Clinical Trials Register

Summary
EudraCT Number:	2014-005111-16
Sponsor's Protocol Code Number:	XP-IIT-0029
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2015-01-26
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

Spain - AEMPS

A.2

EudraCT number

2014-005111-16

A.3

Full title of the trial

Response to gabapentin enacarbil in two groups of RLS patients: Previously exposed to long-term treatment with dopaminergic agents versus dopaminergic treatment-naive patients.

?Respuesta al tratamiento con gabapentina enacarbil en dos grupos de pacientes con Síndrome de Piernas Inquietas: pacientes previamente expuestos al tratamiento a largo plazo con fármacos dopaminérgicos vs. nunca tratados?

A.3.1

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

Response to gabapentin enacarbil in two groups of RLS patients: Previously exposed to long-term treatment with dopaminergic agents versus dopaminergic treatment-naive patients.

A.4.1

Sponsor's protocol code number

XP-IIT-0029

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	Instituto de Investigaciones del Sueño
B.1.3.4	Country	Spain
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	Instituto Investigaciones del Sueño
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	FUNDACION TEOFILO HERNANDO
B.5.2	Functional name of contact point	JAVIER SORIANO VENTURA
B.5.3	Address:
B.5.3.1	Street Address	ARZOBISPO MORCILLO 4
B.5.3.2	Town/ city	MADRID
B.5.3.3	Post code	28029
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34915202425
B.5.5	Fax number	+34915202425
B.5.6	E-mail	javier.soriano@uam.es

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	Yes
D.2.1.1.1	Trade name	Horizant
D.2.1.1.2	Name of the Marketing Authorisation holder	Xenoport
D.2.1.2	Country which granted the Marketing Authorisation	United States
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	HORIZANT
D.3.2	Product code	HORIZANT
D.3.4	Pharmaceutical form	Tablet
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	Gabapentin enacarbil
D.3.9.1	CAS number	478296-72-9
D.3.9.2	Current sponsor code	Horizant
D.3.9.3	Other descriptive name	GABAPENTIN ENACARBIL
D.3.9.4	EV Substance Code	SUB35115
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	600
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	Tablet
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

RLS

Sidrome de Piernas inquietas

E.1.1.1

Medical condition in easily understood language

RLS

Síndrome de piernas inquietas

E.1.1.2

Therapeutic area

Diseases [C] - Nervous System Diseases [C10]

MedDRA Classification

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 compare the IRLS response to a two-week treatment with gabapentin enacarbil (600 mg/d) in treatment-naïve RLS patients vs. a similar group of patients previously treated with dopaminergics for at least 90% of the time during the last five years, as judged by the clinical impression of the investigator.

? Comparar la eficacia terapéutica frente a placebo sobre los síntomas de SPI en base a la puntuación total de la escala IRLS en dos grupos de pacientes: no previamente tratados con dopaminérgicos vs. pacientes que han sido tratados con fármacos dopaminergicos durante la mayor parte del tiempo (?90%) a lo largo de los últimos 5 años.

E.2.2

Secondary objectives of the trial

-To compare the response on the RLS-6 to a two-week treatment with gabapentin enacarbil in treatment-naïve RLS patients vs. a similar group of patients previously treated with dopaminergics for at least 90% of the time during the last five years. - tocompare the response on sleep to a two-week treatment with gabapentin enacarbil in treatment-naïve RLS patients vs. a similar group of patients previously treated with dopaminergics for at least 90% of the time during the last five years.
-To compare the response on pain to a two-week treatment with gabapentin enacarbil in treatment-naïve RLS patients vs. a similar group of patients previously treated with dopaminergics for at least 90% of the time during the last five years.? To compare general toxicity between both groups to two-weeks treatment with gabapentin enacarbil (600 mg/d) in treatment-naïve RLS patients vs. a similar group of patients previously treated with dopaminergics for at least 90% of the time during the last five years.

