| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| transfusiondependent ß-thalassaemia |
| beta-talassemia trasfusione-dipendente |
|
| E.1.1.1 | Medical condition in easily understood language |
| Transfusion-dependent Thalassemia |
| talassemia trasfusione-dipendente |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Congenital, Hereditary, and Neonatal Diseases and Abnormalities [C16] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 22.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10081911 |
| E.1.2 | Term | Transfusion dependent thalassaemia |
| E.1.2 | System Organ Class | 100000004850 |
|
| 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 |
| The primary objective of this study is to evaluate the efficacy of 3 multiple doses of VIT-2763: 60 mg once daily (QD), 60 mg twice daily (BID) and 120 mg BID versus placebo, as measured by reduction in RBC transfusion burden from Week 13 to Week 24 of treatment, to identify the most efficacious and safe dose |
| L’obiettivo primario di questo studio è valutare l’efficacia di 3 dosi multiple di VIT-2763: 60 mg una volta al giorno (QD), 60 mg due volte al giorno (BID) e 120 mg BID rispetto al placebo, misurata mediante riduzione del carico della trasfusione di globuli rossi dalla Settimana 13 alla Settimana 24 del trattamento, con l’obiettivo di identificare la dose più efficace e sicura. |
|
| E.2.2 | Secondary objectives of the trial |
The secondary objectives are to evaluate the effects of VIT-2763 on the following
measures:
* To evaluate the reduction in number of RBC transfusions (units) over Weeks 13 to 24.
* To evaluate the proportion of subjects showing 50% RBC transfusion burden reduction assessed over any consecutive 12-week interval during the treatment period of 24 weeks.
* To evaluate the proportion of subjects showing 33% RBC transfusion burden reduction assessed over any consecutive 12-week interval during the treatment period of 24 weeks.
* To evaluate mean change from baseline in symptoms and quality of life (QoL). |
Gli obiettivi secondari sono la valutazione degli effetti di VIT-2763 sulle seguenti misure:
¿ Valutare la riduzione del numero di trasfusioni di globuli rossi (unità) nelle Settimane da 13 a 24.
¿ Valutare la percentuale di soggetti che mostrano una riduzione del carico della trasfusione di globuli rossi del 50% valutata in intervalli di 12 settimane consecutive durante il periodo di trattamento di 24 settimane.
¿ Valutare la percentuale di soggetti che mostrano una riduzione del carico della trasfusione di globuli rossi del 33% valutata in intervalli di 12 settimane consecutive durante il periodo di trattamento di 24 settimane.
¿ Valutare la variazione media dei sintomi e della qualità della vita (QoL) rispetto al basale. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female gender.
2. 18 to 65 years of age at screening.
3. Body weight =40.0 kg and =100 kg at screening (adult male and female subjects).
4. Documented diagnosis of ß-thalassaemia or Hb E/ß-thalassaemia (ß thalassaemia with mutation and/or multiplication of a-globin is allowed).
5. RBC transfusion dependence, defined as at least 6 RBC units in the 24 weeks prior to randomisation and no transfusion-free period for =35 days during that period.
In order to verify RBC transfusion dependence, 12 weeks of transfusion history will be collected prospectively during the screening/run-in period, and 12 weeks of transfusion history will be collected retrospectively from subjects’ history. In those cases where sites have the transfusion records only in volumes (cc or ml), a conversion of volume to defined units will be performed, in order to obtain the number of units within the last24 weeks to assess the eligibility. Specifications how to convert RBC volumes to units are given in Section 5.2 of the protocol.
6. Ability to understand the requirements of the study, and abide by the study restrictions, and agreement to return for the required assessments.
7. Subject (and/or legally acceptable representative) must understand and has provided voluntarily the appropriate written informed consent using the Informed Consent Form (ICF). Subject must provide written informed consent before any study-specific procedures are performed including screening procedures, see Section 12.12.2 of the protocol.
8. Female subjects of childbearing potential must have a negative serum pregnancy test at screening confirmed by a negative urine pregnancy test at randomisation, must have stopped breastfeeding as of first dose, and must either commit to true abstinence from
heterosexual contact (which must be reviewed on a monthly basis and source documented) or must be willing to use adequate contraceptive precautions (i.e., highly effective method of birth control). Female subjects must agree to use adequate contraception during the study and for 1 month after the last dose of study medication or according to local requirements, whichever is longer. Effective contraception (highly effective method of birth control i.e., with a failure rate of <1% per year, when used consistently and correctly) such as implants, injectables, combined oral contraceptives, bilateral tubal occlusion, intrauterine devices, sexual abstinence, or vasectomised partner must be used. Non-childbearing potential includes being surgically sterilised at
least 6 months prior to the study.
