Clinical Trials Register

Summary
EudraCT Number:	2020-000302-28
Sponsor's Protocol Code Number:	EffICIENCY
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-05-10
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

2020-000302-28

A.3

Full title of the trial

Open randomized low interventional clinical trial to compare efficiency in symptom control between fluticasone propionate/formoterol k-haler at medium strength versus an high strength ICS/LABA for the treatment of patients with persistent asthma for 24 weeks

Ensayo clínico abierto aleatorizado de baja intervención para comparar la eficacia en el control de los síntomas entre el propionato de fluticasona/formoterol k-haler a dosis media versus un ICS/LABA a dosis altas para el tratamiento de pacientes con asma persistente durante 24 semanas

A.3.1

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

Efficiency in symptom control of fluticasone/formoterol k-haler (medium strength) vs ICS/LABA (high strength) in asthma patients

Eficiencia en el control de síntomas en pacientes asmáticos tratados con fluticasona/formoterol k-haler a dosis medias vs otros CI/LABA a dosis altas

A.4.1

Sponsor's protocol code number

EffICIENCY

A.5.2

US NCT (ClinicalTrials.gov registry) number

NCT04271839

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	Mundipharma Pharmaceuticals S.L.
B.1.3.4	Country	Spain
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	Mundipharma Pharmaceuticals S.L.
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	Mundipharma Pharmaceuticals S.L.
B.5.2	Functional name of contact point	Mundipharma Pharmaceuticals S.L.
B.5.3	Address:
B.5.3.1	Street Address	Calle Bahía de Pollensa 11
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28042
B.5.3.4	Country	Spain
B.5.6	E-mail	ruben.lesmes@mundipharma.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	Flutiform K-haler 125 micrograms / 5 micrograms / inhalation, suspension for inhalation in a pressure container.
D.2.1.1.2	Name of the Marketing Authorisation holder	Mundipharma Pharmaceuticals S.L.
D.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	Pharmaceutical form	Pressurised inhalation, suspension
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Inhalation use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Fluticasone propionate
D.3.9.1	CAS number	80474-14-2
D.3.9.4	EV Substance Code	SUB02241MIG
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	125
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Formoterol
D.3.9.1	CAS number	183814-30-4
D.3.9.3	Other descriptive name	FORMOTEROL FUMARATE DIHYDRATE
D.3.9.4	EV Substance Code	SUB25660
D.3.10	Strength
D.3.10.1	Concentration unit	µg microgram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
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	Yes
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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Persistent moderate asthma uncontrolled

Asma persistente moderada no controlada

E.1.1.1

Medical condition in easily understood language

Persistent asthma

Asma persistente

E.1.1.2

Therapeutic area

Diseases [C] - Respiratory Tract Diseases [C08]

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

Demonstrate whether, in patients with moderate asthma treated with IC / LABA at medium doses, but not controlled, a similar degree of control is achieved by increasing this treatment (IC / LABA at high dose) versus switching to fluticasone / formoterol k-haler at medium dose, under conditions of usual clinical practice.

Demostrar si, en pacientes con asma moderada tratados con CI/LABA a dosis medias, pero no controlados, se alcanza un grado de control similar al realizar un step-up de ese tratamiento (CI/LABA a dosis alta) frente a cambiar a fluticasona/formoterol k-haler a dosis media, en condiciones de práctica clínica habitual.

E.2.2

Secondary objectives of the trial

• Differences between arms with respect to:
o Degree of control according to GINA (well controlled, partially and poorly controlled).
o Success in treatment (Defined as progression from poorly controlled to partially or well controlled, or from partially controlled to controlled, with no change in baseline treatment after randomization)
o Adherence to treatment (by TAI-12 and electronic prescription)
o Number of critical errors with the inhaler
o Patient satisfaction with the inhaler (Through the FSI-10)
o Quality of Life (Through Mini-AQLQ)
o Severe asthmatic exacerbations
o Pulmonary function (Using FEV1, FVC and spirometry FEV1 / FVC ratio)
o Safety: type and incidence of adverse reactions

