Clinical Trials Register

Summary
EudraCT Number:	2018-004875-11
Sponsor's Protocol Code Number:	CAMG334AIT03
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:	2021-01-07
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-004875-11

A.3

Full title of the trial

A RandomizEd, double-blind, cross-over Study to assess Erenumab effecT on BRAIN networks function and structure in comparison to placebo in episodic migraine patients (RESET BRAIN)

Studio randomizzato, in doppio cieco, con disegno cross-over per valutare l’effetto di erenumab sulla funzionalità e sulla struttura delle reti neurali cerebrali a confronto con placebo in pazienti con emicrania episodica. (Studio RESET BRAIN)

A.3.1

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

Functional MRI study of the central effects of erenumab in patients with episodic migraine.

Studio con risonanza magnetica funzionale (functional Magnetic Resonance Imaging, fMRI) sugli effetti centrali di erenumab in pazienti con emicrania episodica.

A.3.2

Name or abbreviated title of the trial where available

RESET BRAIN

A.4.1

Sponsor's protocol code number

CAMG334AIT03

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 FARMA S.P.A.
B.1.3.4	Country	Italy
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 Farma S.p.A.
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	Novartis Farma S.p.A.
B.5.2	Functional name of contact point	Drug Regulatory Affairs
B.5.3	Address:
B.5.3.1	Street Address	Largo Umberto Boccioni, 1
B.5.3.2	Town/ city	Origgio
B.5.3.3	Post code	21040
B.5.3.4	Country	Italy
B.5.4	Telephone number	0296541
B.5.5	Fax number	029659066
B.5.6	E-mail	info.studiclinici@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	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	AMG334
D.3.2	Product code	[AMG334]
D.3.4	Pharmaceutical form	Solution for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Erenumab
D.3.9.1	CAS number	1582205-90-0
D.3.9.2	Current sponsor code	AMG334
D.3.9.3	Other descriptive name	Erenumab
D.3.9.4	EV Substance Code	SUB183612
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	70
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	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	Solution for injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Episodic migraine

Emicrania episodica

E.1.1.1

Medical condition in easily understood language

Headache

Mal di testa

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	10027599
E.1.2	Term	Migraine
E.1.2	System Organ Class	10029205 - Nervous system disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

1. To evaluate, in a cohort of episodic migraine patients, whether the prophylactic treatment of 3 months with erenumab is able to produce significant changes versus placebo in the functional recruitment and connectivity of multisensory processing areas and, as such, modulate the dysfunctional pain network (chosen as primary area of interest) in the CNS of these patients.

2. To evaluate whether the changes of functional recruitment and connectivity in multisensory processing areas are different between the two groups of clinical responders (reduction by 50% in monthly migraine days, MMD, in the last month vs baseline) and non-responders within each 3-months treatment group.

1. Valutare, in una coorte di pazienti con emicrania episodica, se il trattamento profilattico della durata di 3 mesi con erenumab è in grado di produrre variazioni significative rispetto a placebo nel reclutamento funzionale e nella connettività delle aree di elaborazione multisensoriale e, in tal modo, modulare le reti del dolore disfunzionali (scelte come area primaria di interesse) nel sistema nervoso centrale (Central Nervous System – CNS) di questi pazienti.

2. Valutare se le variazioni del reclutamento funzionale e della connettività delle aree di elaborazione multisensoriale sono diverse tra i due gruppi di responder clinici (riduzione = 50% dei giorni con emicrania in un mese -(Monthly Migraine Days –, MMD-, nell’ultimo mese rispetto al basale) e non-responder entro ciascun gruppo di trattamento della durata di 3 mesi.

E.2.2

Secondary objectives of the trial

1. To evaluate whether the functional changes in the pain network produced by prophylactic treatment of 3 months with erenumab correlate with the clinical response over 3 months; 2. To evaluate whether prophylaptic treatment of 3 months with erenumab is able to produce significant changes versus placebo in the functional recruitment and connectivity of multisensory processing areas mediating symptoms commonly experienced by migraine patients, such as allodynia, photophobia, phonophobia, nausea, anxiety and depression; 3. To evaluate whether the functional changes produced by prophylaptic treatment of 3 months with erenumab in the dysfunctional brain regions mediating allodynia, photophobia, phonophobia, nausea and emotional control of pain correlate with the clinical response in terms of reduction of these respective symptoms over 3 months; 4. To evaluate whether there are baseline functional MRI markers predictive of good clinical response to erenumab at 3 months.

