Clinical Trials Register

Summary
EudraCT Number:	2019-003830-17
Sponsor's Protocol Code Number:	ACH228-110
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-06-23
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2019-003830-17

A.3

Full title of the trial

A Phase 2 Open-Label Proof of Concept Study to Assess the Efficacy, Safety, and Pharmacokinetics of the Oral Factor D (FD) Inhibitor ACH-0145228 in Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients as Monotherapy and with an Approved C5 Inhibitor as Background Therapy

Studio di prova di concetto in aperto di fase 2 volto a valutare l’efficacia,
la sicurezza e la farmacocinetica dell’inibitore orale del fattore D ACH-0145228
somministrato in monoterapia e in associazione a un inibitore di C5 approvato
come terapia di base a pazienti affetti da emoglobinuria parossistica notturna
(EPN)

A.3.1

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

Study of the Oral Factor D (fD) Inhibitor ACH-0145228 in Paroxysmal Nocturnal Hemoglobinuria (PNH) Patients as Monotherapy and with background use of an Approved C5 Inhibitor

Studio dell’inibitore orale del fattore D ACH-0145228 somministrato in
monoterapia e in associazione a un inibitore di C5 approvato come terapia di base a pazienti affetti da EPN

A.4.1

Sponsor's protocol code number

ACH228-110

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04170023

A.5.3

WHO Universal Trial Reference Number (UTRN)

U1111-1241-2441

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	Achillion Pharmaceuticals, Inc., a wholly owned subsidiary of Alexion Pharmaceuticals Inc.
B.1.3.4	Country	United States
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	Achillion Pharmaceuticals, Inc. a wholly owned subsidiary of Alexion Pharmaceuticals Inc.
B.4.2	Country	United States
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Alexion Europe SAS
B.5.2	Functional name of contact point	European Clinical Trial Information
B.5.3	Address:
B.5.3.1	Street Address	103-105 Rue Anatole France
B.5.3.2	Town/ city	Levallois-Perret
B.5.3.3	Post code	92300
B.5.3.4	Country	France
B.5.4	Telephone number	+33147100615
B.5.5	Fax number	+33147100611
B.5.6	E-mail	clinicaltrials.eu@alexion.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	ALXN2050
D.3.2	Product code	ACH-0145228
D.3.4	Pharmaceutical form	Capsule
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	N/A
D.3.9.1	CAS number	2086178-00-7
D.3.9.2	Current sponsor code	ALXN2050
D.3.9.3	Other descriptive name	ACH-0145228
D.3.9.4	EV Substance Code	SUB204167
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	40
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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ALXN2050
D.3.2	Product code	ACH-0145228
D.3.4	Pharmaceutical form	Capsule
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	N/A
D.3.9.1	CAS number	2086178-00-7
D.3.9.2	Current sponsor code	ALXN2050
D.3.9.3	Other descriptive name	ACH-0145228
D.3.9.4	EV Substance Code	SUB204167
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	60
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

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)

Emoglobinuria Parossistica Notturna (EPN)

E.1.1.1

Medical condition in easily understood language

Paroxysmal Nocturnal Hemoglobinuria (PNH)

Emoglobinuria Parossistica Notturna (EPN)

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

To evaluate the efficacy of ACH-0145228 based on improvement hemoglobin (Hgb) relative to baseline at Week 12 of treatment

Valutare l’efficacia di ACH-0145228 sulla base del miglioramento dei livelli di emoglobina (Hb) rispetto al basale alla Settimana 12 del trattamento

E.2.2

Secondary objectives of the trial

• To evaluate the efficacy of ACH-0145228 based on reduction in transfusion requirements
• To evaluate the efficacy of ACH-0145228 on lactate dehydrogenase (LDH) relative to baseline at Week 12 of treatment
• To assess laboratory markers of hemolysis and other markers relevant in patients with paroxysmal nocturnal hemoglobinuria (PNH)
• To evaluate the safety and tolerability of 12 weeks of treatment with ACH-0145228 with or without the use of background therapy with an approved C5 inhibitor, based on treatment-emergent adverse events, (TEAEs), serious adverse events (SAEs), and events leading to discontinuation of study medication

