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    EudraCT Number:2015-004919-20
    Sponsor's Protocol Code Number:StudioLAM
    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:2016-08-11
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2015-004919-20
    A.3Full title of the trial
    A pilot study of nintedanib for lymphangioleiomyomatosis (LAM)
    A pilot study of nintedanib for lymphangioleiomyomatosis (LAM)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A pilot study of nintedanib for lymphangioleiomyomatosis (LAM)
    Studio pilota sul Nintedanib nella Linfangioleiomiomatosi ( LAM )
    A.3.2Name or abbreviated title of the trial where available
    A pilot study of nintedanib for lymphangioleiomyomatosis (LAM)
    A pilot study of nintedanib for lymphangioleiomyomatosis (LAM)
    A.4.1Sponsor's protocol code numberStudioLAM
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorMULTIMEDICA S.P.A.
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportB.4.1 Azienda Farmaceutica: Boehringer Ingelheim Pharma GmbH &Co. KG
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMultiMedica SpA
    B.5.2Functional name of contact pointServizio di Data Management
    B.5.3 Address:
    B.5.3.1Street Addressvia Milanese 300
    B.5.3.2Town/ citySesto San Giovanni
    B.5.3.3Post code20099
    B.5.4Telephone number0224209237
    B.5.5Fax number0224209837
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D. name Ofev
    D. of the Marketing Authorisation holderBoehringer Ingelheim International GmbH
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/13/1123
    D.3 Description of the IMP
    D.3.4Pharmaceutical form Capsule, soft
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another 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.1.1Medical condition(s) being investigated
    Female subjects affected by Llymphangioleiomyomatosis (LAM)
    La linfangioleiomiomatosi(LAM)è una malattia multisistemica che colpisce prevalentemente le donne in età fertile.E’ caratterizzata da proliferazione di cellule muscolari lisce anomale(cellule LAM)che causano la formazione di cisti aeree all’interno del polmone,alterazioni cistiche lungo il decorso dei vasi linfatici(linfangioleiomiomi)e angiomiolipomi, tumori benigni generalmente riscontrati nel rene.Può essere sporadica o interessare fino al 80% delle donne affette da Sclerosi Tuberosa (TSC).
    E.1.1.1Medical condition in easily understood language
    ymphangioleiomyomatosis (LAM) is a rare, progressive, systemic disease that typically results in cystic lung destruction and predominantly affects women, especially during child bearing years

    Malattia del polmone caratterizzata da sostituzione della normale architettura del polmone con cisti aeree.
    E.1.1.2Therapeutic area Diseases [C] - Respiratory Tract Diseases [C08]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level PT
    E.1.2Classification code 10049459
    E.1.2Term Lymphangioleiomyomatosis
    E.1.2System Organ Class 10038738 - Respiratory, thoracic and mediastinal disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objective is to demonstrate a reduction of lung function decline, as measured by a
    change of the yearly rate of decline of FEV1
    E’ la risposta sul FEV1, espressa come la variazione del FEV1 (slope) in millilitri per mese. Dove FEV1 è Volume Espiratorio Massimo ad 1 Secondo" (VEMS, FEV1 in inglese)
    E.2.2Secondary objectives of the trial
    Functional respiratory evaluation after treatment compared to basal
    - Safety and tolerability
    - FVC variation compared to basal
    - DLCO variation compared to basal
    - Serum VEGF-D variation compared to basal
    - Efficacy of Nintedanib in angiomyolipoma size reduction (in patients with angiomyolipomas not greater than 5 cm of diameter).
    - Efficacy of Nintedan
    - Valutazione della funzione respiratoria e sua stabilizzazione in seguito a trattamento rispetto al basale
    - Sicurezza e tollerabilità
    - Variazione della FVC (Capacità vitale forzata - CVF o FVC)
    - Variazione della DLCO (Capacità di Diffuzione Polmonare per il monossido di carbonio) rispetto al basale
    - Variazione del livello di VEGF-D sierico rispetto al basale.
    - Valutare se il nintedanib può ridurre la dimensione di angiomiolipomi in pazienti affetti
    - Valutare se il nintedanib riduce il numero di cellule LAM circolanti e se tale effetto persiste alla sospensione della terapia.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Written Informed Consent for participating to trial e to genetic tests,
    2. Patient aged ≥ 18 years at visit 1,
    3. sporadic or TSC associated LAM, classified as ‘‘definite’’ by the European Respiratory Society
    criteria and /or serum VEGFD level >/= 800 mg/ml, and evidence of a 10% deterioration in FEV1
    and /or loss of 80 ml of FEV1 or more in the last year (post bronchodilator). Also LAM patients
    with proven side effects and/or toxicities/ contraindications to sirolimus therapy will be eligible for this study.
    Le pazienti sono eleggibili per lo studio se di età pari a 18 anni o superiore, sono affette da LAM sporadica o associata a TSC, classificata come LAM certa secondo i criteri della European Respiratory Society (20) o con Tac ad alta risoluzione o HRTC del torace caratteristica per LAM e valori di VEGF-D sierico ≥ 800 mg/ml, e con evidenza di riduzione del FEV1 del 10% e/o riduzione di 80mL del FEV1 o più nell’ultimo anno (misurato dopo broncodilatazione). Potranno essere eleggibili anche pazienti con effetti collaterali o tossicità da sirolimus o con controindicazione alla terapia con sirolimus.
    E.4Principal exclusion criteria
    Previous treatment with nintedanib
    Other investigational therapy (participation in research trial) received within 8 weeks of visit
    Thoracic, abdominal, gynecological, neurologic surgical procedures planned to occur during
    trial period.
