Clinical Trials Register

Summary
EudraCT Number:	2020-001049-38
Sponsor's Protocol Code Number:	CLNP023A2301
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-11-02
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2020-001049-38

A.3

Full title of the trial

A multi-center, randomized, double-blind, placebo-controlled, parallel group, phase III study to evaluate the efficacy and safety of LNP023 in primary IgA nephropathy patients

Etude de phase III, multicentrique, randomisée, en double aveugle, en groupes parallèles, contrôlée par placebo, évaluant l’efficacité et la sécurité d’emploi de LNP023 chez des patients atteints de néphropathie primaire à IgA

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Study of efficacy and safety of LNP023 in primary IgA nephropathy patients

Etude du efficacité et sécurité de LNP023 chez des patients atteints de néphropathie primaire à IgA

A.4.1

Sponsor's protocol code number

CLNP023A2301

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Novartis Pharma AG
B.1.3.4	Country	Switzerland
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Novartis Pharma AG
B.4.2	Country	Switzerland
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Novartis Pharma S.A.S
B.5.2	Functional name of contact point	Information&Communication Médicales
B.5.3	Address:
B.5.3.1	Street Address	8/10 rue Henry Sainte Claire Deville, CS 40150
B.5.3.2	Town/ city	Rueil-Malmaison
B.5.3.3	Post code	92563
B.5.3.4	Country	France
B.5.4	Telephone number	+33 1 5547 6600
B.5.5	Fax number	+33 1 5547 6100
B.5.6	E-mail	icm.phfr@novartis.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	iptacopan
D.3.2	Product code	LNP023
D.3.4	Pharmaceutical form	Capsule, hard
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	iptacopan
D.3.9.2	Current sponsor code	LNP023
D.3.9.3	Other descriptive name	LNP023 HYDROCHLORIDE SALT
D.3.9.4	EV Substance Code	SUB180361
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Capsule, hard
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

IgA Nephropathy

Néphropathie à IgA

E.1.1.1

Medical condition in easily understood language

Kidney disorder

Troubles rénaux

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10021263
E.1.2	Term	IgA nephropathy
E.1.2	System Organ Class	10038359 - Renal and urinary disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

To demonstrate superiority of LNP023 vs. placebo in the reduction of proteinuria at 9 months by measuring UPCR sampled from a 24h urine collection.

To demonstrate superiority of LNP023 vs. placebo in slowing renal disease progression measured by the annualized total slope of Estimated Glomerular Filtration Rate (eGFR) decline over 24 months.

Démontrer la supériorité de LNP023 versus placebo sur la réduction de la protéinurie à 9 mois, mesurée par le rapport protéinurie/créatininurie (RPCU) à partir d’un échantillon de la collecte des urines de 24 heures

Démontrer la supériorité de LNP023 versus placebo sur le ralentissement de la progression de la maladie rénale, mesuré par la pente totale annualisée de la diminution du débit de filtration glomérulaire estimé (DFGe) sur 24 mois

E.2.2

Secondary objectives of the trial

To assess the effect of LNP023 vs. placebo on the proportion of study participants reaching proteinuria below 1g/g of UPCR (sampled from 24h urine collection) at 9 months; To evaluate the effect of LNP023 vs. placebo on slowing renal disease progression measured by the annualized total slope of eGFR decline over 1 year; To assess the effect of LNP023 vs. placebo on the change from baseline to 9 months in fatigue scale measured by the FACIT-Fatigue questionnaire; To demonstrate the superiority of LNP023 vs. placebo on: delaying the time to first occurrence of a composite renal endpoint of reaching either at least 30% decline in eGFR, ESRD or renal death; in the reduction of proteinuria by measuring UPCR sampled from a 24h urine collection; on the proportion of study participants reaching proteinuria below 1g/g of UPCR (sampled from 24h urine collection) at 9 months; on the change from baseline to 9 months in the fatigue scale measured by FACIT-Fatigue questionnaire

