Clinical Trials Register

Summary
EudraCT Number:	2019-000717-37
Sponsor's Protocol Code Number:	AMGEVITA-HVM2019
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:	2019-06-28
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

2019-000717-37

A.3

Full title of the trial

LOSS OF RESPONSE OF THE ADALIMUMAB BIOSIMILAR COMPARED WITH THE LOSS OF RESPONSE OF THE ADALIMUMAB ORIGINAL: CONTROLLED, RANDOMIZED, NON-INFERIORITY OPEN STUDY.
"ADA-SWITCH Study"

PÉRDIDA DE RESPUESTA DEL FÁRMACO BIOSIMILAR DE ADALIMUMAB COMPARADA CON LA PÉRDIDA DE RESPUESTA DEL FÁRMACO ORIGINAL: ESTUDIO CONTROLADO, RANDOMIZADO, DE NO INFERIORIDAD Y ABIERTO.
“Estudio ADA-SWITCH”

A.3.1

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

Loss of response of the Adalimumba biosimilar compared with the original drug

Perdida de respuesta del biosimilar de Adalimumab comparada con el medicamento original

A.3.2

Name or abbreviated title of the trial where available

ADA-SWITCH Study

Estudio ADA-SWITCH

A.4.1

Sponsor's protocol code number

AMGEVITA-HVM2019

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	Fundación Publica Andaluza para la Gestión de Salud en Sevilla (FISEVI)
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	own funding
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	Unidad de Investigación Clínica y Ensayos Clínicos
B.5.2	Functional name of contact point	UICEC-HUVR
B.5.3	Address:
B.5.3.1	Street Address	Avenida Manuel Siurot S/N
B.5.3.2	Town/ city	Sevilla
B.5.3.3	Post code	41013
B.5.3.4	Country	Spain
B.5.4	Telephone number	0034955012144
B.5.5	Fax number	0034955095338
B.5.6	E-mail	claram.rosso.sspa@juntadeandalucia.es

D. IMP Identification
D.IMP: 1
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	AMGEVITA®
D.2.1.1.2	Name of the Marketing Authorisation holder	Amgen Europe B.V.
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.3.1	Product name	AMGEVITA (Adalimumab biosimilar )
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.3.11 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	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.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	HUMIRA ®
D.2.1.1.2	Name of the Marketing Authorisation holder	AbbVie Deutschland GmbH Co. KG
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.3.1	Product name	Humira (adalimumab original)
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.3.11 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	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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Inflammatory Bowel Disease: Crohn's Disease and Ulcerative Colitis

Enfermedad Inflamatoria intestinal: Enfermedad de Crohn y Colitis Ulcerosa

E.1.1.1

Medical condition in easily understood language

Inflammatory Bowel Disease

Enfermedad Inflamatoria intestinal

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

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 loss of response of the switch (replacement) from Adalimumab original (Humira®) to Adalimumab biosimilar (Amgevita®) vs the maintenance of the Adalimumab original in patients with inflammatory bowel disease.

Comparar la pérdida de respuesta del switch (sustitución) de Adalimumab original (Humira®) por Adalimumab biosimilar (Amgevita®) vs el mantenimiento del medicamento original en pacientes con enfermedad inflamatoria intestinal.

E.2.2

Secondary objectives of the trial

- Compare the safety of the Adalimumab original switch (Humira®) to Adalimumab biosimilar (Amgevita®) vs the maintenance of the original medication in patients with inflammatory bowel disease.
- Compare the antibody formation rate with Adalimumab(immunogenicity) after the switch.
- Compare the score of the specific quality of life questionnaire in patients with inflammatory bowel disease (IBDQ-9) before and after the switch.
- Compare the score of the visual analogue scale (VAS) of pain at the puncture site after the switch.
- Determine prognostic factors for the maintenance of biochemical remission (C-reactive protein, calprotectin), and drug (drug levels, formation of antibodies against ADA drug).

Comparar la seguridad del switch de Adalimumab original (Humira®) a Adalimumab biosimilar (Amgevita®) vs el mantenimiento del medicamento original en pacientes con enfermedad inflamatoria intestinal.
Comparar la tasa de formación de anticuerpos contra el fármaco (inmunogenicidad) tras el switch.
Comparar la puntuación del cuestionario de calidad de vida específico en pacientes con enfermedad inflamatoria intestinal (IBDQ-9) antes y después del switch.
Comparar la puntuación de la escala análoga visual (EVA) de dolor en el sitio de punción tras el switch.
Determinar factores pronósticos para el mantenimiento de la remisión bioquímicos (PCR, calprotectina), como del medicamento (niveles de fármaco, formación de anticuerpos contra fármaco ADA).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Be male or female over 18 years of age
- Be a Patient with a previous confirmed diagnosis of Crohn´s disease an Ulcerative Colitis
- Previous treated with original Adalimumab for at least 6 months with regular maintenance dose (40 mg every 15 days) and in clinical and biological remission.
- Patients under treatment with intensified Adalimumab (40mg every 7 days or 80mg every 7 days) to maintain clinical and biological remission for at least 6 months.
- Patients with oral mesalazine with a stable dose for more than 30 days.
- Patients with immunosuppressive therapy (methotrexate, azathioprine) with a minimum intake time> 60 days.
- Patients may be accepted with corticosteroids at the established doses: prednisone <20mg / dl, budesonide <9mg / dl.
- Patients who have a tuberculosis (TB) study (Mantoux / QuantiFERON-TB test) updated in the last two year, with a negative result.
- Patient with serology hepatitis B and C, updated at the begining of the treatment with Humira®
- Sign an informed consent document indicating that he/she understands the purpose of, and procedures required for, the study and are willing to participate in the study.

- Hombre o mujeres mayores de 18 años
- Paciente con diagnostico confirmado de Enfermedad de Crohn y Colitis Ulcerosa
- Tratamiento previo con Adalimumab original durante al menos 6 meses con dosis regular de mantenimiento (40 mg cada 15 días) y que se encuentren en remisión clínica y biológica.
-Pacientes en tratamiento con Adalimumab intensificado (40mg cada 7 días u 80mg cada 7 días) que se mantengan remisión clínica y biológica por al menos 6 meses. -
-Pacientes con mesalazina oral con dosis estables por más de 30 días.
-Pacientes con terapia inmunosupresora (metotrexato, azatioprina) con un mínimo de tiempo de toma > 60 días.
- Se podrá incluir pacientes con toma de corticoides a las dosis establecidas: prednisona < 20mg/dl, budesónida <9mg/dl.
- Pacientes que tenga estudio de Tuberculosis (TBC) (Mantoux/quantiferon) actualizado en el último año, con resultado negativo.
- Paciente con serología hepatitis B y C actualizada al inicio del tratamiento con Humira®
- Firma de consentimiento informado indicando el proposito del estudio, los procedimientos a efectuarse, y la aceptación de participación.

E.4

Principal exclusion criteria

-Pregnant or nursing women
- Patients with uncontrolled comorbidities, active cancer, diabetes mellitus, severe cardiovascular disease, obstructive pulmonary disease, serious active infections.
- Patients with oral mesalazine initiated less than 30 days.
- Patients with immunosuppressive therapy (methotrexate, azathioprine) with a minimum intake time of <60 days.
- Patient with original Adalimumab who do not meet a minimum of 6 months of stable dose (40 mg every 7 or 15 days)
- Patient on corticosteroid therapy at doses: prednisone> 20mg / dl, budesonide = 9mg / dl, or with IV corticoids within 14 days prior screening date.
- Patients with mental disorders, alcohol / other substance abuse, or conditions that do not allow adherence to the study protocol.
- Patients with active TB
- Patients with defined Hepatitis B and C defined as:
HBV: hepatitis B surface antigen (HbsAg) positive together with positive HBV deoxyribonucleic acid (DNA) polymerase chain reaction (PCR).
HCV: HCV ribonucleic acid (RNA) detectable in any patient with positive anti-HCV antibody (IgG)

-Mujeres embarazadas o en lactancia
-Pacientes con comorbilidades no controladas, cáncer activo, diabetes mellitus, Enfermedad cardiovascular severa, enfermedad pulmonar obstructiva, infecciones graves activas.
-Pacientes con mesalazina oral iniciada en menos de 30 días.
-Pacientes con terapia inmunosupresora (metotrexato, azatioprina) con un mínimo de tiempo de toma < 60 días.
-Paciente con Adalimumab original que no cumplan mínimo 6 meses de dosis estable (40 mg cada 7 o 15 días)
-Paciente en terapia con corticoides a dosis: prednisona > 20mg/dl, budesónida = 9mg/dl, o con corticoides intravenosos durante los 14 días previos a la fecha de selección-
-Pacientes con trastornos mentales, abuso de alcohol/otras sustancias, u condiciones que no permitan la adherencia al protocolo de estudio.
-Pacientes con TBC activa
-Pacientes con Hepatitis B y C definido:
VHB: Hepatitis B antígeno de superficie positivo (HbsAg+) junto con DNA VHB positivo.
VHC: RNA detectable con IgG positivo;

