| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Endogenous Cushing¿s syndrome (CS) |
| Sindrome di Cushing endogena (SC) |
|
| E.1.1.1 | Medical condition in easily understood language |
| In this condition patients produce an excessive level of a steroid hormone known as cortisol |
| In questa condizione i pazienti producono un livello eccessivo di un ormone steroideo conosciuto come cortisolo |
|
| E.1.1.2 | Therapeutic area | Body processes [G] - Metabolic Phenomena [G03] |
| MedDRA Classification |
| 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 | 10011657 |
| E.1.2 | Term | Cushings syndrome |
| E.1.2 | System Organ Class | 100000004860 |
|
| 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 |
| To determine the effect of withdrawing to placebo versus continuing treatment with levoketoconazole on the cortisol therapeutic response previously established during open-label levoketoconazole therapy. |
Stabilire l¿effetto della sospensione con placebo rispetto al trattamento continuato con
levoketoconazolo sulla risposta terapeutica del cortisolo precedentemente determinata durante la terapia con levoketoconazolo in aperto. |
|
| E.2.2 | Secondary objectives of the trial |
To compare the effects of levoketoconazole with placebo on:
- cortisol status during Randomized Withdrawal and Restoration Phases;
- changes in clinical signs & symptoms of Cushing¿s syndrome (CS);
- changes in biomarkers of CS comorbidities;
- To assess the safety and tolerability of levoketoconazole;
- To evaluate the population pharmacokinetics of levoketoconazole in
subjects with CS
NOTE: Secondary Objectives 4 & 5 are not subjects of hypothesis tests
Exploratory Objectives:
1. To assess changes in anti-diabetic, anti-cholesterol, anti-hypertensive, and chronic anti-inflammatory therapies;
2. To describe the effects & durations of levoketoconazole action with respect to cortisol status, health-related quality of life, and symptoms of depression
3. To describe the dose-response relationship of levoketoconazole with respect to safety and tolerability
4. To describe the effects of levoketoconazole on glucose tolerance among subjects with impaired fasting glucose (IFG). |
Confrontare gli effetti del levoketoconazolo con il placebo sullo:-stato del cortisolo durante la fase di sospensione randomizzata e la successiva fase di ripristino;-sui cambiamenti nei segni e nei sintomi clinici della sindrome di Cushing (CS);-sui cambiamenti nei biomarcatori delle comorbilit¿ della CS;-Valutare la sicurezza e la tollerabilit¿ del levoketoconazolo;-Valutare la farmacocinetica di popolazione del levoketoconazolo in soggetti con CS
NOTA:Gli obiettivi secondari 4 e 5 non sono soggetti a test delle ipotesi.Obiettivi Esploratori:1.Valutare i cambiamenti nelle terapie antidiabetiche,anticolesterolo,antipertensive e antinfiammatorie croniche;2.Descrivere gli effetti e la durata dell¿azione del levoketoconazolo rispetto allo stato del cortisolo,alla qualit¿ della vita correlata alla salute e ai sintomi della depressione;3.Descrivere il rapporto dose-risposta del levoketoconazolo rispetto alla sicurezza e alla tollerabilit¿.4.Descrivere gli effetti del levoketonazolo sulla |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Inclusion Criteria for Specified Subjects Completing the SONICS Study:
SONICS-completers, including those receiving open-label treatment after SONICS as part
of an Expanded Access Program (EAP) or OLE study, whose completion of the M12 visit
occurred not more than 6 months prior to the anticipated Randomization Visit (RW0), may
be eligible for the study if the following two inclusion criteria are met:
1. Completed the final SONICS visit (M12) and have demonstrated maintenance of clinical
response (partial or complete) on a stable Therapeutic Dose of levoketoconazole for at
least 12 weeks prior to study entry (Visit RW0)
2. Able and willing to provide written informed consent prior to any study procedures
being performed; eligible subjects must be able to understand the informed consent form
prior to inclusion into the study
Inclusion Criteria for All Others:
The following categories of potential subjects, categorized by prior use of
levoketoconazole, may be eligible if the following 11 inclusion criteria are all met:
• Naïve to levoketoconazole (defined as having never participated in SONICS);
• Completers of SONICS visit M12 more than 6 months prior to the expected RW0 visit of
the current study;
• Completers of SONICS visit M12 within the 6 months prior to the expected RW0 visit who
have not been receiving a stable Therapeutic Dose of levoketoconazole for at least 12
weeks prior to the start of screening.
