CHART-C3G/CLNP023B12011

Age at baseline in years

Female Male

Academic hospital Other sites

Body mass index reported at baseline, or the closest value before baseline. In the absence of records for body mass index, it can be calculated using records of height and weight.

No Yes

No Yes 24-hour uPCR < 1 g/g 24-hour uPCR ≥ 1 g/g

No Yes Spot uPCR < 1 g/g Spot uPCR ≥ 1 g/g

Absolute value of uPCR based on a 24-hour urine collection

Absolute value of uPCR based on a spot urine collection

No Yes

No Yes

Absolute value of uACR based on a 24-hour urine collection

No Yes

No Yes Microscopic (≥3RBCs/HPF) Macroscopic (visible to the naked eye)

0-2 red blood cells

≥3 red blood cells

Number of red blood cells detected through urinalysis

Presence of edema. No Yes

Blood pressure measurement

Defined as systolic blood pressure ≥140 mmHg or a diastolic blood pressure ≥90 mmHg No Yes

Absolute value of serum creatinine

Based on medical records of eGFR

2021 CKD-EPI creatinine 2021 CKD-EPI creatinine-cystatin C 2012 CKD-EPI cystatin C 2012 CKD-EPI creatinine-cystatin C 2009 CKD-EPI creatinine MDRD (based on creatinine) Cockroft-Gault (based on creatinine) Schwartz equation (based on creatinine) Not specified

eGFR computed in the study analysis

Reference range: LLN = 4.33-5.00 μmol/L ULN = 9.05-11.16 μmol/L

Time since the first C3G diagnosis to baseline

No Yes Stage 1 Stage 2 Stage 3 Stage 4 Stage 5

No Yes (either of the categories below) eGFR ≤ 15 History of dialysis History of kidney transplant

No Yes Dialysis at diagnosis of C3G Maintenance dialysis Other types

Concerns only patients with dialysis at or before baseline

Concerns only patients with dialysis at or before baseline

No (native kidney) Yes Biopsy-confirmed disease in native kidney No evidence of disease recurrence Recurrent disease in transplanted kidney

Concerns only patients with a kidney transplant (or kidney transplant failure) at or before baseline

Concerns only patients with a kidney transplant (or kidney transplant failure) at or before baseline

Concerns only patients with a kidney transplant (or kidney transplant failure) at or before baseline.

No Yes

For example, history of heart failure, history of stroke, diabetes mellitus, dementia, malignancy

No Yes

No Yes

Mild Moderate Severe

Mild Moderate Severe

Presence of cells in capillary loops with loop occlusion 0 = 0% (Essentially normal or no lesion)

• = 1-25% (Only a small fraction of loops are occluded by hypercellularity)
• = 26-50% (About one-quarter to half of the loops show occlusion)
• = ≥51% (More than half of the loops are occluded, indicating extensive endocapillary proliferation)

0 = 0% (No neutrophils in any capillary loops of the glomerulus)

• = 1-25% (Mild involvement: neutrophils present in up to ¼ of loops)
• = 26-50% (Moderate involvement: neutrophils in about ¼ to half of loops)
• = ≥51% (Severe involvement: neutrophils in more than half of loops)

More than 4 cells in a mesangial area away from the hilum

0 = 0% (No mesangial areas with >4 cells)

• = 1-25% (Mild involvement: 1-25% of mesangial areas show hypercellularity)
• = 26-50% (Moderate involvement: 26-50% of mesangial areas affected)
• = ≥51% (Severe involvement: More than half of mesangial areas show hypercellularity)

Necrosis in glomerular pathology refers to active destructive lesions characterized by:

Disruption of the glomerular basement membrane (GBM) Fibrin exudation into Bowman's space or capillary loops Karyorrhexis (fragmentation of nuclei of inflammatory cells) - at least 2 of these 3 lesions need to be present to meet the criteria for necrosis.

