Clinical Trials Register

Summary
EudraCT Number:	2018-000137-13
Sponsor's Protocol Code Number:	ORARIALS-01
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-01-22
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

Expand All Collapse All

A. Protocol Information

A.1

Member State Concerned

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-000137-13

A.3

Full title of the trial

A Phase 3, Randomised, Placebo-Controlled Trial of Arimoclomol in Amyotrophic Lateral Sclerosis

Studio di fase 3, randomizzato, controllato con placebo, su Arimoclomol per il trattamento della sclerosi laterale amiotrofica

A.3.1

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

A study to compare the use of Arimoclomol with placebo in patients with
Amyotrophic Lateral Sclerosis

Uno studio per comparare l'uso di Arimoclomol con placebo in pazienti affetti da sclerosi laterale amiotrofica

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

ORARIALS-01

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT03491462

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	ORPHAZYME APS
B.1.3.4	Country	Denmark
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	Orphazyme A/S
B.4.2	Country	Denmark
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Orphazyme A/S
B.5.2	Functional name of contact point	Senior Clinical Trial Manager
B.5.3	Address:
B.5.3.1	Street Address	Ole Maaløes Vej 3
B.5.3.2	Town/ city	Copenhagen N
B.5.3.3	Post code	DK-2200
B.5.3.4	Country	Denmark
B.5.4	Telephone number	004531391062
B.5.6	E-mail	hda@orphazyme.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/3/06/406
D.3 Description of the IMP
D.3.1	Product name	Arimoclomol
D.3.2	Product code	[BRX-345]
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	ARIMOCLOMOL
D.3.9.1	CAS number	368860-21-3
D.3.9.2	Current sponsor code	BRX-345
D.3.9.4	EV Substance Code	SUB187159
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Amyotrophic Lateral Sclerosis

Sclerosi laterale amiotrofica

E.1.1.1

Medical condition in easily understood language

Amyotrophic Lateral Sclerosis

Sclerosi laterale amiotrofica

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

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	10002026
E.1.2	Term	Amyotrophic lateral sclerosis
E.1.2	System Organ Class	10029205 - Nervous system 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 determine the efficacy of chronic treatment with arimoclomol 1200 mg/day (400 mg TID) compared to placebo over 76 weeks in subjects with ALS as assessed with Combined Assessment of Function and Survival (CAFS)

Determinazione dell’efficacia del trattamento cronico a base di arimoclomol a una dose di 1200 mg/giorno (400 mg TID) rispetto al placebo in un periodo di 76 settimane in soggetti affetti da SLA, valutata utilizzando il punteggio CAFS (Combined Assessment of Function and Survival, valutazione combinata di funzione e sopravvivenza)

E.2.2

Secondary objectives of the trial

To evaluate the impact of arimoclomol 1200 mg/day (400 mg TID) compared to placebo on:
• Time to permanent assisted ventilation (PAV)/tracheostomy free survival
• Disease progression as measured by change from Baseline of the ALSFRS-R
• Progression of respiratory dysfunction as measured by change from Baseline of the slow vital capacity (SVC)

Valutazione dell’impatto di una dose di arimoclomol da 1200 mg/giorno (400 mg TID) rispetto al placebo su:
• Tempo necessario per raggiungere l’obiettivo della sopravvivenza senza ventilazione assistita permanente (PAV)/tracheotomia
• Progressione della malattia misurata valutando la variazione del punteggio ALSFRS-R dal baseline
• Progressione della disfunzione respiratoria misurata valutando la variazione della capacità vitale lenta (SVC) dal baseline

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

Other types of substudies
Specify title, date and version of each substudy with relative objectives: Optional Muscle-strength and Electromyography testing.
Muscle-strength and Electromyography will be measured in a sub-study conducted in approximately 40 subjects at selected trial sites.
Electrophysiology and muscle-strength testing will be performed in the same subset of subjects at the following in-person visits; Baseline, Week 20, Week 52 and Week 76 (or end of trial).
The assessments will only be performed if appropriate in the opinion of the investigator. Subjects will signed a separate consent form indicating their willingness to have this testing.

Altre tipologie di sottostudi
specificare il titolo, la data e la versione di ogni sottostudio con i relativi obiettivi: Test facoltativi di forza muscolare ed elettromiografia.
La forza muscolare e l'elettromiografia saranno misurate in un sotto-studio condotto in circa 40 soggetti in centri selezionati.
Le prove di elettrofisiologia e di forza muscolare saranno eseguite nello stesso sottogruppo di soggetti alle seguenti visite di persona; Basale, Settimana 20, Settimana 52 e Settimana 76 (o fine della sperimentazione).
Le valutazioni verranno eseguite solo se appropriato, secondo il parere dello sperimentatore. I soggetti firmeranno un modulo di consenso separato che indica la loro volontà di sottoporsi a questo test.

