levels as mean of visits between Day 126 and Day 168 where 
the strategy applied to transfusions is treatment policy. The summary measure is the mean 
change from baseline of ARC levels.
•
Percent change from baseline in LDH between Day 126 and Day 168 where the strategy 
applied to transfusions is treatment policy. The summary measure is derived from the mean 
log transformed ratio to baseline in LDH between Day 126 and Day 168.
•
Difference in scores of the global satisfaction, effectiveness and convenience domains of 
the TSQM-9 between baseline and Day 84 and Day 168 assessed after switching from SoC 
(anti-C5) to iptacopan. The summary measure is the mean difference in patient-reported 
scores (for each of the three TSQM-9 domains).
•
Change from baseline in patient-reported scores for FACIT-F collected at Day 84 and Day 
168. The summary measure is the mean change from baseline in patient-reported scores for 
FACIT-F.
•
Rates of occurrences of BTH reported through Day 168. The summary measure is 
occurrences per year.
•
Rates of occurrences of MAVEs occurring through Day 168. The summary measure is 
occurrences per year.
4
Study design
4.1
Overall design
This is a multicenter, single-arm, open label trial, with iptacopan treatment for 24 weeks in adult 
PNH patients. Eligible participants must have a mean Hb ≥10 g/dL in response to a stable 
regimen with anti-C5 for at least 6 months and must be transfusion free for the same period. 
This study is comprised of two periods:
•
A Screening period lasting up to 8 weeks.
Baseline for primary and key secondary objectives is defined as the mean of three Hb 
assessments conducted at central laboratory: two during screening and the third on Day 1 before 
starting treatment.
Baseline for all other objectives is defined as Day 1 or, in case of missing data on Day 1, any 
previous assessment done during Screening.
•
A 24-week open-label, iptacopan Treatment period.

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Protocol No. CLNP023C12303
A total of approximately 50 participants will be enrolled in the trial. All participants must 
provide written informed consent prior to start of any study-related activities.
The study design is shown in the schematic in Section 1.2.
Screening
Screening period starts at the time of Informed Consent Form (ICF) signing and lasts until the 
day preceding Day 1 of the Treatment period.
Participants will be asked to review and sign the ICF prior to starting the screening assessments. 
After signing the ICF, inclusion and exclusion criteria will be assessed to verify participants' 
eligibility for enrollment into the study. This will be followed by the visit's assessment as 
outlined in Table 1-1, as applicable.
By signing the ICFs, the participants will provide access to the following medical records for 
the last 6 to 12 months prior to Screening:
•
Date and result of PNH WBC clone size test performed in the 12 months prior to screening
•
Hb levels, MAVEs and anti-C5 antibody regimen reported in the past 6 months
•
the number of transfusions and unit numbers of packed-RBC received in the past 12 months.
Participants must be vaccinated as outlined in Section 5.1 Inclusion criteria. Vaccines should 
cover as many serotypes as possible (including meningococcal serotypes A, C, Y, W-135 and 
B). To minimize participant burden, the use of multivalent vaccines is recommended as locally 
available and per local guidelines and regulations (e.g. quadrivalent vaccine for N. meningitidis 
which covers serotypes A, C, Y and W-135 and Pneumovax-23 which covers 23 S. pneumoniae 
serotypes). For the vaccination type and booster requirements use local guidelines, and locally 
available vaccines (and refer to the package insert of those, or local guidelines).
If eligibility criteria are not met due to any assessment, the participant should be considered as 
having failed the screening and does not proceed to treatment period. The participant can be 
rescreened as described in detail in Section 5.3.
Treatment period
Participants who meet all the eligibility criteria will proceed to the treatment period. Treatment 
with iptacopan at a dose of 200 mg b.i.d. will start on the first day (Day 1) and continue for 24 
weeks with study visits and corresponding assessments according to schedule described in 
Table 1-1.
Refer to Section 6.8.1 which provides details about the protocol-specific guidelines for 
participants who need to receive a packed-RBC transfusion during the treatment period.
Because of the known increased risk of infections with encapsulated bacteria, all participants 
will be provided with a Participant Safety Card. Participants will be instructed to be vigilant for 
any clinical sign of bacterial infections and to contact the Investigator or local physician 
immediately in case of suspicion of infection and start antibiotic treatment as soon as possible. 
In patients with suspicion or confirmation of bacterial infection, bacterial cultures should be 
taken.

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For participants who permanently discontinue iptacopan administration, close monitoring and 
treatment proposals are indicated in Section 7.1. Every effort must be made to keep participants 
in the study to complete all visits and assessments up to Day 168 visit. The treatment period 
will end with the completion of the Day 168 visit assessments.
After completion of the treatment period, participants who complete this trial while still 
receiving iptacopan and who continue to derive clinical benefit from the treatment based on the 
Investigator's evaluation will be able to join the Roll-over extension program (REP; 
CLNP023C12001B), which will provide access to iptacopan and enable long-term safety 
monitoring.
For participants not agreeing to continue in the REP after completing Day 168 visit, they may 
follow the recommended procedures defined in Section 7.1.
4.2
Scientific rationale for study design
CLNP023C12303 is a multicenter, single arm, open-label study designed to evaluate the 
efficacy and safety of iptacopan at a dose of 200 mg b.i.d. orally in adult PNH patients who 
have Hb ≥10 g/dL in response to anti-C5 SoC treatment (eculizumab or ravulizumab) switching 
to iptacopan.
The patient population is chosen for this study for the following reasons:
•
The study intends to demonstrate non-inferiority to SoC as well as assessing safety in 
patients who have already a good/major/complete hematological response to SoC, applying 
hematologic response categories reported by Risitano et al (2019) by assessing the effect of 
iptacopan on the change from baseline in Hb levels.
•
The data generated will give scientific evidence to switch from the SoC iv infusion to oral 
iptacopan treatment in adult PNH patients with Hb ≥10 g/dL; according to 
Debureaux et al 2019, about 60% of the PNH population treated with SoC have Hb >10 g/dl 
but still suffer from EVH and BTH; according to results from PEGASUS trial, targeting 
both IVH and EVH may provide an incremental benefit to PNH patients compared to anti-
C5 treatment.
•
The study will assess frequency of major PNH complications, such as BTH and MAVEs
•
The study will also assess PROs, including patient preference on drug administration route, 
symptoms of fatigue and other specific PNH signs and symptoms.
The single arm, open-label design is widely used in rare diseases due to challenges associated 
with conducting studies in these patient populations (Bell, Smith (2014)). Several measures 
have been included in the study design to minimize biases associated with this single arm open-
label design, including:
•
Primary and majority of secondary, efficacy endpoints are objectively measured via 
laboratory assessments (i.e. hematological response parameters, Hb, LDH, ARC, 
transfusion avoidance and BTH).
•
Protocol-specific guidelines (see Section 6.8.1) are defined to reduce potential bias due to 
events (such as transfusions) that may affect the main endpoints.
A multicenter setting has been chosen to ensure adequate recruitment and representative 
patients’ enrollment into the study in this rare indication.

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A screening duration of 8 weeks was considered appropriate
•
to allow for relevant vaccinations
•
to allow for switching from ravulizumab or eculizumab in a safe manner, reducing the risk 
of BTH, while minimizing potential carry-over effects of prior treatment. The initiation of 
iptacopan treatment has an overlap of 1 (eculizumab) or 2 (ravulizumab) weeks.
A treatment duration of 24 weeks is considered appropriate to assess the effect of iptacopan on 
the primary and secondary efficacy endpoints as well as on safety and tolerability. The 24-week 
treatment duration has been previously used in studies with PNH patients, including the recent 
Phase 3 studies with eculizumab and ravulizumab (Kulasekararaj et al 2019, Lee et al 2019). 
Moreover, the treatment duration of 24 weeks is implemented in the iptacopan Phase 3 studies 
in PNH patients (CLNP023C12301 and CLNP023C12302); thus ensuring alignment within the 
program.
The primary objective is to assess efficacy of iptacopan after 24 weeks of treatment in PNH 
patients who have Hb ≥10 g/dL in response to SoC and switch to iptacopan by demonstrating 
non-inferiority in change from baseline in Hb levels between Day 126 and Day 168. It is 
proposed to use a non-inferiority margin based on clinical data and experience as well as on 
precedence with Hb stabilization as endpoint in the Phase 3 PRINCE trial and set it at 1 g/dL 
of Hb. Assuming that patients have stable Hb at study entry, the mean change from baseline in 
Hb level between Day 126 and Day 168 is expected to be unchanged should patients continue 
on anti-C5 treatment. Non-inferiority will be concluded and primary objective will be 
considered met if the lower bound of the estimated two-sided 95% CI is greater than -1 g/dL.
Secondary objectives include superiority testing over anti-C5 on Hb level, assessment of the 
proportion of participants achieving sustained Hb levels ≥12 g/dL in the absence of RBC 
transfusions, BTH rates, MAVEs, changes from baseline in ARC and LDH, transfusion 
avoidance as well as PRO measure of treatment satisfaction (TSQM) and fatigue (FACIT-
fatigue). These endpoints were selected to supplement the primary efficacy endpoint and are 
clinically meaningful endpoints for PNH.
4.2.1
Participant input into design
Representatives of Aplastic Anemia & MDS Foundation and of Canadian Association of PNH 
Patients were consulted for the design of the study. The representatives agreed with the 
proposals in terms of patient population, duration of study, number of visits and types of 
assessments. Two concerns were raised:
•
the compliance to treatment, which as per protocol Section 6.4 will be checked at each visit 
and that could be supported by an app to remind patients to take iptacopan;
•
the efficacy of iptacopan, which was tested in APPLY-PNH and APPOINT-PNH studies 
supports this claim.
4.3
Justification for dose
A dose of 200 mg iptacopan b.i.d. was chosen based on the available efficacy and safety data 
from the IA of the two ongoing Phase 2 PNH studies (CLNP023X2201 and CLNP023X2204) 
and is supported by Pharmacokinetic Pharmacodynamic (PKPD) modeling results. Furthermore, 
the dose of 200 mg b.i.d. is the dose chosen for the two Phase 3 studies (APPLY-PNH and 

N o v arti s
C o nfi d e nti al
P a g e 3 0 of 9 2
A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
A P P OI N T- P N H) a n d 
was e x pecte d t o pr o vi de o pti mal efficac y re q uire d f or P N H as 
m o n ot hera p y wit h a n a de q uate safet y pr ofile. I n A P P L Y- P N H st u d y, res ults of t he 2 4 Wee k 
ra n d o mize d treat me nt peri o d s h o we d t hat oral i ptac o pa n 2 0 0 m g b.i. d res ulte d i n a si g nifica nt 
maj orit y of patie nts ac hie vi n g cli nicall y mea ni n gf ul H b i ncreases a n d H b ≥1 2  g/ d L (Peffa ult de 
Lat o ur et al 2 0 2 2 ). Res ults of t he 2 4- wee k c ore treat me nt peri o d of A P P OI N T- P N H st u d y 
de m o nstrate d t hat 2 0 0 m g b.i. d. i ptac o pa n m o n ot hera p y res ulte d i n a cli nicall y mea ni n gf ul 
i ncrease i n H b le vels ( ≥ 2 g/ d L fr o m baseli ne), wit h maj orit y of patie nts ac hie vi n g H b le vels of 
≥ 1 2 g/ d L, si g nifica ntl y re d uci n g t he nee d f or R B C tra nsf usi o ns i n nearl y all patie nts (Risita n o 
et al 2 0 2 3).
Fi nal res ults fr o m C L N P 0 2 3 X 2 2 0 1 a n d C L N P 0 2 3 X 2 2 0 4 st u dies were c o nsiste nt wit h I A res ults 
a n d j ustif y a d ose of 2 0 0 m g i ptac o pa n b.i. d i n t his st u d y.
I n t he C L N P 0 2 3 X 2 2 0 1 st u d y, a t otal of 1 6 patie nts wit h P N H wit h si g ns of acti ve he m ol ysis 
des pite ≥ 3 m o nt hs of sta ble treat me nt wit h S o C were treate d i n t he st u d y; 1 0 patie nts i n C o h ort 
1 (i ptac o pa n 2 0 0 m g b.i. d. + a nti- C 5 t hera p y f or ≥6  m o nt hs, i ptac o pa n 2 0 0 m g b.i. d. 
m o n ot hera p y t hereafter) a n d 6 patie nts i n C o h ort 2 (i ptac o pa n 5 0 or 2 0 0 m g b.i. d. + a nti- C 5 
t hera p y f or ≥ 6 m o nt hs, i ptac o pa n 2 0 0 m g b.i. d. m o n ot hera p y t hereafter). All 1 6 patie nts 
c o m plete d t he c ore 1 3 wee ks of st u d y treat me nt, a n d 1 3 patie nts c o m plete d t he e ntire st u d y ( u p 
t o wee k 1 7 6).
•
St u d y ac hie ve d its pri mar y o bjecti ve. T he pri mar y efficac y res ults s h o we d a cli nicall y 
mea ni n gf ul re d ucti o n i n L D H: at Da y 9 2 ( Wee k 1 3), i ptac o pa n i n a d diti o n t o S o C treat me nt 
res ulte d i n a mea n ( 9 0 % CI) re d ucti o n fr o m baseli ne i n L D H of 4 3. 6 % ( −5 3. 5 7, −3 3. 5 8). 
T he re d ucti o n i n L D H was greater i n C o h ort 1. A t otal of 7/ 1 5 patie nts ( 4 6. 7 %) s h o we d 
c o m plete n or malizati o n of L D H le vels ( < 2 5 0 U/ L) at 1 3 wee ks.
•
Tra nsf usi o n-free he m o gl o bi n n or malizati o n was o bser ve d i n 9/ 1 5 patie nts ( 6 0 %), wit h a 
ra pi d i ncrease i n mea n he m o gl o bi n fr o m baseli ne ( + 3. 2 0 g/ d L fr o m baseli ne t o 1 2. 6 6 g/ d L) 
at 1 3 wee ks. Ni ne patie nts ha d n or mal he m o gl o bi n le vels at Wee k 1 3. 
•
T he maj orit y of patie nts ( 1 4/ 1 6; 8 7. 5 %) were tra nsf usi o n free u p t o Da y 9 2. 
•
C o ntr ol of he m ol ysis was ass ociate d f urt her wit h t he re d ucti o n of A R C a n d bilir u bi n (t otal 
a n d i n direct).
•
 o n P N H R B Cs ra pi dl y decrease d, a n d a 
 
, as a res ult of he m ol ysis c o ntr ol.
•
A cli nicall y i m p orta nt i m pr o ve me nt i n fati g ue as assesse d b y F A CI T- Fati g ue sc ore wit h 
i ncrease fr o m 3 6. 3 p oi nts at baseli ne t o 4 4. 8 p oi nts at Wee k 1 3 [ mea n c ha n ge ( S D) fr o m 
baseli ne: 8. 1 4 p oi nts ( 1 3. 1 1 4)].
•
T he effects of i ptac o pa n were d ura ble, s uc h t hat e ve n after patie nts disc o nti n ue d S o C (as 
all o we d per pr ot oc ol after ≥ 6 m o nt hs) t he treat me nt be nefits, i ncl u di n g i m pr o ve me nts i n 
L D H, he m o gl o bi n, A R C, F A CI T- Fati g ue sc ores, bilir u bi n, a n d i ncrease i n P N H R B C cl o ne 
size, as well as t he re d ucti o n i n C 3 de p ositi o n o n R B Cs were mai ntai ne d u p t o Wee k 1 7 6. 
Of t he 1 6 patie nts starti n g treat me nt, 1 2 re mai ne d tra nsf usi o n-free t hr o u g h o ut t he e ntire 
st u d y ( 3 patie nts re q uire d tra nsf usi o n i n t he e xte nsi o n peri o d).
C CI
C CI

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Iptacopan as add-on treatment to anti-C5 therapy inhibited hemolysis (intra- and extravascular) 
with a rapid onset of effect. As a result, anemia improved in absence of RBC transfusions in the 
majority of patients, demonstrating clear hematological benefits, as well as symptomatic 
improvement in patient reported fatigue. Iptacopan at the dose regimen of 200 mg b.i.d. led to 
a numerically better and more complete inhibition of hemolysis. Following discontinuation of 
SoC after 6 months and continuation with iptacopan monotherapy, treatment effects were 
maintained and durable up to 176 weeks.
In the CLNP023X2204 study in PNH patients not treated with eculizumab/complement 
inhibitors, participants were randomized to iptacopan monotherapy in two sequences with 
forced titration after 4 weeks from iptacopan 25 mg b.i.d. to 100 mg b.i.d (sequence 1) or 
iptacopan 50 mg b.i.d. to 200 mg b.i.d. (sequence 2). The study enrolled 13 patients with PNH 
and active hemolysis: 7 in Cohort 1 (25 mg/100 mg b.i.d. dose) and 6 in Cohort 2 (50 mg/200 
mg b.i.d. dose). Twelve patients were assessed for the primary endpoint (1 patient in Cohort 2 
discontinued on Study Day 2 due to a non-severe AE of headache). All 12 patients included in 
the primary endpoint analysis were complement inhibitor treatment naïve.The study achieved 
its primary objective. Iptacopan monotherapy resulted in rapid and sustained reduction of LDH, 
and all 12 patients (100%) assessed achieved the primary endpoint (≥ 60% reduction in LDH 
from baseline or LDH normalization) up to Week 12.
•
The inhibition of IVH was reflected by hematological benefits including clinically 
meaningful increase in total hemoglobin levels observed (mean increases of 2.34 g/dL and
3.71 g/dL at Week 12, in Cohorts 1 and 2 respectively), and improvement of other markers
of hemolysis (free hemoglobin, total bilirubin, ARC, erythrocyte count) up to Week 12. 
Among the 12 patients who completed 12 weeks on study, all except 1 patient remained 
transfusion-free.
•
An early, sustained, and marked increase in PNH RBC (Type II + III) clone size was 
observed with iptacopan treatment. C3 fragment deposition on PNH RBCs was negligible 
at baseline and remained so during treatment with iptacopan.
•
Symptomatic improvement in fatigue was observed, as assessed by FACIT-Fatigue score, 
with a clinically important improvement in mean scores from 37.6 and 38.2 points at 
baseline to 46.8 and 48.6 points at Week 12 in Cohorts 1 and 2, respectively. 
The treatment benefits of iptacopan were durable: improvements, including reductions in LDH, 
bilirubin, ARC, and patient-reported fatigue, and in increases in hemoglobin and PNH clone 
size were subsequently sustained up to Week 108 of treatment. Among the 11 patients who 
were followed up until end of study, 10 patients remained transfusion free. Persistence of 
iptacopan efficacy was also consistently observed up to Week 108 for other efficacy parameters, 
including improvement in erythrocyte, reduction in bilirubin, increases in PNH RBC clone size 
and decrease in C3 fragment deposition on PNH RBCs. There were also no thromboembolic 
events reported in the entire study.
Iptacopan at a dose of 200 mg b.i.d. was safe and well tolerated by participants in both Phase 2 
studies, Phase 3 APPLY and APPOINT studies in PNH, as well as at the same dose in patients 
with IgA nephropathy (study CLNP023X2203) and C3 glomerulopathy (CLNP023X2202), 
supporting its use in Phase 3 PNH studies.