    Pregnant women or women who are breast feeding or of child bearing potential not using
    two effective methods of birth control (one barrier and one highly effective non-barrier) for
    at least 1 month prior to enrolment (and until 3 months after treatment end).
    Female patients will be considered to be of childbearing potential unless surgically sterilised
    by hysterectomy or bilateral tubal ligation, or postmenopausal for at least two years or if
    women use a barrier method of contraception includes condom or occlusive cap with
    spermicidal (foam, gel, film, cream, suppository) or male sterilization (with appropriate
    post-vasectomy documentation of the absence of sperm in the ejaculate), or if they use an
    intrauterine device
    · International normalized ratio (INR) > 2 at visit 1
    Pazienti HIV positive o con epatite
    -Presenza di versamenti chilosi
    -Pneumotorace recidivante
    -Presenza di angiomiolipoma con diametro > 5 cm
    -Terapia con inibitori di mTOR nell’ultimo mese
    -Pazienti in lista per trapianto polmonare
    -Terapia ormonale nell’ultimo mese
    -Pazienti sottoposti a trapianto polmonare
    -Storia di pneumotorace, versamento chiloso, angiomiolipoma complicato da sanguinamento negli ultimi 6 mesi.
    -ALT, AST > 1.5 il limite di normalità (ULN) alla visita 1
    -Bilirubina totale > 1.5 il limite di normalità alla visita 1
    -Storia di infarto del miocardio nei 6 mesi precedenti la visita 1 o di angina instabile nel mese precedente la visita 1.
    Rischio di emorragia:
    • Predisposizione genetica nota al sanguinamento
    • Pazienti che richiedono fibrinolisi, dose piena di terapia anticoagulante (es. antagonisti della vitamina K, eparina, NAO) o alte dosi di terapia antiaggregante.
    • Storia di evento emorragico cerebrale nei 12 mesi precedenti la visita 1.
    • Storia di emottisi o ematuria, emorragia gastro-enterica o ulcera e/o trauma o chirurgia maggiore nei 3 mesi precedenti la visita 1.
    • International normalised ratio (INR) > 2 alla visita 1.
    • Tempo di protrombina (PT) e tempo di tromboplastina (PTT) > 150% il limite di normalità (ULN) alla visita 1.
    -Intervento di chirurgia maggiore programmato durante il periodo di partecipazione allo studio, inclusi trapianto polmonare, chirurgia addominale o intestinale.
    -Storia di evento trombotico (inclusi lo stroke e l’attacco ischemico transitorio) nei 12 mesi precedenti la visita 1.
    -Insufficienza renale end-stage con necessità di dialisi
    -Abuso di alcol o di sostanze che secondo il parere del medico potrebbe interferire con la terapia.
    -Donne in gravidanza, in allattamento o che pianifichino una gravidanza durante il periodo dello studio.
    -Pazienti non in grado di eseguire le PFR o di fornire un consenso informato.

    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome measure will be the FEV1 response, which will be assessed as the change in FEV1 (FEV1 slope) in milliliters per month ( post bronchodilator).
    E’ la risposta sul FEV1, espressa come la variazione del FEV1 (slope) in millilitri per mese.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 and 18 months
    12 e 18 mesi
    E.5.2Secondary end point(s)
    The proportion of patients achieving a stabilization of the lung function during treatment. A patient will be considered stabilized if her value of the FEV1 measured at 12-month visit will be equal or above the baseline value. - Safety and Tolerability - Rate of decline of FVC over the course of the study - Rate of decline Dlco over the course of the study over the course of the study -VEGF-D levels: change from baseline at the end of treatment period - To assess if nintedanib can reduce renal angiomyolipomas (presence determined from MRI and defined as lesions with a maximum diameter of a least 1 cm). Reduction is defined as a decrease of total volume of target angiomyolipomas (sum of volume of all target lesions indentified at baseline) of at least 30% relative to baseline. New angiomyolipoma ≥ 1 cm in diameter, kidney increases in volume > 20%, and angiomyolipoma related bleeding must be excluded. - To test if nintedanib reduces the number of circulating LAM cells in treated pts and if the loss of circulating LAM cells persists after treatment discontinuation. - Quality of
    - Valutazione della funzione respiratoria e sua stabilizzazione in seguito a trattamento rispetto al basale - Sicurezza e tollerabilità - Variazione della FVC (Capacità vitale forzata - CVF o FVC) - Variazione della DLCO (Capacità di Diffuzione Polmonare per il monossido di carbonio) rispetto al basale - Variazione del livello di VEGF-D sierico rispetto al basale. - Valutare se il nintedanib può ridurre la dimensione di angiomiolipomi in pazienti affetti - Valutare se il nintedanib riduce il numero di cellule LAM circolanti e se tale effetto persiste alla sospensione della terapia.
    E.5.2.1Timepoint(s) of evaluation of this end point
    12 and 18 months
    12 e 18 mesi
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E. trial design description
    gruppo di controllo storico (MILES trial)
    Hystorical control group (MILES trial)
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E. description
    NA - Nessun comparatore
    NA- No Comparator
    E.8.2.4Number of treatment arms in the trial0
    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 No
    E.8.4.1Number of sites anticipated in Member State concerned1
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months18
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 28
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 2
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male No
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women 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 2016-08-11. Yes
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state30
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 30
    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)
    pneumological outpatient visits
    Visite pneuomologica ambulatoriale
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-03-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-11-17
    P. End of Trial
    P.End of Trial StatusOngoing
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