Clinical Trials Register

Summary
EudraCT Number:	2005-001009-25
Sponsor's Protocol Code Number:	DR04-07-02
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2006-03-15
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

2005-001009-25

A.3

Full title of the trial

Efficacy, safety and tolerability of Atorvastatin 40 mg in patients with Relapsing-remitting multIple sclerosis in treAtment with INterferoN-betA.

Efficacia, sicurezza e tollerabilita` dell`Atorvastatina 40 mg in pazienti con sclerosi multipla recidivante remittente in trattamento con Interferone beta. (ARIANNA)

A.3.2

Name or abbreviated title of the trial where available

ARIANNA

A.4.1

Sponsor's protocol code number

DR04-07-02

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	DR DIMENSIONE RICERCA
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
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation
B.5.2	Functional name of contact point

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	TORVAST*10CPR 10MG
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER ITALIA Srl
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.3.4	Pharmaceutical form	Film-coated tablet
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.3.8	INN - Proposed INN	Atorvastatin
D.3.9.1	CAS number	134523-03-8
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	40
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.IMP: 2
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	TORVAST*10CPR 10MG
D.2.1.1.2	Name of the Marketing Authorisation holder	PFIZER ITALIA Srl
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.3.4	Pharmaceutical form	Film-coated tablet
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.3.8	INN - Proposed INN	Atorvastatin
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.3	Concentration number	10
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Film-coated tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Multiple sclerosis treatment

Trattamento della sclerosi multipla

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	14.1
E.1.2	Level	PT
E.1.2	Classification code	10028245
E.1.2	Term	Multiple sclerosis
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

The primary endpoint of the study is the efficacy of Atorvastatin compared to placebo, in patients RRMS already in treatment with Interferon-beta, evaluating the disease activity measured by the changes in brain atrophy after 24 months of treatment.

Efficacia dell Atorvastatina, in confronto al placebo, somministrata in pazienti con sclerosi multipla recidivante-remittente (SMRR) gia` in trattamento con interferone beta, valutando l attivita` di malattia attraverso la misurazione del cambiamento dell atrofia cerebrale dopo 24 mesi di trattamento.

E.2.2

Secondary objectives of the trial

1.Clinical disease progression (EDSS, MSFC)2.Functional systems subscores of EDSS and MSFC 3.Cognitive performance by Rao battery tests4.Proportion of patients relapse-free after 12 and 24 months of treatment5.Relapse rate after 12 and 24 months of treatment6. Hazard rate of relapses7.Time to first relapse 8. Number of T1 lesions for each patient after 12 and 24 months of treatment 9. Number of T2 lesions for each patient after12 and 24 months of treatment10. New T2 lesions after 24 months 11.Number of Gd-enhancing lesion on T1-weighted images after 12 and 24 months of treatment12. Volume changes of total T2 lesions after 12 and 24 months of treatment13.Volume changes of total T1 lesions after 12 and 24 monthsoftreatment 14.Proportion of patients without increase of total lesion volume after 12 and 24 months of treatment 15.Changes in brain volume,(atrophy after 12months, grey matter and white matterafter12and24 months)16.NAband MxAtitles17Serum lipid levels18.Correlationof APOE

Progressione clinica della malattia(EDSS,MSFC)2.Sottopunteggi dei sistemi funzionali di EDSS e MSFC 3.Performance cognitiva4.Proporzione di paz liberi da ricadute dopo 12 e 24 mesi di tratt 5.Tasso di ricadute dopo 12 e 24 mesi di tratt 6.Tasso di rischio di ricaduta 7.T alla prima ricaduta 8.NR di lesioni T1 per ciascun paz dopo 12 e 24 mesi di tratt 9.Numero di lesioni T2 per ciascun paz dopo 12 e 24 mesi di tratt 10.Proporzione di paz con nuove lesioni in T2 dopo 24 mesi di tratt.11.NR di lesioni captanti gadolinio in immagini T1 pesate dopo 12 e 24 mesi di tratt 12.Variaz di volume di tutte le lesioni in T2 dopo 12 e 24 mesi di tratt 13.Variaz di volume di tutte le lesioni in T1 dopo 12 e 24 mesi di tratt 14.Proporzione di paz senza aumento del volume totale di lesioni dopo 12 e 24 mesi di tratt 15.Modificazioni del volume cerebrale(atrofia dopo 12 mesi,sostanza grigia e bianca dopo 12 e 24 mesi)16.Titolazioni di NAB e MxA 17.Livelli plasmatici dei lipidi