Evaluer l’effet de LNP023 versus placebo sur:
- la proportion de patients obtenant une protéinurie inférieure à 1 g/g à 9 mois, mesurée par le RPCU (collecte des urines de 24 heures)
- le ralentissement de la progression de la maladie rénale, mesuré par la pente totale annualisée de la diminution du débit de filtration glomérulaire estimé (DFGe) sur 12 mois ;
- le changement à 9 mois par rapport à la baseline de la fatigue (questionnaire FACIT-Fatigue) ; Démontrer la supériorité de LNP023 versus placebo sur le délai jusqu’à la 1ère apparition d’un critère d’évaluation composite : diminution d’au moins 30 % du DFGe, insuffisance rénale terminale ou insuffisance rénale conduisant au décès du patient, réduction de la protéinurie à 9 mois, mesurée par le RPCU (urines de 24 heures), proportion de patients obtenant une protéinurie inférieure à 1 g/g à 9 mois, mesurée par le RPCU (urines de 24 heures), changement à 9 mois de la fatigue mesurée à l’aide du questionnaire FACIT-Fatigue

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

optional genetic research component

E.3

Principal inclusion criteria

•Male and female patients ≥ 18 years of age with an eGFR level and biopsy-confirmed IgA nephropathy as follows:
•For patients eGFR* ≥ 45ml/min/1.73m2, a qualifying biopsy performed within the last 5 years is required.
•For patients with eGFR* 30 to <45ml/min/1.73m2 a qualifying biopsy performed within 2 years with < 50% tubulointerstitial fibrosis is required.
• For patients with eGFR* 20 to <30ml/min/1.73m2,a qualifying biopsy performed at any time.
In all cases, if a historical biopsy is not available, one may be performed during screening. *eGFR calculated using the CKD-EPI formula (or modified MDRD formula according to specific ethnic groups and local practice guidelines)
•Proteinuria due to primary diagnosis of IgA nephropathy as assessed at screening by UPCR ≥1 g/g (113 mg/mmol) sampled from FMV or 24h urine collection, as well as at the completion of the run-in period by UPCR ≥1 g/g (113 mg/mmol) calculated as the mean of two 24h urine collections obtained within 14 days of each other at baseline.
•Vaccination against Neisseria meningitidis infection is required prior to the start of study treatment. If the patient has not been previously vaccinated, or if a booster is required, vaccine should be given according to local regulations at least 2 weeks prior to first study drug administration. If study treatment has to start earlier than 2 weeks post vaccination, prophylactic antibiotic treatment should be initiated.
•If not previously vaccinated, vaccination against Streptococcus pneumoniae and Haemophilus influenzae infections should be given, if available and according to local regulations, at least 2 weeks prior to first study drug administration. If study treatment has to start earlier than 2 weeks post vaccination, prophylactic antibiotic treatment should be initiated.
•All patients must have been on supportive care including stable dose regimen of ACEi or ARB at either the locally approved maximal daily dose or the maximally tolerated dose (per investigators’ judgment) for at least 90 days before first study drug administration. In addition, if patients are taking diuretics or other antihypertensive therapy, the doses should also be stabilized for at least 90 days prior to the first dosing of study treatment.

Other protocol-defined inclusion criteria may apply.

