E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Severe or Moderate Hemophilia A |
Emofilia a severa o moderata |
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E.1.1.1 | Medical condition in easily understood language |
Hemophilia A is an inherited bleeding disorder in which blood does not clot normally. People with hemophilia A will bleed more than normal for example after an injury, surgery, or dental procedure. |
L'emofilia A è una malattia emorragica ereditaria. Le persone con emofilia A sanguineranno più del normale per esempio dopo un infortunio, un intervento chirurgico o una procedura dentale. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Blood and lymphatic diseases [C15] |
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 | 10053753 |
E.1.2 | Term | Hemophilia A without inhibitors |
E.1.2 | System Organ Class | 100000004850 |
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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 evaluate the impact of emicizumab treatment on joint health and health-related quality of life (HRQoL) outcomes of participants with hemophilia A as well as their physical activity |
Valutare gli effetti del trattamento con emicizumab sulla salute articolare e sugli esiti della qualità di vita correlata alla salute (HRQoL) in partecipanti affetti da emofilia, nonché valutare l’attività fisica dagli stessi svolta. |
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E.2.2 | Secondary objectives of the trial |
• To evaluate the safety of emicizumab • To evaluate the immune response to emicizumab
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-Valutare la sicurezza di emicizumab -Valutare la risposta immunitaria a emicizumab |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
• Age >=13 and <70 years at time of signing Informed Consent Form • Diagnosis of severe congenital hemophilia A (intrinsic FVIII level <1%) or moderate congenital hemophilia A (intrinsic FVIII level <=5%) if previously prescribed prophylaxis • A negative test for FVIII inhibitor (i.e., <0.6 BU) within 8 weeks of enrollment • Participants who completed successful immune tolerance induction (ITI) at least 5 years before screening are eligible, provided they have had no evidence of inhibitor recurrence (permanent or temporary) as may be indicated by detection of an inhibitor, FVIII half-life < 6 hours, or FVIII recovery < 66% since completing ITI • Participants who were on standard FVIII prophylaxis, defined as the regular administration of FVIII to prevent bleeding, for at least the last 24 weeks, can be enrolled regardless of the number of bleeds during this period • Adequate hematologic, hepatic and renal function • For women of childbearing potential: agreement to remain abstinent (refrain from heterosexual intercourse) or use contraception during the treatment period and for at least 24 weeks after the final dose of emicizumab
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-Età >= 13 e < 70 anni al momento della sottoscrizione del modulo di consenso informato -Diagnosi di emofilia A congenita grave (livello intrinseco di FVIII < 1%) o emofilia A congenita moderata (livello intrinseco di FVIII = 5%), in caso di precedente prescrizione di terapia profilattica. -Test negativo per gli inibitori anti-FVIII (ossia < 0,6 UB) nelle 8 settimane precedenti l’arruolamento. -I partecipanti che hanno completato con successo l’induzione di immunotolleranza (Immmune Tolerance Induction, ITI) almeno 5 anni prima della fase di screening sono ritenuti idonei allo studio, purché non mostrino evidenza di ricomparsa (permanente o temporanea) degli inibitori, come potrebbe essere indicato dal rilevamento di un inibitore, dall’emivita del FVIII < 6 ore o dal recupero del FVIII < 66% dal completamento dell’ITI -I partecipanti che sono stati sottoposti a profilassi standard con FVIII, intesa come somministrazione periodica di FVIII per la prevenzione degli episodi emorragici, per almeno le ultime 24 settimane, possono essere arruolati indipendentemente dal numero di sanguinamenti durante il suddetto periodo -Adeguata funzionalità ematologica, epatica e renale -Per le donne in età fertile: consenso a praticare l’astinenza dai rapporti eterosessuali o a fare uso dei metodi contraccettivi durante il trattamento e per almeno 24 sett. Dopo l’ultima dose di emicizumab |
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E.4 | Principal exclusion criteria |
• Inherited or acquired bleeding disorder other than severe congenital hemophilia A (intrinsic FVIII level <1%) or moderate congenital hemophilia A (intrinsic FVIII level <=5%) without FVIII inhibitors who were previously prescribed prophylaxis for at least 24 weeks • Participants who have previously received emicizumab prophylaxis • Participants who had joint replacement, joint procedure, synovectomy or synoviorthesis less than 5 years ago, or participants who had joint replacement, joint procedure, synovectomy or synoviorthesis more than 5 years ago but are still experiencing pain in the joint (only the specific joint will be excluded from the study), or participants that plan to have joint replacement, joint procedure, synovectomy or synoviorthesis, or participants that are deemed suitable candidates for joint replacement, joint procedure, synovectomy or synoviorthesis at screening • Participants who have conditions other than hemophilia A that can affect joint health and structure (e.g., osteoarthritis) or with severely impaired mobility due to conditions other than hemophilia A • Participants with reduced bone mineral density defined as clinically relevant vitamin D deficiency • Participants with pre-existing cardiovascular disease not receiving controlled and targeted medication or in a stable condition • Participants not eligible for MRI • History of illicit drug or alcohol abuse within 48 weeks prior to screening • Participants who are at high risk for thrombotic microangiopathy (TMA) • Previous (within the last 12 months) or current treatment for thromboembolic disease (with the exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing) or signs of thromboembolic disease • Other conditions (e.g., certain autoimmune diseases) that may currently increase the risk of bleeding or thrombosis • History of clinically significant hypersensitivity associated with monoclonal antibody therapies or components of the emicizumab injection • Planned surgery during the emicizumab loading dose phase. Surgeries in participants on emicizumab from Week 5 onwards are allowed • Known HIV infection not controlled by medication • Concomitant disease, condition, significant abnormality on screening evaluation or laboratory tests, or treatment that could interfere with the conduct of the study, or that would in the opinion of the investigator, pose an additional unacceptable risk in administering study drug to the participant • Receipt of any of the following: o An investigational drug to treat or reduce the risk of hemophilic bleeds within 5 half-lives of last drug administration at screening o A non-hemophilia-related investigational drug within last 30 days or 5 half-lives at screening, whichever is shorter o Any other investigational drug currently being administered or planned to be administered • Inability to comply with the study protocol • Pregnant or breastfeeding, or intending to become pregnant during the study
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-Disturbo del sanguinamento ereditario o acquisito diverso da emofilia A congenita grave/moderata senza inibitori del FVIII, con prec. terapia profilattica per almeno 24 sett. -Precedente profilassi con emicizumab -Precedente artroplastica, procedura articolare, sinoviectomia o sinoviortesi da meno di 5 anni o da più ma con dolore tuttora avvertito oppure intenzione di sottoporsi oppure riscontro allo screening della candidabilità ad artroplastica, procedura articolare, sinoviectomia o sinoviortesi -Presenza di patologie diverse da emofilia A che incidono su salute e struttura delle articolazioni o grave compromissione della mobilità per patologie diverse da emofilia A -Riduzione della densità minerale ossea, carenza rilevante di vitamina D -Cardiovasculopatia preesistente senza terapia controllata e mirata o stabile -Inidoneità a sottoporsi a RM -Positività per abuso di alcol o sostanze stupefacenti nelle 48 sett. precedenti lo screening -Esposizione a un rischio elevato di TMA -Trattamento precedente (negli ultimi 12 mesi) o in corso per malattia tromboembolica o segni di malattia -Altre condizioni che potrebbero aumentare il rischio di emorragia o trombosi -Ipersensibilità significativa associata a terapie a base di anticorpi monoclonali o componenti di emicizumab. -Intervento chirurgico programmato, sono ammessi nei partecipanti trattati con emicizumab a partire dalla wk 5 -Infezione accertata da HIV non controllata da terapia -Malattia, condizione, anomalia rilevata allo screening o nelle analisi di lab. o tratt. che potrebbe interferire con lo studio o che rappresenta un rischio aggiuntivo inaccettabile -Tratt. con: farmaco sperim. per rischio sanguinamenti entro 5 emivite; farmaco sperim. non legato al tratt. di emofilia negli ultimi 30 gg o nelle ultime 5 emivite; qualsiasi altro farmaco sperim. somministrato pianificato -Incapacità di rispettare lo studio -Gravidanza o allattamento al seno oppure intenzione di iniziare una gravidanza |
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E.5 End points |
E.5.1 | Primary end point(s) |
1. Joint status over time based on centrally reviewed Haemophilia Early Arthropathy Detection with Ultrasound (HEAD-US) scores with a specific focus on the synovitis score in participants with synovitis 2. Clinical joint status over time based on the Hemophilia Joint Health Score (HJHS v2.1), excluding gait assessment 3. Joint status at screening and month 36 based on centrally reviewed International Prophylaxis Study Group (IPSG) score (with MRI) 4. Number of problem joints and proportion of problem joints, defined as joints having chronic joint pain and/or limited range of movement due to compromised joint integrity (i.e., chronic synovitis and/or hemophilic arthropathy) with or without persistent bleeding, over time 5. Number of target joint bleeds over time (target joints are defined as joints with >=3 bleeds occurring in the same joint during the last 24 weeks) 6. HRQoL, as assessed through use of the Comprehensive Assessment Tool of Challenges in Hemophilia (CATCH) Questionnaire over time 7. Change in the level of physical activity during the study as measured with a wearable activity tracker (Fitbit) 8. Change in daily step count, active minutes metabolic equivalents of tasks (METs), moderate to vigorous physical activity (MVPA; as per activity tracker default categorization), and type of physical activities 9. Change in the time and intensity level of physical activity as measured by the International Physical Activity Questionnaire Short Format (IPAQ-SF) 10. Number of all bleeds (i.e., those treated and untreated with FVIII), treated bleeds, spontaneous bleeds, joint bleeds, treated joint bleeds, and target joint bleeds (i.e., bleed rate) over time (ABR) as assessed through use of the Bleed and Medication Questionnaire (BMQ) 11. