Study of Efficacy and Safety of Iptacopan in Patients With C3 Glomerulopathy.

C3G Clinical Trial

— APPEAR-C3G  

Official title:

A Multicenter, Randomized, Double-blind, Parallel Group, Placebo-controlled Study to Evaluate the Efficacy and Safety of Iptacopan (LNP023) in Complement 3 Glomerulopathy.

Clinical Trial Details — Status: Recruiting

Administrative data

• NCT number: NCT04817618
• Other study ID #: CLNP023B12301
• Secondary ID: 2020-004589-21
• Status: Recruiting
• Phase: Phase 3
• Start date: July 28, 2021
• Est. completion date: July 4, 2026

Study information

• Verified date: June 2024
• Source: Novartis
• Contact: Novartis Pharmaceuticals
• Phone: 1-888-669-6682
• Email: novartis.email[@]novartis.com
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

The Primary Completion Date and Study Completion Date have been updated to reflect completion of the adolescent cohort, which has been added to the protocol.

The study is designed as a multicenter, randomized, double-blind, parallel group, placebo-controlled study to evaluate the efficacy and safety of iptacopan (LNP023) in complement 3 glomerulopathy.

Description:

The purpose of this study is to evaluate the efficacy and safety of iptacopan compared to placebo and standard of care in patients with native C3G. CLNP023B12301 is a Phase 3 pivotal trial for registration of iptacopan in C3G. The study aims to determine the reduction in UPCR and improvement in eGFR in participants treated with iptacopan compared to placebo, as well as the proportion of participants who achieve a composite renal endpoint consisting of eGFR and UPCR elements. These effects of iptacopan in conjunction with increases in serum C3 levels will provide support for an iptacopan profile that includes stabilization of eGFR, clinically meaningful reductions in proteinuria and inhibition of the complement AP. Kidney biopsies will be performed in adult participants to evaluate histopathological improvements in immunofluorescence and light microscopy that support these functional benefits of iptacopan.

Recruitment information / eligibility

• Status: Recruiting
• Enrollment: 98
• Est. completion date: July 4, 2026
• Est. primary completion date: March 27, 2026
• Accepts healthy volunteers: No
• Gender: All
• Age group: 12 Years to 60 Years

Eligibility

Inclusion Criteria:

• Male and female participants age = 12 and = 60 years at screening.

• Diagnosis of C3G as confirmed by renal biopsy within 12 months prior to enrollment in adults and within 3 years in adolescents.

• Prior to randomization, all participants must have been on a maximally recommended or tolerated dose of an angiotensin converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB) for at least 90 days. The doses of other antiproteinuric medications including mycophenolic acid, corticosteroids and mineralocorticoid receptor antagonists should be stable for at least 90 days prior to randomization.

• Reduced serum C3 (defined as less than 0.85 x lower limit of the central laboratory normal range) at Screening.

• UPCR = 1.0 g/g sampled from the first morning void urine sample at Day -75 and Day -15.

• Estimated GFR (using the CKD-EPI formula for ages = 18 years and modified Schwartz formula for ages 12 to 17 years) or measured GFR = 30 ml/min/1.73m2 at screening and Day -15.

• Mandatory vaccination against Neisseria meningitidis and Streptococcus pneumoniae prior to the start of study treatment.

• If not previously vaccinated or if a booster is required, vaccination against Haemophilus influenzae infections should be given, if available and according to local regulations, at least 2 weeks prior to the first study treatment administration. If study treatment has to start earlier than 2 weeks post vaccination, prophylactic antibiotic treatment should be initiated.

Exclusion Criteria:

• Participants who have received any cell or organ transplantation, including a kidney transplantation.

• Rapidly progressive crescentic glomerulonephritis defined as a 50% decline in the eGFR within 3 months with renal biopsy findings of glomerular crescent formation seen in at least 50% of glomeruli.

• Renal biopsy showing interstitial fibrosis/tubular atrophy (IF/TA) of more than 50%

• Monoclonal gammopathy of undetermined significance (MGUS) confirmed by the measurement of serum free light chains or other investigation as per local standard of care.

• Participants with an active systemic bacterial, viral or fungal infection within 14 days prior to study treatment administration

• The presence of fever = 38°C (100.4°F) within 7 days prior to study treatment administration.

• A history of recurrent invasive infections caused by encapsulated organisms, e.g., N. meningitidis and S. pneumoniae.

• The use of inhibitors of complement factors (e.g., Factor B, Factor D, C3 inhibitors, anti C5 antibodies, C5a receptor antagonists) within 6 months prior to the Screening visit.

• The use of immunosuppressants (except mycophenolic acids), cyclophosphamide or systemic corticosteroids at a dose >7.5 mg/day (or equivalent for a similar medication) within 90 days of study drug administration.

• Acute post-infectious glomerulonephritis at screening based upon the opinion of the investigator.