1. Male or female and at least 18 years of age.
2. Able and willing to provide written informed consent
3. Confirmed newly diagnosed, persistent or recurrent endogenous Cushing’s syndrome of
any etiology, except secondary to malignancy (including pituitary or adrenal carcinoma).
Persistence will not be considered confirmed until 6 weeks or more post-surgery
4. Elevated mean 24 hour UFC levels at least 1.5X ULN of the normative range of the
study’s central laboratory assay and from a minimum of three measurements from
adequately collected urine; the study’s central laboratory must be used for all
qualifying measurements.
5. Presence of abnormal values from at least one of these two diagnostic tests
(discrepancies between test findings will not be investigated nor considered
exclusionary):
• Abnormal Dexamethasone Suppression Test (DST): Elevated 8 AM blood cortisol at least
1.8 µg/dL (50 nmol/L) after 1 mg dexamethasone orally at 11 PM the evening prior with
concurrent dexamethasone blood concentration greater than 5.6 nmol/liter (220 ng/dL)
(results from within the 2 months prior to start of Screening or newly tested with
results available by the Baseline Visit [TM0]) OR
• Elevated LNSC concentrations (at least two measurements) each greater than the ULN of
the study’s central laboratory normative range; the study’s test kit and lab must be
used for all qualifying measurements.
6. Non-candidates for CS-specific surgery, refuse surgery or surgery will be delayed
until after study completion and agree to complete this study prior to surgery.
7. If post-surgical for CS-specific surgery, then no significant post operative sequelae
remain and the risk of such sequelae is considered negligible.
8. Agree to the following minimum washout periods prior to the Baseline Visit (TM0) (as
applicable):
• Ketoconazole or metyrapone: 2 weeks;
• Dopamine agonists: bromocriptine (2 weeks), cabergoline (8 weeks);
• Octreotide acetate LAR, lanreotide Autogel®, pasireotide LAR: 12 weeks;
• Lanreotide SR: 8 weeks;
• Octreotide acetate (immediate release) or short-acting pasireotide: 1 week;
• Mifepristone (RU 486, KORLYM®): 4 weeks;
• Megestrol acetate or medroxyprogesterone acetate (and selected other synthetic
progestins): 6 weeks.
9. Females who are either of non-child bearing potential (i.e. incapable of becoming
pregnant):
• Post-menopausal, defined as age 50 or older with amenorrhea for more than 1 year or
any age with serum follicle stimulating hormone (FSH) at least 23 mIU/mL and estradiol
no more than 40 pg/mL (140 pmol/L) OR |
Criteri di inclusione per i soggetti che hanno completato lo studio SONICS :
I soggetti che hanno completato lo studio SONICS, compresi quelli che ricevono un trattamento in aperto dopo lo studio SONICS come parte di un programma di accesso allargato (Expanded Access Program, EAP) o studio OLE, la cui visita M12 è stata completata non oltre 6 mesi prima della visita di randomizzazione prevista (RW0), possono essere idonei per lo studio se soddisfano i criteri seguenti:
1. Hanno completato l’ultima visita SONICS (M12) e hanno dimostrato il mantenimento della risposta clinica (parziale o completa, così come definita dal protocollo SONICS, COR-2012-01) con una dose terapeutica stabile di levoketoconazolo per almeno 12 settimane prima dell’ingresso nello studio (ovvero, la visita RW0).
2. Volontà e capacità di fornire il consenso informato scritto prima che venga eseguita qualsiasi procedura dello studio; i soggetti idonei devono essere in grado di comprendere il
modulo di consenso informato prima dell’inclusione nello studio.