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The exposure-response model developed with data from the First-In-Human (FIH) study with 
iptacopan in healthy volunteers predicts that a dose of about 200 mg b.i.d. would be needed to 
achieve >90% inhibition of the AP (Wieslab assay) in >70% of subjects. Given the risk of 
hemolysis and breakthroughs in cases of insufficient inhibition of complement activity, full 
inhibition is desired and modelling results provide additional support for the choice of the dose 
of 200 mg b.i.d. for PNH. For further details, please refer to the iptacopan IB.
4.3.1
Rationale for choice of background therapy
Stable background treatment is allowed as per standard of care in PNH. Common treatments, 
including but not limited to, are folic acid supplementation to increase RBC production; iron 
supplementation to treat a deficiency caused by chronic hemoglobinuria; anticoagulant 
prophylaxis to reduce the risk of thrombosis in patients with a substantial proportion of PNH 
cells, high platelet counts (>100 x109/L) and no known hemorrhagic risk. Vaccination against 
Neisseria meningitidis and S. pneumoniae infection are required and vaccination against 
Haemophilus influenzae infections is recommended. If participants are not already vaccinated 
or need a booster vaccine dose, it can be administered as per Section 5.1 and according to local 
regulations. Antibiotics for prophylaxis are permitted if vaccines are administered in less than 
2 weeks of first study treatment dose. Background treatment regimen should be stable prior to 
starting iptacopan in order to reduce the potential confounding effect on primary and secondary 
endpoints. Refer to Section 6.8 for the full list of concomitant medication allowed.
4.4
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Not applicable as this is a single arm study.
4.5
Rationale for public health emergency mitigation procedures
In the event of a public health emergency as declared by local or regional authorities (i.e. 
pandemic, epidemic or natural disaster), mitigation procedures may be required to ensure 
participant safety and trial integrity and are listed in relevant sections of the study protocol. 
Notification of the public health emergency should be discussed with Novartis prior to 
implementation of mitigation procedures and permitted/approved by local or regional health 
authorities and ethics committees as appropriate.
4.6
Purpose and timing of interim analyses/design adaptations
If deemed required (e.g., to support regulatory submissions to Health Authorities), interim 
safety analyses may be produced while the study is still ongoing. 
4.7
End of study definition
Study completion is defined as when the last participant finishes their End of Study, Day 168 
visit, and any repeat assessments associated with this visit have been documented and followed-
up appropriately by the Investigator or, in the event of an early study termination decision, the 
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4.8
Rationale for planned off-site procedures
Off-site procedures are planned in this study to minimize burden on participants and offer them 
increased flexibility to participate in the study from an off-site location (as describe in Section 3 
and defined in Section 8.11). This has the potential to broaden access to clinical trials for both 
participants and Investigators. The hybrid approach will allow participants to maintain contact 
with the Investigator, both in person, during clinic visits at site, and through the telemedicine 
platform during off-site participation.
5
Study population
This study will enroll PNH patients with Hb ≥10 g/dL in response to anti-C5 antibody treatment, 
on stable regimen (dose and intervals) for at least 6 months and who did not receive any RBC 
transfusion in the previous 6 months, as well as during screening.
The study targets enrollment of at least 60% of patients with Hb <12 g/dL, therefore the number 
of patients with mean Hb ≥ 12 g/dL at screening will be restricted to maximum 40%.
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. Male and female participants ≥ 18 years of age, at the time of ICF signatures and with a 
diagnosis of PNH confirmed by PNH clone size WBCs ≥ 10% based on historical data 
performed up to 12 months prior to Screening visit 1.
3a. Stable regimen as per the locally approved label (dose and intervals) of anti-C5 antibody 
treatment (either eculizumab or ravulizumab) for at least 6 months prior to screening
4. Mean hemoglobin level ≥10 g/dL, documented by the mean of all available Hb assessments 
(minimum 2 measurements) over a period of 6 months before screening visit, collected at 
any laboratory. In addition to fulfill the Hb eligibility criterion, participants must have two 
different samples collected during the screening period and tested by the central laboratory 
with the mean ≥10 g/dL, prior to starting iptacopan. Note: the study will target enrollment 
of at least 60% of patients with mean Hb <12 g/dL defined by the central laboratory 
assessment at screening, therefore the number of patients with mean Hb ≥ 12 g/dL at 
screening will be restricted to maximum 40%
5. Vaccination against Neisseria meningitidis and S. pneumoniae infection are required prior 
to the start of iptacopan treatment. If the patient has not been previously vaccinated, or if a 
booster is required, vaccines are to be given according to local regulations, at least 2 weeks 
prior to first dosing. However, administration of these vaccines less than 2 weeks prior to 
start of iptacopan treatment is at the discretion of the investigator. If iptacopan treatment is 
started less than 2 weeks post-vaccination, participant must be given prophylactic antibiotic 
at the start of iptacopan and for at least 2 weeks after vaccination.
6. If not received previously, vaccination against Haemophilus influenzae infections is 
recommended, if available and according to local regulations. The vaccines should be given 
at least 2 weeks prior to initiation of iptacopan treatment. However, administration of these 
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investigator. If iptacopan treatment is started less than 2 weeks post-vaccination, participant 
must be given prophylactic antibiotic at the start of iptacopan and for at least 2 weeks after 
vaccination.
7. Able to communicate well with the investigator, to understand and comply with the 
requirements of the study
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. Participation in any other investigational drug trial or use of other investigational drugs at 
the time of enrollment, or within 5 elimination half-lives of enrollment, or within 30 days 
of enrollment whichever is longer; or longer if required by local regulations
2. Patients requiring RBC transfusion in the 6 months prior to screening or during screening
3. History of hypersensitivity to any of the study drugs or its excipients or to drugs of similar 
chemical classes
4. Known or suspected hereditary complement deficiency at screening
5. History of hematopoietic stem cell transplantation or any solid organ transplantation
6. Patients with laboratory evidence of bone marrow failure (reticulocytes <100x109/L; 
platelets <30x109/L; neutrophils <0.5x109/L). The ARC (only) can be assessed either at 
local or central laboratory during the Screening period to determine participant’s eligibility.
7. Active systemic bacterial, viral (incl. COVID-19) or fungal infection within 14 days prior 
to study drug administration
8. Presence of fever ≥ 38.0 °C (100.4 °F) within 7 days prior to study drug administration
9. Human immunodeficiency virus (HIV) infection (known history of HIV or test positive for 
HIV antibody at Screening)
10. A history of recurrent invasive infections caused by encapsulated organisms, e.g. 
meningococcus or pneumococcus
11. Major concurrent comorbidities including but not limited to severe kidney disease (e.g., 
eGFR < 30 mL/min/1.73 m2, dialysis), advanced cardiac disease (e.g., NYHA class IV), 
severe pulmonary disease (e.g., severe pulmonary hypertension) (WHO class IV), or hepatic 
disease (e.g., active hepatitis)
12. Liver disease, such as active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection 
defined as HBsAg positive or HCV RNA positive, or liver injury indicated by abnormal 
liver function tests at Screening:
•
Any single parameter of ALT/AST, gamma-glutamyl transferase (GGT), alkaline 
phosphatase (ALP) must not exceed 3 x ULN
13. Unstable medical condition including, but not limited to, myocardial ischemia, active 
gastrointestinal bleeding, coexisting chronic anemia unrelated to PNH, or unstable 
thrombotic event not amenable to active treatment as judged by the investigator at Screening.
14. 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 of 
whether there is evidence of local recurrence or metastases.
15. Ongoing drug or alcohol abuse that could interfere with patient's participation in the trial.

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16. Concomitant use of any of the following medications is prohibited if not on a stable regimen 
for the time period indicated below prior to Screening and those listed in  Section 6.8.3:
•
Erythropoiesis-stimulating agents (ESAs) for at least 8 weeks
•
Any immunosuppressants for at least 8 weeks
•
Systemic corticosteroids given for hematological conditions (less than 10 mg or 
equivalent prednisolone per day) for at least 4 weeks
•
Vitamin K antagonists (e.g. warfarin) with a stable international normalized ratio (INR) 
for at least 4 weeks
•
Low-molecular-weight heparin, and the direct oral anticoagulants (DOACs) 
rivaroxaban, apixaban and edoxaban, for at least 4 weeks
•
Iron supplements, vitamin B12, or folic acid for at least 4 weeks
•
Androgens for at least 4 weeks
17. Any medical condition deemed likely to interfere with the patient's participation in the study
18. Female patients who are pregnant or breastfeeding, or intending to conceive during the 
course of the study
19. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during dosing 
of study treatment and for 1 week after stopping iptacopan, 5 months after stopping 
eculizumab and 8 months after stopping ravulizumab. Effective contraception methods 
include:
•
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant). Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
postovulation methods) and withdrawal are not acceptable methods of contraception
•
Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks before 
taking study treatment. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment
•
Male sterilization (at least 6 months prior to screening). For female participants on the 
study, the vasectomized male partner should be the sole partner for that participant
•
Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/vaginal 
suppository
•
Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device (IUD) or intrauterine system (IUS)
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal if they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor 
symptoms). Women are considered not of child-bearing potential if they are 
postmenopausal or have had surgical bilateral oophorectomy (with or without 

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hysterectomy), total hysterectomy or bilateral tubal ligation at least six weeks prior to 
enrollment on the study. 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 not of child-bearing potential.
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF.
5.3
Screen failures
A screen failure occurs when a participant who consents to participate in the clinical study is 
subsequently found to be ineligible and therefore not entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure 
participants to meet the Consolidated Standards of Reporting Trials (CONSORT) publishing 
requirements and to respond to queries from regulatory authorities. Minimal information 
includes demography, screen failure details, eligibility criteria, and any serious adverse event 
(SAE). Participants who sign an ICF and are subsequently found to be ineligible will be 
considered a screen failure.
The following must be completed for screen failure participants on the applicable Case Report 
Form (CRF): reason for screen failure, demographic information, informed consent, and 
Inclusion/Exclusion criteria which excluded the participant from the study. No other data will 
be entered into the clinical database for participants who are screen failures, unless the 
participant experienced a serious adverse event during the screening phase (see SAE Section 
for reporting details). Adverse events that are not SAEs will be followed by the Investigator and 
collected only in the source data.
Participants who sign an ICF and are considered eligible but fail to be started on treatment for 
any reason will be considered an early terminator. The reason for early termination should be 
captured on the appropriate disposition CRF.
Rescreening participants
It is permissible to re-screen a participant once if the participant fails the first screening, 
however, 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 exclusion criteria, the assessment may be repeated once prior to starting study treatment. 
If the repeat value remains outside of the specified ranges, the participant is considered to have 
failed screening.
5.3.1
Replacement policy
Participants will not be replaced in the study.
5.3.2
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 

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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 re-screen the participant after a 
participant has screen failed, and the participant will be assigned a new Participant No.
6
Study treatment(s) and concomitant therapy
6.1
Study treatment(s)
All participants starting study treatment in this single arm open label study will receive 
iptacopan 200 mg b.i.d.
The timing of the first iptacopan administration will provide a seamless switch from prior anti-
C5 antibody treatment to iptacopan, allowing for some overlap of exposure to anti-C5 antibody 
treatment when starting the oral agent while limiting the potential risk of BTH, as the iptacopan 
exposure builds-up.
•
First iptacopan dose administration for participants on prior eculizumab regimen must occur 
at Days 7 to 8 after the last infusion
•
First iptacopan dose administration for participants on prior ravulizumab iv regimen must 
occur at Days 41 to 43 after the last infusion
Participants will then continue taking 200 mg iptacopan b.i.d. monotherapy.
The investigational drug iptacopan as 200 mg capsules, will be prepared by Novartis and 
supplied to Investigator sites as open-label participant packs.
Table 6-1
Investigational and control drug
Treatment Title
Iptacopan
Treatment Description
Open label, oral capsule 200 mg taken twice a day
Type
Drug
Dose Formulation
Hard gelatin capsule
Unit Dose Strength(s)
200 mg
Dosage Level(s)
200 mg b.i.d.
Route of 
Administration
Oral
Use
Experimental
IMP
Yes
Sourcing
Provided centrally by the sponsor.
Packaging and 
Labeling
Study treatment will be provided in bottles. Each bottle will be labeled as required 
per country requirement.
6.1.1
Additional study treatments
No other treatment beyond iptacopan (investigational drug) are included in this trial.

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6.1.2
Treatment arms/group
This is a single arm study; all participants will receive iptacopan at a dose of 200 mg orally 
b.i.d.
6.1.3
Treatment duration
The planned treatment duration is 24 weeks. If a participant’s study treatment is discontinued 
for any reason, every effort must be made to continue with the study assessments up to the Day 
168 visit.
Refer to Section 7.1 for recommendations for participants who discontinue iptacopan for any 
reason during the treatment period.
Participants who complete this trial while still receiving iptacopan and continue to derive 
clinical benefit from the treatment with iptacopan, based on the investigator’s evaluation, may 
join the REP, or other sources of post-trial supply of iptacopan could be considered.
6.2
Preparation, handling, storage, and accountability
Each study site will be supplied with iptacopan in packaging as described under Table 6-1 
Investigational Drug Section.
A unique medication number is printed on the study medication label.
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the Interactive Response Technology (IRT) and obtaining the medication number(s). 
The study medication has a 2-part 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 iptacopan 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 continue administration of the study treatment even 
without performing an on-site visit.
The dispatch of iptacopan 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 (as per scheduled visits) will 
occur between the site and the participant for instructional purposes, safety monitoring, drug 
accountability, investigation of any adverse events, 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 

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site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the IMP bottle label.
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. Participants will be asked to return all unused study treatment and 
packaging at the end of the study or at the time of discontinuation of study treatment. For study 
treatment compliance, refer to Section 6.4.
At the conclusion of the study, and as appropriate during the course of the study, 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.
6.2.2
Handling of other treatment
The administration of RBC transfusion when needed will be monitored continuously during the 
treatment period as described in Section 6.8.1 .
6.2.3
Instruction for prescribing and taking study treatment
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
Participants must take iptacopan at the dose of 200 mg twice per day (in the morning and in the 
evening) at approximately the same times each day and ideally with 12-hours interval between 
morning and evening dosing. On study visit days, the participants should not take that day's 
morning dose until instructed by the site staff following the completion of study assessments.
Participants should take iptacopan irrespective of food intake. Each dose should be taken with 
a glass of water.
Participants should be instructed to swallow whole capsules and not to chew or open them.
During the course of treatment, if vomiting occurs within 4 hours of dosing, the Investigator 
will instruct the participant to take a dose of iptacopan, if participant does not feel nauseated. 
Participants should not take the study treatment (iptacopan) again before the next scheduled 
dose, if vomiting occurs after 4 hours of previous dose.
In case of single missed dose, participants should take the missed dose as soon as possible and 
then continue with the regular regimen. In case of multiple missed doses, participants should 
take a dose of iptacopan as soon as possible but not make up for all missed doses, then continue 
with the regular regimen and contact immediately the Investigator, who should contact the 
medical monitor for guidance.

