Clinical Trials Register

Summary
EudraCT Number:	2011-001318-32
Sponsor's Protocol Code Number:	P261-401
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:	2012-03-08
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

2011-001318-32

A.3

Full title of the trial

A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Intranasal Midazolam (USL261) in the Outpatient Treatment of Subjects with Seizure Clusters ARTEMIS-1: Acute Rescue Therapy in Epilepsy with Midazolam Intranasal Spray-1

Studio randomizzato, in doppio cieco, controllato con placebo, per la valutazione della sicurezza ed efficacia di Midazolam intranasale (USL261) nel trattamento delle crisi epilettiche a grappolo in pazienti ambulatoriali

A.3.1

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

Study to evaluate efficacy and safety of Midazolam administered via a nasal spray to treat cluster epilepsy seizure in outpatients selected randomly in comparison with patients treated with a substance of no efficacy (placebo)

Studio per valutare l'efficacia e la sicurezza di Midazolam somministrato in uno spray per via nasale nel trattamento delle crisi epilettiche a grappolo in pazienti ambulatoriali che saranno selezionati in maniera casuale e confrontati con pazienti trattati con un farmaco inefficace (placebo)

A.3.2

Name or abbreviated title of the trial where available

ARTEMIS-1

A.4.1

Sponsor's protocol code number

P261-401

A.5.4

Other Identifiers

Name:

US- IND number

Number:

77,421

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	UPSHER-SMITH LABORATORIES
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	Upsher-Smith Laboratories 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	Pharmanet Ltd
B.5.2	Functional name of contact point	Regulatory Operations
B.5.3	Address:
B.5.3.1	Street Address	Glory Park Avenue, Building Two
B.5.3.2	Town/ city	Wooburn Green, Bucks
B.5.3.3	Post code	HP10 ODF
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	+44 870 242 0780
B.5.5	Fax number	+44 870 242 0781
B.5.6	E-mail	RegOpsEurope@pharmanet.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	Midazolam
D.3.2	Product code	NA
D.3.4	Pharmaceutical form	Nasal spray, solution
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Nasal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	MIDAZOLAM
D.3.9.1	CAS number	59467708
D.3.9.2	Current sponsor code	USL261
D.3.9.3	Other descriptive name	NA
D.3.9.4	EV Substance Code	SUB08950MIG
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	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	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	Nasal spray, solution
D.8.4	Route of administration of the placebo	Nasal use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Epilepsy

Epilessia

E.1.1.1

Medical condition in easily understood language

Epilepsy

Epilessia

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	14.1
E.1.2	Level	HLT
E.1.2	Classification code	10000332
E.1.2	Term	Absence seizures
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

- To evaluate the efficacy of USL261 compared with that of IN placebo for the outpatient treatment of seizure clusters based on Treatment Success, - To evaluate the safety and tolerability of USL261 for the treatment of seizure clusters

- Valutare l`efficacia di USL261 rispetto al placebo intranasale (IN) nel trattamento ambulatoriale di crisi a grappolo in base al successo del trattamento, definito come l`ottenimento di entrambe le seguenti: a.interruzione della/delle crisi entro 10 minuti dall’assunzione del farmaco di studio;b.nessuna recidiva della/delle crisi entro 4 ore dalla somministrazione del farmaco di studio; - Valutare la sicurezza e la tollerabilita' di USL261 nel trattamento delle crisi a grappolo

E.2.2

Secondary objectives of the trial

-To evaluate the efficacy of USL261 compared with that of IN placebo for the outpatient treatment of seizure clusters using the following:a. Occurrence of seizure(s) within 6 hours after study drug administration; b. Time to next seizure after study drug administration;c. Frequency of seizure(s) within 6 hours after study drug administration

Valutare l'efficacia di USL261 rispetto al placebo intranasale (IN) nel trattamento delle crisi a grappolo in pazienti ambulatoriali utilizzando le seguenti misure: a. comparsa della/delle crisi entro 6 ore dalla somministrazione del farmaco di studio; b. periodo fino alla crisi successiva dopo la somministrazione del farmaco di studio; c. frequenza della/delle crisi entro 6 ore dalla somministrazione del farmaco di studio