? Comparar la eficacia terapéutica frente a placebo sobre los síntomas de SPI en base a la puntuación total de la escala CGI-I en dos grupos de pacientes
? Comparar la eficacia terapéutica frente a placebo sobre los síntomas de SPI en base a la puntuación total de la escala RLS-6 en dos grupos de pacientes.
? Comparar la eficacia terapéutica frente a placebo sobre el sueño en base a la puntuación total de la escala MOS en dos grupos de pacientes.
? Comparar la eficacia terapéutica frente a placebo sobre el dolor en base a la puntuación total de la escala analógica de dolor en dos grupos de pacientes.
? Comparar la toxicidad general frente a placebo en dos grupos de pacientes: no previamente tratados con dopaminérgicos vs. pacientes que han sido tratados con fármacos dopaminergicos durante la mayor parte del tiempo (?90%) a lo largo de los últimos 5 años.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Idiopathic RLS, according to diagnostic criteria established by the International RLS Study Group (Allen et al., 2003).
2. A history (if currently controlled on medication) or the presence of RLS symptoms on 3 or more days per week for at least 12 months.
3. For Group A: An IRLS score ?20 at baseline assessment
For Group B: An IRLS score ?15 both during dopaminergic treatment and an IRLS score ? 20 following wash-out, during the baseline visit.
4. Aged 18 - 80 years.
5. Creatinine clearance >60 ml/min
6. Women of childbearing potential must have a negative pregnancy test at screen and must agree to use medically accepted methods not to become pregnant.
7. Prior to any study-specific procedures, a personally signed and dated informed consent document indicating that the patient has been informed of all pertinent aspects of the trial.

? SPI idiopático
? Historia de síntomas de SPI en ? 3 días/semana, durante al menos 12 meses.
? Para el grupo A: Puntuación total IRLS ? 20 en la visita basal.
? Para el grupo B: Puntuación total RLS ?15 durante el tratamiento dopaminérgico y ?20 en la visita basal tras el periodo de lavado.
? 18 - 80 años.
? Aclaramiento urinario de creatinina >60 ml/min

E.4

Principal exclusion criteria

1. Any secondary forms of RLS.
2. Current or previous augmentation according to the MPI diagnostic criteria for augmentation (particularly important for Group B)
3. History or current diagnosis of other clinically relevant diseases that may confound assessments or RLS symptoms.
4. Serum ferritin <18 mcg/ml
5. If the patient is currently being treated with drugs likely to influence sleep architecture or motor manifestations during sleep (such as neuroleptics, hypnotics, sedatives, antidepressants, anxiolytics, anticonvulsants, psychoactive medications, steroids, barbiturates and opiates), a wash-out period of at least five half-lives will be undertaken. The washout period for previous intake of L-DOPA or dopamine agonists will be two weeks.
7. Employed in shift work (for example, employment hours disruptive to the normal circadian sleep-wake cycle such as nighttime or variable rotating shifts) or irregular sleep-wake schedules.
8. Patients who require prescription medication for concurrent conditions which could interfere with efficacy assessments.
9. Surgery within 180 days of baseline visit, which in the opinion of the investigator would negatively impact the patient?s participation in the study.
10. A significant medical or psychiatric disorder (see below 7.4.)
11. Any other clinically significant condition or laboratory assay abnormality, which would interfere with the patient?s ability to participate in the study.
12. Other severe acute or chronic medical or psychiatric condition or laboratory assay abnormality that may increase the risk associated with study participation or study drug administration or may interfere with the interpretation of study results and would make the patient inappropriate for entry into this study.
13. Breastfeeding.

? SPI secundario
? Reunir actualmente criterios de Aumento dopaminérgico o haberlo hecho en el pasado (Garcia-Borreguero, 2007)
? Otros diagnósticos en el presente o en el pasado, cuya presencia pueda dificultar la evaluación de síntomas de SPI.
? Ferritina sérica de <18 mcg/ml
? Si el paciente ha recibido tratamiento con fármacos que pueden afectar la arquitectura del sueño o la función motora, deberá efectuarse un periodo de lavado equivalente a al menos 5 semividas plasmáticas. Si el tratamiento ha sido con L-DOPA o con agonistas dopaminérgicos, el lavado deberá ser de al menos 2 semanas.
? Trabajo a turnos u horarios de sueño irregulares.
? Tratamiento para enfermedades que pueden interferir con las mediciones de eficacia.
? Intervenciones quirúrgicas durante los 180 días anteriores, que pudieran interferir con la participación en el estudio.
? Cualquier enfermedad médica o psiquiátrica, o anomalía de laboratorio que resulte clínicamente significativa, que pueda incrementar el riesgo de la participación en el estudio o que pueda interferir con la interpretación de los resultados del mismo.
? Lactancia.