E.3

Principal inclusion criteria

1. Capable of- and willing to- provide written informed consent and comply with trial procedures.
2. Subject is male or female =18 years of age.
3. Subject meets revised El Escorial criteria for clinically possible, clinically probable / clinically probable ALS laboratory-supported or clinically definite ALS, or familial ALS.
4. 18 months or less since first appearance of weakness (e.g. limb weakness, dysarthria, dysphagia, shortness of breath).
5. ALSFRS-R =35 and erect SVC % predicted = 70% at Screening.
6. Able and willing to travel to the site, and in the investigator's opinion is likely to attend visits for at least 24 weeks.
7. All sexually active female subjects of child-bearing potential (postmenarchal)* must agree not to intend to become pregnant and use a highly effective method of contraception** during the trial through 1 month after the last dose of trial medication. If the subject is a sexually active male with female partners of child-bearing potential (postmenarchal) he must use a condom with or without spermicide in addition to the birth control used by their partners during the trial until 3 months after the last dose of trial medication.
8. Stable dose of riluzole (50 mg twice daily) for a minimum of 14 days prior to Day 1 (Baseline), or has not taken it for 14 days prior to Day 1.

1. Il soggetto è in grado di e disponibile a fornire il proprio consenso informato scritto e attenersi alle procedure previste dalla sperimentazione.
2. Il soggetto è di sesso maschile o femminile e di età =18 anni.
3. Il soggetto soddisfa i criteri di El Escorial per SLA clinicamente possibile, SLA clinicamente probabile, SLA clinicamente probabile con supporto di laboratorio, SLA clinicamente definita o SLA familiare clinicamente definita con supporto di laboratorio.
4. Sono trascorsi meno di 18 mesi dalla prima comparsa di segni di debolezza (es. debolezza degli arti, disartria, disfagia, respiro corto).
5. Il soggetto presenta punteggio ALSFRS-R =35 e SVC prevista in posizione eretta (seduto) = 70% al momento dello screening.
6. Il soggetto è in grado di e disponibile a viaggiare per raggiungere il centro e, secondo il parere dello sperimentatore, e` probabile che si presenti alle visite per almeno 24 settimane.
7. Tutte le donne sessualmente attive e in età fertile (fase post-menarcale)* devono acconsentire a non volere rimanere incinte e ad usare un metodocontraccettivo altamente efficace** durante la sperimentazione e fino a 1 mese dopo l’assunzione dell’ultima dose del farmaco sperimentale. Gli uomini sessualmente attivi con partner di sesso femminile in età fertile (fase post-menarcale) devono utilizzare un preservativo con o senza spermicida in aggiunta al metodo contraccettivo utilizzato dalla partner durante la sperimentazione e fino a 3 mesi dopo l’assunzione dell’ultima dose del farmaco sperimentale.
8. Il soggetto ha ricevuto una dose stabile di riluzolo (50 mg due volte al giorno) per un minimo di 14 giorni prima del giorno 1 (baseline) oppure non ha assunto la dose nei 14 giorni antecedenti al giorno 1.

E.4

Principal exclusion criteria

1. Tracheostomy or use of non-invasive ventilation for more than 2 hours during waking hours at the time of Screening and Baseline visits.
2. Pregnant or breast-feeding.
3. Current or anticipated use of diaphragmatic pacing during the trial.
4. Exposure to any investigational treatment within 4 weeks or <5 halflives of the Screening visit, whichever is longest and/or advanced therapy medicinal product (ATMP), i.e. treatments based on genes, cells or tissues and/or participated in any prior ALS clinical trial receiving active drug treatment (with the exception described in exclusion criterion 5).
5. Treatment with edaravone within 4 weeks of the Baseline visit. However, up to 18 subjects on stable (i.e. minimum 6 months') treatment with edaravone and who otherwise fulfil the eligibility criteria
are planned for enrolment (limited to countries where edavarone has a marketing authorisation for treatment of ALS).
6. Any of the following medically significant conditions:
a) Neurological impairment/dysfunction or unstable psychiatric illness that in the investigator's opinion is likely to interfere with assessment of ALS disease progression.
b) Clinically significant unstable medical condition other than ALS, which would present a risk to a subject to participate in the trial
c) Presence of dementia that impairs the ability of the subject to provide informed consent according to the PI decision.
d) Known or suspected allergy or intolerance to the IMP (arimoclomol or constituents);
e) Chronic infection particularly HIV or Hepatitis B or C.
f) Clinically significant renal or hepatic disease
g) Aspartate aminotransferase and/or alanine aminotransferase, and/or lactate dehydrogenase =3 times the upper limit of normal [ULN], bilirubin=2 times the ULN, or creatinine =1.5 times the ULN). Laboratory tests may be repeated once at Screening. Reasons to repeat laboratory tests may include that the medication causing laboratory abnormality was suspended, any other suspected cause may no longer exist, or to rule out laboratory error.
h) Cancer that is currently under active treatment or is likely to require treatment during the trial that may alter the subject´s function and thereby interfere with assessment of ALS disease progression.
i) Any other condition that in the investigator's opinion would present a risk to a subject to participate in the trial, interfere with the assessment of safety or has an increased risk of causing death during the trial.