•Valutare l’efficacia di ACH-0145228 sulla base della riduzione del fabbisogno trasfusionale
• Valutare l’efficacia di ACH-0145228 sulla base della lattato deidrogenasi (LDH) rispetto al basale alla Settimana 12 del trattamento
• Valutare i marcatori di laboratorio dell’emolisi e altri marcatori pertinenti nei pazienti affetti da emoglobinuria parossistica notturna (EPN)
•Valutare la sicurezza e la tollerabilità di 12 settimane di trattamento con ACH-0145228 con o senza l’uso di terapia di base con un inibitore di C5 approvato, sulla base di eventi avversi emergenti dal trattamento (TEAE), eventi avversi seri (SAE) ed eventi che portano all’interruzione del farmaco dello studio

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Male or female greater than or equal to 18 years of age, female subjects of child-bearing potential

For newly identified PNH patients must meet one of the following conditions:
1. PNH patients not currently receiving an approved C5 inhibitor must have:
- PNH Type III erythrocyte and/or granulocyte clone size ≥10% with adequate reticulocytosis (absolute reticulocyte count ≥100×10⁹/L).
- Anemia (Hgb <10.5 g/dL).
- LDH ≥1.5× upper limit of normal (ULN).
- Platelet count ≥30,000/µL without the need for platelet transfusions.
- Absolute neutrophil count (ANC) ≥750/ µL.

2. PNH patients with a sub-optimal response to background therapy with an approved C5 inhibitor must have:
- Stable background regimen of an approved C5 inhibitor (at least 24 weeks for eculizumab, or at least 2 doses for ravulizumab), without change in dose or interval for at least the past 8 weeks.
- Anemia (Hgb <10 g/dL).
- Adequate reticulocytosis (absolute reticulocyte count ≥100×109/L).
Platelet count ≥30,000/µL without the need for platelet transfusions.
- Absolute neutrophil count (ANC) ≥750/ µL.

Maschio o femmina di età pari o superiore a 18 anni, soggetti di sesso femminile in etá fertile.

I pazienti con EPN recentemente identificati devono soddisfare una delle seguenti condizioni:
1. I pazienti con EPN che attualmente non assumono un inibitore di C5 approvato devono avere:
- Dimensione del clone EPN di eritrociti e/o granulociti di tipo III ≥10% con adeguata reticolocitosi (conta assoluta dei reticolociti ≥ 100×109/l)
- Anemia (Hb < 10,5 g/dl)
- LDH ≥ 1,5 volte il limite superiore alla norma (ULN)
- Conta piastrinica ≥ 30.000/μl senza necessità di trasfusioni di piastrine
- Conta assoluta dei neutrofili (ANC) ≥ 750/ μl

2. I pazienti con EPN che ricevono la terapia di base devono avere:
- Regime di base stabile (almeno 24 settimane per eculizumab o almeno 2 dosi per ravulizumab), senza variazioni di dose o intervallo almeno per le 8 settimane precedenti
- Anemia (Hb < 10 g/dl)
- Reticolocitosi adeguata (conta assoluta dei reticolociti ≥ 100×109/l)
- Conta piastrinica ≥ 30.000/μl senza necessità di trasfusioni di piastrine
- Conta assoluta dei neutrofili (ANC) ≥ 750/ μl

E.4

Principal exclusion criteria

- Estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2 and/or are on dialysis.
- History of a major organ transplant (e.g., heart, lung, kidney, liver) or hematopoietic stem cell/marrow transplant ([HSCT] unless HSCT engraftment has failed).
- History of dosing with an investigational agent other than danicopan within 30 days or 5 half-lives of the investigational agent prior to ACH 0145228 administration, whichever is greater.
- New patients in the monotherapy group with a history of dosing with eculizumab at any dose or interval within the past 75 days before study medication administration or 300 days for ravulizumab.
- Known or suspected complement deficiency.
- Contraindication to one or more of the required vaccinations that may be used in the study.
- History of seizure disorder unless seizure free without the use of antiepileptic medications for the past 5 years prior to screening.