E.5 End points

E.5.1

Primary end point(s)

1. Comparison between both patient groups of:
Placebo-corrected change in IRLS total score (Walters et al., 2003)
This scale will be completed on every visit.
This subject-based scale has been validated in a large-scaled multi-national multi-center trial17. The IRLS, has been shown to be a valid measure of RLS symptom severity in both clinical and self-referred subject samples.

Comparación entre ambos grupos de pacientes en la diferencia frente a placebo en la puntuación total de IRLS (Walters, 2003). Esta escala utiliza 10 items, de 0 a 4, siendo 0 ausencia de síntomas y 4 síntomas severos. El rango de la escala es de 0 a 40. Se utiliza en todas las visitas.

E.5.1.1

Timepoint(s) of evaluation of this end point

5 weeks

5 semanas

E.5.2

Secondary end point(s)

1. Comparison between both patient groups of:

a. Clinical Global Impressions (CGI)-Severity (Guy, 1976)
Will be performed at every visit. At visits Screening and BL where no treatment is administered to the subjects, only item 1 has to be completed.
The CGI-S Scale had been initially developed for a risk-benefit estimation within the treatment of mentally ill subjects. Nowadays, the four global scales (severity of illness, change in severity from baseline, therapeutic efficacy and tolerability of treatment) are used as different measures of treatment outcome in different kinds of pharmacological studies. The CGI-S is considered also as a highly valid (?gold standard?) outcome measure for evaluation of treatments in RLS subjects.

b. RLS-6 scale
The RLS-6 scale49 has been increasingly used in clinical trials, particularly in Europe. Six 11-point scales with ranges between 0=not at all to 10=maximum are used to assess the severity of RLS in the course of treatment, they were include in diaries. These scales proved to be sensitive both for description of changes in severity during the study as well as for the demonstration of differences between active treatment and placebo. The following four scales of the RLS-6 are designed to assess severity of RLS and be used at every visit:
? Severity of RLS at time falling asleep
? Severity of RLS during the night
? Severity of RLS during the day at rest
? Severity of RLS during the day when engaged in daytime activities.
Two further scales are added which cover sleep and daytime tiredness:
? Satisfaction with sleep
? Severity of daytime tiredness/sleepiness.

c. Medical Outcomes Study (MOS) Scale (Hays, 2005)

The MOS scale includes questions on subjective perception of sleep initiation, sleep maintenance, perceived sleep quality, daytime somnolence and sleep breathing disorders (REF). As RLS affects sleep, this rating scale will have the opportunity to measure any improvements in sleep and thereby, of health as a result of treatment. The MOS scale has been used before in other large therapeutic studies in RLS. The MOS scale measures specific aspects of sleep in subjects that might have different simultaneous medical disorders, and is thus adequate for patient populations that are diverse from a medical point of view.

d. PAIN-VAS

e. Epworth Sleepiness Scale (EES) (Johns, 1991)
This is a self-administered questionnaire, which has been shown to provide a measurement of the subject's general level of daytime sleepiness. Patients are asked to rate on a scale of 0-3 (0 = would never doze, 3 = high chance of dozing) their propensity to fall asleep in eight situations for a score totaling from 0 to 24. ESS scores greater than 16 indicate a high level of daytime sleepiness, although not diagnostic for any particular disorder. Normal scores range from 0-10.

f. Incidence rate of general toxicity

g. Multiple Suggested Immobilization Test (Garcia-Borreguero et al, 2013):

Objective measurement of sensory and motor RLS symptoms by means of a multiple suggested immobilization test, -mSIT- (Garcia-Borreguero et al., 2013) performed at 6P, 8P, 10P and 12 midnight.

Comparison between both patient groups of:
Placebo-corrected change in m-SIT-ds
Placebo-corrected change in LMW

Comparación entre ambos grupos de pacientes en la diferencia frente a placebo en la escala CGI-I (Guy, 1976).

b) Comparación entre ambos grupos de pacientes en la diferencia frente a placebo en la escala RLS-6

c) Comparación entre ambos grupos de pacientes en la diferencia frente a placebo en la escala MOS (Hays, 2005)

d) Comparación entre ambos grupos de pacientes en la diferencia frente a placebo en la escala analógica visual de dolor.

E.5.2.1

Timepoint(s) of evaluation of this end point

5 weeks

5 semanas

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

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)

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

Yes

E.8.4

The trial involves multiple sites in the 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

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

last patient last visit

Ultima visita del último paciente

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

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:

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

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

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.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)

General treatment

Práctica clínical habitual

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

2015-02-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-12-11

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

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