1. Tracheotomia o ventilazione non invasiva per più di 2 ore durante le ore di veglia al momento delle visite di screening e baseline.
2. Gravidanza o allattamento.
3. Uso corrente o previsto di pacing diaframmatico durante la sperimentazione.
4. Esposizione a qualsiasi trattamento sperimentale nelle 4 settimane o <5 emivite, a seconda di qual è il periodo più lungo, antecedenti la visita di screening e/o medicinali per terapie avanzate (ATMP), cioè trattamenti basati su geni, cellule o tessuti e/o partecipazione a qualsiasi sperimentazione precedente sulla SLA che prevedeva l’assunzione di un trattamento farmacologico attivo (l’unica eccezione è descritta nel criterio d'esclusione 5.
5. Trattamento a base di edaravone entro le precedenti 4 settimane dalla visita basale. Tuttavia, è previsto l’arruolamento di un massimo di 18 soggetti riceventi un trattamento stabile (almeno 6 mesi) a base di edaravone e che soddisfano gli altri criteri di eleggibilità (questa possibilità vale solo per i paesi in cui edaravone dispone dell’autorizzazione all’immissione in commercio per il trattamento della SLA).
6. Una qualsiasi delle seguenti condizioni clinicamente significative:
a) Compromissione neurologica/disfunzione o patologia psichiatrica instabile che, secondo il parere dello sperimentatore, potrebbe interferire con la valutazione della progressione della SLA.
b) Patologia instabile clinicamente significativa diversa dalla SLA, che potrebbe costituire un rischio per il soggetto che partecipa alla sperimentazione.
c) Presenza di demenza che comprometta la capacità del soggetto di fornire il proprio consenso informato, secondo quanto deciso dallo sperimentatore principale.
d) Allergia o intolleranza nota o sospetta all’IMP (ad arimoclomol o ai suoi componenti).
e) Infezione cronica, specialmente da HIV oppure epatite B o C.
f) Patologia epatica o renale clinicamente significativa.
g) Aspartato aminotransferasi e/o alanina aminotransferasi e/o L-lattato deidrogenasi =3 volte il limite superiore del normale (ULN), bilirubina =2 volte l’ULN o creatinina =1,5 volte l’ULN. I test di laboratorio possono essere ripetuti una volta in occasione dello screening. È possibile ripetere i test di laboratorio se l’assunzione del farmaco che causava anomalie nei test è stata sospesa, se eventuali altre cause potrebbero non essere più rilevanti, oppure per escludere errori di laboratorio.
h) Tumore attualmente trattato o che potrebbe richiedere un trattamento durante la sperimentazione, in grado di alterare le funzionalità del soggetto e quindi interferire con la valutazione della progressione della SLA.
i) Qualsiasi altra condizione che, secondo il parere dello sperimentatore, potrebbe costituire un rischio per il soggetto che partecipa alla sperimentazione, interferire con la valutazione della sicurezza oppure aumentare il rischio di morte durante la sperimentazione.

E.5 End points

E.5.1

Primary end point(s)

Combined assessment of function and survival (CAFS) over a treatment period of 76 weeks (or end-of-trial)

Valutazione combinata di funzione e sopravvivenza (CAFS) in un periodo di trattamento di 76 settimane (o al termine della sperimentazione)

E.5.1.1

Timepoint(s) of evaluation of this end point

76 weeks (or end-of-trial)

76 settimane (o al termine della sperimentazione)

E.5.2

Secondary end point(s)

• Time to PAV/tracheostomy/death
• Change from Baseline to Week 76 (or end-of-trial) in ALSFRS-R
• Change from Baseline to Week 76 (or end-of-trial) in SVC

• Tempo trascorso prima di PAV/tracheotomia/morte
• Variazione del punteggio ALSFRS-R dal baseline alla settimana 76 (o al termine della sperimentazione)
• Variazione della SVC dal baseline alla settimana 76 (o al termine della sperimentazione)

E.5.2.1

Timepoint(s) of evaluation of this end point

76 weeks (or end-of-trial)

76 settimane (o al termine della sperimentazione)

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

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

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

Information not present in EudraCT

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

Canada

United States

Belgium

France

Germany

Italy

Netherlands

Poland

Spain

Sweden

Switzerland

United Kingdom

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:

160

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

132

F.4.2.2

In the whole clinical trial

231

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)

Subjects who complete 76 weeks of randomised treatment will be offered participation in a separate open-label extension trial through means of a separate clinical trial protocol.

Ai soggetti che completano le 76 settimane di trattamento randomizzato sarà proposto di partecipare a un altro studio di estensione in aperto con un protocollo a sé.

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

2018-09-19

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-10-08

P. End of Trial
P.	End of Trial Status	Completed

Select Country:	Select Age Range:
Select Trial Status:	Select Trial Phase:
Select Gender:
Select Date Range: to
Select Rare Disease:
IMP with orphan designation in the indication
Orphan Designation Number:
Results Status:
Clear advanced search filters

Austria
Belgium
Bulgaria
Croatia
Cyprus
Czechia
Denmark
Estonia
Finland
France
Germany
Greece
Hungary
Iceland
Ireland
Italy
Latvia
Liechtenstein
Lithuania
Luxembourg
Malta
Netherlands
Norway
Poland
Portugal
Romania
Slovakia
Slovenia
Spain
Sweden
United Kingdom
Outside EU/EEA

Clinical trials