Criteri di inclusione per tutti gli altri:
Le seguenti categorie di soggetti potenziali, classificati in base all’uso precedente di
levoketoconazolo, possono essere idonee se soddisfano tutti gli 11 criteri di inclusione
seguenti:
• Soggetti naïve al levoketoconazolo (definito come nessuna partecipazione precedente
allo studio SONICS);
• Soggetti che hanno completato la visita M12 dello studio SONICS più di 6 mesi prima
della visita
RW0 prevista dello studio corrente;
• Soggetti che hanno completato la visita M12 dello studio SONICS entro 6 mesi prima
della visita
RW0 prevista che non hanno ricevuto una dose terapeutica stabile di levoketoconazolo per
almeno
12 settimane prima dell’inizio dello screening.
1. Soggetti di sesso maschile o femminile e di almeno 18 anni di età.
2. Volontà e capacità di fornire il consenso informato scritto prima che venga eseguita
qualsiasi
procedura dello studio; i soggetti idonei devono essere in grado di comprendere il
modulo di consenso informato prima dell’inclusione nello studio.
3. Sindrome di Cushing endogena confermata recentemente diagnosticata, persistente o
ricorrente di qualsiasi eziologia, tranne se secondaria a un tumore maligno (compreso il
carcinoma surrenalico o
ipofisario). La persistenza non sarà considerata confermata fino a = 6 settimane post intervento
chirurgico.
La seguente evidenza storica sarà considerata sufficiente a stabilire la causa della
sindrome di Cushing endogena come dovuta alla malattia di Cushing (ovvero, dipendente
dall’ormone adrenocorticotropo [ACTH] di origine ipofisaria), nello specifico:
• Conferma patologica (ad esempio, colorazione da ormone adrenocorticotropo [ACTH]) o
postchirurgica della diagnosi di CD (ovvero, insufficienza surrenalica documentata
postadenomectomia o post-ipofisectomia) OPPURE
• ACTH nel plasma intermedio, normale o elevato (ovvero, almeno 5 pg/ml [1,1 pmol/l])
OLTRE A
Per tumori di = 6 mm rilevati mediante diagnostica per immagini:
a) Gradiente centro:periferia della concentrazione plasmatica di ACTH misurata mediante
cateterismo dei seni petrosi inferiori (Inferior petrosal sinus sampled, IPSS) di almeno
2 prima del trattamento con ormone di rilascio della corticotropina
(corticotropinreleasing hormone, CRH) o almeno 3 dopo CRH, OPPURE in assenza di IPSS:
b) Risposta positiva dell’ACTH e/o del cortisolo al CRH o alla desmopressina o alla
stimolazione combinata con CRH-desmopressina più soppressione del cortisolo ematico con
alte dosi (8 mg) di desametasone, preferibilmente in più di una occasione, OPPURE
c) Altri test diagnostici adeguati. Tali cause devono essere discusse con il Medical
Monitor e da questi esplicitamente approvate e occorre documentare i criteri diagnostici
specifici usati per stabilire la diagnosi di CD.
Per i restanti criteri di inclusione, fare riferimento alla sinossi per superamento del
limite dei caratteri disponibili. |
|
| E.4 | Principal exclusion criteria |
Subjects will be excluded from the study if ANY of the following criteria are met (NOTE:
exclusion criteria apply to and must be assessed in both cohorts):
1. Enrolled in SONICS but have not completed SONICS through Visit M12
2. Pseudo-Cushing’s syndrome based on assessment of the Investigator
3. Cyclic Cushing’s syndrome with multi-week periods of apparent spontaneous CS
remission
4. Non-endogenous source of hypercortisolism, including pharmacological
corticosteroids or ACTH
5. Radiotherapy of any modality directed against the source of hypercortisolism within
the last 5 years
6. Treatment with mitotane within 6 months of enrollment
7. History of malignancy, including adrenal or pituitary carcinomas (other than low
risk, well-differentiated carcinomas of thyroid, breast or prostate that are very
unlikely to require further treatment in the opinion of the treating physician, or
squamous cell or basal cell carcinoma of the skin)