0 = 0% (No glomeruli show necrosis)

• = 1-10% (Mild: 1-10% of glomeruli have necrosis)
• = 11-25% (Moderate: 11-25% of glomeruli affected)
• = ≥25% (Severe: More than 25% of glomeruli show necrosis)

0 = 0% (No crescents in any glomeruli)

• = 1-10% (Mild: 1-10% of glomeruli have crescents)
• = 11-25% (Moderate: 11-25% of glomeruli affected)
• = >25% (Severe: More than 25% of glomeruli show crescents)

A score between 0 and 15, calculated by summing up the scores from the activity index parameters above (Endocapillary hypercellularity,. Neutrophils in capillary lumens, Mesangial hypercellularity, Necrosis and Cellular or fibrocellular crescents).

Score 0: No active lesions. The kidney shows chronic changes only, but no ongoing inflammation.

Higher score implies not aggressively active, and kidney damage is likely stable or progressing slowly.

Both continuous (score inflammation assessment scale) and categorically (none, mild, moderate, severe).

Continuous Scale (Numeric Score)

• Low score (e.g., 0-3) Minimal inflammatory activity
• High score (e.g., ≥9) Extensive active lesions (necrosis, crescents, heavy infiltration)

Categorical Scale (None, Mild, Moderate, Severe)

• None: No significant inflammation; likely chronic or inactive disease.
• Mild: Small, focal involvement; early or controlled disease.
• Moderate: Widespread but not diffuse; active disease needing treatment.
• Severe: Diffuse, aggressive inflammation; high risk of rapid progression to renal failure.

Type of inflammation: none, mild, moderate, severe

0 = ≤10%

• = 11-25%
• = 26-50%
• = ≥51%

0 = none

• = ≤25%
• = 26-50% 3= >51%

0 = ≤5%

• = 6-25%
• = 26-50%
• = ≥51%

0 = ≤5%

• = 6-25%
• = 26-50%
• = ≥51%

A score between 0 and 12, calculated by summing up the scores from the chronicity index parameters above (Glomerular (or segmental) sclerosis, Fibrous crescents, Tubular atrophy and Interstitial fibrosis)

Lower scores indicate less chronic damage, higher scores indicate more scarring and poor prognosis.

0-3 (Minimal to Mild)

→ Very little irreversible damage. Prognosis is generally favorable if activity index is also low.

4-6 (Moderate)

• Significant chronic changes; recovery potential is limited. 7-12 (Severe)
• Extensive scarring; immunosuppression unlikely to reverse damage

No Yes

Concerns only patients with kidney failure during follow-up

No Yes Maintenance dialysis Other types

Concerns only patients with dialysis during follow-up

Concerns only patients with dialysis during follow-up

Concerns only patients with maintenance dialysis during follow-up

Concerns only patients with maintenance dialysis during follow-up

Concerns only patients with maintenance dialysis during follow-up

No Yes

Non-nephrotic-range proteinuria (0.15-3.5 g of protein in a 24-hour urine collection) Nephrotic-range proteinuria (> 3.5 g of protein in a 24- hour urine collection)

No Yes Renal relapse Progression to a higher CKD stage Chronic renal replacement therapy

Transplant failure is defined as a follow-up record of either maintenance dialysis, sustained eGFR <15 mL/min/1.73m², or re-transplant

No Yes Stage 1 Stage 2 Stage 3 Stage 4 Stage 5

No (native kidney) Yes Biopsy-confirmed disease in native kidney No evidence of disease recurrence Recurrent disease in transplanted kidney

No Yes No transplant failure during follow-up Transplant failure during follow-up

Concerns only patients with a kidney transplant (or kidney transplant failure) during follow-up

Concerns only patients with a kidney transplant (or kidney transplant failure) during follow-up and a post-transplant C3G disease recurrence during follow-up

Concerns only patients with a kidney transplant during follow-up and a transplant failure during follow-up

Concerns only patients with a kidney transplant (or kidney transplant failure) during follow-up.