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6.3
Measures to minimize bias: randomization and blinding
6.3.1
Treatment assignment, randomization
No randomization will be performed in this study.
All eligible participants will be assigned medication kits via IRT. The Investigator or his/her 
delegate will contact the IRT after confirming that the participant fulfills all the 
inclusion/exclusion criteria. The IRT will assign a unique medication number for the first 
package of study treatment (iptacopan) to be dispensed to the participant.
6.3.2
Treatment blinding
Not applicable as this is an open label study.
6.3.3
Emergency breaking of assigned treatment code
Not applicable as this is an open label study.
6.4
Study treatment compliance
The Investigator must promote compliance by instructing the participant to take the study 
treatment exactly as prescribed and by explaining that compliance is necessary for the 
participant’s safety and the validity of the study. The participant must also be instructed to 
contact the Investigator if he/she is unable for any reason to take the study treatment as 
prescribed.
Compliance with iptacopan must be assessed by the Investigator and/or study personnel at each 
visit using capsule counts and information provided by the participant. This information must 
be captured in the source document at each visit.
All study treatment dispensed and returned must be recorded in the Drug Accountability Log.
6.4.1
Recommended treatment of adverse events
Infections
The participants and treating staff need to be instructed to be vigilant for any clinical signs of 
bacterial infections (e.g., malaise, chills, fever, nausea, photophobia, generalized muscle and 
joint pain) and to measure the body temperature at minimum at the times of symptoms of 
presumed infection. Participants will be instructed to contact the study physician immediately 
in case of suspicion of infection or elevated body temperature (> 38.3°C by oral or tympanic 
method) for a ‘phone directed’ triage.
In patients with a suspicion of or confirmed bacterial infection, cultures should be taken and 
treatment, including appropriate antibiotics, should be considered as per investigator’s clinical 
judgement. 
In case of any (bacterial and non-bacterial incl. COVID-19) severe infection, interruption of 
iptacopan dosing could be considered, on a case-by-case basis. However, every effort should 
be made to keep the participant on study treatment unless the risk outweighs the benefit in the 
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Prophylactic antibiotics and early booster vaccinations should be considered in patients with 
recurrent infections and/or in patients taking concomitant immunosuppressants, as per the 
investigator's clinical judgement.
If iptacopan treatment is to be permanently discontinued, please refer to Section 7.1 for the 
appropriate actions.
Medication used to treat AEs must be recorded on the appropriate CRF.
All participants will be provided with a Participant Safety Card. Participants will be instructed 
to be vigilant for any clinical sign or symptom of infection and to contact the Investigator or 
local physician immediately.
6.5
Dose modification
Iptacopan will be administered at a dose of 200 mg b.i.d. Dose adjustments are not allowed. 
Dose interruptions must be justified by clinical judgement and should take into consideration 
the risk of BTH and other potential AEs.
6.5.1
Definitions of dose limiting toxicities (DLTs)
Not applicable.
6.5.2
Follow-up for toxicities
Not applicable
6.6
Continued access to study treatment after the end of the study
6.6.1
Post trial access
After completion of the treatment period, participants who complete this trial while still 
receiving iptacopan and continue to derive clinical benefit from the treatment based on the 
Investigator’s evaluation may receive post-trial access by joining the REP, which will provide 
access to iptacopan and enable long-term safety monitoring, or other sources of post trial supply 
of iptacopan could be considered.
6.7
Treatment of overdose
The dose of study treatment is 200 mg b.i.d in all participants. If any participant takes more 
than 200 mg b.i.d of study treatment (except in case of a missed scheduled dose or vomit, please 
refer to Section 6.2.3), it will be considered as an overdose.
In the event of an overdose, the Investigator should:
•
Contact the medical monitor immediately
•
Document the quantity of the excess dose as well as the duration of the overdose in the 
appropriate CRF page
•
Evaluate the participant to determine, in consultation with the medical monitor, whether 
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•
Closely monitor the participant for any AE/SAE and laboratory abnormalities for 7 days 
from the date of the overdose of study treatment Report any AE/SAE as outlined in 
Section 8.6
•
If requested by the medical monitor, obtain a plasma sample for PK analysis within 1 day 
from the date of the overdose of study treatment determined on a case by case basis.
6.7.1
Reporting of study treatment errors including misuse/abuse
Study treatment errors are unintentional errors in the prescribing, dispensing, administration of 
a study treatment while under the control of a healthcare professional, participant or consumer 
(EMA definition).
Study treatment misuse refers to situations where the study treatment is intentionally and 
inappropriately used not in accordance with the protocol.
Study treatment abuse corresponds to the persistent or sporadic, intentional excessive use of study 
treatment, which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol, including misuse or 
abuse, must be reported on the AE (or SAE, if the event meets the definition of an SAE) CRF. 
Misuse or abuse will be collected and reported in the safety database irrespective of it being 
associated with an AE/SAE immediately, without undue delay, under no circumstances later 
than within 24 hours of Investigator’s awareness. (Note: If more stringent, local regulations 
regarding reporting timelines prevail).
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections.
Table 6-2
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Yes
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
6.8
Concomitant and other therapy
6.8.1
RBC transfusions and recommendations for breakthrough hemolysis 
(BTH)
6.8.1.1
RBC transfusion
The need for administration of RBC transfusion will be monitored continuously during the 
treatment period.
To standardize criteria for administration, transfusion criteria have been established and will 
apply starting from Day 1 of the study.
Packed RBC transfusions will be administered to participants in the following cases:

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•
Hb ≤ 9 g/dL with signs /and or symptoms of sufficient severity to warrant a transfusion
•
Hb ≤ 7 g/dL, regardless of presence of clinical signs and/or symptoms
The level of Hb, the number and unit of transfusion administered as well as the signs and/or 
symptoms if applicable will be recorded in the CRFs. Symptoms typically associated with or 
precipitating participant’s need for transfusion are listed below:
•
Severe or worsening of fatigue
•
Severe or worsening dyspnea / shortness of breath
•
Palpitation/angina (or worsening symptoms)
•
Change in mental status (syncope, light-headedness, confusion, stroke, transient ischemic 
attack)
If a participant meets the transfusion criterion, the Investigator will determine the appropriate 
number of units of packed-RBC to be transfused.
The Hb value on which the Investigator will base the need for administering a packed-RBC 
transfusion may be from the local laboratory due to the turnaround time for central lab results. 
However, the Investigator must collect a separate sample for Hb assessment by the central 
laboratory for analysis at the same time as taking a sample for local laboratory analysis.
It is recommended that the transfusion is administered within 2-3 days of the assessment of the 
Hb/event that triggered the requirement. In case the Investigator or participant decides not to 
give or receive a transfusion despite meeting the criteria specified above, the reason should be 
clearly documented in the CRF page.
6.8.1.2
Recommendations for BTH
For management of BTH and depending on the severity, the Investigator should consider the 
following supportive treatments (and record them in the appropriate CRF pages):
•
Blood transfusion (packed RBCs), see Section 6.8.1.1
•
Anticoagulation as appropriate
•
Any other supportive treatment or therapy (incl. hydration) as judged by the Investigator
6.8.2
Concomitant therapy
All medications, procedures, and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the participant was enrolled into the study must be 
recorded on the appropriate CRFs.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication during screening period. If in doubt, the Investigator should contact the Novartis 
medical monitor before enrolling a participant or allowing a new medication to be started. If 
the participant is already enrolled, contact Novartis to determine if the participant should 
continue participation in the study.
6.8.2.1
Permitted concomitant therapy requiring caution and/or action
Erythropoiesis-stimulating agents (ESAs) and hypoxia inducible factors prolyl hydroxylase 
inhibitors (HIF-PHIs) are allowed to be used if on stable dose at least 8 weeks before Screening. 

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During the study, it is recommended to adjust the dose and/or discontinue dosing of ESAs 
and/or HIF-PHIs based on participant’s hemoglobin level as per local guidelines and practice. 
As a general guide, it is recommended to reduce the ESAs and/or HIF-PHIs dose by 50% if Hb 
≥12 g/dL and/or to stop ESAs and/or HIF-PHIs dosing if Hb ≥13 g/dL. Use particular caution 
in participants with coexisting cardiovascular disease, stroke and chronic kidney disease.
Systemic corticosteroids are allowed to be used for hematological conditions if on stable dose 
(less than 10 mg or equivalent prednisolone per day) at least 4 weeks before Screening. During 
the study, the dose should not be changed during the treatment period (up to Day 168 Visit)From 
in vitro data examining potential iptacopan drug interactions, iptacopan was identified as a 
substrate of drug transporters OATP1B1/1B3 and drug metabolizing enzyme CYP2C8. In 
addition, iptacopan may impact pharmacokinetics (PK) of P-glycoprotein (P-gp) and OATP 
substrates. Thus, a DDI study (CLNP023A2104) was conducted where iptacopan was co 
administered with clopidogrel (CYP2C8 inhibitor), cyclosporin (OATP1B1/1B3 inhibitor) and 
digoxin (P-gp substrate), rosuvastatin (OATP substrate). The effect of clopidogrel and 
cyclosporin on iptacopan PK was not considered to be clinically relevant and there was a 
negligible impact of iptacopan on PK of the P-gp or OATP substrates. 
6.8.3
Prohibited medication
Use of the treatments listed below are not allowed during iptacopan administration.
•
Live vaccines are prohibited for the entire study treatment duration.
Concomitant medication listed under exclusion criterion 16 is prohibited if not on a stable 
regimen prior to Screening, for the time periods indicated.
•
Combination treatment with other complement inhibitors including anti-C5 antibody 
treatment is prohibited
6.8.4
Rescue medicine
Rescue medication is allowed to treat serious complications, such as thrombosis with anti-
thrombotic treatment, and management of this complication as per local guidelines and practice. 
For serious BTH (refer to Section 8.6.2 for SAE definition) requiring rescue medication in the 
opinion of the investigator, rescue medication is allowed and should be managed as per local 
guidelines and practice.
When rescue medication is administered, Investigator is to contact Novartis medical monitor 
for guidance on study drug.
7
Discontinuation of study treatment and participant 
discontinuation/withdrawal
7.1
Discontinuation of study treatment
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
Investigator.

N o v arti s
C o nfi d e nti al
P a g e 4 5 of 9 2
A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
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.
St u d y treat me nt m ust be disc o nti n ue d u n der t he f oll o wi n g circ u msta nces:
•
Partici pa nt/ g uar dia n decisi o n
•
A n y sit uati o n i n w hic h st u d y partici pati o n mi g ht res ult i n a safet y ris k t o t he partici pa nt
If a fe male bec o mes pre g na nt d uri n g t he st u d y, it is rec o m me n de d t o disc o nti n ue treat me nt wit h 
i ptac o pa n. H o we ver, after a n i n di vi d ual be nefit-ris k assess me nt b y t he I n vesti gat or, i ptac o pa n 
c o nti n uati o n ma y be c o nsi dere d i n e xce pti o nal circ u msta nces. C o u nseli n g s h o ul d be pr o vi de d 
t o t he partici pa nt o n t he a p pr o priate treat me nt f or P N H d uri n g pre g na nc y. T he o utc o me of t he 
disc ussi o n wit h t he partici pa nt, reflecti n g be nefit-ris k c o nsi derati o ns, s h o ul d be d oc u me nte d i n 
t he partici pa nt's file.
If treat me nt wit h i ptac o pa n has t o be disc o nti n ue d it is rec o m me n de d t o pr o m ptl y re-i nitiate 
alter nati ve a nti-c o m ple me nt treat me nt, as j u d ge d b y t he I n vesti gat or a n d disc uss wit h me dical 
m o nit or f or case- b y-case g ui da nce.
Cl ose m o nit ori n g of partici pa nts f or si g ns a n d s y m pt o ms of he m ol ysis s h o ul d be perf or me d 
u p o n i ptac o pa n disc o nti n uati o n as defi ne d i n t he Sc he d ule of Assess me nts ( Ta ble 1- 1 ). It is 
rec o m me n de d t o m o nit or at mi ni m u m f or: i ncrease i n L D H, decrease i n H b le vel, i ncrease i n 
ser u m creati ni ne, c oa g ulati o n/t hr o m b osis mar kers ( P T/I N R, a P T T, D- di mer a n d fi bri n o ge n), 
di pstic k uri nal ysis, P N H si g ns a n d s y m pt o ms, all A Es a n d c ha n ge i n me ntal stat us.  T he 
descri be d assess me nts s h o ul d be perf or me d after 1 wee k a n d after 2 wee ks fr o m i ptac o pa n 
disc o nti n uati o n ( F oll o w- u p visit 1 a n d 2). Sa m ples f or ce ntral la b orat or y a nal ysis s h o ul d als o 
be c ollecte d f or t he sa me para meters. All data c ollecte d s h o ul d be e ntere d o n t he a p pr o priate 
C R F pa ge.
 are als o t o be c ollecte d at i ptac o pa n 
disc o nti n uati o n, b ut res ults ma y n ot be a vaila ble i m me diatel y a n d will n ot dri ve me dical 
ma na ge me nt of t he patie nts.
If seri o us he m ol ysis occ urs, t he I n vesti gat or s h o ul d c o nsi der t he f oll o wi n g s u p p orti ve 
treat me nts (a n d rec or d t he m i n t he a p pr o priate C R F pa ges):
•
Bl o o d tra nsf usi o n ( pac ke d R B Cs)
•
A ntic oa g ulati o n 
•
A n y ot her s u p p orti ve treat me nt or t hera p y (i ncl u di n g h y drati o n) as j u d ge d b y t he 
I n vesti gat or
If disc o nti n uati o n of st u d y treat me nt occ urs, t he I n vesti gat or s h o ul d ma ke a reas o na ble eff ort 
t o u n dersta n d t he pri mar y reas o n f or t he partici pa nt’s pre mat ure disc o nti n uati o n of st u d y 
treat me nt a n d rec or d t his i nf or mati o n.
Partici pa nts w h o disc o nti n ue st u d y treat me nt or w h o deci de t he y d o n ot wis h t o partici pate i n 
t he st u d y f urt her s h o ul d N O T be c o nsi dere d wit h dra w n fr o m t he st u d y U N L E S S t he y wit h dra w 
t heir c o nse nt (see Secti o n 7. 3 ).
Per ma ne nt treat me nt disc o nti n uati o n is defi ne d as disc o nti n ui n g treat me nt bef ore t he E o S visit 
( Da y 1 6 8 visit).
C CI

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Participants who permanently discontinue study medication during the treatment period, should 
complete the Early Treatment Discontinuation (ETD) visit as soon as possible after permanent 
treatment discontinuation, follow-up visit 1 and 2 and visits as scheduled up to Day 168. If they 
fail to return for these assessments for unknown reasons, every effort (e.g. telephone, e-mail, 
letter) should be made to contact the participant/pre-designated contact as specified in the lost 
to follow-up section. This contact should preferably be done according to the study visit 
schedule.
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 made as detailed in Section 1.3 Schedule of Activities.
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 the 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 
communication or follow-up.

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If the participant agrees, a final evaluation at the time of the participant’s withdrawal of 
consent/exercise data privacy rights should be made as detailed in Section 1.3 Schedule of 
Activities.
Further details on withdrawal of consent or the exercise of participants' data privacy rights are 
included in the corresponding informed consent form.
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 the end of the study.
7.5
Early study termination by the Sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination:
•
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 drug development in PNH
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 (for an 
EoS visit) and treated as a prematurely withdrawn participant. 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 sponsor depending 
on local regulation will be responsible for informing IRBs/IECs of the early termination of the 
trial.
8
Study Assessments and Procedures
The assessment schedule (Table 1-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation.
Unless specified, all assessments should be performed prior to dose administration on the day 
of visits.
Participants should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 1-1) or as close to the designated day/time as possible. Missed or rescheduled visits 
should not lead to automatic discontinuation. If one visit is delayed, the following visits must 
keep the original planned dates from Day 1. For the second screening visits and for visits on 
Day 14/21, Day 28, Day 56, Day 112, Day 126, Day 140 and Day 154, participants that the 

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investigator identifies as suitable for off site visits may have Off-site Research Nursing 
available to them (see  Section 8.11).
Participants who discontinue iptacopan treatment during the treatment period should continue 
in the study up to Day 168 visit, completing all scheduled visits assessments. Refer to 
Section 7.1 for details on the recommended procedures to follow in case of permanent 
discontinuation.
At the final visit, all dispensed investigational product should be reconciled, and the adverse 
event and concomitant medications recorded on the CRF.
8.1
Screening
Screening activities must be initiated only after the participant has signed the ICF.
8.1.1
Hemoglobin assessments during Screening
When signing the ICF, the participant allows the retrospective review and reporting of Hb 
values during the last 6 months prior to screening. The mean/average of all Hb assessments 
collected in those 6 months (minimum of 2 values) must be ≥10 g/dL, without having received 
any RBC transfusion, to proceed with screening activities.
During the screening period, two Hb measurements will be analyzed by central laboratory; 
mean Hb must be ≥10 g/dL to be eligible for the study.
8.1.2
Absolute Reticulocytes Count during Screening
The ARC will be measured at Screening to determine eligibility with regards to exclusion 
criterion # 6. The ARC as assessed by the central or local laboratory during the Screening period 
(only) can be used to determine participant’s eligibility (protocol defined threshold of absolute 
reticulocytes <100x109/L). The results of the local laboratory values (including reference ranges) 
should be included in the eCRF to document eligibility.
8.2
Participant demographics/other baseline characteristics
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF.
Participants demographic data: full date (only if required and permitted) or year of birth or age, 
sex, race/predominant ethnicity (if permitted) and baseline characteristic data  will be collected 
on all eligible participants. 
Participant race/ethnicity are collected and analyzed to identify variations in safety or efficacy 
due to these factors as well as to assess the diversity of the study population as required by 
Health Authorities.
Relevant medical history/current medical conditions will include: date for diagnosis of PNH 
(and age or disease duration will be derived up to the date of screening); date and result of PNH 
WBC clone size in the 12 months prior to Screening; vaccination history; MAVE history (dates 
and type); the RBC transfusion received in the last 12 months prior to Screening; Hb values in 
the last 6 months prior to Screening; relevant medical history and current medical conditions 
till the date of signature of ICF; smoking/vaping and alcohol history will also be collected.

