Clinical Trials Register

Summary
EudraCT Number:	2018-001094-25
Sponsor's Protocol Code Number:	PHEMI
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2021-05-20
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-001094-25

A.3

Full title of the trial

Phenylbutyrate Therapy in Mitochondrial Disease with lactic acidosis: an opel label clinical trial in MELAS and PHD deficiency patients

Phemi: Terapia con Fenilbutirrato nelle malattie mitocondriali con acidosi lattica: un trial open label nella sindrome MELAS e nell’Encefalopatia da difetto di PDH

A.3.1

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

Clinical trial with Phenilbutirrate to reduce lactic acid in patients affected with Melas Syndrome and PHD deficency encephalopathy

Sperimentazione Terapeutica con Fenilbutirrato per ridurre l'accumulo di acido lattico in pazienti affetti da Sindrome di Melas ed nell’Encefalopatia da difetto di PDH

A.3.2

Name or abbreviated title of the trial where available

PHEMI

A.4.1

Sponsor's protocol code number

PHEMI

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	FONDAZIONE IRCCS ISTITUTO NEUROLOGICO CARLO BESTA
B.1.3.4	Country	Italy
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Fondazione IRCCS Istituto Neurologico Carlo Besta
B.5.2	Functional name of contact point	Dipartimento di Ricerca e Sviluppo
B.5.3	Address:
B.5.3.1	Street Address	Via Celoria 11
B.5.3.2	Town/ city	Milano
B.5.3.3	Post code	20133
B.5.3.4	Country	Italy
B.5.4	Telephone number	0223943568
B.5.5	Fax number	0223943568
B.5.6	E-mail	crc@istituto-besta.it

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	Feburane
D.2.1.1.2	Name of the Marketing Authorisation holder	042917
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	pheburane
D.3.2	Product code	[A042917017]
D.3.4	Pharmaceutical form	Granules for oral suspension
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.3.9.2	Current sponsor code	A042917017
D.3.10	Strength
D.3.10.1	Concentration unit	mg/g milligram(s)/gram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	483
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	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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	Yes
D.3.11.13.1	Other medicinal product type	substrato

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

Melas Syndrome and PDH deficency enchephalopathy

Sindrome di Melas, Encefalopatia da deficit di PDH

E.1.1.1

Medical condition in easily understood language

Mitochondrial disease

malattia mitocondrilae

E.1.1.2

Therapeutic area

Diseases [C] - Nutritional and Metabolic Diseases [C18]

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	10053872
E.1.2	Term	MELAS syndrome
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

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	10053872
E.1.2	Term	MELAS syndrome
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10062950
E.1.2	Term	Leigh syndrome
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic disorders

E.1.3

Condition being studied is a rare disease

Yes

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to investigate the efficiency and safety of PB in patients with PDH deficiency and MELAS .

Verificare la tollerabilità del PB nei pazienti con Encefalopatia da PDH e pazienti MELAS

E.2.2

Secondary objectives of the trial

The secondary objectives are to identify novel biomarkers for these two diseases and to evaluate whether the clinical/biochemical efficacy detected in patients correlates with the response observed in the skin fibroblasts of PDH deficiency/MELAS patients and in cybrids from MELAS patients incubated with PB.

Verificare l’efficacia del PB sulla base di dati biochimici e clinici nei pazienti con Encefalopatia da PDH e pazienti MELAS; Valutare la correlazione dei dati biochimici e clinici con la risposta al PB nei fibroblasti dei pazienti PDH e nei cibridi dei pazienti MELAS e identificare nuovi biomarker per questi due gruppi di malattie

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

The inclusion criteria are:
1. Age between 3 and 65 years old
2. Confirmed molecular diagnosis: mutations in PDHA1 and m.3 243A>G mtDNA point mutation
3. Plasma lactic acid =2100 umol/l (normal value . 580-2100)
4. Availability of brain MRI and MRSI at baseline (pre-treatment);
5. Availability of PDH residual activity in cultured fibroblasts in PDH1A patients at baseline (pre-treatment)
6. Written informed consent (and assent when applicable) obtained from subject or subject’s legal representative and ability for subject to comply with the requirements of the study.