No Yes C3G disease recurrence post-transplant Transplant failure C3G disease recurrence post-transplant and transplant failure

Concerns only patients with the combination of kidney transplant during follow-up, C3G disease recurrence post-transplant, and subsequent transplant failure

Concerns patients with a kidney transplant (or kidney failure) at any time, including baseline and follow-up, and post-transplant C3G disease recurrence at any time, including baseline and follow-up

No Yes

Concerns only patients with death during follow-up. Kidney failure Infectious disease Cardiovascular disease Other causes

Serum creatinine (preferred) or eGFR

Average eGFR slope computed using baseline computed eGFR and available historical serum creatinine values (preferred) or eGFR

Difference in absolute value of reported eGFR between end of follow-up and baseline

Equation used in reported 12-month follow-up eGFR:

2021 CKD-EPI creatinine 2021 CKD-EPI creatinine-cystatin C 2012 CKD-EPI cystatin C MDRD (based on creatinine) Cockroft-Gault (based on creatinine) Schwartz equation (based on creatinine) Not specified

Serum creatinine (preferred) or eGFR at 6 months after baseline

Average eGFR slope computed using available follow-up serum creatinine values (preferred) or eGFR

Difference in absolute value of computed eGFR between end of follow-up and baseline

No Yes 24-hour uPCR < 1 g/g 24-hour uPCR ≥ 1 g/g

No Yes Spot uPCR < 1 g/g Spot uPCR ≥ 1 g/g

Absolute value of uPCR based on a spot urine collection

Absolute value of uPCR based on a 24-hour urine collection

Difference in absolute value of 24-hour uPCR from baseline to 12-month follow-up, in g/g

Difference in absolute value of spot uPCR from baseline to 12-month follow-up, in g/g

Change of uPCR based on a 24-hour urine collection from baseline to 12-month follow-up, in mg/mmol Below 100 mg/mmol Above 100 mg/mmol

Change of uPCR based on a spot urine collection from baseline to 12-month follow-up, in mg/mmol Below 100 mg/mmol Above 100 mg/mmol

Change of uPCR based on a 24-hour urine collection from baseline to 12-month follow-up, in mg/mmol Below 1 g/g Above 1 g/g

Change of uPCR based on a spot urine collection from baseline to 12-month follow-up, in mg/mmol Below 1 g/g Above 1 g/g

No Yes

No Yes

Absolute value of uACR based on a 24-hour urine collection

Absolute value of uACR based on a spot urine collection

Difference in absolute value of 24-hour uACR from baseline to 12-month follow-up

Difference in absolute value of spot uACR from baseline to 12-month follow-up

No Yes Microscopic Macroscopic

0-2 red blood cells

≥3 red blood cells

Number of red blood cells detected through urinalysis

No change From no to yes From yes to no

Difference in absolute number of red blood cells detected through urinalysis from baseline to 12-month follow-up

No Presence of any of the below autoantibodies C3NeF C4NeF C5NeF Anti-factor H autoantibodies Anti-factor B autoantibodies Anti-C3b autoantibodies

CH50: The 50% activity of the classic pathway of the complement CH100: Total activity of the classic pathway of the complement

AH50: The 50% activity of the alternative pathway of the complement AH100: Total activity of the alternative pathway of the complement

Wieslab activity values are provided on a scale such that 100% of activity is normal activity. Full inhibition of alternative pathway corresponds to a value of 0

Serum C3 Reference range: LLN = 4.33-5.00 µmol/L ; ULN = 9.05-11.16 µmol/L Serum C4 Reference range: LLN = 0.50-0.70 µmol/L ; ULN = 2.00-2.60 µmol/L Serum C5 Reference range: LLN = 50 µg/mL ; ULN = 115 µg/mL

Reference range:

LLN = 1437 µg/L ULN = 3966 µg/L

Reference range:

LLN = 338 ng/mL ULN = 1164 ng/mL

Reference range:

LLN = 0.49 mg/L ULN = 1.42 mg/L

Reference range: LLN = 95 µg/L ULN = 467 µg/L

Vaccination status at baseline Neisseria meningitidis Staphylococcus pneumoniae Vaccinated for both Received prophylactic antibiotic treatment

Iptacopan daily dose at initiation and at the end of follow-up (or at discontinuation)

Dose increase Dose decrease No modification

Time from baseline to the first modification of the daily dose of iptacopan

Reason of modification of iptacopan dosage during follow-up

0 1-2 3-4 5 or more

Immunosuppressive medication used before baseline and/or discontinued before baseline.

No Yes Corticosteroids Prednisolone Methylprednisolone Cyclophosphamide Complement inhibitors C5 inhibitors (e.g., eculizumab) Other complement inhibitors (specify) Mycophenolate mofetil Rituximab Tacrolimus mTORi (everolimus/sirolimus) Other C3G medication (specify)

Concerns only patients with prior use of complement inhibitors.