Note: For female subjects participating in this study, continuous use of hormonal contraception alone is not sufficient, because potential interactions via cytochrome P450 (CYP) enzymes may alter the efficacy of hormonal contraception. The continuous use
of hormonal contraception by a female subject should be combined with the use of a condom by the male partner.
9. Male subjects must practice true abstinence or agree to use a condom during sexual contact with their sexual partner, pregnant female or a female of childbearing potential while participating in the study, and for at least 1 month (sufficiently exceeding 5 times the mean t1/2 of VIT-2763 based on multiple dose human PK data) following investigational product discontinuation, even if he has undergone a successful vasectomy. |
1. Sesso maschile o femminile.
2. Età compresa tra 18 e 65 anni al momento dello screening.
3. Peso corporeo =40,0 kg e =100 kg al momento dello screening (soggetti adulti di sesso maschile e femminile).
4. Diagnosi documentata di ß-talassemia o Hb E/ß-talassemia (è consentita ß-talassemia con mutazione e/o moltiplicazione di a-globina).
5. Dipendenza da trasfusione di globuli rossi, definita come almeno 6 unità di globuli rossi nelle 24 settimane precedenti la randomizzazione e nessun periodo privo di trasfusione per =35 giorni durante tale periodo.
Al fine di verificare la dipendenza da trasfusione di globuli rossi, saranno raccolte prospetticamente 12 settimane di anamnesi di trasfusione durante il periodo di screening/run-in e retroattivamente 12 settimane di anamnesi di trasfusione dall’anamnesi del soggetto. Nei casi in cui le registrazioni delle trasfusioni siano effettuate solo in volumi (cc o ml), al fine di valutare l’idoneità verrà eseguita una conversione del volume in unità definite, al fine di ottenere il numero di unità nelle ultime 24 settimane. Le specifiche sulle modalità di conversione dei volumi di globuli rossi in unità sono riportate nel paragrafo 5.2 del protocollo.
6. Capacità di comprendere i requisiti dello studio e di rispettarne le restrizioni, nonché accettare di tornare per le valutazioni richieste.
7. Il soggetto (e/o rappresentante giuridicamente accettabile) deve comprendere e aver fornito volontariamente il consenso informato scritto appropriato mediante il modulo di consenso informato. Il soggetto deve fornire il consenso informato scritto prima di sottoporsi a qualsiasi procedura specifica dello studio, tra cui le procedure di
screening; consultare il paragrafo 12.12.2 del protocollo.
8. Le donne in età fertile devono avere un test di gravidanza sierologico negativo al momento dello screening confermato da un test di gravidanza sulle urine negativo al momento della randomizzazione, devono aver interrotto l’allattamento al seno al momento della prima dose e devono astenersi concretamente dal contatto eterosessuale (che deve essere esaminato su base mensile e documentato da fonti) o essere disposte ad adottare misure contraccettive adeguate (ovvero un metodo di controllo delle nascite altamente efficace). I soggetti di sesso femminile devono accettare di adottare un adeguato metodo contraccettivo nel corso dello studio e per 1 mese dopo l’ultima dose del farmaco in studio o secondo le disposizioni locali, a seconda di quale sia il periodo più lungo.
Metodi contraccettivi efficaci (metodo di controllo delle nascite altamente efficace, ovvero con una percentuale di fallimento <1% all’anno, se usato in modo corretto e uniforme), quali impianti, iniezioni, contraccettivi orali combinati, occlusione bilaterale delle tube, dispositivi intrauterini, astinenza sessuale o vasectomizzazione del partner. La paziente non in età fertile deve essere sterilizzata chirurgicamente almeno 6 mesi prima dello studio.
Nota: per i soggetti di sesso femminile che partecipano a questo studio, l’uso continuo di contraccezione ormonale da solo non è sufficiente, poiché le potenziali interazioni attraverso gli enzimi del citocromo P450 (CYP) possono alterare l’efficacia della contraccezione ormonale. L’uso continuo di contraccezione ormonale da parte di un
soggetto di sesso femminile deve essere associato all’uso di un preservativo da parte del partner di sesso maschile.