1 Valutare se le variaz funzionali nelle reti neurali del dolore prodotte dal tratt profilattico della durata di 3mesi con erenumab sono correlate alla risposta clinica nel corso di 3mesi; 2 Valutare se il tratt profilattico della durata di 3mesi con erenumab è in grado di produrre variaz significative rispetto a placebo nel reclutamento funzionale e nella connettività delle aree di elaborazione multisensoriale medianti i sintomi comunemente manifestati dai pazienti con emicrania,quali allodinia,fotofobia,fonofobia,nausea,ansia e depressione; 3 Valutare se le variaz funzionali prodotte dal tratt profilattico della durata di 3mesi con erenumab nelle regioni cerebrali disfunzionali che mediano l’allodinia,la fotofobia,la fonofobia,la nausea e il controllo emotivo del dolore sono correlate alla risposta clinica in termine di riduzione di questi rispettivi sintomi nel corso di 3mesi; 4 Valutare se vi sono marker di fMRI al basale predittivi di buona risposta clinica a erenumab a 3mesi.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Adult patients, aged between 18 and 65 years
2) Provided informed consent
3) History of migraine with or without aura for at least 12 months prior to screening according to IHS classification ICHD-3, based on medical records and/or patient self-report
4) Migraine frequency: = 4 and < 15 migraine days per month on average across the 3 months prior to screening and confirmed during the baseline phase based on diary evaluation
5) Headache frequency: <15 headache days per month on average across the 3 months prior to screening and confirmed during the baseline phase based on diary calculation
6) Failure to 2 or more previous prophylactic treatment categories locally indicated for migraine

1. Pazienti adulti di età compresa tra 18 e 65 anni.
2. Consenso informato scritto
3. Anamnesi di emicrania con o senza aura da almeno 12 mesi prima dello screening secondo la classificazione IHS ICHD-3, in base alle cartelle cliniche e/o a quanto riportato dal paziente.
4. Frequenza dell’emicrania: = 4 e < 15 giorni di emicrania al mese in media nei 3 mesi precedenti lo screening e confermata durante la fase basale in base alla valutazione del diario.
5. Frequenza della cefalea: <15 giorni di cefalea al mese in media nei 3 mesi precedenti lo screening e confermata durante la fase basale in base al calcolo del diario.
6. Insuccesso di 2 o più categorie di trattamento profilattico pregresso indicato a livello locale per l’emicrania.

E.4

Principal exclusion criteria

1) Older than 50 years of age at migraine onset.
2) History of cluster headache or hemiplegic migraine headache.
3) History of head trauma or seizure or major psychiatric disorders.
4) Currently receiving (or have received less than 60 days or 5 half-lives prior to the start of the baseline period, during the baseline period, or treatment period) any other prophylactic treatment for migraine and/or prohibited medications, non-pharmacologic interventions or devices (any substance, non-pharmacologic intervention or device acting at central nervous system).
5) Pregnant or breastfeeding.
6) All the clinical conditions for which undergoing an MRI scan is contraindicated.

1. Età d’esordio dell’emicrania dopo i 50 anni
2. Anamnesi di cefalea a grappolo o emicrania emiplegica.
3. Anamnesi di trauma cranico o crisi epilettiche o disturbi psichiatrici maggiori.
4. Pazienti attualmente in trattamento (o in trattamento meno di 60 giorni o 5 emivite prima dell’inizio del periodo basale, durante il periodo basale o durante il periodo di trattamento) con qualsiasi altro trattamento profilattico per l’emicrania e/o con farmaci, interventi non farmacologici o dispositivi non consentiti (qualsiasi sostanza, intervento non farmacologico o dispositivo che agisce a livello del sistema nervoso centrale).
5. Donne in gravidanza o allattamento.
6. Tutte le condizioni cliniche per cui è controindicato sottoporsi ad una risonanza magnetica.

E.5 End points

E.5.1

Primary end point(s)

1. Between-treatment groups difference in change of resting state functional connectivity strength in the brain areas involved in pain processing measured as z-score maps.

2. Change of resting state functional connectivity strength in the areas of interest including pain processing brain regions measured as z-score maps, between clinical response groups (reduction by 50% in monthly migraine days ,MMD, in the last month vs baseline) within the two treatment groups.

1. Differenza tra gruppi di trattamento nella variazione della forza della connettività funzionale a riposo nelle aree cerebrali coinvolte nell’elaborazione del dolore,misurati come mappe z-score.

2. Variazione della forza della connettività funzionale a riposo nelle aree di interesse comprese le regioni cerebrali di elaborazione del dolore misurate come mappe z-score, tra gruppi di risposta clinica (riduzione = 50% nei giorni di emicrania al mese, MMD, nell’ultimo mese rispetto al basale) entro in due gruppi di trattamento.