Use of other C3G treatment in concomitance to iptacopan. No Yes ACEi/ARB Corticosteroids Prednisolone Methylprednisolone Cyclophosphamide Complement inhibitors C5 inhibitors (e.g., eculizumab) Other complement inhibitors (specify) Mycophenolate mofetil Rituximab SGLT2i Tacrolimus mTORi (everolimus/sirolimus) Other C3G medication (specify)

Duration of each of the following C3G treatments during the follow-up:

ACEi/ARB Corticosteroids Prednisolone Methylprednisolone Cyclophosphamide Complement inhibitors C5 inhibitors (e.g., eculizumab) Other complement inhibitors (specify) Mycophenolate mofetil Rituximab SGLT2i Tacrolimus mTORi (everolimus/sirolimus) Other C3G medication (specify)

treatments during the follow-up: ACEi/ARB Corticosteroids Prednisolone Methylprednisolone Cyclophosphamide Complement inhibitors C5 inhibitors (e.g., eculizumab) Other complement inhibitors (specify) Mycophenolate mofetil Rituximab SGLT2i Tacrolimus mTORi (everolimus/sirolimus) Other C3G medication (specify)

Any antibiotic therapy during follow-up No Yes

PDC calculated as the total number of days between iptacopan initiation and treatment discontinuation or death. Patients are censored upon disenrollment or reaching the end of follow-up

PDC < 80% PDC ≥ 80%

Number of participants with discontinuation of iptacopan during follow-up and reason for discontinuation of iptacopan

Time from iptacopan initiation to iptacopan discontinuation or death. Patients are censored upon disenrollment or reaching the end of follow-up

Reason of discontinuation of each of the following C3G treatments during the follow-up:

ACEi/ARB Corticosteroids Prednisolone Methylprednisolone Cyclophosphamide Complement inhibitors C5 inhibitors (e.g., eculizumab) Other complement inhibitors (specify) Mycophenolate mofetil Rituximab SGLT2i Tacrolimus mTORi (everolimus/sirolimus) Other C3G medication (specify)

Any antibiotic therapy during follow-up No Yes

PDC calculated as the total number of days between iptacopan initiation and treatment discontinuation or death. Patients are censored upon disenrollment or reaching the end of follow-up

PDC < 80% PDC ≥ 80%

Discontinuation of iptacopan, with no resumption during the follow-up period. No Yes

Concerning only patients with iptacopan discontinuation during follow-up. Infection Other adverse effects Death Loss to follow-up Other reasons (to be potentially defined during analysis)

Time from iptacopan initiation to iptacopan discontinuation or death. Patients are censored upon disenrollment or reaching the end of follow-up

Concerning only patients with iptacopan discontinuation during follow-up. No Yes ACEi/ARB Corticosteroids Prednisolone Methylprednisolone Cyclophosphamide Complement inhibitors C5 inhibitors (e.g., eculizumab) Other complement inhibitors (specify) Mycophenolate mofetil Rituximab SGLT2i Tacrolimus mTORi (everolimus/sirolimus) Other C3G medication (specify)

Number of hospitalizations, for any cause, during the 12- month period before baseline

Concerns only patients with 1 or more hospitalizations during the 12-month period before baseline.

Concerns only patients with 1 or more hospitalizations during the 12-month period before baseline

Concerning only patients with 2 or more hospitalizations during the 12-month period before baseline

Concerns only patients with 2 or more hospitalizations during the 12-month period before baseline

Number of hospitalizations due to infection during the 12-month period before baseline by Type (incl. pathogen) of infections

Number of hospitalizations, for any cause, from baseline to 12-month follow-up

Concerns only patients with 1 or more hospitalizations during the follow-up period.

Categories to be defined at the analysis stage.

Concerns only patients with 1 or more hospitalizations during the follow-up period

Concerning only patients with 2 or more hospitalizations during the follow-up period.

Categories to be defined at the analysis stage.

Concerning only patients with 2 or more hospitalizations during the follow-up period

Number of hospitalizations due to infection during follow-up and Type (incl. pathogen) of infections