Hommes et femmes ≥ 18 ans atteints de IgAN confirmée par biopsie accompagnée d’un DFGe comme suit :
• Pour les patients ayant un DFGe* ≥ 45 ml/min/1,73 m², la biopsie répondant aux critères d’inclusion doit avoir été réalisée au cours des 5 années précédentes.
• Pour les patients ayant un DFGe* de 30 à < 45 ml/min/1,73 m², la biopsie répondant aux critères d’inclusion doit avoir été réalisée au cours des 2 années précédentes et présenter une fibrose tubulo-interstitielle < 50 %.
• Pour les patients ayant un DFGe* de 20 à < 30 ml/min/1,73 m², la biopsie répondant aux critères d’inclusion peut avoir été réalisée à tout moment.
Dans tous les cas, si les résultats d’une ancienne biopsie qui confirme l’IgAN ne sont pas disponibles, une nouvelle biopsie pourra être réalisée au cours de la sélection.* DFGe calculé selon l’équation CKD-EPI (pour Chronic Kidney Disease-Epidemiology Collaboration) (ou MDRD [pour Modification of Diet in Renal Disease] selon les groupes ethniques spécifiques et les recommandations de pratique en vigueur).
•Protéinurie causée par l’IgAN primaire évaluée par un RPCU ≥ 1 g/g (113 mg/mmol) : à la sélection, dans les premières urines du matin ou un échantillon pris des urines de 24 heures, ainsi qu’à la fin de la partie préalable, calculé par la moyenne de deux mesures effectuées dans un échantillon pris de la collecte des urines de 24 heures recueillis dans les 14 jours précédant la baseline.
•Vaccination contre les infections à Neisseria meningitidis requise avant le début du traitement à l’étude. Si le patient n’a pas été vacciné auparavant, ou si une dose de rappel est nécessaire, le vaccin devra être administré, selon les réglementations en vigueur, au moins 2 semaines avant le début du traitement à l’étude. Si le traitement à l’étude doit commencer avant ces 2 semaines post-vaccination, une antibiothérapie prophylactique devra être instaurée.
• Si le patient n’a pas été vacciné auparavant contre les infections à Streptococcus pneumoniae et Haemophilus influenzae, un vaccin devra lui être administré, selon la disponibilité et les réglementations en vigueur, au moins 2 semaines avant le début du traitement à l’étude. Si le traitement à l’étude doit commencer avant ces 2 semaines post-vaccination, une antibiothérapie prophylactique devra être instaurée.
•Tous les patients doivent avoir reçu un traitement de soutien, incluant une dose stable d’IEC ou d’ARA-II à la dose maximale quotidienne tolérée autorisée localement ou à la dose maximale tolérée (selon le jugement du médecin-investigateur), depuis au moins 90 jours avant la première prise du traitement à l’étude. En outre, les patients sous diurétiques ou autres anti-hypertenseurs doivent recevoir une dose stable depuis au moins 90 jours avant le début du traitement à l’étude.

D'autres critères d'inclusion définis par le protocole peuvent s'appliquer.

E.4

Principal exclusion criteria

•Any secondary IgAN as defined by the investigator; secondary IgAN can be associated with cirrhosis, celiac disease, Human Immunodeficiency Virus (HIV) infection, herpetiformis, seronegative arthritis, small-cell carcinoma, lymphoma, disseminated tuberculosis, bronchiolitis obliterans, and inflammatory bowel disease, familial mediterranean fever, etc.
•Sitting office SBP >140 mmHg or DBP >90 mmHg at the randomization visit
• Patients previously treated with immunosuppressive or other immunmodulatory agents such as but not limited to cyclophosphamide, rituximab, infliximab, eculizumab, canakinumab, hydroxychloroquine, mycophenolate mofetil (MMF) or mycophenolate sodium (MPS), cyclosporine, tacrolimus, sirolimus, everolimus, or systemic corticosteroids exposure (>10 mg/d prednisone/prednisolone equivalent) within 90 days (or 180 days for rituximab) prior to first study drug administration
•Prior use of LNP023 or prior enrollment in any other LNP023 clinical trial where study drug was taken, including matching placebo
•History of recurrent invasive infections caused by encapsulated organisms, such as meningococcus and pneumococcus.
•Active systemic bacterial, viral (including COVID-19) or fungal infection within 14 days prior to study drug administration.

Other protocol-defined exclusion criteria may apply.