E.5 End points

E.5.1

Primary end point(s)

Loss of response: measured as the proportion of patients with a loss of response at twelve months (adalimumab original vs adalimumab biosimilar)

Pérdida de respuesta: medida como la proporción de pacientes con pérdida de respuesta durante los doce meses en cada grupo (adalimumab original vs adalimumab biosimilar)

E.5.1.1

Timepoint(s) of evaluation of this end point

12-months

Doce meses

E.5.2

Secondary end point(s)

Loss of response:
- Proportion of patients who need treatment intensification
- Proportion of patients who need corticosteroids
- Proportion of patients who need to change biological due to loss of response
- Proportion of patients with changes in the quality of life index (IBDQ-9) after the switch.
- Proportion of patients presenting a higher score on the analogous scale of pain after the drug switch.

Immunogenicity
Immunogenicity rate: measured as the proportion of patients that generate anti- drug antibodies after the switch

Safety
- Rate of adverse events: measured as the proportion of adverse events during the clinical study. (all types of adverse events will be reported, and they will be graduated according to their severity and will collected in CRF)
- Hospital admission rate measured as the proportion of patients requiring hospital admissions related to a disease outbreak during follow-up.
- Surgery rate: measured as the proportion of patients requiring surgery related to disease activity during follow-up.

Perdida de respuesta:
Proporción de pacientes que necesitan intensificación de tratamiento
Proporción de pacientes que necesitan la toma de corticoides
Proporción de pacientes que necesitan cambiar de biológico por perdida de respuesta
Proporción de pacientes con cambios en la encuesta de calidad de vida (IBDQ-9) tras la sustitución del medicamento.
Proporción de pacientes que presentan puntuación elevada en la escala análoga del dolor tras la sustitución del fármaco.

Inmunogenicidad:

Tasa inmunogenicidad: medida como la proporción de pacientes que generan anticuerpos antifármaco tras el switch

Seguridad :

Tasa de acontecimientos adversos: medida como la proporción de eventos adversos durante el estudio clínico. (se reportarán todo tipo de eventos adversos que serán graduados según gravedad y anotados en CRD)
Tasa de ingresos hospitalario medida como la proporción de pacientes que requieren ingresos hospitalarios relacionados con brote de la enfermedad durante el seguimiento.
Tasa de cirugía: medida como la proporción de pacientes que requieren cirugía relacionada con actividad de la enfermedad durante el seguimiento.

E.5.2.1

Timepoint(s) of evaluation of this end point

loss of response : 12 months
Safety : 16 months

Perdida de respuesta: 12 meses
Seguridad: 16 meses

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

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

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

A subject will be withdrawn from the study for any of the following reasons:
The patient (or the subject´s representative) withdraws of consent for study participation
The patient experiences serious adverse reactions related to the treatment during the follow-up
The patient develops a malignancy including squamous cell skin cancer.
Serious opportunistic infections occur
Loss of follow-up

Criterios de finalización o interrupción del estudio
- El pacientes ( o su representante) retiren el consentimiento informado
- Paciente presente eventos adversos serios durante el seguimiento
- El pacientes desarrolle un tumor incluido cancer de piel
- Infecciones oportunistas serias
- Perdida del seguimiento
- Perdida de eficacia
- Pacientes que no cumplan adherencia al tto.
- Autoadministración de corticoides orales o mesalazina.

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:

116

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

Information not present in EudraCT

F.4 Planned number of subjects to be included

F.4.1

In the member state

136

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

136

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)

The clinical study will be completed after 12 months of follow-up of the last patient included in the clinical study.

After the study is considered complete, patients will continue with the same treatment in routine clinical practice.

El ensayo clínico se completará después de 12 meses de seguimiento del ultimo paciente incluido.

Después que el estudio termine, los pacientes continuaran con el mismo tratamiento en las consultas clínicas habituales.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	UICEC-HUVR
G.4.3.4	Network Country	Spain

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2019-06-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-05-27

P. End of Trial
P.	End of Trial Status	Prematurely Ended
P.	Date of the global end of the trial	2020-06-08

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