9. I soggetti di sesso maschile devono adottare una reale astinenza o accettare di usare un preservativo durante il contatto sessuale con la propria partner, una donna incinta o una in età fertile mentre partecipa allo studio e per almeno 1 mese (sufficientemente superiore a 5 volte la media t1/2 di VIT-2763 sulla base dei dati farmacocinetici umani a dosi multiple) dopo l’interruzione del prodotto in studio, anche se si sono sottoposti a una vasectomia efficace. |
|
| E.4 | Principal exclusion criteria |
1. Documented diagnosis of Hb S/ß-thalassaemia, a-thalassaemia (e.g., Hb H disease), or delta beta (dß)-thalassaemia, or hereditary persistence of foetal Hb.
2. Known previous or concomitant serious illness, medical condition or physical condition that may be associated with increased risk to the subject, or may interfere with study assessments, outcomes, or the ability to provide written informed consent or comply with study procedures, in the Investigator’s opinion.
Note: A subject tested positive using nucleic acid amplification testing, antigen, or antibody detection for SARS-CoV-2 test within 2 weeks preceding screening or during screening, will be excluded but can be rescreened once at a later time point as per Investigator’s judgment and if confirmation of a negative SARS-CoV-2 test is available based on standard of care.
3. Subjects with history of partial or total splenectomy within 4 months prior to screening.
4. History of myocardial iron overload as defined by a cardiac T2* <20 ms by MRI, and/or a documented LIC >15 mg/g liver dry weight assessed through MRI.
Note: Results from existing T2* or LIC MRI results will be taken into account for eligibility assessment in case the examinations were performed within 12 months prior to screening. In those cases, where cardiac T2* MRI results or LIC MRI results are not available from the subject's history, the results from the cardiac T2* and LIC MRI will be assessed during screening.
5. Chronic liver disease or history of liver cirrhosis, and/or alanine aminotransferase (ALT) or aspartate aminotransferase (AST), above 3-fold the upper limit of normal (ULN) range at screening.
6. Clinically relevant renal disease, including estimated glomerular filtration rate (eGFR) =45 ml/min/1.73 m2 (according to chronic kidney disease classification Stage 4 or higher), and/or significant urinary albumin/creatinine ratio >3 mg/mmol at screening.
Note: eGFR should be estimated according to Chronic Kidney Disease Epidemiology Collaboration formula (CKI-EPI).
7. Any history or clinically important finding of cardiac disorders, such as clinically relevant cardiac arrhythmia, cardiac insufficiency, cardiomyopathy, coronary disease, family history of congenital long QT syndrome, family history of sudden death, valve disorder, or heart failure according to New York Heart Association (NYHA) Classification 3-4.
8. Clinically relevant abnormal 12-lead ECG findings during screening or prior to randomisation (as deemed by the Investigator), including (but not limited to) second, or third degree atrioventricular block or QTcF >450 msec.
9. Any history of clinically significant lung disease, including idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, or pulmonary hypertension Grade 3 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0.
10. Clinically significant bacterial, fungal, parasitic, or viral infection which requires therapy at the time of screening. Note: A subject meeting this criterion should delay screening and/or enrolment until 2 weeks post-therapy, or would be excluded but can be rescreened at maximum 2 times at a later time point.
11. [...] |
1. Diagnosi documentata di Hb S/ß-talassemia, a-talassemia (ad es. malattia da HbH) o talassemia delta beta (dß) oppure persistenza ereditaria di Hb fetale.
2. Malattie o condizioni mediche oppure fisiche gravi, pregresse o concomitanti note che possono essere associate a un aumento del rischio per il soggetto o possono interferire con le valutazioni, gli esiti dello studio o la capacità di fornire un consenso informato scritto o di conformarsi alle procedure dello studio, secondo il parere dello sperimentatore.
Nota: un soggetto risultato positivo al test mediante test di amplificazione degli acidi nucleici, rilevamento dell’antigene o dell’anticorpo per il test SARS-Cov-2 nelle 2 settimane precedenti lo screening o nel corso dello screening sarà escluso, ma può essere nuovamente sottoposto a screening una volta in un secondo momento, secondo il giudizio dello sperimentatore e se è disponibile la conferma di un test SARS-COV-2 negativo in base allo standard di cura.