8. Clinical or radiological signs of compression of the optic chiasm
9. Major surgery within 1 month of Screening (or within 6 weeks for pituitary surgery)
10. Clinically significant abnormality in 12-lead ECG during the Screening Phase
requiring medical intervention
11. QTc interval above 470 msec during the Screening Phase
12. History of Torsades des Pointes, ventricular tachycardia, ventricular fibrillation,
history of prolonged QT syndrome
13. Use of medications associated with possible, probable, or definite QT/QTc
prolongation
14. Pre-existing hepatic disease
15. Hepatitis B surface antigen (HbsAg) or hepatitis C-positive
16. Human immunodeficiency virus (HIV)-positive.
17. History of symptomatic cholelithiasis with intact gallbladder
18. History of pancreatitis
19. Liver safety tests during the Screening Phase as follows:
- ALT and/or AST above 3X ULN
- Alkaline phosphatase or TBN above 2X ULN
Subjects with isolated indirect TBN up to 3X ULN are presumed to have Gilbert’s syndrome
and may be enrolled if all other liver safety tests are within normal levels
20. History of documented or suspected drug-induced liver injury to ketoconazole or any
other azole drug
21. Serum potassium below 3.0 mEq/L
22 Abnormal free thyroxine (FT4), unless subsequently corrected and stable for at least
4 weeks. Subjects with thyroid-stimulating hormone (TSH) less than the lower limit of
normal (LLN) and normal FT4 are potentially eligible without intervention
23. History of persistent uncontrolled hypertension
24. Hypercholesterolemia currently treated with atorvastatin, lovastatin or simvastatin
and unwilling or unable to change to alternative therapy with: pravastatin, fluvastatin,
pitavastatin or rosuvastatin (must switch statin at least 2 weeks prior to dosing) or
another allowed therapy. For
25. More than one hospitalization for hyperglycemia or complication of diabetes during
the last 12 months
26. Decreased renal function as defined by eGFR below 40 mL/min/1.73 m2, using MDRD
equation for eGFR
27. Pregnant or lactating
28. Body habitus preventing repeated venipuncture as required by protocol
29. Any other clinically significant medical condition, as determined by the
Investigator that precludes enrollment and participation in the study through
completion, including conditions that would preclude the subject from being able to
follow instructions or perform necessary procedures
30. History of alcohol or drug abuse in the 6-month period prior to Screening
31. Currently participating in another study or has received any investigational
treatment (drug, biological agent or device) other than levoketoconazole, within prior
30 days or five half-lives of treatment, whichever is longer
32. Current use of any H2-receptor antagonists, proton-pump inhibitors, or sucralfate
(all inhibit absorption of levoketoconazole; subjects may be allowed to enroll after
washout). A list of acceptable oral antacids will be provided; if used, antacids must be
ingested at least 2 hours after dosing of levoketoc |
I soggetti saranno esclusi dallo studio se viene soddisfatto UNO QUALSIASI dei criteri
seguenti (NOTA: i criteri di esclusione si applicano e devono essere valutati in
entrambe le coorti):
1. Arruolamento nello studio SONICS ma studio SONICS non completato fino alla visita
M12
2. Pseudo-sindrome di Cushing in base alla valutazione dello sperimentatore.
3. Sindrome di Cushing ciclica con periodi plurisettimanali di apparente remissione
spontanea della CS.
4. Fonte non endogena di ipercortisolismo, compresi i corticosteroidi farmacologici o
ACTH.
5. Radioterapia di qualsiasi modalità diretta contro la fonte di ipercortisolismo negli
ultimi 5 anni.
6. Trattamento con mitotano entro 6 mesi dall’arruolamento.
7. Anamnesi di tumore maligno, compresi i carcinomi surrenalici o ipofisari (diversi
dai carcinomi a basso rischio e ben differenziati della tiroide, della mammella o della
prostata che hanno bassissime probabilità di richiedere un ulteriore trattamento secondo
l’opinione del medico curante, oppure dal carcinoma a cellule squamose o basocellulare
della pelle).