1. Età compresa tra i 3 ed i 65 anni
2.Diagnosi molecolare (mutazione in PDHA1 o mutazione m.3243A>G nel DNA mitocondriale per i pz MELAS )
3.Lattato plasmatico>2100 Umol/l (vn 580-2100)
4.Disponibilità della RM encefalo e della spettroscopiaprima dell’inizio del trattamento (baseline)
5.Disponibilità del dato di attività della PDH nei fibroblasti dei pz con Encefalopatia da difetto della PDH alla baseline
6. Disponibilità del consenso informato scritto

E.4

Principal exclusion criteria

The exclusion criteria will be:
1) Comorbidity with other chronic diseases.
2) Other experimental treatment in the previous 6 months.
3) Pregnant, breastfeeding, or unwilling to practice birth control during participation in the study
4) At Screening, the estimated glomerular filtration rate (eGFR) < 30 mL/min/1.73 m2.
5) At Screening presence of history of liver failure.
6) Subject has undergone an in-patient hospitalization within the 30 days prior to the Baseline Visit or has a planned hospitalization or a surgical procedure during the trial.
7) Subject has a history of active substance abuse during the year before the Baseline Visit, in the opinion of the Investigator.
8) Subject has any prior or current medical condition that, would prevent the subject from safely participating in and/or completing all trial requirements .
9) The patient will be excluded from the study if he presents a hart insufficiency ( FE < 40% ) severe renal failure (GRF GFR between 29 and 15 ml/min) clinical conditions in which sodium retention is found with edema, fructose intolerance, glucose / galactose malabsorption or saccharose or isomaltase enzyme deficiencies.
10) Hypersensitivity to the drug or to the excipients.
11) Not able to obtain written informed consent (and assent when applicable) from subject or subject’s legal representative and ability for subject to comply with the requirements of the study.

Criteri di esclusione:
1. Comorbidità con altre patologie croniche,
2.Pazienti sottoposti ad altre terapie sperimentali nei 6 mesi precedenti ..
3. Paziente in gravidanza o in allattamento, o non disposto a praticare il controllo delle nascite durante la partecipazione allo studio
4. Allo screening (eGFR) < 30 mL/min/1.73 m2
5. Allo screening anamnesi positiva per epatopatia
6. Soggetto che ha subito un ricovero ospedaliero entro i 30 giorni precedenti la visita di base o ha un ricovero ospedaliero pianificato o una procedura chirurgica durante lo studio.
7. Anamnesi positiva per abuso di sostanza stupefacenti o alcolitici
8.Condizione medica precedente o attuale che, impedirebbe al soggetto di partecipare in sicurezza e / o completare lo studio.
9. Grave insufficienza cardiaca (FE <40%), una grave insufficienza renale (GRF GFR tra 29 e 15 ml / min) o condizioni cliniche per cui ha ritenzione di sodio con edema, intolleranza al fruttosio, glucosio / malassorbimento di galattosio o carenze di enzimi saccarosio o isomaltasi.
10. Ipersensibilità al farmaco o ai suoi eccipienti
11. Non in grado di fornire il consenso informato scritto (o l'assenso quando applicabile) o impossibilità di ottenere il consenso dal rappresentante legale del soggetto e incapacità del soggetto di conformarsi ai requisiti dello studio.

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint of the study is the reduction of lactic acidosis.

Riduzione della concentrazione di acido lattico plasmatico .

E.5.1.1

Timepoint(s) of evaluation of this end point

All along the trial

Tutto il tempo della sperimentazione

E.5.2

Secondary end point(s)

A. Clinical efficiency of PB
B. To evaluate the biochemical efficiency of PB,

Efficacia clinica del PB
Efficacia biochimica del PB

E.5.2.1

Timepoint(s) of evaluation of this end point

All along the trial

Tutta la durata della sperimentazione

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

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)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

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

Yes

E.8.2.3.1

Comparator description

non esiste comparatore

No comparison

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

Information not present in EudraCT

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

La sperimentazione si riterrà conclusa con l'ultima visita di follow up dell'ultimo paziente incluso

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.1.1.1

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

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

Yes

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Underage with tutor

Soggetti minorenni con tutore legale

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

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)

Patients will continue to be followed up in outpatients setting . If case of efficiacy of the drug the therphy will be manteined

I pazienti saranno mantenuti in follow-up clinico come prima dello studio. Se dimostrata l'efficacia della terapia verrà continuato il trattamento

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

2019-09-12

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-01-16

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

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