Clinical Trials Register

Summary
EudraCT Number:	2018-000137-13
Sponsor's Protocol Code Number:	ORARIALS-01
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2018-10-09
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

Spain - AEMPS

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

Ensayo en fase III aleatorizado y controlado con placebo de arimoclomol en esclerosis lateral amiotrófica

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

Ensayo controlado con placebo de arimoclomol en esclerosis lateral amiotrófica

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 A/S
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 Project 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	004553706909
B.5.6	E-mail	rbe@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	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

Amyotrophic Lateral Sclerosis

Esclerosis lateral amiotrófica

E.1.1.1

Medical condition in easily understood language

Amyotrophic Lateral Sclerosis

Esclerosis lateral amiotrófica

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	20.0
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)

Determinar la eficacia del tratamiento crónico con 1200 mg/día (400 mg TID) de arimoclomol en comparación con placebo durante 76 semanas en sujetos con ELA según la evaluación mediante CAFS (Evaluación combinada de función y supervivencia, Combined Assessment of Function and Survival)

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)

Evaluar el impacto del tratamiento con 1200 mg/día (400 mg TID) de arimoclomol en comparación con placebo respecto a lo siguiente:
•Tiempo transcurrido hasta necesitar ventilación mecánica permanente (VMP)/supervivencia sin traqueotomía
•Progresión de la enfermedad medida mediante el cambio en la ALSFRS-R respecto a la visita basal
•Progresión de la alteración de la función respiratoria medida según el cambio respecto a la visita basal en la capacidad vital lenta (CVL)

E.2.3

Trial contains a sub-study

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. Capaz y dispuesto a dar su consentimiento informado por escrito y cumplir los procedimientos del ensayo.
2. Los sujetos serán hombres o mujeres de al menos 18 años de edad.
3. Los sujetos deben cumplir los criterios revisados de El Escorial de ELA clínicamente posible, ELA clínicamente probable/clínicamente probable respaldada por los valores analíticos, ELA clínicamente definida o ELA familiar.
4. 18 meses o menos desde la primera aparición de debilidad (por ejemplo, debilidad en las extremidades, disartria, disfagia, dificultades respiratorias).
5. ALSFRS-R ≥ 35 y pronóstico de % de VCL de pie ≥ 70 % en la selección.
6. Capaz y dispuesto a desplazarse hasta el centro y, en opinión del investigador, es probable que acuda a las visitas durante al menos 24 semanas.
7. Todas las mujeres sexualmente activas potencialmente fértiles (posmenarquia*) deben aceptar no intentar quedarse embarazadas y usar un método anticonceptivo de gran eficacia** durante el ensayo hasta 1 mes después de la administración de la última dosis de la medicación del ensayo. Si un sujeto es un varón sexualmente activo con parejas femeninas potencialmente fértiles (posmenarquia), debe usar preservativo con o sin espermicida además del método anticonceptivo que usen sus parejas durante el ensayo hasta 3 meses después de la administración de la última dosis del fármaco del ensayo.
8. Dosis estable de riluzol (50 mg dos veces al día) durante al menos los 14 días anteriores al día 1 (visita basal) o no haberlo tomado durante los 14 días anteriores al día 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 half-lives of the Screening visit, whichever is longest and/or participated in any prior ALS clinical trial receiving active drug treatment (with the exception described in exclusion criterion 5).
5. Previously or currently treated with edaravone. 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 edaravone 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, alanine aminotransferase, and 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.

* Non child-bearing potential is defined as post-menopausal (minimum of 12 months with no menses and follicle-stimulating hormone in the post-menopausal range) or sterilisation (hysterectomy, oophorectomy, or bilateral tubal ligation).

** Highly effective methods of contraception include combined (oestrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation (oral, intravaginal, or transdermal); progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, or implantable); intrauterine device; intrauterine hormone-releasing system; bilateral tubal occlusion; and vasectomised partner.

According to the recommendations from the Clinical Trial Facilitation Group (CTFG, 2014), sexual abstinence is considered a highly effective birth control method only if it is defined as refraining from heterosexual intercourse during the trial until 1 week after the last dose of trial medication (for female subjects of child-bearing potential) and for 3 months after the last dose of trial medication (for male subjects with female partners of child-bearing potential). The reliability of sexual abstinence needs to be evaluated by the investigator in relation to the duration of the clinical trial and the preferred and usual lifestyle of the subject.