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.Subject has a competent, adult caregiver who can recognize and observe the subject’s seizure cluster episodes;2. Subject has an established diagnosis of partial or generalized epilepsy that includes all of the following:a) A documented history of seizure clusters lasting > 10 minutes and < 6 hours, with a pattern that is observable, stereotyped, and recognizably different from the subject’s other non-cluster seizure activity, if any; b)A seizure cluster pattern composed of multiple (≥ 2) partial or generalized seizures; c) A seizure cluster pattern established > 3 months before Visit 1; d)A frequency of ≥ 4 seizure clusters during the year before Visit 1;e) At least 1 seizure cluster occurring ≤ 3 months before Visit 1; f)Seizure cluster pattern is confirmed by a central reviewer;3.Currently on a stable dosing regimen of AEDs since Visit 1 and for ≥ 7 days before Visit 2, with or without intermittent use of benzodiazepines at a constant dose

1. Il soggetto ha uno (o piu') caregiver competente(i), adulto(i) in grado di riconoscere e osservare le crisi a grappolo del soggetto; 2. Il soggetto ha una diagnosi confermata di epilessia parziale o generalizzata che include tutto quanto segue: a)Anamnesi documentata di crisi a grappolo di durata > 10 minuti e < 6 ore, con un pattern osservabile, stereotipato e chiaramente diverso dalle altre crisi non a grappolo del soggetto, se presenti; b)Un pattern di crisi a grappolo composto da crisi multiple (≥ 2) parziali o generalizzate; c)Un pattern di crisi a grappolo confermato da almeno 3 mesi prima della Visita 1, con un pattern osservabile, stereotipato e chiaramente diverso dalle altre crisi non a grappolo del soggetto, se presenti; d)Una frequenza di crisi a grappolo ≥ 4 nell’anno precedente la Visita 1, con un pattern osservabile, stereotipato e chiaramente diverso dalle altre crisi non a grappolo del soggetto, se presenti;e) Almeno 1 (una) crisi a grappolo nel periodo ≤ 3 mesi prima della Visita 1, con un pattern osservabile, stereotipato e chiaramente diverso dalle altre crisi non a grappolo del soggetto, se presenti; f)Il pattern di crisi a grappolo descritto precedentemente e' confermato da un revisore centrale. 3. Il soggetto si trova in regime stabile con farmaco antiepilettico (ossia senza variazioni nel tipo o nel dosaggio degli antiepilettici) dalla Visita 1 e per ≥ 7 giorni prima della Visita 2, con o senza uso intermittente di benzodiazepine a una dose costante;

E.4

Principal exclusion criteria

1.Subject has a neurological disorder that is likely to progress in the next year;2.Subject has had psychogenic, non-epileptic seizure(s) within the 5 years before Visit 1;3.Subject has a history of their stereotypical seizure cluster progressing to status epilepticus within the 2 years before Visit 1 or has a history of seizure clusters progressing to status epilepticus despite therapeutic intervention;4.Subject has a history of acute narrow-angle glaucoma;5.Subject has had an active suicidal plan/intent or active suicidal thoughts in the 6 months before Visit 1 or any lifetime suicide attempt;6.Subject is taking felbamate for less than 18 consecutive months before Visit 1or has discontinued felbamate within 30 days before Visit 1;7.Subject is currently taking or has taken vigabatrin within 1 year before Visit 1;8.Subject has taken vigabatrin in the past and has either no documentation of visual field exam or dcumentation on an abnormal visual field exam;9.Subject is currently using a vagal nerve stimulator (VNS) unless the device has been implanted for at least 6 months and the settings have not changed within 4 weeks before Visit 1