8. Segni clinici o radiologici di compressione del chiasma ottico.
9. Intervento di chirurgia maggiore entro 1 mese dallo screening (o entro 6 settimane
dall’intervento ipofisario).
10. Anomalia clinicamente significativa nell’elettrocardiogramma (ECG) a 12 derivazioni
durante la fase di screening che richiede un intervento medico (può essere idoneo dopo
la stabilizzazione, da determinarsi caso per caso).
11. Intervallo QTc superiore a 470 msec durante la fase di screening, tramite
interpretazione del lettore centrale.
12. Anamnesi di torsade des pointes, tachicardia ventricolare, fibrillazione
ventricolare, anamnesi di sindrome del QT lungo (compresa un’anamnesi familiare di primo
grado).
13. Uso di farmaci associati a QT/QTc prolungato possibile, probabile o definito (tranne
se successivamente soggetti a washout).
14. Epatopatia pre-esistente (tranne epatopatia steatosica non alcolica da lieve a
moderata documentata da esami di diagnostica per immagini o biopsia e con valori della
transaminasi entro i limiti consentiti).
15. Positività all’antigene di superficie dell’epatite B (HBsAg) o all’epatite C.
16. Positività al virus dell’immunodeficienza umana (Human immunodeficiency virus, HIV).
17. Anamnesi di colelitiasi sintomatica con colecisti intatta.
18. Anamnesi di pancreatite.
19. Test di sicurezza epatica durante la fase di screening con i risultati seguenti:
• Alanina aminotransferasi (Alanine aminotransferase, ALT) e/o aspartato
aminotransferasi (aspartate aminotransferase, AST) 3 volte l’ULN
• Fosfatasi alcalina o bilirubina totale 2 volte l’ULN.
Si presume che i soggetti con bilirubina indiretta isolata fino a 3 volte l’ULN siano
affetti dalla sindrome di Gilbert e possono essere arruolati se tutti gli altri test di
sicurezza epatica sono entro i livelli normali.
20. Anamnesi di lesione epatica indotta da farmaco documentata o sospetta dovuta a
ketoconazolo o altri farmaci azolici.
21. Potassio sierico inferiore a 4,0 mEq/l (tranne se successivamente corretto e
stabile).
22. Tiroxina libera anomala (FT4), tranne se successivamente corretta e stabile per
almeno 4 settimane. I soggetti con ormone tireostimolante (thyroid-stimulating hormone,
TSH) inferiore al limite inferiore della norma (lower limit of normal, LLN) e FT4
normale sono potenzialmente idonei senza intervento.
23. Anamnesi di ipertensione persistente e incontrollata nonostante l’intervento medico.
24. Ipercolesterolemia attualmente trattata con atorvastatina, lovastatina o
simvastatina e indisponibilità o incapacità a passare a una terapia alternativa con:
pravastatina, fluvastatina, pitavastatina o rosuvastatina (la statina deve essere
cambiata almeno 2 settimane prima della somministrazione della dose) o ad altra terapia
consentita. Per i soggetti nei
Per i restanti criteri di esclusione, fare riferimento alla sinossi per superamento del
limite dei caratteri |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Proportion of subjects with loss of therapeutic response to levoketoconazole upon withdrawing to placebo compared with the proportion of subjects with loss of therapeutic response upon continuing
treatment with levoketoconazole. Loss of therapeutic response (i.e. relapse) is inferred based on mUFC from of three 24-hour urinary free cortisol (UFC) measurements obtained at any visit from second through final Randomized Withdrawal Phase visits (RW1 through RW5 inclusive) when:
(1) mUFC is above 1.5X the ULN of the central laboratory's reference range, OR
(2) mUFC is more than 40% above the baseline (RW0) value, if the RW0 value is at or above the ULN (i.e. =1.0X ULN) , OR
(3) an early rescue criterion is met, necessitating open-label therapy |
Proportion of subjects with loss of therapeutic response to levoketoconazole upon withdrawing to placebo compared with the proportion of subjects with loss of therapeutic response upon continuing
treatment with levoketoconazole. Loss of therapeutic response (i.e. relapse) is inferred based on mUFC from of three 24-hour urinary free cortisol (UFC) measurements obtained at any visit from second through final Randomized Withdrawal Phase visits (RW1 through RW5 inclusive) when:
(1) mUFC is above 1.5X the ULN of the central laboratory's reference range, OR
(2) mUFC is more than 40% above the baseline (RW0) value, if the RW0 value is at or above the ULN (i.e. =1.0X ULN) , OR
(3) an early rescue criterion is met, necessitating open-label therapy |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Loss of therapeutic response is inferred based on the mean of three 24-
hour UFC measurements (mUFC) obtained at any visit from second
through final Randomized Withdrawal Phase visits (RW1 through RW5
inclusive) |
Loss of therapeutic response is inferred based on the mean of three 24-
hour UFC measurements (mUFC) obtained at any visit from second
through final Randomized Withdrawal Phase visits (RW1 through RW5
inclusive) |
|
| E.5.2 | Secondary end point(s) |
1. Changes from Baseline (RW0) in mUFC and LNSC at all post-Baseline visits with these assessments through the final study visit (RES2)—applies to Secondary Objective 1;
2. Proportion of subjects with normalization of mUFC at RES2—applies to Secondary Objective 1;
3. Proportion of subjects with normalization of mUFC at the end of Randomized Withdrawal Phase—applies to Secondary Objective 1;
4. Changes from Baseline (RW0) in biomarkers of CS comorbidities (fasting glucose, fasting insulin, homeostatic model assessment-insulin resistance [HOMA-IR], hemoglobin A1c [HbA1c], total cholesterol, low density lipoprotein-cholesterol [LDL-C], and high-sensitivity C-reactive protein [hsCRP]) at all post-Baseline visits with these measurements through the final study visit (RES2)—applies to Secondary Objective 2;
5. Changes from Baseline (RW0) in health-related QoL and symptoms of depression at all post-Baseline visits with these assessments through the final study visit (RES2) – applies to Secondary Objective 3;
6. Changes from Baseline (RW0) in acne, hirsutism and peripheral edema at all post-Baseline visits with these assessments through the final study visit (RES2) – applies to Secondary Objective 4;
7. Incidence and severity of adverse events (AEs), particularly adverse events of special interest (AESIs) during levoketoconazole open-label therapy in the Dose-Titration and Maintenance (TM) Phase (levoketoconazole-naïve cohort), and during blinded therapy in the Randomized Withdrawal Phase and Restoration Phase (both cohorts)—applies to Secondary Objective 5.
8. Estimates of the following PK parameters: clearance (CL/F), volume of distribution (V/F), absorption rate constant (Ka), with associated between-subject variability where feasible. These parameters will be used to calculate half-life (t½), area under the concentration time curve (AUC) and peak concentration (Cmax), if feasible—applies to Secondary Objective 6;
9. Estimates of the following pharmacodynamic (PD) parameters: levoketoconazole concentration producing half maximal UFC suppression (IC 50), maximal suppression of UFC (Imax) and associated estimates of between-subject variability, if feasible. UFC concentrations in relation to dose and plasma exposure will be explored—applies to Secondary Objective 6
10. Frequency of usage and changes from Baseline (RW0) in frequency of usage of anti-diabetic, anti-cholesterol, anti-hypertensive, and chronic anti-inflammatory therapies at all post-Baseline visits; changes in corresponding biomarkers accounting for changes in medication usage will also be explored—applies to Exploratory Objective 1;
11. Time from RW0 to first time of loss of response, when:
(1) mUFC is above 1.5X the ULN of the central laboratory’s reference range, OR
(2) mUFC is more than 40% above the RW0 value, if the RW0 value is above the ULN [i.e. >1.0X ULN] , OR
(3) an early rescue criterion is met—applies to Exploratory Objective 2;
12. Time to first normalization of mUFC beginning from RW5 (subset with mUFC above 1.5X ULN at RW5)—applies to Exploratory Objective 2;
13. Time to first normalization of LNSC beginning from RW5 (subset with LNSC above ULN at RW5)—applies to Exploratory Objective 2;