E.2.3

Trial contains a sub-study

Yes

E.2.3.1

Full title, date and version of each sub-study and their related objectives

ALTRI SOTTOSTUDI:
1. Dosaggio delle proteine MxA 2. Dosaggio Apolipoproteina E

E.3

Principal inclusion criteria

1. Patients with relapsing-remitting forms of Multiple Sclerosis (according to McDonald s criteria; 28) with disease duration > 3 months and - 5 years. 2. EDSS score between 1.0 and 5.5, inclusive. 3. Currently treated with, and tolerating, Interferon beta, and having received this treatment for more than 3 and less than 12 months. 4. Age between 18 and 50 years, inclusive. 5. Patients must agree to avoid macrolids, including erytromicine and claritromicine for the whole study duration. 6. A woman of child-bearing potential must agree to adapt the proper behaviour adequately to avoid pregnancy while on study. 7. Negative pregnancy test results at screening day (all women of childbearing potential only). 8. Consent to go on the diet (appendix 2). 9. Written informed consent. 10. Serum lipid profile, as defined in appendix 3. 11. Adequate bone marrow, renal, and hepatic function, as defined in appendix 4.

1. Pazienti con SMRR (clinicamente definita sec. i criteri di McDonald) con durata della malattia > 3 mesi e - 5 anni 2. EDSS compresa tra 1.0 e 5.5 incluso 3. Pazienti in trattamento, ben tollerato, con Interferone beta da almeno 3 mesi e non piu` di 12 4. Eta` compresa tra 18 e 50 anni compiuti 5. Pazienti disponibili ad evitare terapie con macrolidi, incluso eritromicina e claritromicina, per tutta la durata dello studio 6. Pazienti di sesso femminile in eta` fertile disponibili ad adattare il proprio comportamento per evitare di contrarre una gravidanza per tutta la durata dello studio 7. Test di gravidanza negativo al giorno della selezione (per le pazienti di sesso femminile in eta` fertile) 8. Consenso a seguire una dieta (appendice 2) 9. Consenso informato scritto 10. Profilo lipidico sierico come da valori riportati nell appendice 3 11. Funzione midollare, renale ed epatica adeguate come da valori riportati in appendice 4

E.4

Principal exclusion criteria

1. Any disease other than Multiple Sclerosis that would better explain the patient s signs and symptoms. 2. Primary progressive MS. 3. Secondary progressive MS. 4. Uncontrolled, clinically significant heart diseases, such as dysrhythmias, angina, or uncompensated congestive heart failure. 5. Previous confirmed venous thromboembolic disease including deep vein phlebitis and/or pulmonary embolism or known hemostatic disorder predisposing to thromboembolic complications. 6. Uncontrolled Seizure disorder. 7. Myopathy or clinically significant liver disease. 8. Medical or psychiatric conditions that compromise the ability to give informed consent, to comply with the protocol, or to complete the study. 9. Inability, in the opinion of the principal investigator or staff, to comply with protocol requirements for the duration of the study. 10. Well-known hypersensitivity to either Atorvastatin or Interferon β or other human proteins including albumin.11. Well-known hypersensitivity to gadolinium. 12. Inability to undergo a MRI scan. 13. A relapse started within 30 days prior to screening or between screening and baseline. 14. A history of substance abuse (hard and soft drugs, alcoholic drinks) in the 90 days prior to screening. 15. Previous (at any time ) therapy with any of the following: monoclonal antibodies, cytotoxic or immunosuppressive therapy (excluding systemic steroids and adrenocoticotropic hormone; ACTH), total lymphoid irradiation. 16. Previous therapy, administrated for ≥12 months, with other interferon beta drugs, Mitoxantrone, Azathioprine or Glatiramer acetate in the 12 months before start of the currently interferon beta treatment.. 17. Previous treatment (at any time) with statins. 18. Treatment with any of the following in the 30 days before baseline: systemic corticosteroids, ACTH, or other investigational drugs.