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Prior concomitant medications (including vitamins, herbal preparations, over the counter 
medications, and those medications highlighted in the entry criteria, as well as start date, dose 
and dose interval of anti‑C5 treatment) and procedures (any therapeutic intervention including 
surgery, biopsies, or non-pharmacological therapy) taken prior to Screening will be recorded in 
the CRFs.
Prior anti-C5 antibody treatment regimen for PNH (eculizumab or ravulizumab), which must 
be stable for the 6 months preceding and during screening (Section 5.1), will be recorded on a 
dedicated CRF page.
Investigators have the discretion to record abnormal test findings on the medical history eCRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
8.3
Efficacy assessments
Efficacy/pharmacodynamics assessments are specified below. Planned time points for all 
efficacy assessments are provided in Section 1.3 Schedule of Activities. Section 3 shows the 
correlation of the assessments with the objectives.
8.3.1
Hemoglobin, reticulocytes, LDH and other PNH-related laboratory 
parameters
Blood samples for hematology and clinical chemistry will be collected according to Table 1-1 
for the treatment period.
The following laboratory parameters are performed to evaluate efficacy at all visits:
•
Hb and RBCs
•
LDH as a marker of IVH
•
Haptoglobin, ARC and bilirubin as markers of EVH
•
aPTT, PT, INR, D-dimer and fibrinogen as markers of risk of thrombosis
Refer to central laboratory manual regarding sample collection, numbering, processing and 
shipment.
8.3.2
Breakthrough hemolysis
The occurrence of BTH will be monitored continuously during the treatment period.
The criteria for clinical breakthrough is defined in Table 8-1 below if either one of the two 
clinical criteria is met, in presence of the laboratory evidence of IVH and should be reported in 
the 'Breakthrough hemolysis' CRF page in addition to the AE page. The management of clinical 
BTH is reported in Section 6.8.1.2. In contrast to clinical breakthrough as defined, the isolated 
laboratory evidence of increased IVH, without meaningful decrease in Hb and without other 
clinical signs or symptoms of hemolysis (per Table 8-1), is defined as subclinical BTH, and 
should not be reported in the 'Breakthrough hemolysis' CRF page.
In case the event of BTH also qualifies for serious hemolysis the recommended treatment is 
reported in Section 6.8.4

N o v arti s
C o nfi d e nti al
P a g e 5 0 of 9 2
A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
T a bl e 8- 1  
Br e a kt hr o u g h d efi niti o n
Cli ni c al crit eri a
L a b or at or y crit eri a
H e m o gl o bi n l e v el s
Si g n s or s y m pt o m s
L D H l e v el
Cli ni c al 
br e a kt hr o u g h *
D e cr e a s e e q u al t o or 
m or e t h a n 2 g/ d L 
( c o m p ar e d t o t h e l at e st 
a s s e s s m e nt)
Gr o s s h e m o gl o bi n uri a, p ai nf ul 
cri si s, d y s p h a gi a or a n y ot h er 
si g nifi c a nt cli ni c al P N H-r el at e d 
si g n s & s y m pt o m s
> 1. 5-ti m e s U L N a n d 
i n cr e a s e d a s c o m p ar e d t o t h e 
l a st 2 a s s e s s m e nt s
S u b cli ni c al 
br e a kt hr o u g h
D e cr e a s e l e s s t h a n 2 
g/ d L ( c o m p ar e d t o t h e 
l at e st a s s e s s m e nt)
N o cli ni c al si g n s or s y m pt o m s, 
e x c e pt m o d er at e 
h e m o gl o bi n uri a
> 1. 5-ti m e s U L N a n d 
i n cr e a s e d a s c o m p ar e d t o t h e 
l a st 2 a s s e s s m e nt s
L D H: l a ct at e d e h y dr o g e n a s e; U L N: U p p er Li mit of N or m al;
* T h e br e a kt hr o u g h i s d efi n e d cli ni c al if eit h er o n e of t h e t w o cli ni c al crit eri a i s d e m o n str at e d, i n pr e s e n c e of 
l a b or at or y e vi d e n c e of I V H ( L D H l e v el)
T he assess me nt c o ul d be base d o n t he l ocal la b orat or y res ults. H o we ver, t he I n vesti gat or s h o ul d 
als o c ollect at t he sa me ti me a sa m ple f or t he ce ntral la b orat or y assess me nt of H b, L D H a n d 
Bilir u bi n (t otal a n d fracti o ns), w he ne ver p ossi ble. A P K sa m ple, a 
 
 a n d a n a d diti o nal 
 ( defi ne d i n Secti o n 8. 8 ) s h o ul d als o be c ollecte d 
i n case of cli nical B T H; t he a nal ysis of t hese para meters is e x pl orat or y i n nat ure a n d will n ot 
dri ve decisi o n ma ki n g o n B T H treat me nt.
8. 3. 3 
P N H-r el at e d si g n s a n d s y m pt o m s
P N H si g ns a n d s y m pt o ms will be c ollecte d acc or di n g t o Ta ble 1- 1 . T he I n vesti gat or ( or 
desi g nee) will rec or d t he prese nce of t he f oll o wi n g si g ns a n d s y m pt o ms:
•
Re d dis h or c ola-c ol ore d uri ne es peciall y i n t he m or ni n g / or he m o gl o bi n uria
•
Feeli n g wea k or tire d
•
S h ort ness of breat h / d ys p nea
•
D ys p ha gia / diffic ult y s wall o wi n g
•
C hest pai n
•
A b d o mi nal / bell y pai n
•
Erectile d ysf u ncti o n /i m p ote nc y
T hese si g ns a n d s y m pt o ms of P N H will be re p orte d i n t he C R F at eac h visit.
8. 3. 4  
M aj or A d v er s e V a s c ul ar E v e nt s ( M A V E s)
Assess me nts of M A V Es occ ur acc or di n g t o Ta ble 1- 1  a n d will be re p orte d i n t he de dicate d C R F 
pa ge, i n a d diti o n t o t he A E pa ge. T he descri pti o n of t he M A V Es i ncl u di n g dia g n osis (i.e., 
ultras o u n d, a n gi o gra m, ma g netic res o na nce i ma gi n g, etc.), date of dia g n osis. Start date, e n d 
date (if a p plica ble) a n d stat us ( o n g oi n g /res ol ve d) will be c ollecte d i n t he C R Fs. A M A V E is 
defi ne d as per t he list bel o w.
•
Ac ute peri p heral vasc ular occl usi o n
•
A m p utati o n ( n o n-tra u matic; n o n dia betic)
•
Cere bral arterial occl usi o n/cere br o vasc ular acci de nt
•
Cere bral ve n o us occl usi o n
•
Der mal t hr o m b osis
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•
Gangrene (non-traumatic; nondiabetic)
•
Hepatic/portal vein thrombosis (Budd‑Chiari syndrome)
•
Mesenteric/visceral arterial thrombosis or infarction
•
Mesenteric/visceral vein thrombosis or infarction
•
Myocardial infarction
•
Pulmonary embolus
•
Renal arterial thrombosis
•
Renal vein thrombosis
•
Thrombophlebitis / deep vein thrombosis
•
Transient ischemic attack
•
Unstable angina
•
Other, please specify
8.3.5
Appropriateness of efficacy assessments
The efficacy assessments including laboratory parameters Hb (to determine the degree of 
anemia), LDH (as marker for IVH), reticulocytes, bilirubin and haptoglobin (as markers for 
EVH), and the need of RBC transfusions are important parameters for assessing treatment 
response in PNH. In fact, Hb and, the need of RBC transfusions are the determining parameters 
for classifying treatment response to complement inhibitor therapy with LDH and reticulocytes 
as ancillary parameters (Risitano et al 2019). BTH is a phenomenon reported with eculizumab 
and also ravulizumab, therefore is part of the efficacy assessments for iptacopan, a new 
complement inhibitor, in this study. As thromboembolism is the leading cause of mortality in 
patients with PNH (Hill et al 2013), it is important to assess MAVEs for iptacopan treatment in 
PNH patients. The majority of these efficacy assessments have been used in the eculizumab and 
ravulizumab registrations studies and will provide clinically relevant results for PNH.
PROs are also part of the efficacy evaluation of iptacopan treatment and are discussed in 
Section 8.5.1. The FACIT-Fatigue Scale will measure various aspects of fatigue, one of the 
most debilitating and commonly reported symptom generally among PNH patients 
(Hill et al 2007), and among patients currently treated with eculizumab (Socié et al 2019). The 
use of the FACIT-F in PNH patients has been reported in several publications and is sensitive 
to changes in disease status, allowing demonstration of statistically significant and clinically 
meaningful results (Kulasekararaj et al 2019, Ueda et al 2018, Brodsky et al 2008). It has been 
well validated in general populations (Webster et al 2003; Yellen et al 1997) and content 
validity has been completed specifically in PNH patients (Weitz et al 2013). From the 302 study 
(Kulasekararaj et al 2019) with eculizumab/ravulizumab and baseline mean Hb ≥10 g/dL, the 
percentage of patients presenting with fatigue at baseline was ~30% (rav) and 40% (ecu) and a 
3-point improvement in FACIT-Fatigue score, considered clinically meaningful, was observed 
after 26 weeks of treatment (37.1% (rav) vs 33.7% (ecu)).
Given differences in route of administration, convenience and potential for additional 
incremental improvement, it will be important to assess areas of satisfaction and preference 
with the switch study, through use of PRO measures such as TSQM-9.

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8.4
Safety assessments
Safety assessments are specified below with Section 1.3 Schedule of Activities detailing when 
each assessment is to be performed.
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).
For details on AE collection and reporting, refer to AE Section 8.6.
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, regular 
phone or virtual calls may occur (as per scheduled visits) for safety monitoring and discussion 
of the participant´s health status until it is safe for the participant to visit the site again.
8.4.1
Physical examinations
A complete physical examination will include the examination of general appearance, skin, 
neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, 
extremities, vascular, and neurological. If indicated, based on medical history and/or symptoms, 
rectal, external genitalia, breast, and pelvic exams will be performed.
Height in centimeters (cm) is collected at Screening only; body weight (to the nearest 0.1 
kilogram (kg) assessed in indoor clothing, but without shoes) will be measured.
The same route (temporal, tympanic, or axillary) and modality (temporal scanner, tympanic 
probe, thermometer) for measuring body temperature should be used for ongoing patient 
observations, as to allow for accurate temperature trend evaluation.
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 Adverse Event must be recorded 
as an adverse event.
8.4.2
Vital signs
Vital signs include blood pressure (BP) and pulse measurements. After the participant has been 
sitting for five minutes, with back supported and both feet placed on the floor, systolic and 
diastolic blood pressure will be measured with an appropriately sized cuff. If the value reported 
is out of range, a repeat sitting measurements will be made at 5 - 10 minute later and the second 
measurement will be used/entered in the CRFs. In specific visits defined in the SoA (Section 1.3) 
the vital signs may be collected by an Off-site Research Nurse (see Section 8.11)
8.4.3
Electrocardiograms
Electrocardiograms (ECGs) must be recorded after 10 minutes rest in the supine position and 
conducted as a 12-lead recording according to the assessment schedules in Table 1-1. The 
preferred sequence of cardiovascular data collection during study visits is outlined in 
Figure 8-1 and includes ECG collection first, followed by vital signs, and blood sampling 

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(including PK sampling). The Fridericia QT correction formula (QTcF) should be used for 
clinical decisions.
Unless auto-calculated by the ECG machine, the investigator must calculate QTcF according to 
the following formula, where QT interval is in milliseconds (ms) and RR interval in seconds 
(s):
QTcF = QT/³√RR
Single 12-lead ECGs are to be collected with ECG machines available at the site. The original 
ECGs and a certified copy on non-heat sensitive paper, appropriately signed, must be collected 
and archived at the study site.
For any ECGs with participant safety concerns (please refer to Section 10.3.1 for notable 
abnormalities), two additional ECGs must be performed to confirm the safety finding. If 
confirmed, a copy of the assessment should be sent to the Novartis global team for expedited 
review. Clinically significant abnormalities must be recorded on the CRF as either medical 
history/current medical conditions or adverse events, as appropriate. Any identifier details must 
be redacted e.g. participant initials, date of birth.
Figure 8-1
Timing of study procedures
8.4.4
Clinical safety laboratory tests
Unless specified in the table below, a central laboratory will be used for the analysis of the 
specimens collected. Details of collection, shipment, and reporting by the laboratory is provided 
to the Investigator in the laboratory manual.
Clinically notable laboratory findings are defined in Section 10.5 and Section 10.6.
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate.
Table 8-2
Laboratory tests
Test category
Test Name
Hematology - full list
Hematocrit (Ht), Hemoglobin (Hb), Mean corpuscular hemoglobin (MCH), 
Haptoglobin, Absolute Reticulocytes count (ARC*), Red blood cells (RBC) count, 
RBC distribution width (RDW), RBC mean corpuscular volume (MCV), white 
blood cell (WBC) count with differentials (absolute and %) and platelet count
Clinical Chemistry (full)
Albumin, Alkaline phosphatase (ALP), ALT, AST, Gamma-glutamyl-transferase 
(GGT), Lactate dehydrogenase (LDH), Calcium, Magnesium, Phosphorus, 
Sodium, Potassium, eGFR, hs-C-reactive protein (hsCRP), Serum creatinine, 
Creatine kinase (CK), Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, Total 
Cholesterol, LDL, HDL, Triglycerides, Blood Urea Nitrogen (BUN) /Urea, Uric 
Acid, Amylase, Lipase, Glucose (non-fasting), Ferritin, Folate, Iron
Clinical Chemistry 
(abbreviated)
LDH, ALT, AST, ALP, GGT, eGFR, hs-CRP, Serum creatinine, Total Bilirubin 
and fractions, CK, total cholesterol, LDL, HDL, Triglycerides
Urinalysis/urine dipstick 
assessments
Dipstick measurements for protein, bilirubin, blood, glucose, ketones, nitrites, pH, 
specific gravity, urobilinogen, and leukocyte esterase will be performed at the 

N o v arti s
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P a g e 5 4 of 9 2
A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
T e st c at e g or y
T e st N a m e
sit e’ s l o c al l a b or at or y.
R e s ult s fr o m  di p sti c k m e a s ur e m e nt will b e c a pt ur e d i n t h e e C R F. Mi cr o s c o p y 
m u st b e a s s e s s e d l o c all y f oll o wi n g a n a b n or m al di p sti c k t e st a n d al s o b e 
c a pt ur e d i n e C R F.
C o a g ul ati o n/ m ar k er s of 
t hr o m b o si s
Pr ot hr o m bi n ti m e ( P T), 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), 
fi bri n o g e n, D- di m er
Pr e g n a n c y t e st
S er u m t e st at s cr e e ni n g / Uri n e pr e g n a n c y t e st at t h e e n d of t h e tri al ( s o ur c e) will 
b e p erf or m e d at t h e sit e' s l o c al l a b or at or y
H e p atiti s m ar k er s
H e p atiti s B Vir u s S urf a c e A nti g e n, H e p atiti s C Vir u s R N A
HI V
HI V s er o p o siti vit y t e sti n g will b e p erf or m e d a s d et ail e d i n t h e C e ntr al l a b or at or y 
m a n u al a n d i n li n e wit h l o c al r e g ul at or y r e q uir e m e nt s
 
 
 
 
* R ef er t o e x cl u si o n crit eri o n # 6: A R C m a y b e p erf or m e d l o c all y f or eli gi bilit y, b ut m u st b e p erf or m e d c e ntr all y i n 
all ot h er vi sit s.
8. 4. 5 
Pr e g n a n c y t e sti n g
All pre- me n o pa usal w o me n w h o are n ot s ur gicall y sterile will ha ve pre g na nc y testi n g 
perf or me d acc or di n g t o t he Assess me nt Sc he d ule i n Ta ble 1- 1 . A d diti o nal pre g na nc y testi n g 
mi g ht be perf or me d if re q ueste d b y l ocal re q uire me nts.
At scree ni n g, a ser u m pre g na nc y test will be perf or me d, w hile at t he e n d of t he st u d y uri nar y 
pre g na nc y test will be perf or me d. L ocal pre g na nc y tests a n d ass ociate d res ults will n ot be 
c ollecte d o n C R F.
T he partici pa nt s h o ul d i nf or m t he i n vesti gat or if t he y belie ve t he y mi g ht be pre g na nt. Please 
refer t o Secti o n 7. 1  o n rec o m me n dati o ns f or i ptac o pa n t hera p y i n case of a pre g na nc y.
A s s e s s m e nt s of f ertilit y
Refer t o Secti o n 5. 2  f or criteria t o deter mi ne w o me n t hat are n ot of c hil d- beari n g p ote ntial.
S u bse q ue nt h or m o ne le vel assess me nt t o c o nfir m t he w o ma n is n ot of c hil d- beari n g p ote ntial 
m ust als o be a vaila ble as s o urce d oc u me ntati o n i n t he f oll o wi n g cases:
•
S ur gical bilateral o o p h orect o m y wit h o ut a h ysterect o m y
•
Re p orte 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.
I n t he a bse nce of t he a b o ve me dical d oc u me ntati o n, F S H testi n g is re q uire d of a n y fe male 
partici pa nt re gar dless of re p orte d re pr o d ucti ve/ me n o pa usal stat us at scree ni n g/ baseli ne.
A w o ma n is c o nsi dere d of c hil d beari n g p ote ntial fr o m me narc he a n d u ntil bec o mi n g p ost-
me n o pa usal u nless per ma ne ntl y sterile. Per ma ne nt sterilizati o n met h o ds i ncl u de h ysterect o m y, 
bilateral sal pi n gect o m y a n d bilateral o o p h orect o m y. Me dical d oc u me ntati o n of o o p h orect o m y, 
h ysterect o m y, or t u bal li gati o n m ust be retai ne d as s o urce d oc u me nts.
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.
C CI
C CI
C CI
C CI
C CI

