Clinical Trials Register

Summary
EudraCT Number:	2014-005367-32
Sponsor's Protocol Code Number:	PROMISE
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-03-17
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

2014-005367-32

A.3

Full title of the trial

PROTEIN MISFOLDING, AMYOTROPHIC LATERAL SCLEROSIS AND GUANABENZ: A PHASE II RCT WITH FUTILITY DESIGN

MISFOLDING PROTEICO, SCLEROSI LATERALE AMIOTROFICA E GUANABENZ: STUDIO CLINICO RANDOMIZZATO DI FASE II CON DISEGNO DI FUTILITA'

A.3.1

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

Clinical study on the efficacy and tolerabilty of Guabenz in Amiotropic Lateral Sclerosis

STUDIO CLINICO SULL'EFFICACIA E TOLLERABILITA' DEL GUANABENZ COME TRATTAMENTO DELLA SCLEROSI LATERALE AMIOTROFICA

A.3.2

Name or abbreviated title of the trial where available

PROMISE

A.4.1

Sponsor's protocol code number

PROMISE

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	FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA
B.1.3.4	Country	Italy
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	ARISLA
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA
B.5.2	Functional name of contact point	SERVIZIO RICERCA E SVILUPPO CLINICO
B.5.3	Address:
B.5.3.1	Street Address	VIA CELORIA 11
B.5.3.2	Town/ city	MILANO
B.5.3.3	Post code	20133
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390223942321
B.5.5	Fax number	+390223943569
B.5.6	E-mail	crc@istituto-besta.it

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	GUANABENZ ACETATO
D.3.2	Product code	GUANA2015
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	GUANABENZ
D.3.9.1	CAS number	23256-50-0
D.3.9.2	Current sponsor code	GUANA2015
D.3.9.3	Other descriptive name	GUANABENZ
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	8
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.IMP: 2
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
D.2.1.1.2	Name of the Marketing Authorisation holder
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	RILUZOLO
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	RILUZOLO
D.3.9.1	CAS number	1744-22-5
D.3.9.2	Current sponsor code	RILU2015
D.3.9.3	Other descriptive name	RILUZOLO
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	50
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Amiotrophic Lateral Sclerosis

Sclerosi Laterale Amiotrofica

E.1.1.1

Medical condition in easily understood language

Amiotrophic 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	19.1
E.1.2	Level	PT
E.1.2	Classification code	10028003
E.1.2	Term	Motor neurone disease
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 investigate the effect of guanabenz as add-on treatment compared to riluzole alone in reducing the proportion of patients progressed to higher stages of disease over 6 months in sporadic (SALS) or familial ALS (FALS) patients.

Investigare l'effetto di guanabenz come terapia aggiuntiva al riluzolo verso placebo, per 6 mesi di trattamento, nella riduzione della proporzione di pazienti progrediti a uno stadio più grave di patologia, sia per pazienti SLA sporadici che familiari.

E.2.2

Secondary objectives of the trial

To assess safety and tolerability related to alpha2agonist activity of guanabenz. To explore serum biomarkers of ALS progression (creatinine, albumin tau, pNfH, TDP43, cystatin C, fetuin A, transthyretin, and CD14/S100ß and pNfH/C3) in guanabenz and riluzole alone arms at baseline and study end. In patients giving consent the biomarkers will be explored also in the cerebrospinal fluid.

Dimostrare la sicurezza e la tollerabilità dell'attività alpha2agonista di guanabenz.
Studiare i biomarkes sierici di progressione(creatinina, albumina, tau, pNfH, TDP43, cistatina C, fetuina A, transtiretina, e CD14/S100ß e pNfH/C3) nei bracci dello studio al basale e alla fine dello studio. Nei pazienti che forniranno il consenso i biomarkers saranno esplorati anche nel liquor.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Diagnosis of, probable, probable laboratory supported or definite sporadic (SALS) or familiar (FALS) ALS according to the revised El Escorial criteria; 2) age >18 yrs; 3) onset ≤18 months before randomization; 4) sVC ≥70% in spinal onset; 5) riluzole 100 mg/day or no riluzole; 6) written informed consent

1) diagnosi probabile, probabile con supporto di laboratorio o definita di SLA sporadica o familiare in accordo ai criteri di El Escorial rivisti;
2) età >18 anni;
3) esordio di malattia ≤18 mesi prima della randomizzazione;
4) capacità vitale lenta ≥70% nelle forme spinali;
5) trattamento con riluzolo alla dose di 100mg/giorno oppure non assunzione riluzolo;
6) cpnsenso informato scritto.

E.4

Principal exclusion criteria

1) PEG, NIV or tracheotomy; 3) known heart, renal or liver failure; 3) known intolerance to alfa2agonists; 4) known conditions at risk for cardiovascular disorders or symptomatic hypotension; 5) participation in a clinical trial within 3 months prior to the screening; 6) cognitive impairment defined by the Edinburg Cognitive and Behavior ALS Screen (ECAS) scale

1) PEG, Ventilazione non invasiva, tracheostomia;
2) nota insufficienza cardiaca, renale ed epatica;
3) nota intolleranza agli alpha2agonisti;
4) nota condizione di rischio cardiovascolare o ipotensione sintomatica;
5) partecipazione ad altri studi clinci nei 3 mesi precedenti lo screening;
6) deficit cognitivo definto attraverso la scala ECAS ( Edinburg Cognitive and Behavior ALS Screen);

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients progressed to higher stages of disease at 6 months (measured by the ALS-MITOS system) by at least 35% in the guanabenz arm compared to their baseline stage and to the placebo arm (null hypothesis in the futility design).

Proporzione di pazienti progrediti ad un più grave stadio di malattia a 6 mesi ( misurato attraverso la scala MITO) di almento 35% nel braccio con guanabenz rispetto al loro basale e al gruppo placebo (ipotesi nulla del disegno di futilità).

E.5.1.1

Timepoint(s) of evaluation of this end point

6 months

6 mesi

E.5.2

Secondary end point(s)

3) Difference in at least one serum and/or CSF biomarker of neurodegeneration (creatinine, albumin, tau, pNfH, TDP43, cystatin C, fetuin A, transthyretin, and CD14/S100ß and pNfH/C3 assayed by ELISA and Western blot) comparing baseline and study end between guanabenz and placebo arm.

3) Differenza in almento uno dei biomarkes di neurodegenerazione sierici e/o liquorali (creatinina, albumina, tau, pNfH, TDP43, cistatina C, fetuina A, transtiretina, e CD14/S100ß e pNfH/C3 effettuati con ELISA e Western blot) nei bracci di trattamento sia al basale che a fine studio.

E.5.2.1

Timepoint(s) of evaluation of this end point

At baseline and at the end of the study

Basale e fine studio

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

E.6.7

Pharmacodynamic

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

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

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

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Studio di futilità

Futility study

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

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

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

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

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

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

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

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

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

166

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2017-03-17.

Yes

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

208

F.4.2

For a multinational trial

F.4.2.1

In the EEA

208

F.4.2.2

In the whole clinical trial

208

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)

Normal clinical practice

I pazienti proseguiranno secondo normale pratica clinica

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

2016-02-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-10-28

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

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