Due to limit of space, please refer to the protocol; 1. Variazioni dal Baseline (RW0) nell’mUFC e nell’LNSC a tutte le visite post-baseline con queste valutazioni fino all’ultima visita dello studio (RES2) - si applica all’obiettivo secondario 1;
2. Proporzione di soggetti con normalizzazione dell’mUFC a RES2 - si applica all’obiettivo secondario 1;
3. Proporzione di soggetti con normalizzazione dell’mUFC al termine della fase di sospensione randomizzata – si applica all’obiettivo secondario 1;
4. Variazioni dal basale (RW0) nei biomarcatori delle comorbilità della CS (glicemia a digiuno, insulina a digiuno, valutazione del modello omeostatico per l’insulino-resistenza [homeostatic model assessment-insulin resistance, HOMA-IR], emoglobina A1c [hemoglobin A1c, HbA1c], colesterolo totale, colesterolo delle lipoproteine a bassa densità [low density lipoprotein-cholesterol, LDL-C] e proteina C reattiva ad alta sensibilità [high-sensitivity C-reactive protein, hsCRP]) a tutte le visite post-Baseline con queste misurazioni fino all’ultima visita dello studio (RES2) - si applica all’obiettivo secondario 2;
5. Variazioni dal Baseline (RW0) nella QoL correlata alla salute e nei sintomi della depressione a tutte le visite post-baseline con queste valutazioni fino all’ultima visita dello studio (RES2) - si applica all’obiettivo secondario 3;
6. Variazioni dal Baseline (RW0) nei fattori relativi ad acne, irsutismo ed edema periferico a tutte le visite post-baseline con queste valutazioni fino all’ultima visita dello studio (RES2) - si applica all’obiettivo secondario 4;
7. Incidenza e gravità degli eventi avversi (EA), particolarmente degli eventi avversi d’interesse speciale (adverse events of special interest, AESI), durante la terapia in aperto con levoke |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1: at all post-Baseline visits through the final study visit (RES2)
2: at RES2
3: at the end of Randomized Withdrawal Phase
4: at all post-Baseline visits through the final study visit (RES2)
5: at all post-Baseline visits through the final study visit (RES2)
6, 7 and 8: along the study
9: all post-Baseline visits
10: from baseline till first time of loss of response
11: from RES1 till first normalization of mUFC
12: from RES1 till first normalization of LNSC
13: at RES2
14: at all post-Baseline visits through the final study visit (RES2)
15: at all post-Baseline visits through the final study visit (RES2)
16: along the study
17: at all post-Baseline visits through the final study visit (RES2)
18: along the study
19 along the study |
1: tutte le visite dopo-Baseline fino alla visita di fine studio(RES2)
2: alla RES2
3: alla fine della fase di sospensione randomizzata
4: tutte le visite dopo-Baseline fino alla visita di fine studio(RES2)
5: tutte le visite dopo-Baseline fino alla visita di fine studio(RES2)
6, 7 e 8: aper tutto lo studio
9 tutte le visite dopo-Baseline
10 dal baseline fino alla prima perdita di risposta
11 da RES1 fino alla prima normalizzazione dell’mUFC
12 da RES1 fino alla prima normalizzazione di LNSC
13 alla RES2
14: a tutte le visite dopo-Baseline fino alla visita di fine studio(RES2)
15 a tutte le visite dopo-Baseline fino alla visita di fine studio(RES2)
16 along the study
17 tutte le visite dopo-Baseline fino alla visita di fine studio(RES2)
18 per tutto lo studio
19 per tutto lo studio |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | Yes |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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.8.4.1 | Number of sites anticipated in Member State concerned | 7 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 28 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Information not present in EudraCT |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Canada |
| Israel |
| United States |
| Bulgaria |
| Denmark |
| France |
| Greece |
| Hungary |
| Italy |
| Netherlands |
| Poland |
| Romania |
| Spain |
|
| E.8.7 | Trial 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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