N o v arti s
C o nfi d e nti al
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A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
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  
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 selecte d are a p pr o priate f or t his i n dicati o n/ patie nt p o p ulati o n a n d t he 
p ote ntial ris ks ass ociate d wit h i ptac o pa n. T he ris k of i nfecti o n ca use d b y e nca ps ulate d bacteria 
will be cl osel y m o nit ore d t hr o u g h o ut t he st u d y. Partici pa nt vi gila nce f or earl y si g ns a n d 
s y m pt o ms of i nfecti o n is re q uire d a n d s u p p orte d b y pr o vi di n g a n a p pr o priate t o ol ( Partici pa nt 
Safet y Car d) t o e n ha nce a ware ness a n d vi gila nce. Vital si g ns a n d E C Gs will be c ollecte d i n 
or der t o e val uate t he cli nical si g nifica nce of fi n di n gs o bser ve d i n precli nical t o xicit y st u dies.
8. 5  
A d diti o n al a s s e s s m e nt s
8. 5. 1  
Cli ni c al O ut c o m e A s s e s s m e nt s ( C O A s)
P ati e nt r e p ort e d o ut c o m e s ( P R O) a n d P ati e nt I nt er vi e w
T o f urt her u n dersta n d t he partici pa nts’ s y m pt o ms, f u ncti o ni n g, a n d o verall well- bei n g, a n d t heir 
c ha n ges d uri n g t he st u d y, t hree 
, i n a d diti o n t o a 
 
, will be use d i n t his st u d y:
•
F A CI T- Fati g ue
•
T S Q M- 9
•
T he P R Os will be c o m plete d b y partici pa nts, o n a n electr o nic P R O de vice (e P R O), bef ore a n y 
ot her pr oce d ure or assess me nt at t he scree ni n g a n d assess me nt visits (see Ta ble 1- 1  a n d 
Fi g ure 8- 1 ). Detaile d i nstr ucti o ns descri bi n g a d mi nistrati ve pr oce d ures of t he P R Os i ncl u di n g 
partici pa nt c o m pleti o n via e P R O will be pr o vi de d t o t he sites.
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, C O A data 
ma y be c ollecte d re m otel y’.
T he q uesti o n naires s h o ul d be c o m plete d i n t he la n g ua ge i n w hic h t he res p o n de nt is m ost 
fa miliar. T he partici pa nt s h o ul d be gi ve n s ufficie nt s pace a n d ti me t o c o m plete t he q uesti o ns. If 
a partici pa nt is n ot a ble t o self-a d mi nister t he e P R O (e. g. d ue t o illiterac y or bli n d ness) or 
ref uses t o c o m plete a q uesti o n naire t his s h o ul d be d oc u me nte d i n t he s o urce d oc u me nts. A 
s u bject's i na bilit y t o c o m plete a q uesti o n naire(s) is n ot a pr ot oc ol de viati o n. T he partici pa nt 
s h o ul d be ma de a ware t hat c o m plete d meas ure(s) are n ot re vie we d b y t he I n vesti gat or/ st u d y 
pers o n nel.
Brief descri pti o ns of eac h q uesti o n naire are gi ve n bel o w.
F A CI T- F ati g ue
T he F A CI T- Fati g ue is a 1 3-ite m q uesti o n naire t hat assesses self-re p orte d fati g ue a n d its i m pact 
u p o n dail y acti vities a n d f u ncti o n.  It will be use d t o assess patie nt-re p orte d fati g ue. F A CI T-
Fati g ue is o ne of ma n y differe nt F A CI T scales part of a c ollecti o n of Healt h- Relate d Q ualit y of 
C CI
C CI
C CI

N o v arti s
C o nfi d e nti al
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A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
Life 
( H R Q o L) 
q uesti o n naires 
referre d t o 
as t he 
F A CI T 
Meas ure me nt 
S yste m 
(We bster et al 2 0 0 3 , Yelle n e t al 1 9 9 7). T he use of t he F A CI T- Fati g ue i n P N H patie nts has 
bee n re p orte d i n se veral p u blicati o ns a n d is se nsiti ve t o c ha n ges i n disease stat us, all o wi n g 
de m o nstrati o n of statisticall y si g nifica nt a n d cli nicall y mea ni n gf ul res ults ( Br o ds k y et al 2 0 0 8 , 
Ue da et al 2 0 1 8 , K ulase kararaj et al 2 0 1 9 ). All F A CI T scales are sc ore d s o t hat a hi g h sc ore is 
better. As eac h of t he 1 3 ite ms of t he F A CI T- Fati g ue scale ra n ges fr o m 0- 4, t he ra n ge of p ossi ble 
sc ores is 0- 5 2, wit h 0 bei n g t he w orst p ossi ble sc ore a n d 5 2 t he best.
T S Q M- 9
T he Treat me nt Satisfacti o n Q uesti o n naire f or 
Me dicati o n ( T S Q M- 9) is a patie nt re p orte d 
o utc o mes meas ure t hat was desi g ne d t o assess patie nts' satisfacti o n wit h me dicati o n acr oss t hree 
d o mai ns of effecti ve ness, c o n ve nie nce a n d gl o bal satisfacti o n. It has bee n use d i n ma n y 
differe nt t hera pe utic areas wit h s u p p ort f or its vali dit y a n d relia bilit y ( B har mal et al 2 0 0 9 ). T he 
T S Q M- 9 c o ntai ns 3 q uesti o ns i n eac h d o mai n, t hat are a ns were d f or t he past 2 or 3 wee ks. 
D o mai n sc ores ra n ge fr o m 0 – 1 0 0 wit h hi g her re prese nti n g better sc ores f or t he d o mai n.  It 
will be use d i n t his st u d y t o assess c ha n ges i n satisfacti o n after s witc hi n g t hera pies, a n d o ver 
t he c o urse of t he st u d y.
T he 
wit h i n p ut fr o m patie nts a n d 
cli nicia ns. It
 
 
 T his 
 is i ncl u de d i n t he st u d y t o f urt her assess t he 
s y m pt o ms, i m pacts o nce s witc hi n g t hera pies (Nie de g ge n et al 2 0 1 9 , Gr ot h et al 2 0 1 7). D ue t o 
u na vaila bilit y of all la n g ua ge tra nslati o ns, o nl y patie nts w h o are fa miliar wit h t he a vaila ble 
la n g ua ge will ha ve t o c o m plete t he q uesti o n naire.
Partici pa nts i n t he st u d y will ha ve e x perie nce d t he st u d y me dicati o n a n d ma y ha ve fee d bac k 
t hat has n ot bee n as ke d or elicite d t hr o u g h 
. Q ualitati ve patie nt 
fee d bac k o n t he mea ni n gf ul ness of c ha n ges 
 
d uri n g t he cli nical st u dies is of 
i ncreasi n g i nterest t o re g ulat or y b o dies a n d patie nt c o m m u nities, i ntereste d i n t he val ue of ne w 
me dicati o ns, a n d is disc usse d i n F o o d a n d Dr u g A d mi nistrati o n's ( F D A) latest Patie nt F oc use d 
Dr u g De vel o p me nt G ui da nce ( F D A 2 0 2 0 ). 
 
 
 b y researc hers w h o are trai ne d i n 
 
tec h ni q ues t o e ns ure t he q ualit y of t he i nter vie w a n d data pr otecti o n. D uri n g eac h i nter vie w, 
i nter vie wers will f oll o w a 
 g ui de. T his g ui de is n ot i nte n de d as a scri pt 
t o be f oll o we d ver bati m b ut rat her will be refere nce d d uri n g i nter vie ws t o e ns ure t hat rele va nt 
a n d c o m plete i nf or mati o n relate d t o t he researc h q uesti o n is c ollecte d i n as s p o nta ne o us ma n ner 
as p ossi ble. T he trai ni n g of t he i nter vie wers a n d t he o pe n-e n de d a p pr oac h e ns ures t hat st u d y 
partici pa nts are n ot u n d ul y biase d a n d t hat t he la n g ua ge st u d y partici pa nts use t o descri be t heir 
e x perie nces is elicite d or ga nicall y ( Sta u nt o n et al 2 0 1 9 ). 
 
C CI
C CI
C CI
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
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A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
 T he i nter vie ws will be c o n d ucte d acc or di n g t o t he l ocal 
re g ulat or y all o wa nce f or c o n d uct of t hese t y pe of i nter vie ws.
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. 1 a n d Secti o n 8. 6. 2  res pecti vel y.
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, 
assessi n g ca usalit y 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 or S A Es, c o nsi dere d relate d t o t he st u d y treat me nt or t hat 
ca use d partici pa nt t o disc o nti n ue t he st u d y treat me nt (see Secti o n 7 ).
F or t he i n vesti gati o nal pr o d uct a n d f or n o n-a ut h orize d A x M Ps ( w he n a p plica ble), i nf or mati o n 
a b o ut a d verse dr u g reacti o ns a n d h o w t o ma na ge t he m ca n be f o u n d i n t he I n vesti gat or's 
Br oc h ure (I B) or e q ui vale nt d oc u me ntati o n. I nf or mati o n a b o ut a d verse dr u g reacti o ns ca n als o 
be f o u n d i n t he pr o d uct i nf or mati o n f or mar kete d pr o d ucts.
T he met h o d of rec or di n g, e val uati n g, a n d assessi n g ca usalit y of A Es a n d S A Es a n d t he 
pr oce d ures f or c o m pleti n g a n d tra ns mitti n g S A E re p orts are pr o vi de d i n Secti o n 8. 6. 3 .
8. 6. 1  
A d v er s e e v e nt s
A n A E is a n y u nt o war d me dical occ urre nce (e. g. a n y u nfa v ora ble a n d u ni nte n de d si g n 
[i ncl u di n g a b n or mal la b orat or y fi n di n gs], s y m pt o m or disease) i n a cli nical i n vesti gati o n 
partici pa nt after pr o vi di n g writte n i nf or me d c o nse nt f or partici pati o n i n t he st u d y. T heref ore, 
a n A E ma y or ma y n ot be te m p orall y or ca usall y ass ociate d wit h t he use of a me dici nal 
(i n vesti gati o nal) pr o d uct.
T he I n vesti gat or has t he res p o nsi bilit y f or ma na gi n g t he safet y of i n di vi d ual partici pa nt a n d 
i de ntif yi n g A Es.
N o vartis q ualifie d me dical pers o n nel will be rea dil y a vaila ble t o a d vise o n trial-relate d me dical 
q uesti o ns or pr o ble ms.
T he occ urre nce of A Es m ust be s o u g ht b y n o n- directi ve q uesti o ni n g of t he partici pa nt at eac h 
visit d uri n g t he st u d y. A Es als o ma y be detecte d w he n t he y are v ol u nteere d b y t he partici pa nt 
d uri n g or bet wee n visits or t hr o u g h p h ysical e xa mi nati o n fi n di n gs, la b orat or y test fi n di n gs, or 
ot her assess me nts .
All cases of cli nical B T H m ust als o be re p orte d as A E; M A V Es m ust al wa ys be als o re p orte d 
as A E.
F or partici pa nts w h o per ma ne ntl y disc o nti n ue i ptac o pa n a d mi nistrati o n d uri n g t he c o urse of t he 
st u d y, or d o n ot c o nti n ue i nt o t he R E P, A Es will be c ollecte d f or 7 da ys after last d ose of st u d y 
dr u g or u ntil E o S, w hic he ver is l o n ger.
F or partici pa nts w h o c o nti n ue t o t he R E P, A Es will be c ollecte d i n t he data base f or t his st u d y 
u ntil partici pa nt’s last st u d y visit ( Da y 1 6 8/ E o S).
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The investigator will attempt to establish a diagnosis of the event (including lab abnormalities 
that constitute AEs) based on signs, symptoms, and/or other clinical information. Whenever 
possible, the diagnosis (not the individual signs/symptoms) will be documented as the AE.
For each AE, the investigator must assess:
1. The severity grade
•
Mild: A type of AE that is usually transient and may require only minimal treatment or 
therapeutic intervention.  The event does not generally interfere with usual activities of daily 
living.
•
Moderate: A type of AE that is usually alleviated with additional specific therapeutic 
intervention.  The event interferes with usual activities of daily living, causing discomfort 
but poses no significant or permanent risk of harm to the research participant.
•
Severe: A type of adverse event that interrupts usual activities of daily living, or 
significantly affects clinical status, or may require intensive therapeutic intervention.
2. The causality:
The investigator is obliged to assess the relationship between any treatment used in the study 
(study treatment, AxMP(s)) and each occurrence of AE. The investigator will use clinical 
judgement 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 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, should be considered and investigated. 
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.
For causality assessment, the investigator will also consult the IB and/or product information, 
for marketed products.
The causality assessment is one of the criteria used when determining regulatory reporting 
requirements.
2. The duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported
3. Whether it constitutes a SAE (see Section 8.6.2 for definition of SAE) and which 
seriousness criteria have been met
4. Action taken regarding study treatment. All adverse events must be treated appropriately. 
Treatment may include one or more of the following:
•
Dose not changed
•
Dose reduced/increased
•
Drug interrupted/withdrawn
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Conditions that were already present at the time of informed consent should be recorded in the 
medical history of the participant.
Handling of AEs
All adverse events must be treated appropriately. More information about how to manage AEs 
can be found in the IB. Information about adverse drug reactions can also be found in product 
information for marketed products.
Once an AE is detected, the Investigator must pro-actively followed up the participant, until 
resolution of the AE, or until it is judged to be not recovered/not resolved (e.g., continuing at 
the end of the study), or until stabilization, or until the participant is lost to follow-up. Any 
change in severity or suspected relationship to study treatment must be assessed at each visit 
(or more frequently, if necessary).
Timeframe of recording of AEs
AE recording should be continued at least until 7 days after the last dose of study medication, 
or until the first day of dosing in the REP.
Reporting of AEs related to AxMP(s)
All AEs related to any authorized auxiliary medicinal product used in this study must be 
reported to Novartis.
In assessing causality, the investigators will use the points above.
If a suspicion that medical occurrence could be related to study treatment (and/or interaction 
with study treatment) cannot be ruled out, the reporting rules for study treatment apply.
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4
Information about ADRs for the investigational drug can be found in the IB.
Abnormal laboratory values or test results constitute adverse events 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 
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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
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. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
8.6.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety immediately, without undue delay, but under no circumstances later than 24 

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hours of obtaining knowledge of 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 (eSAE with paper back up) Serious Adverse Event 
Report Form; all applicable sections of the form must be completed in order to provide a 
clinically thorough report.
For participants NOT entering the REP, any SAEs experienced by participants up to 30 days 
after EoS should be reported to the Novartis Safety office using a paper SAE form.
The investigator must review and provide an assessment of causality for each SAE. There may 
be situations in which an SAE has occurred, and the investigator has minimal information to 
include in the initial report to Novartis. However, it is very important that the investigator 
always makes an assessment of causality for every event before the initial transmission of the 
SAE data to Novartis. The investigator may change their opinion of causality in light of follow-
up information and send an SAE follow-up report with the updated causality assessment.
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.
Reporting of Suspected Unexpected Serious Adverse Reactions (SUSARs)
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,  Novartis 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 30 day period after the last study 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.
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) 
(In patients with transaminases above the ULN at baseline, the Hy’s Law criteria may be 
changed to increases 2-fold above baseline values). 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 

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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 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.
Reporting of SAEs related to AxMP(s)
All SAEs related to any auxiliary medicinal product (whether authorized or not) used in this 
study must be reported to Novartis within 24 hours of the site becoming aware of it. In assessing 
causality, the investigators will use the points above. If a suspicion that the medical occurrence 
could be related to study treatment (or and interaction with study treatment) cannot be ruled 
out, the reporting rules for study treatment apply.
8.6.4
Pregnancy
If a female trial participant becomes pregnant, the stopping of investigational drug should be 
considered as described in Section 7.1, and the trial participant must be asked to read and sign 
the pregnancy consent form to allow the Study Doctor to ask about her pregnancy. To ensure 
participant safety, each pregnancy occurring after signing the study informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. Details of all pregnancies in 
female participants will be collected after the start of study treatment and until 12 months after 
the birth.
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. 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.
Pregnancy should be recorded and reported by the Investigator to  Novartis. Pregnancy follow-
up should be recorded on the same form and should include an assessment of the possible 
relationship to the study treatment and any pregnancy outcome. Any SAE experienced during 
pregnancy must also be reported.
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.