E.5.1.1

Timepoint(s) of evaluation of this end point

1. From baseline to month 3 of treatment

2. From baseline to month 3 of treatment

1. Dal basale al mese 3 di trattamento

2. Dal basale al mese 3 di trattamento

E.5.2

Secondary end point(s)

Correlation (by treatment groups and in all patients) between the changes in the resting state functional connectivity strength in the regions of interest and
a. the percentage of reduction in monthly migraine days
b. the reduction in monthly average severity of migraine pain (1-10 scale score included in the diary)
c. the percentage of reduction in monthly number of days with use of acute treatments
d. the change in HIT-6 score; Between-treatment groups difference in change of resting state functional connectivity strength in the brain regions involved in the following migraine symptoms:
a. sensory hypersensitivity (allodynia)
b. visual or auditory hypersensitivity (photophobia or phonophobia)
c. neurovegetative symptoms (nausea)
d. altered emotional control of pain; Correlation (by treatment group and in all patients) between:
a. the changes in the resting state functional connectivity strength of the brain regions mediating allodynia and the changes in the Allodynia Symptom Checklist 12 (ASC-12) score at month 3
b. the changes in the resting state functional connectivity strength of the brain regions mediating photophobia and phonophobia and the percentage changes in number of attacks with photophobia and phonophobia at month 3
c. the changes in the resting state functional connectivity strength of the brain regions mediating neurovegetative symptoms and the percentage changes in number of attacks with nausea at month 3
d. the changes in the resting state functional connectivity strength of the brain regions underlying the altered emotional control of pain and the changes in HADS score at month 3; Baseline resting state functional connectivity strength will be evaluated by treatment group and in all patients as potential predictors of treatment clinical response defined by the achievement of at least 50% reduction of monthly migraine days.

Correlazione (per gruppi di trattamento e in tutti i pazienti) tra le variazioni della forza della connettività funzionale a riposo nelle regioni di interesse e
a) la percentuale di riduzione nei giorni di emicrania al mese
b) la riduzione nell’intensità media mensile del dolore dell’emicrania (punteggio su una scala da 1 a 10 incluso nel diario)
c) la percentuale di riduzione dnel numero di giorni mensili con utilizzo di trattamenti in acuto
d) la variazione del punteggio HIT-6; Differenza tra gruppi di trattamento nella variazione della forza della connettività funzionale a riposo nelle regioni cerebrali coinvolte nei seguenti sintomi di emicrania:
a) ipersensibilità sensoriale (allodinia)
b) ipersensibilità visiva o uditiva (fotofobia o fonofobia)
c) sintomi neurovegetativi (nausea)
d) controllo emotivo del dolore alterato; Correlazione (per gruppo di trattamento e in tutti i pazienti) tra:
a) le variazioni nella forza di connettività funzionale a riposo delle regioni cerebrali che mediano l’allodinia e le variazioni nel punteggio ASC-12 (Allodynia Symptom Checklist 12) al mese 3
b) le variazioni nella forza di connettività funzionale a riposo delle regioni cerebrali che mediano la fotofobia e la fonofobia e le variazioni percentuali nel numero di attacchi con fotofobia e fonofobia al mese 3 di trattamento
c) le variazioni nella forza di connettività funzionale a riposo delle regioni cerebrali che mediano i sintomi neurovegetativi e le variazioni percentuali nel numero di attacchi con nausea al mese 3 di trattamento
d) le variazioni nella forza di connettività funzionale a riposo delle regioni cerebrali che soggiacciono ad un alterato controllo emotivo del dolore e le variazioni del punteggio HADS al mese 3 di trattamento; La forza di connettività funzionale a riposo al basale sarà valutata per gruppo di trattamento e in tutti i pazienti come potenziale predittore di risposta clinica al trattamento definita dal raggiungimento di una riduzione di almeno il 50% dei giorni di emicrania mensili .

E.5.2.1

Timepoint(s) of evaluation of this end point

a. At month 3 of treatment vs baseline
b. At month 3 of treatment vs baseline
c. From baseline to month 3
d. From baseline to month 3; From baseline to month 3 of treatment; a. At month 3
b. At month 3
c. At month 3
d. At month 3; At month 3 versus baseline.

a) A 3 mesi di trattamento rispetto al basale
b) Al mese 3 di trattamento rispetto al basale
c) Al basale al mese 3 di trattamento
d) Dal basale al mese 3 di trattamento; Dal basale al mese 3 di trattamento; a) Al mese 3
b) Al mese 3 di trattamento
c) Al mese 3 di trattamento
d) Al mese 3 di trattamento; Al mese 3 di trattamento rispetto al basale.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

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

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

Tolerability.

Tollerabilità

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)

E.7.4

Therapeutic use (Phase IV)

Yes

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

Yes

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

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.1.1.1

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:

137

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

140

F.4.2

For a multinational trial

F.4.2.1

In the EEA

140

F.4.2.2

In the whole clinical trial

140

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)

Standard therapy

Terapia standard

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

2019-05-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-04-11

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

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