1. Qualunque malattia, oltre alla sclerosi multipla, che potrebbe meglio spiegare i segni ed i sintomi riferiti dal paziente 2. Sclerosi Multipla primariamente progressiva 3. Sclerosi Multipla secondariamente progressiva 4. Patologie cardiache, non controllate, clinicamente significative, come aritmie, angina o insufficienza cardiaca congestizia scompensata 5. Malattia venosa tromboembolica precedentemente confermata inclusa la flebite venosa profonda, e/o l embolia polmonare o disordini noti dell emostasi predisponenti a complicazioni tromboemboliche. 6. Epilessia non controllata 7. Miopatia o patologia epatica clinicamente significativa 8. Condizioni mediche o psichiatriche che possano compromettere la capacita` di sottoscrivere il consenso informato, rispettare il protocollo o completare lo studio 9. Impossibilita`, secondo l opinione dello sperimentatore o di un membro dello staff, di rispettare le richieste del protocollo per tutta la durata dello studio 10. Ipersensibilita` nota all Atorvastatina o all Interferone beta o ad altre proteine inclusa l albumina 11. Ipersensibilita` nota al Gadolinio 12. Impossibilita` ad eseguire la Risonanza magnetica 13. Una ricaduta che sia iniziata nei 30 gg prima dello screening o nell intervallo tra giorno della selezione e la visita del giorno 1 14. Storia di tossicodipendenza ( droghe pesanti o leggere ed alcol) nei 90 giorni precedenti giorno della selezione 15. Precedente terapia con: Anticorpi monoclonali e/o farmaci citotossici o immunosoppressivi (escluso corticosteroidi ormone adenocorticotropo e ACTH); radioterapia 16. Nei 12 mesi precedenti l inizio della terapia corrente con interferone beta terapia con Mitoxantrone, Azatioprina o Glatiramer acetato per 12 mesi o piu` 17. Precedente trattamento (in qualunque momento) con statine 18. Trattamento nei 30 giorni precedenti la visita del giorno 1 con corticosteroidi, ACTH o altri farmaci sperimentali

E.5 End points

E.5.1

Primary end point(s)

The primary endpoint variable will be the changes in brain atrophy by brain MRI after 24 months.

La variabile obiettivo primario sara` la misurazione del cambiamento dell atrofia cerebrale rivelata dalla risonanza magnetica dopo 24 mesi di trattamento.

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

Yes

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

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

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)

E.8.2.2

Placebo

Yes

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

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	No
F.1.1	Number of subjects for this age range:	0
F.1.1.1	In Utero	No
F.1.1.2	Preterm newborn infants (up to gestational age < 37 weeks)	No
F.1.1.3	Newborns (0-27 days)	No
F.1.1.4	Infants and toddlers (28 days-23 months)	No
F.1.1.5	Children (2-11years)	No
F.1.1.6	Adolescents (12-17 years)	No
F.1.2	Adults (18-64 years)	Yes
F.1.3	Elderly (>=65 years)	No
F.2 Gender
F.2.1	Female	Yes
F.2.2	Male	Yes
F.3 Group of trial subjects
F.3.1	Healthy volunteers	No
F.3.2	Patients	Yes
F.3.3	Specific vulnerable populations	Yes
F.3.3.1	Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2006-03-15.	Yes
F.3.3.2	Women of child-bearing potential using contraception	Yes
F.3.3.3	Pregnant women	No
F.3.3.4	Nursing women	No
F.3.3.5	Emergency situation	No
F.3.3.6	Subjects incapable of giving consent personally	No
F.3.3.7	Others	No
F.4 Planned number of subjects to be included
F.4.1	In the member state	150

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

2005-07-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2005-04-20

P. End of Trial
P.	End of Trial Status	Completed

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