Related Conditions & MeSH terms

• C3G

Intervention

Drug:
• Placebo
Placebo to iptacopan 200mg b.i.d. (Adults 200mg b.i.d; Adolescents 2x 100mg b.i.d)
• iptacopan
iptacopan 200 mg b.i.d. (Adults 200mg b.i.d; Adolescents 2x 100mg b.i.d)

Locations

Country	Name	City	State
Argentina	Novartis Investigative Site	Buenos Aires
Argentina	Novartis Investigative Site	Caba	Buenos Aires
Argentina	Novartis Investigative Site	Cordoba
Belgium	Novartis Investigative Site	Edegem	Antwerpen
Belgium	Novartis Investigative Site	Leuven
Brazil	Novartis Investigative Site	Belo Horizonte	MG
Brazil	Novartis Investigative Site	Joinville	Santa Catarina
Brazil	Novartis Investigative Site	Santo Andre	SP
Brazil	Novartis Investigative Site	Sao Paulo	SP
Brazil	Novartis Investigative Site	Sao Paulo	SP
Canada	Novartis Investigative Site	London	Ontario
Canada	Novartis Investigative Site	Montreal	Quebec
Canada	Novartis Investigative Site	Toronto	Ontario
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Beijing
China	Novartis Investigative Site	Guangzhou	Guangdong
China	Novartis Investigative Site	Shanghai
China	Novartis Investigative Site	Wuhan
Czechia	Novartis Investigative Site	Praha
France	Novartis Investigative Site	Lille
France	Novartis Investigative Site	Marseille
France	Novartis Investigative Site	Montpellier
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Paris
France	Novartis Investigative Site	Paris 15
Germany	Novartis Investigative Site	Aachen
Germany	Novartis Investigative Site	Erlangen
Germany	Novartis Investigative Site	Essen
Germany	Novartis Investigative Site	Hamburg
Germany	Novartis Investigative Site	Hannover
Germany	Novartis Investigative Site	Heidelberg
Germany	Novartis Investigative Site	Mainz
Greece	Novartis Investigative Site	Athens
Greece	Novartis Investigative Site	Heraklion Crete
Greece	Novartis Investigative Site	Thessaloniki
Greece	Novartis Investigative Site	Thessaloniki	Macedoni
India	Novartis Investigative Site	DehraDun	Uttarakhand
India	Novartis Investigative Site	Hyderabad	Telangana
India	Novartis Investigative Site	Lucknow	Uttar Pradesh
India	Novartis Investigative Site	New Delhi	Delhi
India	Novartis Investigative Site	New Delhi
Israel	Novartis Investigative Site	Petach Tikva
Israel	Novartis Investigative Site	Petach Tikva
Italy	Novartis Investigative Site	Milano
Italy	Novartis Investigative Site	Ranica	BG
Italy	Novartis Investigative Site	Roma	RM
Japan	Novartis Investigative Site	Asahikawa	Hokkaido
Japan	Novartis Investigative Site	Nagoya	Aichi
Japan	Novartis Investigative Site	Niigata
Japan	Novartis Investigative Site	Ohtsu-city	Shiga
Japan	Novartis Investigative Site	Sapporo	Hokkaido
Japan	Novartis Investigative Site	Takatsuki	Osaka
Netherlands	Novartis Investigative Site	Leiden	Zuid Holland
Netherlands	Novartis Investigative Site	Nijmegen
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Barcelona	Catalunya
Spain	Novartis Investigative Site	Madrid
Spain	Novartis Investigative Site	Malaga	Andalucia
Spain	Novartis Investigative Site	Puerto De Sagunto	Comunidad Valenciana
Spain	Novartis Investigative Site	Sevilla	Andalucia
Switzerland	Novartis Investigative Site	Bern
Switzerland	Novartis Investigative Site	Lausanne
Turkey	Novartis Investigative Site	Ankara
Turkey	Novartis Investigative Site	Istanbul
Turkey	Novartis Investigative Site	Istanbul	TUR
Turkey	Novartis Investigative Site	Talas / Kayseri
United Kingdom	Novartis Investigative Site	Glasgow
United Kingdom	Novartis Investigative Site	London	UK
United Kingdom	Novartis Investigative Site	Newcastle Upon Tyne
United States	Albany Medical Center Department of Medicine	Albany	New York
United States	Childrens Hospital Colorado	Aurora	Colorado
United States	Novartis Investigative Site	Baltimore	Maryland
United States	Novartis Investigative Site	Boston	Massachusetts
United States	University of Iowa Health Care	Iowa City	Iowa
United States	Georgia Nephrology Research Inst	Lawrenceville	Georgia
United States	Nicklaus Childrens Hospital .	Miami	Florida
United States	Col Uni Med Center New York Presby	New York	New York
United States	Novartis Investigative Site	Temple	Texas

