Clinical Trials Register

Summary
EudraCT Number:	2016-001714-14
Sponsor's Protocol Code Number:	136PO15274
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2019-12-17
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2016-001714-14

A.3

Full title of the trial

Clinical evaluation of switching to Lithiofor® (Lithium Sulphate Slow –Release, Li-SR tablets) from Carbolithium® (Lithium Carbonate Immediate-Release, Li-IR, capsules) in Bipolar patients, poorly tolerant to lithium immediate-release treatment

A.3.1

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

Switching to the Administration of Lithium slow-release Treatment, from Lithium immediate-release

Cambio di terapia da Litio a rilascio immediato a Litio a rilascio lento

A.3.2

Name or abbreviated title of the trial where available

SALT study (Switching to the Administration of Lithium slow -release Treatment)

Studio SALT (Cambio di Terapia da Litio a rilascio immediato a litio a rilascio lento)

A.4.1

Sponsor's protocol code number

136PO15274

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	AZIENDE CHIMICHE RIUNITE ANGELINI FRANCESCO A.C.R.A.F. S.P.A.
B.1.3.4	Country	Italy
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	AZIENDE CHIMICHE RIUNITE S.p.A.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	AZIENDE CHIMICHE RIUNITE ANGELII FRANCESCO ACRAF S.p.A.
B.5.2	Functional name of contact point	CTAunit
B.5.3	Address:
B.5.3.1	Street Address	Piazzale della Stazione snc
B.5.3.2	Town/ city	S.Palomba-Pomezia
B.5.3.3	Post code	00070
B.5.3.4	Country	Italy
B.5.4	Telephone number	0691045335
B.5.5	Fax number	069109729
B.5.6	E-mail	ctaunit@angelini.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	Lithiofor®
D.2.1.1.2	Name of the Marketing Authorisation holder	Vifor
D.2.1.2	Country which granted the Marketing Authorisation	Germany
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	Lithiofor®
D.3.2	Product code	136
D.3.4	Pharmaceutical form	Prolonged-release tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
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	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	CARBOLITHIUM - 150 MG
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA ITALIA S.R.L.
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	Carbolithium® 150 mg
D.3.2	Product code	Non applicabile
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
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	No
D.IMP: 3
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	CARBOLITHIUM - 300 MG CAPSULE RIGIDE 50 CAPSULE
D.2.1.1.2	Name of the Marketing Authorisation holder	TEVA ITALIA S.R.L.
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	Carbolithium® 300 mg
D.3.2	Product code	Non applicabile
D.3.4	Pharmaceutical form
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP
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	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

Bipolar disorder I or II with or without rapid cycling

Disturbo Bipolare di Tipo I e II con o senza cicli rapidi

E.1.1.1

Medical condition in easily understood language

Bipolar disorder

Disturbo Bipolare

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	21.1
E.1.2	Level	PT
E.1.2	Classification code	10057667
E.1.2	Term	Bipolar disorder
E.1.2	System Organ Class	10037175 - Psychiatric 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

The primary objective of the study is the evaluation of the change in the lithium-induced tremor when switching from lithium IR formulation (Carbolithium®) to a new lithium Slow-Release (SR) formulation (Lithiofor®), after 1 week.

L’obiettivo primario dello studio è la valutazione del cambiamento nel tremore indotto dal litio dopo 1 settimana dal passaggio dal litio, formulazione a Rilascio Immediato IR (Carbolithium®), alla nuova formulazione a Lento Rilascio SR (Lithiofor®).

E.2.2

Secondary objectives of the trial

The secondary objectives will include the assessment of the a) effect on the lithium-induced tremor up to 12 weeks, b) drug-induced polyuria/polydipsia c) manic and depressive symptoms; d) treatment satisfaction e) quality of life f) Clinical Global Impression (CGI) g) safety when switching from a lithium IR formulation (Carbolithium®) to a new lithium SR formulation (Lithiofor®).

Gli obiettivi secondari includeranno la valutazione di: a) effetto sul tremore indotto dal litio fino a 12 settimane; b) poliuria / polidipsia indotta dal farmaco; c) sintomi maniacali e depressivi d) soddisfazione rispetto al trattamento; e) qualità della vita; f) Clinical Global Impression (CGI); g) sicurezza del passaggio dalla formulazione IR (Carbolithium®) alla nuova formulazione di litio SR (Lithiofor®).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Male or female patients aged 18 to 65 years, with no limitation of race. Female patients with childbearing potential should have a negative pregnancy test and should not be breastfeeding. Male and female patients should use an appropriate birth control method 2) Diagnosis of Bipolar disorder I or II (as per DSM-5), with or without rapid cycling, 3) BD patients in treatment with lithium Carbolithium® immediate-release, presenting at the screening and baseline low tolerability in terms of tremor (tremor severity assessment ≥ 2 on single item of the UKU side-effect rating scale), 4) Patients with screening and baseline MADRS score ≤ 10 and YMRS ≤ 12, 5) Patients legally capable to give their consent to participate in a clinical study. A written informed consent to participate to the trial must be signed and dated by the patient prior to the inclusion in the study, 6) Patient able to understand the study procedures and to comply with protocol requirements.