1.Il soggetto presenta un disturbo neurologico che e' verosimilmente destinato a progredire nel corso dell’anno a venire;2.Il soggetto ha avuto crisi psicogene non epilettiche negli ultimi 5 anni prima della Visita 1;3.Il soggetto possiede un’anamnesi di crisi a grappolo stereotipate (per le quali viene arruolato nello studio) che sono progredite a stato epilettico nei 2 anni precedenti la Visita 1 o possiede un’anamnesi di crisi a grappolo che sono progredite a stato epilettico nonostante l’intervento terapeutico;4.Il soggetto presenta glaucoma acuto ad angolo chiuso;5.Il soggetto presenta suicidalita', definita come una delle situazioni seguenti: a) attiva pianificazione/intento suicida o b) attivi pensieri suicidi negli ultimi 6 mesi prima della Visita 1 o c) tentativo di suicidio durante la vita;6. Se il soggetto assume attualmente felbamato, lo assume da < 18 mesi consecutivi prima della Visita 1 o ha interrotto l’assunzione di felbamato nei 30 giorni precedenti la Visita 1;7.Il soggetto assume o ha assunto vigabatrina nell’anno precedente la Visita 1;8.Il soggetto ha assunto vigabatrina e presenta una qualsiasi delle situazioni seguenti: - nessuna documentazione di esame del campo visivo da parte di un oftalmologo o neuro¬oftalmologo oppure documentazione di un’anomalia nel campo visivo da parte di un oftalmologo o neuro¬oftalmologo;9.Il soggetto sta attualmente utilizzando uno stimolatore del nervo vago (VNS), a meno che il dispositivo sia stato impiantato da almeno 6 mesi e le impostazioni non siano state cambiate nelle 4 settimane prima della Visita 1

E.5 End points

E.5.1

Primary end point(s)

The primary efficacy endpoint is the proportion of subjects who meet the criteria for Treatment Success.

L’endpoint primario di efficacia e' la percentuale di soggetti che soddisfino i criteri per il successo del trattamento.

E.5.1.1

Timepoint(s) of evaluation of this end point

Treatment Success is a composite measure of efficacy that will be assessed based upon the first seizure cluster treated during the Comparative Phase. Treatment Success is defined as achieving the following: • Termination of seizure(s) within 10 minutes after study drug administration, and • No recurrence of seizure(s) within 4 hours after study drug administration

Il successo del trattamento e' una misura composita dell’efficacia, che sara' valutata in base alla prima crisi a grappolo trattata durante la fase comparativa. Il successo del trattamento e' definito come l’ottenimento di quanto segue: •interruzione della/delle crisi entro 10 minuti dall’assunzione del farmaco di studio e •nessuna recidiva della/delle crisi entro 4 ore dalla somministrazione del farmaco di studio.

E.5.2

Secondary end point(s)

1)Proportion of subjects with occurrence of seizure(s) within 6 hours after administration of double-blind study drug; 2) Time to next seizure after study drug administration; 3) Frequency of seizure(s) within 6 hours after administration of study drug

1) Percentuale di soggetti con crisi entro 6 ore dalla somministrazione in doppio cieco del farmaco di studio; 2) Tempo alla crisi successiva dopo la somministrazione del farmaco di studio; 3) Frequenza della/delle crisi entro 6 ore dalla somministrazione del farmaco di studio

E.5.2.1

Timepoint(s) of evaluation of this end point

1)Proportion of subjects with occurrence of seizure(s): Within 6 hours after administration of double-blind study drug; 2) Time to next seizure after study drug administration: At occurrence of next seizure after study drug administration; 3)Frequency of seizure(s) within 6 hours after administration of study drug: within 6 hours after administration of study drug

1)Percentuale di soggetti con crisi entro 6 ore dalla somministrazione in doppio cieco del farmaco di studio; 2) Tempo alla crisi successiva dopo la somministrazione del farmaco di studio; 3) Frequenza della/delle crisi entro 6 ore dalla somministrazione del farmaco di 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

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

Yes

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

fase test in aperto, seguita da fase in doppio cieco comparativa

open-label test dose phase, followed by double-blind comparative phase

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

Argentina

Australia

Canada

Israel

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

Yes

F.1.1

Number of subjects for this age range:

105

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)

Yes

F.1.1.6.1

Number of subjects for this age range:

105

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

105

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

adolescent patients aged 14 to 17 years

pazienti adolescenti tra 14-17 anni di eta'

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

155

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)

no difference to the expected normal treatment of that condition

nessuna differenza rispetto al normale trattamento della patologia

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

2012-02-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2011-12-19

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2017-03-20

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