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    Summary
    EudraCT Number:2020-005605-93
    Sponsor's Protocol Code Number:SILYCUS-21
    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:2021-10-22
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2020-005605-93
    A.3Full title of the trial
    Efficacy and safety of Silycus® in Cushing’s disease: a multicenter, single arm, open
    label, dose titration, proof of concept study (Silycus®-21)
    Efficacia e sicurezza di Silycus® nella malattia di Cushing: studio multicentrico,
    a braccio singolo, in aperto, di titolazione, proof of concept (SILYCUS-21)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety of Silycus® in Cushing’s disease: a multicenter, single arm, open
    label, dose titration, proof of concept study (Silycus®-21)
    Efficacia e sicurezza di Silycus® nella malattia di Cushing: studio multicentrico,
    a braccio singolo, in aperto, di titolazione, proof of concept (SILYCUS-21)
    A.3.2Name or abbreviated title of the trial where available
    SILYCUS-21 Trial
    Studio SILYCUS-21
    A.4.1Sponsor's protocol code numberSILYCUS-21
    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 SponsorISTITUTO BIOCHIMICO ITALIANO GIOVANNI LORENZINI S.P.A.
    B.1.3.4CountryItaly
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFullcro S.r.l.
    B.5.2Functional name of contact pointClinical Operations
    B.5.3 Address:
    B.5.3.1Street AddressVia Ignazio Guidi, 3
    B.5.3.2Town/ cityRoma
    B.5.3.3Post code00147
    B.5.3.4CountryItaly
    B.5.4Telephone number06583003026
    B.5.6E-mailmaria.bianchetti@fullcro.org
    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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameSilycus
    D.3.2Product code [na]
    D.3.4Pharmaceutical form
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.9.1CAS number 22888-70-6
    D.3.9.2Current sponsor codena
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number150 to 600
    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.3.11.3.1Somatic cell therapy medicinal product Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    Cushing's disease
    pazienti con malattia di Cushing
    E.1.1.1Medical condition in easily understood language
    Cushing's disease
    pazienti con malattia di Cushing
    E.1.1.2Therapeutic area Diseases [C] - Hormonal diseases [C19]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level SOC
    E.1.2Classification code 10014698
    E.1.2Term Endocrine disorders
    E.1.2System Organ Class 10014698 - Endocrine disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate the efficacy of Silycus® to decrease and/or normalize excess cortisol secretion in
    patients with active Cushing’s disease, assessed by either 24 hour urinary free cortisol, midnight
    salivary cortisol or suppression by low dose dexamethasone
    valutare l'efficacia di Silycus® in pazienti con malattia di Cushing
    per ridurre e/o normalizzare la secrezione di cortisolo, valutata
    mediante cortisolo libero urinario nelle 24 ore, cortisolo salivare
    notturno e soppressione da desametasone a basso dosaggio
    E.2.2Secondary objectives of the trial
    - Evaluate the effect of Silycus® on signs and symptoms of hypercortisolism
    - Assess the safety and tolerability of Silycus® in patients with Cushing’s disease
    - Evaluate the PK profile of silibinin in patients with Cushing’s disease
    ¿ valutare l'effetto di Silycus® su segni e sintomi di ipercortisolismo
    ¿ valutare la sicurezza e la tollerabilità di Silycus® in pazienti con malattia di Cushing
    ¿ valutare il profilo farmacocinetico della silibina in pazienti con malattia di Cushing
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1- Adult, i.e., age >= 18 years, female and male patients with active Cushing’s disease. Cushing’s
    disease will be diagnosed according to established guidelines. Patients will be either de
    novo diagnoses or persistent/recurrent disease Medical records will be collected and
    used to support the diagnosis
    2- Mean value of 24-hour urinary free cortisol (UFC) in at least three collections 1.5 times
    above the upper limit of normal range (ULN)
    and
    elevated late night salivary cortisol (at least 2 measurements > ULN)
    or
    unsuppressed cortisol after 1 mg dexamethasone (i.e., serum cortisol at 8 AM >1.8
    micrograms/deciliter)
    3- Patients on inadequate or not tolerated medical treatments for Cushing’s disease amenable
    to minimum drug wash-out period
    4- Patients with de novo Cushing’s disease if not surgical candidates or if surgery is delayed
    beyond the projected duration of the present study
    5- Patients willing to provide written informed consent to participate in the study and adhere
    to protocol requirements
    1. Pazienti maggiorenni, di sesso femminile e maschile con malattia di
    Cushing attiva
    2. Valore medio del cortisolo libero urinario (UFC) nelle 24 ore,
    ottenuto da almeno tre raccolte, 1,5 volte al di sopra del limite
    superiore del range di normalità (ULN),
    e
    aumento del cortisolo salivare notturno (LNSC) (almeno 2
    misurazioni > ULN)
    o
    cortisolo non soppresso dopo 1 mg di desametasone (ovvero
    cortisolo sierico alle 8:00 >1,8 microgrammi/decilitro)
    3. Pazienti sottoposti a trattamenti medici inadeguati o non tollerati per
    la malattia di Cushing suscettibili di un periodo minimo di wash-out
    dal farmaco
    4. Pazienti con malattia di Cushing de novo se non sono candidati
    chirurgici o se l'intervento è ritardato oltre la durata prevista del
    presente studio
    5. Pazienti disposti a fornire il consenso informato scritto per
    partecipare allo studio e aderire ai requisiti del protocollo
    E.4Principal exclusion criteria
    1- Patients who do not fulfil criteria for active Cushing’s disease
    2- Patients submitted to pituitary radiosurgery/radiotherapy within the past 3 years
    3- Patients with de novo Cushing’s disease who are amenable to surgery which is available
    within the projected duration of the present study
    4- Patients for whom the managing physician considers interruption of ongoing medical
    treatment for Cushing’s disease to be inappropriate
    5- Pregnant and/or lactating women or women unwilling to use contraceptive medication and
    contraceptive devices for up to two months after silibinin withdrawal
    6- Patients with active, severe kidney or liver disease
    7- Patients with history of alcohol or drug abuse in the last 6 months
    8- Patients with known hypersensitivity to components of Silycus®
    9- Patients on mitotane will not be enrolled as a drug washout of at least 6 months is deemed
    unethical
    10- Patients who are unwilling to perform study-related procedures
    11- Any other criteria that may preclude patient participation according to investigator
    judgement.