• Diferencias entre brazos respecto a:
o Grado de control según GINA (bien controlado, parcialmente y mal controlado).
o Éxito en el tratamiento (Definido como progresión de mal controlado a parcialmente o bien controlado, o bien, de parcialmente controlado a controlado, sin cambio en el tratamiento basal tras aleatorización)
o Adhesión al tratamiento (Mediante TAI-12 y Receta electrónica)
o Nº errores críticos con el inhalador
o Satisfacción del paciente con el inhalador (Mediante el FSI-10)
o Calidad de Vida (Mediante Mini-AQLQ)
o Exacerbaciones asmáticas graves
o Función pulmonar (Mediante el FEV1, FVC y ratio FEV1/FVC de la espirometría)
o Seguridad: tipo e incidencia de reacciones adversas

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Age > or = 18 years.
2. Objective diagnosis of asthma (according to GEMA 4.4)
3. Patients in treatment with a stable average dose of IC in a fixed dose combination of IC / LABA *, without changes in the dose or in the inhaler, during the 3 months prior to inclusion, in accordance with its approved indication and Data sheet. * Except for K-Haler®
4. Patients who need, according to medical criteria, a dose increase of IC in the current fixed IC / LABA combination.
5. Inhalation technique: no critical errors with the current inhaler after training.
6. Patient with uncontrolled asthma with an ACQ> 0.75 points (partially controlled or poorly controlled asthma).
7. Informed consent in signed writing.

1. Edad > o = 18 años.
2. Diagnóstico objetivo de asma (según GEMA 4.4)
3. Pacientes en tratamiento con una dosis media estable de CI en una combinación a dosis fija de CI/LABA*, sin cambios en la dosis ni en el inhalador, durante los 3 meses anteriores a la inclusión, de acuerdo con su indicación aprobada y Ficha Técnica. * A excepción de K-Haler®
4. Pacientes que necesiten, según criterio médico, una subida de dosis de CI en la combinación fija CI/LABA actual.
5. Técnica de inhalación: sin errores críticos con el inhalador actual tras entrenamiento.
6. Paciente con asma no controlado con un ACQ>0,75 puntos (asma parcialmente controlada o mal controlada).
7. Consentimiento informado por escrito firmado.

E.4

Principal exclusion criteria

1. Diagnosis of other respiratory pathology other than asthma (clinically relevant bronchiectasis, pulmonary fibrosis, COPD and others at the discretion of the investigator).
2. ≥1 severe exacerbation (require the use of systemic corticosteroids - oral, suspension or injection - or increasing the dose of maintenance therapy for at least 3 days, or hospitalization or emergency room visits due to asthma requiring the use of systemic corticosteroids) in the last month or ≥3 in the previous 12 months.
3. Pregnancy or probability of being pregnant during the study.
4. Patient who, at the discretion of the investigator, does not have the capacity to complete the questionnaires.
5. Patient under treatment with monoclonal antibodies during the study.
6. Patient in another clinical trial.
7. Patient who has received an experimental drug in the last 30 days (12 weeks if it is a systemic steroid).
8. Do not use a MART (Maintenance and Rescue) strategy within 3 months prior to inclusion or during the trial
9. Patient in IC / LABA treatment according to MART strategy (Maintenance and Rescue).
10. Any contraindication expressed in the CI / LABA data sheet used.
11. Patient with poor adherence (TAI-10 ≤ 45)
12. Patients using an inhalation chamber
13. Patients with an index of Packages / year> 10

1. Diagnóstico de otra patología respiratoria que no sea asma (bronquiectasias clínicamente relevantes, fibrosis pulmonar, EPOC y otras a criterio del investigador).
2. ≥1 exacerbación grave (requieren el uso de corticosteroides sistémicos -oral, suspensión o inyección- o el aumento de la dosis de la terapia de mantenimiento durante al menos 3 días, o la hospitalización o las visitas a la sala de emergencias debido al asma que requiere el uso de corticosteroides sistémicos) en el último mes o ≥3 en los 12 meses previos.
3. Embarazo o probabilidad de estar embarazada durante el estudio.
4. Paciente que, a criterio del investigador, no tenga capacidad para cumplimentar los cuestionarios.
5. Paciente en tratamiento con anticuerpos monoclonales durante el estudio.
6. Paciente en otro ensayo clínico.
7. Paciente que ha recibido un fármaco experimental en los últimos 30 días (12 semanas si es esteroide sistémico).
8. No utilizar una estrategia MART (Mantenimiento y Rescate) ni en los 3 meses previos a la inclusión ni durante el ensayo
9. Paciente en tratamiento de CI/LABA según estrategia MART (Mantenimiento y Rescate).
10. Cualquier contraindicación expresa en la ficha técnica del CI/LABA utilizado.
11. Paciente con mala adhesión (TAI-10 ≤ 45)
12. Pacientes que usen cámara de inhalación
13. Pacientes con un índice de Paquetes/año > 10

E.5 End points

E.5.1

Primary end point(s)

The main variable is the total score in the ACQ-7 questionnaire. In each arm we will obtain the mean difference of that score (week 24 minus week 0 (BV)) and, subsequently, both means will be compared. To meet the objective of non-inferiority, the difference between both means must be, at most, 0.5 points. This 0.5 point difference is the minimum difference, clinically relevant and validated for this questionnaire.