1. Traqueotomía o uso de ventilación no invasiva durante más de 2 horas durante las horas de vigilia en el momento de las visitas de selección y basal.
2. Embaraza o en período de lactancia.
3. Usando en la actualidad, o previsión de que vaya a usar un marcapasos diafragmático durante el ensayo.
4. Exposición a algún tratamiento en fase de investigación en las 4 semanas o < 5 semividas anteriores a la visita de selección, lo que sea más largo, y/o ha participado en algún ensayo clínico previo de ELA recibiendo tratamiento farmacológico activo (con la excepción descrita en el criterio de exclusión 5 .).
5. Previamente o actualmente tratado con edaravona. Sin embargo, se prevé la inclusión en el ensayo de hasta 18 sujetos con tratamiento estable (es decir, durante al menos 6 meses) con edaravona y que cumplan todos los demás criterios de idoneidad (limitados a los países en los que la edaravona cuente con autorización de comercialización como tratamiento para la ELA).
6. Alguno de las condiciones médicamente significativos que se indican a continuación:
a)Deterioro/disfunción neurológica o enfermedad psiquiátrica inestable que, en opinión del investigador, probablemente interfiera en la valoración de la progresión de la ELA
b)Enfermedad inestable clínicamente significativa que no sea ELA que supondría un riesgo en caso de que el sujeto participara en el ensayo
c)Presencia de demencia que afecte a la capacidad del sujeto para dar su consentimiento informado, de acuerdo con la decisión del IP
d)Alergia o intolerancia conocida o sospechada al PEI (arimoclomol o sus componentes)
e)Infección crónica, especialmente por el VIH o por el virus de la hepatitis B o C.
f)Nefropatía o hepatopatía clínicamente significativa
g)Valores de aspartato aminotransferasa, alanina aminotransferasa y lactato deshidrogenasa ≥ 3 veces el límite superior de la normalidad (LSN), bilirrubina ≥ 2 veces el LSN o creatinina ≥ 1,5 veces el LSN. Las pruebas analíticas podrán repetirse una vez en durante la selección. Los motivos para repetir las pruebas analíticas pueden incluir el hecho de que se haya suspendido el medicamento que provocaba la alteración analítica, que ya no exista ninguna otra causa de la que se sospechaba o para descartar un error de laboratorio.
h)Cáncer que se encuentre en ese momento en tratamiento activo o que es probable que necesite tratamiento durante el ensayo que pueda alterar la función del sujeto y, por consiguiente, interferir en la evaluación de la progresión de la ELA.
i)Cualquier otro trastorno que, en opinión del investigador, supondría un riesgo para el sujeto en caso de que participara en el ensayo, interferiría en la evaluación de la seguridad o tendría un mayor riesgo de provocar la muerte durante el ensayo.

* Se define «no fértiles» como el estado posmenopáusico (al menos 12 meses sin menstruación y hormona foliculoestimulante en el intervalo posmenopáusico) o la esterilización (histerectomía, ovariectomía o ligadura bilateral de trompas).

** Los métodos anticonceptivos de gran eficacia incluyen la anticoncepción hormonal combinada (que contiene estrógenos y progestágenos) asociada con la inhibición de la ovulación (por vía oral, intravaginal o transdérmica), los anticonceptivos hormonales solo con progestágeno asociados con la inhibición de la ovulación (por vía oral, inyectable o implantable), el dispositivo intrauterino, el sistema de liberación hormonal intrauterino, la oclusión bilateral de las trompas y la vasectomía de la pareja.

Conforme a las recomendaciones del Grupo de Facilitación de Ensayos Clínicos (CTFG, 2014), la abstinencia sexual se considera un método anticonceptivo de gran eficacia únicamente si se define como abstinencia de relaciones sexuales heterosexuales durante el ensayo hasta 1 semana después de la administración de la última dosis de la medicación del ensayo (para mujeres potencialmente fértiles) y durante los 3 meses siguientes a la administración de la última dosis de la medicación del ensayo (para varones con parejas potencialmente fértiles). El investigador debe evaluar la fiabilidad de la abstinencia sexual en relación con la duración del ensayo clínico y el estilo de vida preferido y habitual del sujeto.

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)

Evaluación combinada de función y supervivencia (CAFS) durante un período de tratamiento de 76 semanas (o fin del ensayo)

E.5.1.1

Timepoint(s) of evaluation of this end point

76 weeks (or end-of-trial)

76 semanas (o fin del ensayo)

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

•Tiempo transcurrido hasta la VMP/traqueotomía/muerte
•Cambio en la ALSFRS-R desde la visita basal hasta la semana 76 (o fin del ensayo)
•Cambio en la CVL desde la visita basal hasta la semana 76 (o fin del ensayo)

E.5.2.1

Timepoint(s) of evaluation of this end point

76 weeks (or end-of-trial)

76 semanas (o fin del ensayo)

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

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

Belgium

Canada

France

Germany

Italy

Netherlands

Poland

Spain

Sweden

Switzerland

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

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.

A los sujetos que completen 76 semanas de tratamiento aleatorizado se les ofrecerá la participación en un ensayo de extensión de etiqueta abierta a través de un protocolo de ensayo clínico por separado

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

2018-10-19

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	Ongoing

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