    1. Pazienti che non soddisfano i criteri per la malattia di Cushing attiva
    2. Pazienti sottoposti a radiochirurgia/radioterapia ipofisaria negli
    ultimi 3 anni
    3. Pazienti con malattia di Cushing de novo che sono suscettibili di un
    intervento chirurgico fattibile entro la durata prevista del presente
    studio
    4. Pazienti per i quali il medico curante considera inappropriata
    l'interruzione del trattamento medico in corso per la malattia di
    Cushing
    5. Donne in gravidanza e/o in allattamento o donne che non sono
    disposte a usare farmaci contraccettivi e dispositivi contraccettivi
    fino a due mesi dopo l'interruzione della silibina
    6. Pazienti con malattia renale o epatica attiva, grave
    7. Pazienti con storia di abuso di alcol o droghe negli ultimi 6 mesi
    8. Pazienti con ipersensibilità nota ai componenti di Silycus®
    9. I pazienti in trattamento con mitotano non verranno arruolati poiché
    un washout del farmaco di almeno 6 mesi è considerato non etico
    10. Pazienti che non sono disposti a eseguire procedure relative allo
    studio
    11. Qualsiasi altro criterio che possa precludere la partecipazione del
    paziente secondo il giudizio dello sperimentatore
    E.5 End points
    E.5.1Primary end point(s)
    Efficacy of silibinin will be assessed on UFC, late night salivary cortisol levels and suppression with
    low dose dexamethasone. The composite endpoint comprises: the number and percentage of
    patients in whom UFC normalized or decreased by at least 50% compared to pretreatment values,
    the number and percentage of patients with elevated late night salivary cortisol at baseline in
    whom salivary cortisol normalized and the number and percentage of patients who failed to
    suppress after low dose dexamethasone at baseline in whom normal suppression was restored.
    Efficacy will be assessed after 12 weeks of administration.
    UFC values will be averaged from three consecutive collections at both timepoints and salivary
    cortisol from 2 consecutive samples.
    We assume a primary efficacy response rate of 35%, thus if at least 5 patients fulfill the first
    primary endpoint, then Silycus® will be considered worthy of further research.
    L'efficacia della silibina sarà valutata sull'UFC, sui livelli di cortisolo salivare
    notturno e sulla soppressione con desametasone a basso dosaggio.
    L'endpoint composito comprende: la percentuale di pazienti in cui l'UFC si è
    normalizzato o è diminuito di almeno il 50% rispetto ai valori pretrattamento,
    la percentuale di pazienti con cortisolo salivare notturno elevato al basale in
    cui il cortisolo salivare si è normalizzato e percentuale di pazienti che non
    sono riusciti a sopprimere dopo basse dosi di desametasone al basale in cui
    è stata ripristinata la normale soppressione.
    E.5.1.1Timepoint(s) of evaluation of this end point
    After 12 weeks of treatment
    L'efficacia sarà valutata dopo 12 settimane di somministrazione
    E.5.2Secondary end point(s)
    Effect of silibinin on signs and symptoms of Cushing’s disease.
    Number and percentage of patients that experience changes in features of cortisol excess, as
    assessed by physical examination, case history, blood chemistry, will be calculated. In particular,
    the presence and severity of hypertension, excess weight, hirsutism in women (Ferriman-Gallwey
    score), facial plethora, reduced libido as well as Karnofsky performance status will be established.
    Further, changes in glucose control, electrolyte levels and white blood cell counts as well as any
    reduction in antihypertensive or glucose-lowering drugs will be quantified.
    ¿ stabilire l'effetto di Silycus® sui segni e sintomi clinici della malattia
    di Cushing. Questi effetti saranno valutati dopo 12 settimane di
    somministrazione
    ¿ valutazione della sicurezza e tollerabilità della somministrazione di
    Silycus®
    ¿ valutazione del profilo farmacocinetico della silibina in pazienti con
    malattia di Cushing (dopo la prima dose, alla titolazione e allo
    steady state)
    E.5.2.1Timepoint(s) of evaluation of this end point
    After 12 weeks of treatment
    Questo endpoint sarà valutato dopo 12 settimane di somministrazione
    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 No
    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.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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 No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial1
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned4
    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 Information not present in EudraCT
    E.8.7Trial has a data monitoring committee Yes
    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
    LVLS
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial 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: 15
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 15
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    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 No
    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 state15
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 15
    F.4.2.2In the whole clinical trial 15
    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)
    CLINICAL PRACTICE
    PRATICA CLINICA
    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 Decision2021-12-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-09-29
    P. End of Trial
    P.End of Trial StatusOngoing
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