) Pazienti maschi o femmine di età compresa tra i 18 e 65 anni, di qualunque etnia. Le pazienti donne in età fertile devono avere un test di gravidanza negativo e non devono essere in allattamento. I pazienti, maschi e femmine, devono usare un valido metodo di contraccezione; 2) pazienti con diagnosi di Disturbo Bipolare di tipo I o II (secondo classificazione DSM-5), con o senza cicli rapidi; 3) pazienti con BD in trattamento con Carbolithium® a rilascio immediato, che mostrano allo screening e al basale una scarsa tollerabilità in termini di tremore (gravità del tremore ≥ 2 valutata tramite un singolo item della scala di misurazione degli effetti collaterali UKU); 4) pazienti che alle visite di screening e basale hanno un punteggio alla scala MADRS ≤ 10 e alla scala YMRS ≤ 12; 5) pazienti in grado, dal punto di vista legale, di dare il consenso a partecipare a uno studio clinico; il Consenso Informato scritto alla partecipazione al trial clinico deve necessariamente essere firmato e datato dal paziente prima dell’inclusione nello studio; 6) pazienti in grado di comprendere le procedure dello studio e di aderire a quanto richiesto dal protocollo.

E.4

Principal exclusion criteria

Schizophrenia, psychotic and schizoaffective disorders, unipolar depression; concomitant organic mental disorder or intellectual disability; history of dementia or cognitive disorders, any neurodegenerative diseases; Patients with history of hypersensitivity to lithium or any of study formulations’ excipients; Pharmacological treatments affecting tremor except for patients treated for at least 2 months before the screening visit (i.e. Beta-blockers) Known tremor due to irreversible lithium neurotoxicity Patients at risk for suicidal behavior; Immunocompromised patients, Acute, chronic, or recurrent medical condition that might affect/jeopardize the study results, Any contraindication listed in the Summary of Product Characteristics (SPC) of CARBOLITHIUM® and LITHIOFOR®; Positive history for drugs, Alcohol abuse and Positive urine drug screen for CNS-active drugs at Visit 0, Participation to an interventional clinical study within 3 months prior to the screening visit;

Schizofrenia, disturbi psicotici e schizo-affettivi, depressione unipolare, disturbo mentale di origine organica concomitante o disabilità intellettiva, storia di demenza o disturbi cognitivi, qualsiasi malattia neurodegenerativa; pazienti con storia di ipersensibilità al litio o a qualunque eccipiente utilizzato nelle formulazioni in studio; trattamenti farmacologici che agiscono sul tremore, tranne per pazienti che siano in trattamento da almeno 2 mesi prima della visita di screening (es. betabloccanti); tremore noto per essere causato da neuro tossicità irreversibile da litio; pazienti a rischio di comportamenti suicidari; pazienti immunocompromessi; condizioni mediche acute, croniche o ricorrenti che potrebbero influenzare/mettere a rischio i risultati dello studio; qualsiasi controindicazione che figuri nel riassunto delle caratteristiche del prodotto (RCP) del CARBOLITHIUM® e del LITHIOFOR®; storia di abuso di droghe, alcool; positività al test delle urine per droghe attive sul SNC alla Visita 0; partecipazione ad un altro studio clinico interventistico nei 3 mesi precedenti alla visita di screening

E.5 End points

E.5.1

Primary end point(s)

• proportion of patients with an improvement in tremor assessed by a single item of the UKU side-effect rating scale (item 2.5 tremor) after 1-week treatment period compared to baseline.

• percentuale di pazienti con un miglioramento del tremore, valutato tramite un singolo item della scala di misurazione degli effetti collaterali UKU (item 2.5 tremore), dopo 1 settimana di trattamento rispetto al basale.

E.5.1.1

Timepoint(s) of evaluation of this end point

1 week

1 settimana

E.5.2

Secondary end point(s)

safety assessment (adverse events monitoring, physical examination, vital signs, ECG, laboratory analyses, plasma Lithium concentration

valutazione della sicurezza (monitoraggio degli eventi avversi, esame obiettivo, segni vitali, ECG, esami di laboratorio, concentrazione plasmatica del litio).

E.5.2.1

Timepoint(s) of evaluation of this end point

Through the study

Durante lo studio

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

Yes

E.8.2.3.1

Comparator description

Carbolithium®, 150 mg e Carbolithium® 300 mg

Lithium carbonate 150 mg and Lithium carbonate 150 mg

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.8.5.1

Number of sites anticipated in the EEA

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

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

F.1.1

Number of subjects for this age range:

F.1.1.1

In Utero

Information not present in EudraCT

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

Information not present in EudraCT

F.1.1.3

Newborns (0-27 days)

Information not present in EudraCT

F.1.1.4

Infants and toddlers (28 days-23 months)

Information not present in EudraCT

F.1.1.5

Children (2-11years)

Information not present in EudraCT

F.1.1.6

Adolescents (12-17 years)

Information not present in EudraCT

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

138

F.1.3

Elderly (>=65 years)

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

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

138

F.4.2

For a multinational trial

F.4.2.1

In the EEA

138

F.4.2.2

In the whole clinical trial

138

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)

After the end of the 12 weeks of treatment with both study drugs, lithium formulations available on the market will be prescribed to patients by the investigator, according to his/her judgement.

Alla fine dello studio, concluse le 12 settimane di trattamento con i farmaci in studio, lo Sperimentatore valuterà le condizioni del paziente e in accordo al proprio giudizio clinico gli prescriverà la formulazione di Litio disponibile sul mercato.

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

2018-08-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-07-12

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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