Clinical Trials Register

Summary
EudraCT Number:	2017-000784-33
Sponsor's Protocol Code Number:	TacTremorConversion
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-05-30
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

2017-000784-33

A.3

Full title of the trial

Effect of Envarsus conversion on tacrolimus-associated tremor in renal transplant patients. An open-label, single centre, prospective pharmacodynamic/pharmacokinetic clinical study

Efecto del cambio a Envarsus en el temblor asociado a tacrolimus en pacientes trasplantados de riñón. Estudio clínico prospectivo farmacodinámico y farmacocinético, abierto y unicéntrico

A.3.1

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

Study on the effect of switching to Envarsus in renal transplant patients with tacrolimus-associated tremor

Estudio clínico en pacientes trasplantados de riñón para estudiar el efecto del cambio a Envarsus en el temblor asociado a tacrolimus.

A.4.1

Sponsor's protocol code number

TacTremorConversion

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	Fundació Clínic per a la Recerca Biomèdica
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	Chiesi
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	Fundació Clínic per a la Recerca Biomèdica
B.5.2	Functional name of contact point	Applicant
B.5.3	Address:
B.5.3.1	Street Address	Villarroel 170
B.5.3.2	Town/ city	Barcelona
B.5.3.3	Post code	08036
B.5.3.4	Country	Spain
B.5.4	Telephone number	34932279838
B.5.6	E-mail	jaarnaiz@clinic.cat

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	Envarsus prolonged-release tablets
D.2.1.1.2	Name of the Marketing Authorisation holder	Chiesi Farmaceutici S.p.A.
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	tacrolimus
D.3.2	Product code	EU/1/14/935/004
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.3.11 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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Tacrolimus-associated tremor

Temblor asociado al tratamiento con tacrolimus

E.1.1.1

Medical condition in easily understood language

Tacrolimus-associated tremor

Temblor asociado al tratamiento con tacrolimus

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	10044565
E.1.2	Term	Tremor
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 assess the impact of conversion from prolonged-release tacrolimus Advagraf to Envarsus on the presence and severity of tremor

Evaluar el impacto del cambio de presentación de tacrolimus de liberación prolongada Advagraf a Envarsus en la presencia o intensidad del temblor

E.2.2

Secondary objectives of the trial

1. Assessment of changes in pharmacodynamic and immunologic biomarkers related to neurotoxicity.
2. Study of the modification of the genetic profile induced by the conversion in peripheral blood samples.
3. Assess the impact of the switch from Advagraf to Envarsus on the quality of life of patients.
4. Evaluate dose adjustments in the conversion process.
5. Assess graft and patient survival after switching.
6. Evaluate renal function parameters and incidence of common ADRs related to immunosuppressant therapies.

1. Evaluar los cambios en biomarcadores immunológicos asociados a la neurotoxicidad.
2. Estudiar la modificación del perfil genético inducido por el cambio de formulación en muestras de sangre periférica.
3. Evaluar el impacto del cambio de presentación de tacrolimus de liberación prolongada Advagraf a Envarsus en la calidad de vida de los pacientes.
4. Evaluar los ajustes de dosis necesarios en el proceso de sustitución.
5. Evaluar la supervivencia del paciente y del injerto tras el cambio.
6. Evaluar los parámetros de función renal y la incidencia de RAM asociadas al tratamiento inmunosupresor.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Adult kidney allograft recipients from a deceased or living donor (≥ 18 years old) who underwent transplantation between 12 and 18 months before inclusion in the study;
- Patients receiving a stable un-interrupted oral dose of Advagraf® and achieving stable tacrolimus (TAC) trough concentrations between 5-10 ng/mL, since the last visit (steady state conditions);
- Patients without signs of rejection in the per protocol biopsy performed at month 12 after transplantation;
- Patients experiencing clinically significant tremor measured by DyCare wireless sensor (a wearable tool to evaluate movement disorders).
- Patients that have signed the informed consent form.

Pacientes adultos(≥ 18 años) receptores de alotrasplante de riñón de donante vivo o cadáver que recibieron el trasplante entre 12 y 18 meses antes de su inclusion en el estudio;
- Pacientes que reciben de manera ininterrumpida dosis estables de tacrolimus Advagraf® y mantienen concentraciones valle de tacrolimus (TAC) entre 5-10 ng/mL desde la última visita (equilibrio estacionario);
- Pacientes sin signos de rechazo en la biopsia renal de rutina realizada en el mes 12 postrasplante;
- Pacientes que presentan temblor clínicamente significativo medido mediante el sensor DyCare (que evalúa trastornos del movimiento).
- Pacientes que, tras ser adecuadamente informados, firmen la hoja de consentimiento.