3. Soggetti con anamnesi di splenectomia parziale o totale nei 4 mesi precedenti allo screening.
4. Anamnesi di sovraccarico di ferro miocardico secondo la definizione di un T2* cardiaco <20 ms mediante RM e/o di una LIC documentata >15 mg/g di peso a secco epatico valutato mediante RM.
Nota: i risultati esistenti della RM di T2* o LIC saranno presi in considerazione per la valutazione dell’idoneità nel caso in cui gli esami siano stati eseguiti nei 12 mesi precedenti allo screening. In questi casi, in cui i risultati della RM di T2* cardiaco o
LIC non sono disponibili nell’anamnesi del soggetto, i risultati della RM di T2* cardiaco e LIC saranno valutati in fase di screening.
5. Epatopatia cronica o anamnesi di cirrosi epatica e/o alanina aminotransferasi (ALT) o aspartato aminotransferasi (AST), oltre 3 volte il limite superiore della norma (ULN)
allo screening.
6. Malattia renale clinicamente rilevante, tra cui velocità di filtrazione glomerulare stimata (eGFR) =45 ml/min/1,73 m2 (secondo la classificazione della malattia renale cronica di stadio 4 o superiore) e/o un rapporto significativo di albumina/creatinina urinaria >3 mg/mmol allo screening. Nota: l’eGFR deve essere stimata in base alla formula Chronic Kidney Disease Epidemiology Collaboration (CKI-EPI).
7. Eventuale anamnesi o riscontro di rilievo clinico di patologie cardiache, quali aritmia cardiaca, insufficienza cardiaca, cardiomiopatia, coronaropatia clinicamente rilevanti, anamnesi familiare di sindrome congenita del QT lungo, anamnesi familiare di morte improvvisa, disturbi valvolari o insufficienza cardiaca secondo la classificazione 3-4 della New York Heart Association (NYHA).
8. Risultati dell’ECG a 12 derivazioni anomali clinicamente rilevanti in fase di screening o prima della randomizzazione (secondo quanto ritenuto dallo sperimentatore),
tra cui (a titolo esemplificativo ma non esaustivo) blocco atrioventricolare di secondo o terzo grado o QTcF >450 msec.
9. Eventuale anamnesi di malattia polmonare clinicamente significativa, tra cui fibrosi polmonare idiopatica, malattia polmonare ostruttiva cronica o ipertensione polmonare di grado 3 secondo i Common Terminology Criteria for Adverse Events (CTCAE) versione 5.0
del National Cancer Institute (NCI).
10. Infezione batterica, micotica, parassitaria o virale clinicamente significativa che richiede terapia al momento dello screening. Nota: un soggetto che soddisfi questo criterio deve posticipare lo screening e/o l’arruolamento a 2 settimane dopo la terapia, oppure verrebbe escluso, ma può essere nuovamente sottoposto a screening per un massimo di 2 volte in un secondo momento.
11. [...] |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Proportion of subjects experiencing =33% reduction of RBC units from baseline and a reduction of =2 units assessed consecutively from Week 13 to Week 24, compared to the baseline transfusion burden during the last 12 weeks prior to randomisation for VIT-2763 versus placebo. |
| Percentuale di soggetti con riduzione =33% delle unità di globuli rossi rispetto al basale e una riduzione =2 unità valutate consecutivamente dalla Settimana 13 alla Settimana 24, rispetto al carico trasfusionale al basale nelle ultime 12 settimane prima della randomizzazione per VIT-2763 rispetto al placebo. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Week 13 to Week 24 comparing to Baseline (Day -83 to Day 1) |
| dalla Settimana 13 alla Settimana 24, rispetto al basale (dal giorno -83 al giorno 1) |
|
| E.5.2 | Secondary end point(s) |
- Change from baseline in RBC transfusions over Weeks 13 to 24 compared to the baseline RBC transfusion burden derived using the last 12 weeks prior to randomization.
[Time Frame: Week 13 to Week 24 comparing to Baseline (Day -83 to Day 1)]
- Proportion of patients achieving =50% reduction of RBC transfusions and =2 units assessed over any consecutive 12-
week interval from Week 1 to 24.
