Clinical Trials Register

Summary
EudraCT Number:	2019-004665-40
Sponsor's Protocol Code Number:	CLNP023C12302
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:	2020-09-18
Trial results	View 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

2019-004665-40

A.3

Full title of the trial

A randomized, multicenter, active-comparator controlled, open-label trial to evaluate efficacy and safety of oral, twice daily LNP023
in adult patients with PNH and residual anemia, despite treatment with an intravenous anti-C5 antibody

Etude multicentrique, randomisée, contrôlée par comparateur actif, en ouvert, évaluant l’efficacité et la sécurité d’emploi de LNP023 administré deux fois par jour par voie orale chez des adultes atteints d’hémoglobinurie paroxystique nocturne avec anémie résiduelle malgré un traitement par anticorps anti-C5 intraveineux

A.3.1

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

Study of efficacy and safety of twice daily oral LNP023 in adult PNH patients with residual anemia despite anti-C5 antibody treatment

Etude évaluant l’efficacité et la sécurité d’emploi de LNP023 administré deux fois par jour par voie orale chez des adultes atteints d’hémoglobinurie paroxystique nocturne avec anémie résiduelle malgré un traitement par anticorps anti-C5 intraveineux

A.4.1

Sponsor's protocol code number

CLNP023C12302

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 Médicale
B.5.3	Address:
B.5.3.1	Street Address	8-10 rue Henri Sainte Claire Deville
B.5.3.2	Town/ city	Rueil-Malmaison
B.5.3.3	Post code	92500
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/20/2281
D.3 Description of the IMP
D.3.1	Product name	LNP023
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	not yet established
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	10
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.IMP: 2
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	Yes
D.2.5.1	Orphan drug designation number	EU/3/20/2281
D.3 Description of the IMP
D.3.1	Product name	LNP023
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	not yet established
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.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.1.1.1	Trade name	Soliris
D.2.1.1.2	Name of the Marketing Authorisation holder	Alexion
D.2.1.2	Country which granted the Marketing Authorisation	European Union
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	Yes
D.2.5.1	Orphan drug designation number	EU/3/03/166
D.3 Description of the IMP
D.3.1	Product name	Eculizumab
D.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ECULIZUMAB
D.3.9.1	CAS number	219685-50-4
D.3.9.4	EV Substance Code	SUB25187
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	300
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	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	Yes
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	Yes
D.3.11.13.1	Other medicinal product type	Eculizumab is a humanised monoclonal antibody produced in NS0 cell line by recombinant DNA technology

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Hémoglobinurie paroxystique nocturne

E.1.1.1

Medical condition in easily understood language

Blood disorder

Maladie du sang

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10034042
E.1.2	Term	Paroxysmal nocturnal haemoglobinuria
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

- Proportion of participants achieving a sustained increase in hemoglobin levels of ≥ 2 g/dL in the absence of red blood cell transfusions
- Proportion of participants achieving sustained hemoglobin levels ≥ 12 g/dL in the absence of red blood cell transfusions.

- Proportion de patients obtenant une augmentation durable du taux d’hémoglobine ≥ 2 g/dl par rapport à la baseline sans recours à des transfusions de globules rouges
- Proportion de patients obtenant des taux durables d’hémoglobine ≥ 12 g/dl sans recours à des transfusions de globules rouges

E.2.2

Secondary objectives of the trial

- Proportion of participants who remain free from transfusions
- Average change in hemoglobin
- Change in fatigue score, using the FACIT-Fatigue questionnaire
- Average change in reticulocyte counts
- Average percent change in LDH
- Rate of breakthrough hemolysis (BTH)
- Rates of Major Adverse Vascular Events (MAVEs incl. thrombosis

- Proportion de patients qui n’ont pas recours à des transfusions
- Variation moyenne de l’hémoglobine
- Amélioration de la fatigue à l’aide du questionnaire FACIT-Fatigue
- Variation moyenne du nombre de réticulocytes
- Variation moyenne en pourcentage de LDH
- Poussées d’hémolyse sous traitement
- Taux d’évènements indésirables vasculaires majeurs (incluant les thromboses) lors du traitement par LNP023 par rapport à un anticorps anti-C5

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

Recherche génétique facultative

E.3

Principal inclusion criteria

- Male and female participants ≥ 18 years of age with a diagnosis of PNH confirmed by high-sensitivity flow cytometry with clone size ≥ 10%
- Stable regimen of anti-C5 antibody treatment (either eculizumab or ravulizumab) for at least 6 months prior to randomization
- Mean hemoglobin level <10 g/dL
- Vaccination against Neisseria meningitidis infection is required prior to the start of treatment.
- If not received previously, vaccination against Streptococcus pneumoniae and Haemophilus influenzae infections should be given

Other protocol-defined inclusion criteria may apply

- Hommes et femmes ≥ 18 ans atteints d’HPN dont le diagnostic est confirmé en cytométrie en flux à haute sensibilité sur les globules rouges et/ou confirmé par un ratio ≥ 10 % de la taille du clone de globules blancs
- Traitement par un anticorps anti-C5 (éculizumab ou ravulizumab) selon une posologie stable (dose et fréquence) depuis au moins 6 mois avant la randomisation
- Taux d’hémoglobine moyen < 10 g/dl
- Vaccination contre les infections à Neisseria meningitidis requise avant le début du traitement.
- Si pas effectuées précédemment, les vaccinations contre les infections à Streptococcus pneumoniae et Haemophilus influenzae devront être réalisées