E.4

Principal exclusion criteria

Patients receptors of simultaneous liver-kindey, heart-kidney or reno-pancreatic transplant;
- Diagnosis of Parkinson's disease, or other neurological syndromes characterized by the occurrence of tremor;
- Patients who participated in a clinical trial in the last 30 days;
- Patient unable to swallow study medication;
- Current abuse of drugs or alcohol;
- Patient or donor with current diagnosis or history of malignancy (except basal-cell carcinoma or treated squamous cell carcinoma of the skin);
- Known hypersensitivity to tacrolimus;
- Pregnant or lactating women and all women physiologically capable of becoming pregnant UNLESS willing to use a highly efficacious method of contraception throughout the duration of the study;

Receptores de trasplante simultáneo de hígado/riñón, corazón/riñón o reno-pancreático;
- Diagnóstico de enfermedad de Parkinson u otro trastorno neurológico que curse con temblor;
- Participantes en un ensayo clinico en los últimos 30 días;
- Incapaces de tragar la medicación en estudio;
- Abuso actual de alcohol o drogas;
- Paciente o donante con diagnostic o antecedents de cancer (exceptuando carcinoma basocelular o c. espinocelular tratado);
- Hipersensibilidad conocida a tacrolimus;
- Mujeres embarazadas o en period de lactancia o mujeres fértiles que no deseen utilizer un método contraceptivo de alta efectividad durante todo el estudio;

E.5 End points

E.5.1

Primary end point(s)

Tremor assessment (RMS) using DyCare wireless gyroscope and accelerometer sensor before tacrolimus dosing (T0) and after two, four and six hours (T+2, +4, +6) , at Pre-conversion and same timing after 5 days, 1, 2 and 3 months of conversion.

Evaluación del temblor (RMS) mediante el sensor giroscopio y acelerómetro inalámbrico DyCare antes de la toma de tacrolimus (T0) y a las 2, 4 y 6 horas (T+2, +4, +6), antes de la conversión y el los mismos tiempos al cabo de 5 días, 1, 2 y 3 meses tras la conversión.

E.5.1.1

Timepoint(s) of evaluation of this end point

5, 30, 60 and 90 days

5, 30, 60 y 90 días

E.5.2

Secondary end point(s)

Change of blood and urine biomarkers related with neurotoxicity (before conversion, 30 days and 3 months after conversion):
• Plasma: miRNA analysis (miR-210)
• Urine samples: CXCL10
• Cytokine analysis: IL-12, IL-10
• Residual NFAT gene expression of IL-2, IFN-gamma

- Modification of the genetic profile induced by conversion in peripheral blood samples:
- Changes in the quality of life of the patients (quality of life in essential tremor questionnaire, QUEST) 3 months after the switch comparing to baseline score (pre-switch).
- Treatment failures (death, graft failure, local BPAR (biopsy- proven acute rejection) or lost to follow-up).

Cambio en los biomarcadores en sangre y orina relacionados con la neurotoxicidad (antes de la conversion y a los 30 días y 3 meses tras la conversión):
• Plasma: análisis demiRNA (miR-210)
• Orina: CXCL10
• Citocinas: IL-12, IL-10
• Expresión genética residual de NFAT de IL-2, IFN-gamma
- Modificación del perfil genético inducido por la conversion en muestras de sangre periférica
- Cambios en la calida de vida de los pacientes (cuestionario “quality of life in essential tremor questionnaire”, QUEST) a los tres meses del cambio en comparación con el resultado pre-cambio
- Fracasos del tratamiento (muerte, fracaso del injerto, rechazo agudo local detectado mediante biopsia (BPAR) o pérdida de seguimiento).

E.5.2.1

Timepoint(s) of evaluation of this end point

5, 30, 60 and 90 days

5, 30, 60 y 90 días

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

Yes

E.6.7

Pharmacodynamic

Yes

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

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

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)

E.8.2.2

Placebo

E.8.2.3

Other

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

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:

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

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

2017-07-31

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-07-26

P. End of Trial
P.	End of Trial Status	Ongoing

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