Sponsors (1)

Lead Sponsor	Collaborator
Novartis Pharmaceuticals

Countries where clinical trial is conducted

United States,  Argentina,  Belgium,  Brazil,  Canada,  China,  Czechia,  France,  Germany,  Greece,  India,  Israel,  Italy,  Japan,  Netherlands,  Spain,  Switzerland,  Turkey,  United Kingdom, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Adult cohort: Log-transformed ratio to baseline in UPCR (sampled from a 24-hour urine collection)	To demonstrate the superiority of iptacopan compared to placebo in reducing proteinuria at 6 months of treatment.	6 months (double-blind)
Primary	Adolescent cohort: Log-transformed ratio to baseline in UPCR (sampled from a 24-hour urine collection)	To evaluate the effect of iptacopan on proteinuria at 6 months.	6 months (double-blind)
Primary	Change from baseline in log-transformed UPCR at the 12-month visit (both study treatment arms).	To evaluate the effect of iptacopan on proteinuria at 12 months.	12 months (double-blind and open-label)
Primary	Change in log-transformed UPCR from the 6-month visit to the 12-month visit in the placebo arm	To evaluate the effect of iptacopan on proteinuria at 12 months.	From month 6 to month 12 (open-label)
Secondary	Change from baseline in eGFR.	To demonstrate the superiority of iptacopan vs. placebo in improving eGFR.	6 months (double-blind)
Secondary	Proportion of participants who meet the criteria for achieving a composite renal endpoint	To demonstrate the superiority of iptacopan vs. placebo in the proportion of participants who meet the criteria for achieving a composite renal endpoint.; A participant meets the requirements of the composite renal endpoint if he/she satisfies: (1) a stable or improved eGFR compared to the baseline visit (=15% reduction in eGFR), and (2) a =50% reduction in UPCR compared to the baseline visit.	6 months (double-blind)
Secondary	Adult cohort: Change from baseline in disease total activity score in a renal biopsy.	To demonstrate the effect of iptacopan vs placebo in reducing glomerular inflammation in the kidney.	6 months (double-blind)
Secondary	Change from baseline in the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-Fatigue) score.	To assess the effect of iptacopan compared to placebo in improvement of patient reported fatigue.	6 months (double-blind)
Secondary	Number of participants with abnormal clinically significant vital signs, ECGs and safety laboratory measurements	To evaluate the safety and tolerability of iptacopan compared to placebo.	6 months (double-blind)
Secondary	Number of participants with study drug discontinuation due to an AE	To evaluate the safety and tolerability of iptacopan compared to placebo	6 months (double-blind)
Secondary	Proportion of participants who meet the criteria for achieving a composite renal endpoint	To evaluate the effect at 12 months of iptacopan on a composite renal endpoint. A participant meets the requirements of the composite renal endpoint if he/she satisfies: (1) a stable or improved eGFR compared to the baseline visit (=15% reduction in eGFR), and (2) a =50% reduction in UPCR compared to the baseline visit.	12 months (double-blind and open-label)
Secondary	Proportion of patients achieving a composite renal endpoint from the 6-month visit to the 12-month visit of the placebo arm	To evaluate the effect at 12 months of iptacopan on a composite renal endpoint. A participant meets the requirements of the composite renal endpoint if he/she satisfies: (1) a stable or improved eGFR compared to the baseline visit (=15% reduction in eGFR), and (2) a =50% reduction in UPCR compared to the 6 months visit.	month 6, month 12 (open-label)
Secondary	Change from baseline in the total activity score in a renal biopsy at 12 months	To evaluate the effect at 12 months of iptacopan in reducing glomerular inflammation in the kidney.	Baseline, month 12 (double-blind and open-label)
Secondary	Change in the total activity score in a renal biopsy from the 6-month visit to the 12-month visit of the placebo arm.	To evaluate the effect at 12 months of iptacopan in reducing glomerular inflammation in the kidney.	month 6, month 12 (open-label)
Secondary	Change from baseline in the FACIT-Fatigue score at 12 months	To evaluate the effect at 12 months of iptacopan in improvement of patient reported fatigue	Baseline, month 12 (double-blind and open-label)
Secondary	Change in the FACIT-Fatigue score from the 6-month visit to the 12-month visit of the placebo arm	To evaluate the effect at 12 months of iptacopan in improvement of patient reported fatigue	month 6, month 12 (open-label)
Secondary	Number of participants with abnormal clinically significant vital signs, ECGs and safety laboratory measurements	To evaluate the safety and tolerability of iptacopan during the 6-month open-label treatment period as well as the entire 12- month treatment period	12 months (double-blind and open-label)
Secondary	Number of participants with study drug discontinuation due to an AE	To evaluate the safety and tolerability of iptacopan during the 6-month open-label treatment period as well as the entire 12- month treatment period.	12 months (double-blind and open-label)