- Velocità di filtrazione glomerulare stimata (eGFR) < 30 ml/min/1,73 m2 e/o sono in dialisi.
- Anamnesi di trapianto di organo maggiore (ad es. cuore, polmone, rene, fegato) o trapianto di cellule staminali emopoietiche/midollo osseo (HSCT) (a meno che l’innesto di HSCT non sia andato a buon fine).
- Anamnesi di somministrazione di un agente sperimentale diverso da danicopan entro 30 giorni o 5 emivite dell’agente sperimentale prima della somministrazione di ACH-0145228, a seconda di quale dei due periodi abbia durata maggiore
- Nuovi pazienti nel gruppo trattato in monoterapia con un’anamnesi di somministrazione di eculizumab a qualsiasi dose o intervallo negli ultimi 75 giorni prima della somministrazione del farmaco dello studio o 300 giorni per ravulizumab.
- Deficit di complemento, noto o sospetto.
- Controindicazioni a una o più delle vaccinazioni che possono essere utilizzate nello studio.
- Anamnesi di disturbo convulsivo, a meno che non sia libero da crisi convulsive senza l’uso di farmaci antiepilettici negli ultimi 5 anni prima dello screening.

E.5 End points

E.5.1

Primary end point(s)

Change in Hgb relative to baseline at Week 12

Variazione del livello di Hb rispetto al basale alla Settimana 12

E.5.1.1

Timepoint(s) of evaluation of this end point

at Week 12

Settimana 12

E.5.2

Secondary end point(s)

1.Transfusion requirements: Change in transfusion requirements during the treatment compared to 12 weeks of historical transfusion requirements
2. Lactate dehydrogenase (LDH): Change in LDH relative to baseline at Week 12
3. Reticulocyte count: Change from baseline in absolute reticulocyte count
4. Direct Bilirubin: Change from baseline in direct bilirubin
5. Total Bilirubin: Change from baseline total bilirubin
6. PNH red blood cell (RBC) clone size: Change from baseline in PNH red blood cell (RBC) clone size
7. C3 complement protein (C3) fragment deposition on PNH RBCs: Change from baseline in C3 complement protein (C3) fragment deposition on PNH RBCs at week 12
8. Incidence of Treatment-Emergent Adverse Events [Safety and Tolerability]: Number of TEAEs recorded
9. Incidence of Serious Adverse events [Safety and Tolerability]: Number of SAEs recorded
10. Incidence of adverse events leading to discontinuation [Safety and Tolerability]: Number of events leading to discontinuation of study medication recorded

1. Requisiti trasfusionali: variazione del fabbisogno trasfusionale durante il trattamento rispetto a 12 settimane di dati storici del fabbisogno trasfusionale
2. Lattato Deidrogenasi (LDH): Variazione del livello di LDH rispetto al basale alla Settimana 12
3. Conta reticolocitaria: variazione rispetto al basale della conta assoluta dei reticolociti
4. Bilirubina diretta: variazione rispetto al basale della bilirubina diretta
5. Bilirubina totale: variazione rispetto al basale della bilirubina totale
6. Dimensione del clone EPN dei globuli rossi (RBC): variazione rispetto al basale della dimensione del clone EPN dei globuli rossi (RBC)
7. Deposizione di frammenti C3 della proteina del complemento (C3) sui globuli rossi EPN: variazione rispetto al basale della deposizione di frammenti C3 della proteina del complemento (C3) sui globuli rossi EPN alla settimana 12
8. Incidenza di Eventi Avversi Emergenti dal Trattamento [Sicurezza e Tollerabilitá]: numero di TEAEs registrati
9. Incidenza di Eventi Avversi Seri [Sicurezza e Tollerabilitá]: numero di SAE registrati
10. Incidenza di Eventi Avversi che portano all’interruzione del farmaco dello studio [Sicurezza e Tollerabilitá]: numero di Eventi Avversi che portano all’interruzione del farmaco dello studio regstrati

E.5.2.1

Timepoint(s) of evaluation of this end point

at Week 12

Settimana 12

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

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

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Effect on biomarkers

Effetto sui biomarcatori

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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

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

Italy

Korea, Republic of

New Zealand

United Kingdom

United States

E.8.7

Trial has a data monitoring committee

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

The end of the study is defined as the date of the last visit of the last patient remaining in the study.

La data di conclusione della sperimentazione é definita come l'ultima visita dell'ultimo paziente rimasto in studio

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)

The Sponsor currently does not intend to provide any treatment or care after the subjects have ended the participation in the trial. However the Sponsor considers to review of the decision before the global end of the trial.

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

2021-10-01

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-10-13

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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IMP with orphan designation in the indication
Orphan Designation Number:
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