N o v arti s
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Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
8. 6. 6  
A d v er s e e v e nt s of s p e ci al i nt er e st
A d verse e ve nts of s pecial i nterest ( A E SIs) are defi ne d as e ve nts (seri o us or n o n-seri o us) w hic h 
are of scie ntific a n d me dical i nterest s pecific t o N o vartis’s pr o d uct or pr o gra m, f or w hic h 
o n g oi n g m o nit ori n g ma y be a p pr o priate. S uc h e ve nts ma y re q uire f urt her i n vesti gati o n i n or der 
t o c haracterize a n d u n dersta n d t he m. A d verse e ve nts of s pecial i nterest are defi ne d o n t he basis 
of p ote ntial safet y ris ks f or t he pr o d uct, class effects a n d data fr o m precli nical st u dies.
8. 7
 i n all partici pa nts at t he visits defi ne d i n t he 
assess me nt sc he d ule ( Ta ble 1- 1 ) t o deter mi ne 
 
. A d diti o nal 
 will als o be c ollecte d i n case of 
(see 
Secti o n 8. 3. 2 ) a n d 
 (see Secti o n 7. 1 ).
 c ollecte d at
 are i nte n de d t o
 
 is li mite d t o 
t o li mit t he b ur de n o n patie nts t hat 
are ot her wise sta ble a n d are alrea d y as ke d t o c o me t o t he cli nic m ore ofte n t ha n t heir re g ular 
care w o ul d re q uire.
T he  
 m ust be c ollecte d 
 
a d mi nistrati o n t o meas ure t he
 
 T he I n vesti gat or or re prese ntati ve s h o ul d 
re mi n d t he partici pa nt pri or t o t he visit t hat d uri n g t hat
 
T he I n vesti gat or or re prese ntati ve s h o ul d re mi n d partici pa nts t o 
 
 a n d t o re p ort if t he  
 
 o n t he da y pri or t o t he visit was misse d, as t hese e ve nts nee d t o be ca pt ure d i n t he de dicate d 
e C R F pa ge.
I ptac o pa n will be deter mi ne d i n 
 
.
 t o be deter mi ne d 
a n d re p orte d 
 will re p orte d as  
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.
8. 8
 will be a nal yze d t o i n vesti gate t he effect of i ptac o pa n i n 
 
 
T he 
 
.
 
 
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defi ne d i n Ta ble 1- 1 ; t he y will als o be c ollecte d i n case of 
 (see Secti o n 8. 3. 2 ) a n d 
 (see Secti o n 7. 1 ).
T he list of 
 ma y c ha n ge d uri n g t he c o urse of t he st u d y d ue t o 
 
 
a y als o be a nal yze d retr os pecti vel y 
after cl ose o ut of t he trial wit h decisi o ns de pe n de nt o n st u d y o utc o me or ne w i nf or mati o n o n 
i ptac o pa n's mec ha nis m of acti o n.
W hile t he g oal of t he 
, 
t here ma y be circ u msta nces w he n a decisi o n is ma de t o st o p a c ollecti o n, or n ot perf or m or 
disc o nti n ue a n a nal ysis d ue t o eit her practical or strate gic reas o ns (e. g. 
 
 
 T heref ore, de pe n di n g o n t he 
res ults o btai ne d d uri n g t he st u d y, 
 ma y be o mitte d at t he discreti o n of N o vartis.
T he st u d y i ncl u des a n 
 w hic h re q uires a 
 
. As per mitte d b y l ocal g o ver ni n g 
re g ulati o ns a n d b y I R B/ E C, 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 nt 
t hese o pti o ns t o t he partici pa nt. Sa m ple will be c ollecte d, o n  
 as i n dicate d i n Ta ble 1- 1 . If 
, it ca n be ta ke n at a n y visit t hereafter. T he p ur p ose 
ma y be t o
 
 
 T he g oal 
is t o
, or t o lear n m ore a b o ut  
 
. As tec h n ol o g y c ha n ges 
o ver ti me, t he m ost a p pr o priate tec h n ol o g y will be use d at t he ti me t he 
 
. 
 
 
he use of 
 is e x pl orat or y. 
A n y res ults fr o m t his 
 T o 
ma xi mize c o nfi de ntialit y, 
 
. T his
 
As a n a d diti o nal c o nfi de ntialit y meas ure, 
 
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 e val uate d i n t his st u d y.
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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
 
.
8. 1 1  
Off- sit e Pr o c e d ur e s
At t he I n vesti gat or's discreti o n a n d base d o n be nefit-ris k c o nsi derati o ns of t he partici pa nt’s 
cli nical c o n diti o n, q ualif yi n g partici pa nts ma y be offere d t he o pti o n of Off-site Healt hcare 
pr ofessi o nal ( O H P) pr oce d ures at a n off-site l ocati o n.
Pr oce d ures f or off-site visits utilizi n g O H Ps are f urt her detaile d i n se parate ma n ual (s) pr o vi de d 
t o t he site’s partici pati o ns i n t he off-site visits.
T he off-site pr oce d ures will be utilize d i n certai n c o u ntries a n d sites a n d as deter mi ne d b y t he 
pr ot oc ol nee ds., if S p o ns or all o ws, a n d base d o n nati o nal a n d l ocal/site re g ulati o ns.
Partici pa nts, t hat t he I n vesti gat or i de ntifies as s uita ble f or off-site visits, m ust pr o vi de i nf or me d 
c o nse nt (i.e., si g nat ure o n t he o pti o nal c o nse nt. T he f oll o wi n g c o n diti o ns m ust be met f or off-
site visits t o occ ur:
•
Off-site visits ma y occ ur d uri n g t he st u d y f or t he f oll o wi n g visits: sec o n d scree ni n g visit, 
Da y 1 4/ 2 1, Da y 2 8, Da y 5 6, Da y 1 1 2, Da y 1 2 6, Da y 1 4 0 a n d Da y 1 5 4 or u n der e xce pti o nal 
circ u msta nces (i n t he case of B T H w here t he patie nt ca n n ot tra vel t o t he site) a n d if a gree d 
bet wee n I n vesti gat or a n d S p o ns or.
•
T he partici pa nt m ust ha ve c o m plete d at least Scree ni n g visit 1 (i.e., c o nfir me d eli gi bilit y 
base d o n Scree ni n g visit 1).
•
If a partici pa nt has be g u n off-site visits a n d s/ he s uffers fr o m eit her ( 1) a se vere A E or a n 
S A E ( p ossi bl y relate d t o st u d y me dicati o n), a n d/ or ( 2) a n y c o nc urre nt me dical c o n diti o ns 
w hic h, i n t he o pi ni o n of t he I n vesti gat or, c o ul d ca use u nacce pta ble safet y ris ks, t he n t he 
partici pa nt m ust res u me t he o n-site visits. T he partici pa nt ma y res u me t he off-site visits 
w he n, base d o n t he I n vesti gat or’s j u d g me nt, t here are n o f urt her safet y ris ks f or t he 
partici pa nt.
8. 1 1. 1  
R e s p o n si bilit y of i n v e sti g at or o v er si g ht of off- sit e a cti viti e s
Pr oce d ures t hat are perf or me d off-site re mai n u n der t he o versi g ht of t he I n vesti gat or, w h o 
retai ns acc o u nta bilit y f or t he c o n d uct of all safet y a n d efficac y assess me nts dele gate d t o a n 
O H P, a n d will e ns ure t he ri g hts, safet y, a n d well bei n g of partici pa nts. T his i ncl u des t he 
f oll o wi n g (i ncl u di n g, b ut n ot li mite d t o):
•
t he i de ntificati o n, ma na ge me nt a n d re p orti n g of A Es a n d S A Es are perf or me d i n acc or da nce 
wit h t he pr ot oc ol a n d a p plica ble re g ulati o ns
•
verificati o n t hat 
O H Ps ha ve a p pr o priate q ualificati o ns, trai ni n g, a n d e x perie nce t o 
s uccessf ull y c o n d uct off-site pr oce d ures
•
s o urce data c ollecte d off-site are re vie we d a n d e val uate d i n a ti mel y ma n ner
•
t he I n vesti gat or or dele gate is a vaila ble t o be c o ntacte d b y t he O H P if a n y iss ues or c o ncer ns 
are n ote d d uri n g a n off-site visit
C CI

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•
where relevant, the Investigator or delegate will be present via telemedicine for a portion of 
the off-site visit to support the physical examination.
8.11.2
Responsibility of OHPs
OHPs must have the required qualifications, training, and experience to conduct off-site 
assessments. OHPs are responsible to conduct delegated assessments and collect relevant data 
at off-site visits in accordance with the clinical trial protocol, International Council for 
Harmonization (ICH) Good Clinical Practice (GCP) guidelines, and national and local 
regulations and guidelines.
Any issues or safety concerns identified by the OHP will be promptly communicated to the 
Investigator or delegate according to a pre-defined communication plan.
The ORN may collect vital signs, collect and process laboratory samples according to 
Table 8-2, which will then be shipped to the Central Laboratory. Assessment will be performed 
following the timing indicated in the Schedule of Assessments.
The OHPs will be provided by a third-party vendor sourced by Novartis/Sponsor. Where a site 
wishes to use off-site healthcare professionals that are not provided by Novartis this must be 
agreed with Novartis/Sponsor before use.
9
Statistical considerations
A clinical study report (CSR) will be produced at the time the last participant has completed the 
study. This section describes the methods associated with this report.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
9.1
Analysis sets
The Screening set (SCR) consists of all patients who have been screened. If a patient has been 
screened multiple times then the patient should be included for his/her last screening.
The Full Analysis Set (FAS) comprises all participants with confirmed eligibility to whom 
study treatment has been assigned. This will be the data set used for analysis of all efficacy 
endpoints.
The Safety Set (SAF) includes all participants who received at least one dose of study treatment.
9.2
Statistical analyses
9.2.1
General considerations
Baseline for primary and key secondary objectives is defined as the mean of three Hb 
assessments conducted at central laboratory: two during screening and the third on Day1 before 
starting treatment.
Baseline for FACIT-F is defined as the mean of scores obtained pre-treatment (Screening visit) 
and Day 1. Baseline for all other objectives is defined as the Day 1 assessment or, in case of 
missing data on Day 1, any previous assessment done during Screening.

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9.2.2
Participant demographics and other baseline characteristics
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class and preferred term, for all participants.
Demographic and other baseline data, including disease characteristics, will be listed and 
summarized descriptively for the FAS. In addition, summaries of relevant past or current 
medical conditions will be presented.
Categorical data will be presented as frequencies and percentages. The summary statistics for 
continuous data will be mean, standard deviation (SD), median, 25th and 75th percentiles, 
minimum, and maximum.
9.2.3
Treatments
The SAF will be used for the analyses of exposure to iptacopan described below.
The duration of exposure (in days) to iptacopan, as well as the dose intensity (computed as the 
ratio of actual cumulative dose received and actual duration of exposure) and the relative dose 
intensity (computed as the ratio of dose intensity and planned dose intensity), will be 
summarized by means of descriptive statistics using the safety set.
Concomitant medications and significant non-drug therapies before and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system.
9.3
Primary endpoint(s)/estimand(s) analysis
In the study protocol, 'absence of transfusions' or 'not requiring transfusions' refers to not 
receiving transfusions and not meeting the criteria for administration of transfusions.
9.3.1
Definition of primary endpoint(s)
The primary endpoint is defined as: Change from baseline in Hb levels as mean of visits 
between Day 126 and Day 168.
9.3.2
Statistical model, hypothesis, and method of analysis
The primary objective is to assess the efficacy of iptacopan after 24 weeks of treatment in 
PNH patients who have Hb ≥10 g/dL in response to prior SoC treatment with eculizumab or 
ravulizumab and switch to iptacopan by demonstrating non-inferiority to -1 g/dL in change 
from baseline in Hb levels between Day 126 and Day 168.
It is proposed to use a NI margin based on clinical data and experience as well as on precedence 
with Hb stabilization as endpoints. In the 301 study (Lee et al 2019) and 302 study 
(Kulasekararaj et al 2019) with ravulizumab, Hb stabilization is defined as the avoidance of a 
≥2 g/dL decrease in Hb level from baseline in the absence of transfusion, while in the Phase 3 
PRINCE study with pegcetacoplan, a more conservative cutoff value of -1 g/dL was used 
(Wong et al 2021). Hence a decrease of less than 1 g/dL in Hb level from baseline at Day 168 
does not indicate a decline in hematological response. Moreover, data from the ongoing study 
CLNP023C12301 indicates that the SD (inter-subject variability) of change from baseline in 
Hb levels between Day 126 and Day 168 is around 1.5 g/dL. This indicates that the NI margin 

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of -1 g/dL is within natural variability and is sufficient to demonstrate non-inferiority in Hb 
levels after treatment switch to iptacopan vs baseline (anti-C5).
Assuming that patients have stable Hb at study entry, the mean change from baseline in Hb 
level between Day 126 and Day 168 is expected to be unchanged should patients have continued 
on anti-C5 treatment. Non-inferiority of iptacopan will therefore be tested by the null hypothesis 
(H0) against the alternate hypothesis (H1) comparing the mean change from baseline in Hb 
level in iptacopan between Day 126 and Day 168 (μ) to -1 g/dL:
                                     H0: μ <= -1
                                     H1: μ > -1
Hypothesis testing for the primary objective is a 1-sided test with nominal significance level 
0.025. Non-inferiority will be concluded, and primary objective will be considered met if the 
lower bound of the estimated two-sided 95% CI is greater than -1 g/dL.
The primary analysis of the primary endpoint will be a mixed model for repeated measures 
(MMRM) considering an unstructured covariance structure. The model will include age, sex, 
visit, baseline hemoglobin and the interaction between visits and baseline Hb levels. The 
treatment estimates will be computed as the mean changes from baseline corresponding to the 
average of Hb levels measured between Day 126 and Day 168.
Estimation of change from baseline in Hb levels is under the hypothetical situation in which 
participants would not have received transfusions on iptacopan treatment.
9.3.3
Handling of intercurrent events of primary estimand (if applicable)
Intercurrent events stemming from discontinuations of study medication for any reason, BTH 
events, and MAVEs will be handled with a treatment policy. RBC transfusions will be handled 
using an hypothetical strategy. Hb data 30 days after RBC transfusion will be excluded and 
imputed as if patient would not have received transfusions on iptacopan treatment.
9.3.4
Handling of missing values not related to intercurrent event
Missing Hb data due to withdrawal from study or after treatment discontinuation will be 
imputed based on a “back to pre-treatment level” approach to be consistent with the inclusion 
of Hb data under the treatment policy strategy following all other intercurrent events. For 
participants with intermittent missing data during study follow up where reasons for 
missingness are assumed to be unrelated to response or compliance status, their missing data 
will be handled under the missing at random assumption. The full specification will be provided 
in the SAP.
9.3.5
Multiplicity adjustment (if applicable)
The non-inferiority test of iptacopan on primary endpoint and superiority test of iptacopan will 
be tested hierarchically. Multiplicity adjustment is not needed.

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Figure 9-1
Hierarchy of testing non-inferiority and superiority of iptacopan
9.3.6
Sensitivity analyses
The sensitivity analyses on the primary endpoint and key secondary endpoint will be performed 
where missing central laboratory Hb data will be replaced by available local laboratory data 
collected at the same visit. The MMRM which is used for primary analysis and key secondary 
analysis will be performed for these sensitivity analyses.
9.3.7
Supplementary analysis
Not applicable.
9.4
Secondary endpoint(s)/estimand(s) analysis
9.4.1
Efficacy and/or pharmacodynamic endpoint(s)
The key secondary objective is to assess efficacy of iptacopan after 24 weeks of treatment in 
PNH patients who have Hb ≥10 g/dL in response to SoC and switch to iptacopan by 
demonstrating superiority in change from baseline in Hb levels between Day 126 and Day 168.
Ultomiris CHMP Assessment Report (EMA 2019) indicate that change from baseline in Hb 
levels at Day 168 is close to zero for PNH patients who received anti-C5 treatment. Suppose 

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PNH patients continue anti-C5 treatment without switch to iptacopan, the mean Hb levels at 
Day 168 should be close to mean Hb levels at baseline. Data from the PEGASUS study 
(Hillmen et al 2021) show that the least-square mean change from baseline in Hb was 2.37 g/dL 
with pegcetacoplan and -1.47 g/dL with eculizumab, indicating that patients of treatment with 
eculizumab may also worsen after 4 months of treatment. The results of a supportive analysis 
of the primary end point that included all available data (not censored for transfusions) showed 
that the adjusted mean change from baseline to Week 16 was 2.66 g /dL with pegcetacoplan 
and −0.03 g /dL with eculizumab indicating that the population of patients treated with 
eculizumab remained stable with the support of RBC transfusion. In the eculizumab group, 
patients with fewer than 4 transfusions in the 12 months before screening had a decrease in Hb 
of 0.01 g/dL. This indicated that the margin of 0 g/dL is an acceptable one to declare superiority 
of iptacopan over eculizumab/ravulizumab treatment. Based on the justification, superiority 
will be tested by the null hypothesis (H0) against alternative hypothesis (H1) comparing the 
mean change from baseline in Hb level in iptacopan between Day 126 and Day 168 (μ) to 0:
                                                        H0: μ≤0
                                                        H1: μ>0
Hypothesis testing for the key secondary objective is a 1-sided test with nominal significance 
level 0.025. Superiority will be concluded and the key secondary objective will be considered 
met if the lower bound of the estimated two-sided 95% CI is greater than 0 g/dL. The statistical 
model for the key secondary endpoint is the same as for the primary analysis. The overall study 
Type I error is one-sided 0.025. The non-inferiority test of iptacopan on primary endpoint and 
superiority test of iptacopan will be tested hierarchically. Multiplicity adjustment is not needed.
The proportion of participants achieving sustained Hb levels ≥12 g/dL on three out of four 
measurements assessed between Day 126 and Day 168 in the absence of RBC transfusions will 
be evaluated by means of logistic regression with baseline Hb as a covariate, if feasible. In case 
of non-convergence, crude proportions will be reported. The analysis will be described in detail 
in the SAP.
Transfusion avoidance will be evaluated as the proportion of participants not requiring any RBC 
transfusion between Day 1 and Day 168, i.e., not received and not met the criteria for 
administration as per Section 6.8.1.1 The estimation will be evaluated as the estimand described 
above (logistic regression or crude proportions).
The estimation of the change from baseline in ARC will be derived from an MMRM. The model 
will include age, sex, visit, baseline ARC and the interaction between visits and baseline ARC. 
The treatment estimates will be computed as the mean changes from baseline corresponding to 
the average of ARC measured between Day 126 and Day 168.
The treatment effect on percent change from baseline in LDH will be assessed using an MMRM 
of log-transformed ratio to baseline based on all observations collected during follow-up. The 
model will include age, sex, visit, log-transformed baseline LDH and the interaction between 
visits and log-transformed baseline LDH. The estimation will be derived based on the average 
of the log-transformed ratio estimated between Day 126 and Day 168.
The difference in scores of treatment satisfaction using TSQM-9 and changes from baseline in 
scores of fatigue using the FACIT-F questionnaire will be derived from separate models for 

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repeated measures including test scores collected at all visits. For FACIT-F, the baseline is 
defined as the mean of scores obtained pre-treatment (Screening visit) and Day 1. The model 
will include age, sex, and visit. For Facit-F the model will also include the baseline score and 
the interaction between visits and baseline score.
The estimation of rates of BTH will be carried out using a negative binomial model. No 
covariates are planned to be included.
The estimation of rates of MAVE will be carried out using a negative binomial model. Due to 
the expected low frequency of occurrences, no covariates are planned to be included.
If the negative binomial model fails to converge or to give valid estimates, the Wilson method 
will be applied (Miettinen, Nurminen 1985).
9.4.2
Safety endpoints
The analysis set used for all safety analyses will be the SAF. All tables will be presented. The 
complete details of all safety summaries will be provided in the SAP. The following mentions 
safety outcomes of interest and provides a non-exhaustive description of principles to be 
followed in the preparation of outputs.
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 particular, summary tables for AEs will summarize only on-treatment 
events, with a start date during the on-treatment period (treatment-emergent AEs). In addition, 
a separate summary of death events including on treatment and post treatment deaths will be 
provided if appropriate.
The on-treatment period lasts from the date of first administration of study treatment to 7 days 
after the date of the last actual administration of iptacopan which covers slightly more than 5 
times the estimated half-life of iptacopan.
Adverse events
All information obtained on AEs will be displayed by participant.
The number (and percentage) of participants with treatment emergent AEs (events started after 
the first dose of study medication or events present prior to start of treatment but increased in 
severity based on preferred term) will be summarized in the following ways:
•
by primary system organ class and preferred term.
•
by primary system organ class, preferred term and maximum severity.
Separate summaries will be provided for study medication related AEs, death, SAEs, other 
significant AEs leading to discontinuation, and AEs leading to discontinuation of study 
medication.
The number (and proportion) of participants with AESI / AEs related to identified and potential 
risks will be summarized.
A participant with multiple AEs within a primary system organ class is only counted once 
towards the total of the primary system organ class.