1. Toute IgAN secondaire telle que définie par le médecin-investigateur ; les IgAN secondaires peuvent être associées aux maladies suivantes : cirrhose, maladie coeliaque, infection par le virus de l’immunodéficience humaine (VIH), dermatite herpétiforme, arthrite séronégative, carcinome à petites cellules, lymphome, tuberculose miliaire, bronchiolite oblitérante, maladie inflammatoire de l’intestin, fièvre méditerranéenne familiale, etc.
• Pression artérielle en position assise > 140 mmHg (systolique) ou > 90 mmHg (diastolique) à la visite de randomisation.
• Patients ayant reçu un traitement immunosuppresseur ou immunomodulateur (cyclophosphamide, rituximab, infliximab, éculizumab, canakinumab, hydroxychloroquine, mycophénolate mofétil ou mycophénolate de sodium, cyclosporine, tacrolimus, sirolimus, évérolimus, entre autres) ou des corticoïdes systémiques (> 10 mg/jour de prednisone/ou équivalent de prednisolone) au cours des 90 jours (ou 180 jours pour le rituximab) précédant la première prise du traitement à l’étude.
• Traitement antérieur par LNP023 ou inclusion antérieure dans toute étude évaluant LNP023 (que le patient ait pris LNP023 ou un placebo).
• Antécédents d’infections invasives récurrentes dues à des organismes encapsulés, par ex. à méningocoques ou à pneumocoques.
• Infection systémique active bactérienne, virale (y compris COVID-19) ou fongique au cours des 14 jours précédant le début du traitement à l’étude.

D'autres critères d'exclusion définis par le protocole peuvent s'appliquer

E.5 End points

E.5.1

Primary end point(s)

- Log-transformed ratio to baseline in UPCR (sampled from 24h urine collection) at 9 months
- Annualized total Estimated Glomerular Filtration Rate (eGFR) slope estimated over 24 months).

E.5.1.1

Timepoint(s) of evaluation of this end point

baseline and 9 months
baseline and 24 months

E.5.2

Secondary end point(s)

-Proportion of participants reaching Urine Protein To Creatinine Ratio <1g/g at 9 months, without receiving Corticosteroids/ Immunosuppressant or other newly approved drugs for treatment of IgAN or initiating Renal Replacement Therapy.
-Annualized total Estimated Glomerular Filtration Rate slope estimated over 12 months
- Change from baseline to 9 months in the fatigue scale measured by the Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire
- Time from randomization to first occurrence of composite renal endpoint event, defined as reaching either ≥30% decline in Estimated Glomerular Filtration Rate (eGFR) relative to baseline, or End Stage Renal Disease (ESRD), or renal death
-Log-transformed ratio to baseline in Urine Protein-To-Creatinine Ratio (sampled from 24h urine collection)
-Proportion of participants reaching Urine Protein-To-Creatinine Ratio <1g/g at 9 months without receiving Corticosteroids/ Immunosuppressant Therapy or other newly approved drugs for treatment of IgAN or initiating renal replacement therapy
-Change from baseline to 9 months in the fatigue scale measured by the Functional Assessment Of Chronic Illness Therapy-Fatigue questionnaire.

E.5.2.1

Timepoint(s) of evaluation of this end point

baseline and 9 months
Baseline and 12 months
baseline and 9 months
up to 24 months
24 months
baseline and 24 months
baseline and 24 months

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

Yes

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

E.7.3

Therapeutic confirmatory (Phase III)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

Yes

E.8.2.3

Other

E.8.2.4

Number of treatment arms in the trial

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Argentina

Australia

Belgium

Brazil

Canada

China

Colombia

Czechia

Denmark

Finland

France

Germany

Hungary

India

Israel

Italy

Japan

Korea, Republic of

Malaysia

Mexico

Netherlands

Norway

Russian Federation

Singapore

Spain

Sweden

Taiwan

Thailand

Turkey

United Kingdom

United States

Vietnam

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

441

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

450

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

Participants can receive post-trial access by joining the roll-over extension program to allow participants' access to LNP023 and in order to enable long-term safety monitoring.

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2020-12-07

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-01-13

P. End of Trial
P.	End of Trial Status	Ongoing

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