[Time Frame: Any consecutive 12-week interval from Week 1 to Week 24 comparing to Baseline (Day -83 to Day 1)]
- Proportion of patients achieving =33% reduction of RBC transfusions and =2 units assessed over any consecutive 12-week interval from Week 1 to 24.
[Time Frame: Any consecutive 12-week interval from Week 1 to Week 24 comparing to Baseline (Day -83 to Day 1)]
- Mean change from baseline in Quality of Life (QoL) total score Transfusion-dependent QoL Questionnaire (TranQuol): a disease-specific, validated, QoL measure developed for thalassaemia patients. The adult version includes 36 questions grouped into 5 domains: physical health, emotional health, sexual health, family functioning, and school/career functioning. The total score ranges from 0 (worst) to 100 (best).
[Time Frame: Week 15 and Week 24 comparing to Baseline (Day 1)] |
- Change from baseline in RBC transfusions over Weeks 13 to 24 compared to the baseline RBC transfusion burden derived using the last 12 weeks prior to randomization.
[Time Frame: Week 13 to Week 24 comparing to Baseline (Day -83 to Day 1)]
- Proportion of patients achieving =50% reduction of RBC transfusions and =2 units assessed over any consecutive 12-
week interval from Week 1 to 24.
[Time Frame: Any consecutive 12-week interval from Week 1 to Week 24 comparing to Baseline (Day -83 to Day 1)]
- Proportion of patients achieving =33% reduction of RBC transfusions and =2 units assessed over any consecutive 12-week interval from Week 1 to 24.
[Time Frame: Any consecutive 12-week interval from Week 1 to Week 24 comparing to Baseline (Day -83 to Day 1)]
- Mean change from baseline in Quality of Life (QoL) total score Transfusion-dependent QoL Questionnaire (TranQuol): a disease-specific, validated, QoL measure developed for thalassaemia patients. The adult version includes 36 questions grouped into 5 domains: physical health, emotional health, sexual health, family functioning, and school/career functioning. The total score ranges from 0 (worst) to 100 (best).
[Time Frame: Week 15 and Week 24 comparing to Baseline (Day 1)] |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
- Change from baseline in RBC transfusions over Weeks 13 to 24 compared to the baseline RBC transfusion burden
Week 13 to Week 24 comparing to Baseline (Day -83 to Day 1)
- Proportion of patients achieving =50% reduction of RBC transfusions
Any consecutive 12-week interval from Week 1 to Week 24 comparing to Baseline (Day -83 to Day 1)
- Proportion of patients achieving =33% reduction of RBC transfusions
Any consecutive 12-week interval from Week 1 to Week 24 comparing to Baseline (Day -83 to Day 1)
- Mean change from baseline in Quality of Life (QoL) total score Transfusion-dependent QoL Questionnaire (TranQuol)
Week 15 and Week 24 comparing to Baseline (Day 1) |
- Change from baseline in RBC transfusions over Weeks 13 to 24 compared to the baseline RBC transfusion burden
Week 13 to Week 24 comparing to Baseline (Day -83 to Day 1)
- Proportion of patients achieving =50% reduction of RBC transfusions
Any consecutive 12-week interval from Week 1 to Week 24 comparing to Baseline (Day -83 to Day 1)
- Proportion of patients achieving =33% reduction of RBC transfusions
Any consecutive 12-week interval from Week 1 to Week 24 comparing to Baseline (Day -83 to Day 1)
- Mean change from baseline in Quality of Life (QoL) total score Transfusion-dependent QoL Questionnaire (TranQuol)
Week 15 and Week 24 comparing to Baseline (Day 1) |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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 | Yes |
| 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 | 4 |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 |
| Egypt |
| Israel |
| Lebanon |
| Malaysia |
| Thailand |
| Turkey |
| United States |
| Bulgaria |
| Italy |
| United Kingdom |
| Greece |
|
| 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
|
| The end of the study is defined as the date of the last visit of the last subject in the study or last scheduled procedure shown in Table 1 of the study Protocol for the last subject |
| La fine dello studio è definita come la data dell'ultima visita dell'ultimo soggetto o dell'ultima procedura programmata riportata nella Tabella 1 del Protocollo di studio per l'ultimo soggetto |
|
| 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 | 0 |
| E.8.9.1 | In the Member State concerned days | 20 |
| 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 | 3 |
| E.8.9.2 | In all countries concerned by the trial days | 26 |
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