N o v arti s
C o nfi d e nti al
P a g e 7 2 of 9 2
A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
Vit al si g ns
S u m mar y statistics will be pr o vi de d b y visit/ti me. S u m mar y occ urre nce of a b n or malities ma y 
be pr o vi de d if a p pr o priate.
1 2-le a d E C G
P R, Q R S, Q T, Q Tc F a n d P P i nter vals will be o btai ne d fr o m 1 2-lea d E C Gs f or eac h partici pa nt 
d uri n g t he st u d y. E C G data will be rea d a n d i nter prete d l ocall y.
Cate g orical A nal ysis of Q T/ Q Tc i nter val data base d o n t he n u m ber of partici pa nts meeti n g or 
e xcee di n g pre defi ne d li mits i n ter ms of a bs ol ute Q T/ Q Tc i nter vals or c ha n ges fr o m baseli ne 
will be prese nte d. I n a d diti o n, a listi n g of t hese partici pa nts will be pr o d uce d.
S u m mar y statistics will be pr o vi de d b y visit/ti me.
Cli nic al l a b or at or y e v al u ati o ns
La b orat or y data f or partici pa nts wit h rele va nt a b n or malities will be liste d b y partici pa nt a n d 
visit/ti me relati ve t o t he start of st u d y 
me dicati o n. S u m mar y statistics a n d descri pti ve 
s u m maries will be pr o vi de d b y visit/ti me.
9. 4. 3 
P ati e nt r e p ort e d o ut c o m e s
I n t his st u d y, t he q uesti o n a d dresse d b y t he a nal ysis of P R O meas ure me nts is w het her treat me nt 
wit h i ptac o pa n i m pr o ves patie nt-re p orte d fati g ue s y m pt o ms as meas ure d b y t he F A CI T- Fati g ue, 
a n d satisfacti o n as meas ure d b y t he T S Q M- 9, a n d t hese a nal yses are sec o n dar y e n d p oi nts 
descri be d wit h t he sec o n dar y e n d p oi nts/esti ma n ds.
9. 5 
E x pl or at or y e n d p oi nt( s)/ e sti m a n d( s) a n al y si s
Detaile d i nf or mati o n o n t he a nal ysis of t he e x pl orat or y e n d p oi nts is pr o vi de d i n t he S A P. T he 
f oll o wi n g e n d p oi nts ha ve bee n i de ntifie d as e x pl orat or y e n d p oi nts, bet wee n Da y 1 a n d Da y 
1 6 8:
•
Res p o nse defi ne d as H b ≥1 2  g/ d L assesse d bet wee n visits Da y 1 2 6 a n d Da y 1 6 8 o n t hree 
o ut of f o ur meas ure me nts ta ke n at t he visits occ urri n g i n last si x wee ks i n t he a bse nce of 
•
•
 bet wee n Da y 1 
a n d Da y 1 6 8
•
 
 bet wee n Da y 1 
a n d Da y 1 6 8
•
 at Da y 1 6 8
•
Partici pa nt res p o nses t o a
 
. T hese res ults ma y be re p orte d se paratel y. 
•
•
Occ urre nce of 
 bet wee n Da y 
1 a n d Da y 1 6 8
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 3 of 9 2
A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
T he 
 
are descri be d i n s u bse q ue nt secti o ns.
T he e x pl orat or y 
 
 
 will be s u m marize d descri pti vel y.
T he pr o p orti o n of patie nts wit h 
 
will be s u m marize d descri pti vel y.
T he 
 will be s u m marize d descri pti vel y.
T he details of eac h a nal ysis will be pr o vi de d i n S A P.
9. 5. 1 
P h ar m a c o ki n eti c s
All i ptac o pa n plas ma c o nce ntrati o n data c ollecte d will be s u m marize d b y visit/sa m pli n g ti me 
p oi nt, i ncl u di n g t he fre q ue nc y ( n, %) of c o nce ntrati o ns bel o w t he L L O Q. C o nce ntrati o ns bel o w 
t he L L O Q will be re p orte d as zer o. S u m mar y statistics will be prese nte d as mea n (arit h metic 
a n d ge o metric), S D, c oefficie nt of variati o n ( 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. B o x pl ots b y visit/sa m pli n g ti me ma y be pr o vi de d as s u m maries if a p pr o priate. 
If a data set c o ntai ns c o nce ntrati o ns bel o w t he L L O Q a ge o metric mea n a n d t he c orres p o n di n g 
ge o metric mea n C V % will n ot be re p orte d.
D ue t o t he s parse nat ure of t he 
, c o n ve nti o nal n o nc o m part me ntal 
 
will n ot be calc ulate d. 
 val ues will be 
re p orte d.
A n y m o del- base d a nal yses usi n g t he P K a n d P D data c ollecte d i n t his st u d y will be se paratel y 
d oc u me nte d a n d n ot i ncl u de d i n t he C S R.
9. 5. 2  
Bi o m ar k er s
Bi o mar ker data c o nstit ute e x pl orat or y o bjecti ves a n d t heref ore are n ot descri be d i n ter m of 
esti ma n ds. Bi o mar kers assess me nt is m ostl y a b o ut mec ha nistic effect of t he dr u g a n d t heref ore 
i n t his c o nte xt s u m maries base d o n e ntiret y of t he data are a p pr o priate.
Assessi n g t he effect of i ptac o pa n o n 
 a n d 
 is a n e x pl orat or y o bjecti ve of t he st u d y. He nce t he f oll o wi n g e n d p oi nts o n 
are e x pl orat or y:
•
Perce nta ge of 
 Da y 1 a n d Da y 1 6 8
•
 
c ollecte d 
bet wee n Da y 1 a n d Da y 1 6 8
T he bi o mar kers will be s u m marize d usi n g descri pti ve statistics. Gra p hical de picti o ns of 
perce nta ge of 
 
 
 o ver ti me will be pr o vi de d. T here will be se parate s u m maries 
prese nte d o n o n-treat me nt bi o mar ker data a n d all a vaila ble (i ncl u di n g data after patie nts ha ve 
C CI
C CI
C CI
C CI
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 4 of 9 2
A m e n d e d Pr ot o c ol V er si o n N o 0 2 ( Cl e a n)
Pr ot o c ol N o. C L N P 0 2 3 C 1 2 3 0 3
disc o nti n ue d treat me nt) bi o mar ker data. O n-treat me nt bi o mar ker data refers t o data o n 
bi o mar kers c ollecte d bet wee n first da y of a d mi nistrati o n a n d last da y of a d mi nistrati o n + 1 da y.
A d diti o nal bi o mar kers, i ncl u di n g b ut n ot li mite d t o 
 ma y als o 
be a nal yse d t o better c haracterize t he 
 
.
9. 5. 3
 st u dies are desi g ne d t o i n vesti gate t he ass ociati o n 
 
w hic h are c ollecte d d uri n g t he cli nical trial. 
Wit h o ut pri or e vi de nce of a str o n g ass ociati o n, a n u m ber of p ossi ble ass ociati o ns are e val uate d 
wit h 
. A ra n ge of statistical tests are use d f or t he a nal yses. A d diti o nal data, 
fr o m ot her cli nical trials, are ofte n nee de d t o c o nfir m ass ociati o ns. Alter nati vel y, if t he n u m ber 
of partici pa nts e nr olle d i n t he st u d y is
 
 
.
Data ge nerate d o n h y p ot hesis-free platf or ms will be re p orte d se paratel y (e. g. C S R a d de n d u m).
9. 5. 4
As 
 
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
If dee me d re q uire d (e. g., t o s u p p ort re g ulat or y s u b missi o ns t o Healt h A ut h orities), i nteri m 
safet y a nal yses ma y be pr o d uce d w hile t he st u d y is still o n g oi n g.
9. 9 
S a m pl e si z e d et er mi n ati o n
Sa m ple size is calc ulate d base d o n t he ass u m pti o n t hat t he tr ue a vera ge c ha n ge fr o m baseli ne 
i n H b le vels as mea n of visits bet wee n Da y 1 2 6 a n d Da y 1 6 8 is 1. 0 g/ d L wit h S D 2. 0 g/ d L.
9. 9. 1 
Pri m ar y e n d p oi nt( s)
F or a sa m ple size of 5 0 partici pa nts, t he p o wer f or testi n g a gai nst a NI mar gi n of - 1 g/ d L w o ul d 
be m ore t ha n 9 4 % base d o n t he ass u m pti o n t hat t he tr ue mea n c ha n ge fr o m baseli ne i n H b le vels 
as mea n of visits bet wee n Da y 1 2 6 a n d Da y 1 6 8 is m ore t ha n 0 g/ d L wit h S D of 2. 0 g/ d L.
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI
C CI

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Table 9-1
Power for non-inferiority test based on different assumptions
True mean change from baseline 
in Hb (g/dL)
Standard deviation (g/dL)
Power
 0.8
2.0
>99%
 0.8
1.5
>99%
 0.2
2.0
  99%
 0.2
1.5
>99%
 0.0
2.0
  94%
 0.0
1.5
>99%
-0.2
2.0
  81%
-0.2
1.5
  96%
-0.6
2.0
  29%
-0.6
1.5
  47%
9.9.2
Secondary endpoint(s)
For a sample size of 50 participants, the power for testing against superiority would be 94% 
based on the same assumption the true mean change from baseline in Hb levels as mean of visits 
between Day 126 and Day 168 is 1.0 g/dL with SD of 2.0 g/dL.
Table 9-2
Power for superiority test based on different assumptions
True mean change from baseline 
in Hb levels (g/dL)
Standard deviation (g/dL)
Power
1.5
2.0
>99%
1.5
1.5
>99%
1.2
2.0
  99%
1.2
1.5
>99%
1.0
2.0
  94%
1.0
1.5
>99%
0.8
2.0
  81%
0.8
1.5
  96%
0.6
2.0
  56%
0.6
1.5
  81%
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

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The protocol, protocol amendments, ICF, Investigator’s Brochure, [IDFU], 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), European Medical Device Regulation 2017/745 for clinical device research (if 
applicable), European In Vitro Diagnostic Regulation (IVDR) (EU) 2017/746 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.
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 or their legally authorized representative 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.

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I nf or me d c o nse nt m ust be o btai ne d bef ore c o n d ucti n g a n y st u d y-s pecific pr oce d ures (e. g. all of 
t he pr oce d ures descri be d i n t he pr ot oc ol). T he pr ocess of o btai ni n g i nf or me d c o nse nt m ust be 
d oc u me nte d i n t he partici pa nt s o urce d oc u me nts.
T he me dical rec or d m ust i ncl u de a state me nt t hat writte n i nf or me d c o nse nt was o btai ne d bef ore 
t he partici pa nt was e nr olle d i n t he st u d y a n d t he date t he writte n c o nse nt was o btai ne d. T he 
a ut h orize d pers o n o btai ni n g t he i nf or me d c o nse nt m ust als o si g n t he I C F.
A c o p y of t he I C F(s) 
m ust be pr o vi de d t o t he partici pa nt or t heir le gall y a ut h orize d 
re prese ntati ve.
Partici pa nts w h o are rescree ne d are re q uire d t o si g n a ne w I C F.
T he I C F will c o ntai n a se parate secti o n t hat a d dresses t he use of re mai ni n g ma n dat or y sa m ples 
f or o pti o nal a d diti o nal researc h. T he I n vesti gat or or a ut h orize d desi g nee will e x plai n t o eac h 
partici pa nt t he o bjecti ves of t he a d diti o nal researc h. Partici pa nts will be t ol d t hat t he y are free 
t o ref use t o partici pate a n d ma y wit h dra w t heir c o nse nt at a n y ti me a n d f or a n y reas o n d uri n g 
t he st ora ge peri o d. A se parate si g nat ure will be re q uire d t o d oc u me nt a partici pa nt’s a gree me nt 
t o all o w a n y re mai ni n g s peci me ns t o be use d f or a d diti o nal researc h. Partici pa nts w h o decli ne 
t o partici pate i n t his o pti o nal a d diti o nal researc h will d oc u me nt t his.
Eli gi ble partici pa nts ma y o nl y be i ncl u de d i n t he st u d y after pr o vi di n g ( wit nesse d, w here 
re q uire d b y la w or re g ulati o n), I R B/I E C-a p pr o ve d i nf or me d c o nse nt.
If a p plica ble, i n cases w here t he partici pa nt's re prese ntati ve(s) gi ves c o nse nt (if all o we d 
acc or di n g t o l ocal re q uire me nts), t he partici pa nt m ust be i nf or me d a b o ut t he st u d y t o t he e xte nt 
p ossi ble gi ve n his/ her le vel of u n dersta n di n g. If t he partici pa nt is ca pa ble of d oi n g s o, he/s he 
m ust i n dicate a gree me nt b y pers o nall y si g ni n g a n d dati n g t he writte n i nf or me d c o nse nt 
d oc u me nt.
I nf or mati o n a b o ut c o m m o n si de effects alrea d y k n o w n a b o ut t he i n vesti gati o nal treat me nt ca n 
be f o u n d i n t he I B. T his i nf or mati o n will be i ncl u de d i n t he partici pa nt i nf or me d c o nse nt a n d 
s h o ul d be disc usse d wit h t he partici pa nt u p o n o btai ni n g c o nse nt a n d als o d uri n g t he st u d y as 
nee de d. A n y ne w i nf or mati o n re gar di n g t he safet y pr ofile of t he i n vesti gati o nal dr u g t hat is 
i de ntifie d bet wee n I B u p dates will be c o m m u nicate d as a p pr o priate, f or e xa m ple, via a n 
I n vesti gat or n otificati o n or a n a g gre gate safet y fi n di n g. Ne w i nf or mati o n mi g ht re q uire a n 
u p date t o t he i nf or me d c o nse nt a n d t he n m ust be disc usse d wit h t he partici pa nt.
T he f oll o wi n g i nf or me d c o nse nts are i ncl u de d i n t his st u d y:
•
Mai n st u d y c o nse nt, w hic h als o i ncl u de d:
•
A s u bsecti o n t hat re q uires a se parate si g nat ure f or t he ‘ O pti o nal C o nse nt f or A d diti o nal 
Researc h’ t o all o w f ut ure researc h o n data/sa m ples c ollecte d d uri n g t his st u d y
•
O pti o nal c o nse nt f or acti vities t hat ma y be d o ne o utsi de of t he st u d y site
•
Pre g na nc y O utc o mes Re p orti n g C o nse nt f or fe male partici pa nts
•
O pti o nal Ge netics C o nse nt t o pr o vi de a sa m ple f or 
 st u dies
•
O pti o nal c o nse nt f or patie nt e x perie nce i nter vie w
T he st u d y i ncl u des a n o pti o nal  
 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 
C CI
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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 heir 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.
N o vartis has a p pr o priate pr ocesses a n d p olicies i n place t o ha n dle pers o nal data breac hes 
acc or di n g t o a p plica ble pri vac y la ws.
1 0. 1. 4  
C o m mitt e e s str u ct ur e
1 0. 1. 4. 1
D at a M o nit ori n g C o m mitt e e
T here is a D M C f u ncti o ni n g at t he i ptac o pa n pr o gra m le vel a n d a n y si g nifica nt safet y fi n di n gs 
(e. g. S A E, S U S A Rs) fr o m t his st u d y will be s hare d wit h t he D M C.
1 0. 1. 4. 2
St e eri n g C o m mitt e e
T he Steeri n g C o m mittee ( S C) will be esta blis he d c o m prisi n g I n vesti gat ors partici pati n g i n t he 
trial, i.e. n ot bei n g me m bers of t he D M C a n d N o vartis re prese ntati ves fr o m t he Cli nical Trial 
Tea m.
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The SC will ensure transparent management of the study according to the protocol through 
recommending and approving modifications as circumstances require. The SC will review 
protocol amendments as appropriate. Together with the clinical trial team, the SC will also 
develop recommendations for publications of study results including authorship rules. The 
details of the role of the steering committee will be defined in the steering committee charter.
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, contracts.
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the Investigator for 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.
10.1.5.1 Data collection
Data not requiring a separate written record will be defined in the protocol and Section 1.3 
Schedule of Activities and can be recorded directly on the CRFs. All other data captured for 
this study will have an external originating source (either written or electronic) with the CRF 
not being considered as source
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 (recorded on CRFs) (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 the 
investigational site via the EDC system. Designated Investigator site staff are required to 
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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 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Dates of screenings, screen failures and study completion, as well as 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.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and made available for data analysis. 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 
informed consent form 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, e.g. source data 
acknowledgment or monitoring guidelines.
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 Novartis. Additionally, a central 
analytics organization may analyze data & identify risks & trends for 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 last 
participant last visit) 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 