La variable principal es la puntuación total en el cuestionario ACQ-7. En cada brazo obtendremos la diferencia media de esa puntuación (semana 24 menos semana 0 (VB)) y, posteriormente, se compararán ambas medias. Para cumplir el objetivo de no inferioridad, la diferencia entre ambas medias debe ser, como máximo, de 0,5 puntos. Esta diferencia de 0,5 puntos es, la mínima diferencia, clínicamente relevante y validada para este cuestionario.

E.5.1.1

Timepoint(s) of evaluation of this end point

Baseline visit, 4-6 week visit (ACQ-6) and 24 week visit

Visita Basal, visita 4-6 semanas (ACQ-6) y Visita 24 semanas

E.5.2

Secondary end point(s)

o Acording to GINA criterials: Well, partially and poorly controlled
o Progression from poorly controlled to partially or well controlled, or from partially controlled to controlled, with no change in baseline treatment after randomization
o TAI-12 and electronic prescription
o Number of critical errors with the inhaler
o FSI-10
o Mini-AQLQ
o Severe asthmatic exacerbations
o FEV1, FVC and FEV1/FVC
o Adverse reactions

o Según criterios GINA: Bien, parcialmente y mal controlado
o Progresión de mal controlado a parcialmente o bien controlado, o bien, de parcialmente controlado a controlado, sin cambio en el tratamiento basal tras aleatorización
o TAI-12 y Receta electrónica
o Nº errores críticos con inhalador
o FSI-10
o Mini-AQLQ
o Exacerbaciones asmáticas graves
o FEV1, FVC y FEV1/FVC
o Reacciones adversas

E.5.2.1

Timepoint(s) of evaluation of this end point

Baseline visit and 24 week visit

o Acording to GINA criterials: Well, partially and poorly controlled
o Progression from poorly controlled to partially or well controlled, or from partially controlled to controlled, with no change in baseline treatment after randomization
o TAI-12 and electronic Recipe
o No. critical errors with inhaler
o FSI-10
o Mini-AQLQ
o Severe asthmatic exacerbations
o FEV1, FVC and FEV1/FVC
o Adverse reactions

Visit 4-6 weeks

o Acording to GINA criterials: Well, partially and poorly controlled
o Electronic recipe
o Adverse reactions

Visita Basal y Visita 24 semanas

o Según criterios GINA: Bien, parcialmente y mal controlado
o Progresión de mal controlado a parcialmente o bien controlado, o bien, de parcialmente controlado a controlado, sin cambio en el tratamiento basal tras aleatorización
o TAI-12 y Receta electrónica
o Nº errores críticos con inhalador
o FSI-10
o Mini-AQLQ
o Exacerbaciones asmáticas graves
o FEV1, FVC y FEV1/FVC
o Reacciones adversas

Visita 4-6 semanas

o Según criterios GINA: Bien, parcialmente y mal controlado
o Receta electrónica
o Reacciones adversas

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

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

Efficiency: K-haler® has demonstrated a high lung deposit (≈45% of the emitted dose) and is easy to use. If the main objective of this trial is confirmed, it would allow for an efficient therapeutic option in the control of asthma using a lower therapeutic dose, with the consequent saving of inhaled corticosteroids and a lower probability of producing side effects.

Eficiencia: K-haler® ha demostrado un elevado depósito pulmonar (≈45% de la dosis emitida) y ser fácil de usar. De confirmarse el objetivo principal de este ensayo, permitiría disponer de una opción terapéutica eficiente en el control del asma usando una menor dosis terapéutica, con el consiguiente ahorro de corticoide inhalado y menor probabilidad de producir efectos secundarios.

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

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

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)

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.8.6 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 Visit of the Last Subject (LVLS)

Última 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

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:

190

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

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)

None

Ninguno

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

2020-05-04

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-04-30

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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