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

E.4

Principal exclusion criteria

- Participants on a stable eculizumab dose but with a dosing interval of 11 days or less
- Known or suspected hereditary complement deficiency at screening
- History of hematopoietic stem cell transplantation
- Patients with laboratory evidence of bone marrow failure (reticulocytes <100x109/L; platelets <30x109/L; neutrophils <500x106/L).
- Active systemic bacterial, viral or fungal infection within 14 days prior to study drug administration
- A history of recurrent invasive infections caused by encapsulated organisms, e.g. meningococcus or pneumococcus.
- Major concurrent comorbidities including but not limited to severe kidney disease (e.g., 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) that in the opinion of the investigator precludes participant's participation in the study.

Other protocol-defined exclusion criteria may apply

- Patients recevant une dose stable d’éculizumab mais à une fréquence de tous les 11 jours ou moins.
- Déficit en complément héréditaire connu ou suspecté à la sélection.
- Antécédents de greffe de cellules souches hématopoïétiques (CSH)
- Patients ayant des analyses biologiques indiquant une insuffisance médullaire (réticulocytes < 100x109/l ; plaquettes < 30x109/l ; neutrophiles < 500x106/l)
- Infection systémique bactérienne, virale ou fongique active au cours des 14 jours précédant le début du traitement à l’étude
- Antécédents d’infections invasives récurrentes dues à des organismes encapsulés, par ex. à méningocoques ou à pneumocoques
- Comorbidité majeure concomitante incluant entre autres une atteinte rénale sévère (par ex. nécessitant la dialyse), une pathologie cardiaque à un stade avancé (par ex. classe IV selon la classification fonctionnelle de la « New York Heart Association » [NYHA]), une affection pulmonaire sévère (par ex. hypertension pulmonaire sévère [classe IV selon la classification fonctionnelle de l’Organisation mondiale de la santé]) ou une atteinte hépatique (par ex. hépatite active) qui, selon le médecin-investigateur, ne permet pas la participation du patient 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)

- Proportion of participants achieving a sustained increase in hemoglobin levels from baseline of ≥ 2 g/dL in the absence of red blood cell transfusions
- Proportion of participants achieving sustained hemoglobin levels ≥ 12 g/dL in the absence of red blood cell transfusions.

E.5.1.1

Timepoint(s) of evaluation of this end point

Day 126 and Day 168

Aux jours 126 & 168

E.5.2

Secondary end point(s)

1. Proportion of participants who remain free from transfusions
2. Change from baseline in hemoglobin (g/dL) as mean of visits between Day 126 and D168
3. Change from baseline in FACIT-Fatigue scores as mean of visits between Day 126 and Day 168
4. Change from baseline in reticulocyte counts as mean of visits between Day 126 and Day 168
5. Percent change from baseline in LDH levels (U/L) as mean of visits between Day 126 and Day 168
6. Rate of breakthrough hemolysis (BTH)
7. Rates of Major Adverse Vascular Events (MAVEs incl. thrombosis

1. Proportion de patients qui n’ont pas recours à des transfusions
2. Variation moyenne par rapport à la baseline du taux d’hémoglobine (g/dl) lors des visites entre le Jour 126 et le Jour 168
3. Variation moyenne par rapport à la baseline du score FACIT-Fatigue lors des visites entre le Jour 126 et le Jour 168
4. Variation moyenne par rapport à la baseline du nombre de réticulocytes (109/l) lors des visites entre le Jour 126 et le Jour 168
5. Pourcentage de variation par rapport à la baseline de la moyenne du LDH (U/l) mesuré lors des visites entre le Jour 126 et le Jour 168
6. Taux de poussées d’hémolyse
7. Taux d'évènements indésirables vasculaires majeurs entre le Jour 1 et le Jour 168

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Day 14 and Day 168
2. Baseline and as mean of visit Day 126, 140, 154 and 168.
3. Baseline and as mean of visit Day 126, 140, 154 and 168.
4. Baseline and as mean of visit Day 126, 140, 154 and 168.
5. Baseline and as mean of visit Day 126, 140, 154 and 168.
6. Day 1 and Day 168.
7. Day 1 and Day 168.

1. Aux jours 14 et 168
2. Variation moyenne aux jours 126, 140, 154 et 168 par rapport à la baseline
3. Variation moyenne aux jours 126, 140, 154 et 168 par rapport à la baseline
4. Variation moyenne aux jours 126, 140, 154 et 168 par rapport à la baseline
5. Variation moyenne aux jours 126, 140, 154 et 168 par rapport à la baseline
6. Aux jours 1 et 168
7. Aux jours 1 et 168

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

Tolérance

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Ravulizumab and Eculizumab

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

Brazil

Canada

Czech Republic

France

Germany

Hungary

Italy

Japan

Korea, Republic of

Netherlands

Spain

Taiwan

United Kingdom

United States

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

Dernière visite du dernier patient

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:

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

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 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

2020-10-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-11-03

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

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Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
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