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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 
Last Participant Last Visit (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.
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 
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10.2
Appendix 2: Abbreviations and definitions
10.2.1
List of abbreviations
AE
Adverse Event
AESI
Adverse Events of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine Aminotransferase
AP
Alternative Pathway
aPTT
Activated partial thromboplastin time
ARC
Absolute Reticulocyte Count
AST
Aspartate Aminotransferase
AUC
Area under the curve
AxMP
Auxiliary Medicinal Product
b.i.d.
bis in die/twice a day
BMF
Bone Marrow Failure
BP
Blood Pressure
BTH
Breakthrough hemolysis
BTH 
Break through hemolysis
BUN
Blood Urea Nitrogen
CI
Confidence Interval
CIOMS
Council for International Organizations of Medical Sciences
CK
Creatine Kinase
CMO&PS
Chief Medical Office and Patient Safety
CO
Country Organization
COA
Clinical Outcome Assessment
Covid-19
Coronavirus Disease 2019
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
Clinical study report
CV
coefficient of variation
DDI
Drug Drug Interaction
DMC
Data Monitoring Committee
DNA 
deoxyribonucleic acid
EBMT
European Group for Bone Marrow Transplantation
ECG
Electrocardiogram
eCOA
Electronic Clinical Outcome Assessment
EDC
Electronic Data Capture
eGFR
Estimated Glomerular Filtration Rate
EoS
End of Study
ePRO
Electronic Patient Reported Outcome
ESA
Erythropoiesis-stimulating agents
eSAE
Electronic Serious Adverse Event
eSource
Electronic Source
ETD
Early Treatment Discontinuation
EVH
Extravascular Hemolysis
FACIT-F 
Functional Assessment of Chronic Illness Therapy- Fatigue

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FAS 
Full Analysis Set
FB 
Factor B
FDA
Food and Drug Administration
FIH 
First in human
FSH
Follicle Stimulating Hormone
g
Gram
GCP
Good Clinical Practice
GGT
Gamma-glutamyl transferase
h
Hour
Hb
Hemoglobin
HBsAg
Hepatitis B virus surface antigen
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
HDL 
High density lipoprotein
HIF-PHIs
Hypoxia Inducible Factors Prolyl Hydroxylase Inhibitors
HIV
Human immunodeficiency virus
HRQoL
Health-Related Quality of Life
i.v.
intravenous
IA
Interim Analysis
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use
IEC
Independent Ethics Committee
IN
Investigator Notification
INR
International Normalized Ratio
IRB
Institutional Review Board
IRT
Interactive Response Technology
IVDR 
In Vitro Diagnostic Device Regulation
IVH
Intravascular Hemolysis
LDH
lactate dehydrogenase
LFT
Liver function test
LLOQ
lower limit of quantification
LOAEL
lowest dose where effect was seen
MAVE
Major Adverse Vascular Event
MCH
Mean corpuscular hemoglobin
MCV
mean corpuscular volume
MDS
myelodysplastic syndromes
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MMRM
Mixed Model for Repeated Measures
NI
Non-inferiority
NO
Nitric Oxide
NTI
Narrow Therapeutic Index
OATP1B1
Organic Anion-transporting Polypeptide 1B1
OHP
Off-site Healthcare Professional

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P D
P h ar m a c o d y n a mi c( s)
PI G A 
p h o s p h ati d yli n o sit ol N a c et yl gl u c o s a mi n yltr a n sf er a s e s u b u nit A
P K
P h ar m a c o ki n eti c( s)
P N H
P ar o x y s m al n o ct ur n al h e m o gl o bi n uri a
P P D
Pr e m at ur e P arti ci p a nt Di s c o nti n u ati o n
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
 
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
R B C
R e d Bl o o d C ell
R D W 
R e d bl o o d c ell di stri b uti o n wi dt h
R E P
R oll- o v er E xt e n si o n Pr o gr a m
R U
R e s o ur c e Utili z ati o n
S A E
S eri o u s A d v er s e E v e nt
S A F
S af et y S et
S A P
St ati sti c al A n al y si s Pl a n
S C R
S cr e e ni n g s et
S D
st a n d ar d d e vi ati o n
S o A
S c h e d ul e of A cti viti e s
S o C
St a n d ar d of C ar e
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 S Q M
Tr e at m e nt S ati sf a cti o n Q u e sti o n n air e f or M e di c ati o n
U L N
u p p er li mit of n or m al
W B C
W hit e Bl o o d C ell
W H O
W orl d H e alt h Or g a ni z ati o n
1 0. 2. 2  
D efi niti o n s
A d diti o n al 
tr e at m e nt
M e di ci n al pr o d u ct s t h at m a y b e u s e d d uri n g t h e cli ni c al tri al a s d e s cri b e d i n t h e pr ot o c ol, 
b ut n ot a s a n i n v e sti g ati o n al m e di ci n al pr o d u ct ( e. g. a n y b a c k gr o u n d t h er a p y)
A s s e s s m e nt
A pr o c e d ur e u s e d t o g e n er at e d at a r e q uir e d b y t h e st u d y
A u xili ar y M e di ci n al 
Pr o d u ct ( A x M P)
M e di ci n al pr o d u ct u s e d f or t h e n e e d s of a cli ni c al tri al a s d e s cri b e d i n t h e pr ot o c ol, b ut n ot 
a s a n i n v e sti g ati o n al 
m e di ci n al pr o d u ct ( e. g., r e s c u e 
m e di c ati o n, c h all e n g e a g e nt s, 
b a c k gr o u n d tr e at m e nt or m e di ci n al pr o d u ct s u s e d t o a s s e s s e n d p oi nt s i n t h e cli ni c al tri al). 
C o n c o mit a nt t h er a p y i s n ot c o n si d er e d a s A x M P.
Bi ol o gi c S a m pl e s
A bi ol o gi c al s p e ci m e n i n cl u di n g, f or e x a m pl e, bl o o d ( pl a s m a, s er u m), s ali v a, ti s s u e, uri n e, 
st o ol, et c. t a k e n fr o m a st u d y p arti ci p a nt
Cli ni c al O ut c o m e 
A s s e s s m e nt ( C O A)
A m e a s ur e t h at d e s cri b e s or r efl e ct s h o w a p arti ci p a nt f e el s, f u n cti o n s, or s ur vi v e s
Cli ni c al Tri al T e a m
A gr o u p of p e o pl e r e s p o n si bl e f or t h e pl a n ni n g, e x e c uti o n a n d r e p orti n g of all cli ni c al tri al 
a cti viti e s. E x a m pl e s of t e a m m e m b er s i n cl u d e t h e St u d y L e a d, M e di c al M o nit or, Tri al 
St ati sti ci a n et c.
C o h ort
A gr o u p of i n di vi d u al s w h o s h ar e a c o m m o n e x p o s ur e, e x p eri e n c e or c h ar a ct eri sti c, or a 
gr o u p of i n di vi d u al s f oll o w e d- u p or tr a c e d o v er ti m e
Di s c o nti n u ati o n 
fr o m st u d y 
tr e at m e nt
P oi nt/ti m e w h e n t h e p arti ci p a nt p er m a n e ntl y st o p s r e c ei vi n g t h e st u d y tr e at m e nt f or a n y 
r e a s o n ( pri or t o t h e pl a n n e d c o m pl eti o n of st u d y i nt er v e nti o n a d mi ni str ati o n, if a n y). 
P arti ci p a nt a gr e e s t o t h e ot h er pr ot o c ol r e q uir e d a s s e s s m e nt s i n cl u di n g f oll o w- u p. N o 
s p e cifi c r e q u e st i s m a d e t o st o p t h e u s e of t h eir s a m pl e s or d at a.
C CI

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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 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
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.
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 
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.
Medication number
A unique identifier on the label of medication kits
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)
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.
Premature 
Participant 
Withdrawal 
Point/time when the participant exits from the study prior to the planned completion of all 
study drug administration and/or assessments; at this time all study drug administration 
is discontinued and no further assessments are planned
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.
Screen Failure
A participant who did not meet one or more criteria that were required for participation in 
the study

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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.
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.
10.3
Appendix 3: Clinical laboratory tests
10.3.1
Clinically notable laboratory values and vital signs
ECG alert values
•
Resting heart rate sinus rhythm < 30 or a HR decrease ≥ 25% or HR > 130 [bpm]
•
QRS >120 or increase >25% compared to predose baseline [msec]
•
QTcF >500 or increase >60 compared to predose baseline [msec]
•
Ventricular tachycardia
•
New complete heart block (Grade III AV block) or Mobitz II AV block
For any ECGs with participant safety concerns after baseline, two additional ECGs must be 
performed to confirm the safety finding.
10.4
Appendix 4: Participant Engagement
Not applicable
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 in Section 10.5.1 for complete definitions of liver laboratory triggers.

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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 10-1. Repeat 
liver chemistry tests (i.e. ALT, AST, etc.) 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 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:
•
Obtaining a more detailed history of symptoms and prior or concurrent diseases.
•
Obtaining a history of concomitant drug use (including nonprescription medications and 
herbal and dietary supplement preparations), exposure to environmental chemical agents, 
alcohol use, recreational drug use, and special diets.
•
Exclusion of underlying liver disease
These investigations can include based on Investigator’s discretion:
•
Imaging such as abdominal US, Computed Tomography (CT) or Magnetic Resonance 
Imaging (MRI), as appropriate
•
Considering gastroenterology or hepatology consultations.
All follow-up information and procedures performed must be recorded as appropriate in the 
CRF.
10.5.1
Liver event and laboratory trigger definitions & follow-up requirements
Table 10-1
Definitions of Triggers, Actions and Follow-up requirements for liver 
events
Criteria
Actions required
Follow-up monitoring
Potential Hy’s Law case
(Elevated ALT/AST > 3 × 
ULN and TBL > 2 × ULN 
but without notable 
increase in ALP to > 2 × 
ULN – or 3 x ULN in the 
presence of bone 
pathology)
(In patients with 
transaminases above the 
ULN at baseline, the Hy’s 
Law criteria may be 
changed to increases 2-
● Discontinue the study treatment immediately 
(if possibly related to study treatment)
● Hospitalize, if clinically appropriate
● Report as SAE (even before all other possible 
causes of liver injury have been excluded)
● Establish causality (investigate alternative 
etiologies)a
● Record contributing factors (e.g. concomitant 
medication, medical history, laboratory value) in 
the appropriate eCRF
● ALT, AST, TBL, Alb, PT/INR, 
ALP, GGT, CK and GLDH 
(frequency at Investigator 
discretion)
● Monitor for symptomsb
● Report outcomec

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Criteria
Actions required
Follow-up monitoring
fold above baseline 
values)
ALT
> 8 × ULN
● Interrupt the study treatment (if possibly 
related to study treatment)
● Hospitalize if clinically appropriate
● Establish causality (investigate alternative 
etiologies)a
● Record the AE and contributing factors (e.g. 
con meds, med hx, lab) in the appropriate eCRF
● ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT (frequency at 
Investigator discretion)
● Monitor for symptomsb
● Report outcomec
> 3 × ULN and INR > 1.5 
(in the absence of 
anticoagulation)
If elevated at baseline:
> 2 x baseline
or > 300 U/L (whichever 
occurs ﬁrst)
● Interrupt the study treatment (if possibly 
related to study treatment)
● Hospitalize if clinically appropriate
● Establish causality (investigate alternative 
etiologies)a
● Study drug can be restarted only if alternative 
etiology is identified and liver enzymes return to 
baseline
● Record the AE and contributing factors (e.g. 
con meds, med hx, lab) in the appropriate eCRF
● ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolution 
(frequency at Investigator 
discretion)
> 5 to ≤ 8 × ULN
If elevated at baseline:
> 3 x baseline
or > 300 U/L (whichever 
occurs ﬁrst)
● Repeat LFT within 48 hours
● If elevation persists, continue follow-up 
monitoring
● If elevation persists for more than 2 weeks, 
discontinue the study drug
● Establish causality (investigate alternative 
etiologies)a
● Record the AE and contributing factors (e.g. 
con meds, med hx, lab) in the appropriate eCRF
● ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolution 
(frequency at Investigator 
discretion)
> 3 × ULN to ≤ 5 × ULN 
(accompanied by 
symptoms)b
If elevated at baseline:
> 2 x baseline
or > 300 U/L (whichever 
occurs ﬁrst)
● Interrupt the study treatment (if possibly 
related to study treatment)
● Hospitalize if clinically appropriate
● Establish causality (investigate alternative 
etiologies)a
● Study drug can be restarted only if alternative 
etiology is identified and liver enzymes return to 
baseline
● Record the AE and contributing factors (e.g. 
con meds, med hx, lab) in the appropriate eCRF
● ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolution 
(frequency at Investigator 
discretion)
● Monitor for symptomsb
● Report outcomec
> 3 to ≤ 5 × ULN (patient 
is asymptomatic)b
If elevated at baseline:
> 2 x baseline
or > 300 U/L (whichever 
occurs ﬁrst)
● Repeat LFT within the next week
● If elevation is confirmed, initiate close 
observation of the participant
● Investigator discretion
● Monitor LFT within 1 to 4 
weeks
ALP (isolated
> 2 × ULN (in the 
absence of known bone 
pathology)
>3 x ULN in the presence 
of if bone pathology
● Repeat LFT within 48 hours
● If elevation persists, establish causality 
(investigate alternative etiologies)a
● Record the AE and contributing factors (e.g. 
con meds, med hx, lab) in the appropriate eCRF
● Investigator discretion
● Monitor LFT within 1 to 4 
weeks or at next visit
Liver events
Jaundice
● Interrupt the study treatment (if possibly 
related to study treatment)
● Hospitalize the participant
● Establish causality (investigate alternative 
● ALT, AST, TBL, Alb, PT/INR, 
ALP and GGT until resolution 
(frequency at Investigator 
discretion)

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Criteria
Actions required
Follow-up monitoring
etiologies)a
● Study drug can be restarted only if alternative 
etiology is identified and liver enzymes return to 
baseline
● Record the AE and contributing factors (e.g. 
con meds, med hx, lab) in the appropriate eCRF
● Monitor symptomsb
● Report outcomec
Any AE potentially 
indicative of a liver 
toxicityd
● Consider study treatment interruption or 
discontinuation
● Hospitalization if clinically appropriate
● Establish causality (investigate alternative 
etiologies)a
● Record the AE and contributing factors (e.g. 
con meds, med hx, lab) in the appropriate eCRF
● Investigator discretion
a 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
bSevere fatigue, malaise (general), abdominal pain (right upper quadrant), nausea, vomiting or rash with 
eosinophilia
cResolved = return to Day 1 values; Condition unchanged = stable values at three subsequent monitoring visits 
at least 2 weeks apart; Condition deteriorated = values worsen or liver transplantation; and Fatal.
dThese events cover the following: hepatic failure, fibrosis and cirrhosis, and other liver damage-related 
conditions; the non-infectious hepatitis; the benign, malignant and unspecified liver neoplasms.
ALP: alkaline phosphatase; GLDH: glutamate dehydrogenase TBL: total bilirubin; ULN: upper limit of normal
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
•
New onset dipstick proteinuria ≥ 3+
Abnormal renal event findings must be confirmed after ≥24 hours but ≤ 5 days after first 
assessment.  Causes and possible interventions should be considered.

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11
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A p pr o v al Si g n at ures
C o m p o u n d: 
L N P 0 2 3
D oc u me nt Title: 
C L N P 0 2 3 C 1 2 3 0 3 _ Pr ot oc ol a me n d me nt _ V 0 2
D oc u me nt Na me: 
0 2. 0 1. 0 2 0 1 Pr ot oc ol - V 0 2
D oc u me nt Versi o n: 
3. 0
User n a me
User I D
Si g ni n g Re as o n
D ate
C o nte nt A p pr o val
2 0 2 4- 0 1- 2 2
1 5: 2 9: 4 5 ( U T C)
D oc u me nt electr o nic ally si g ne d
C CI
P P D
P P D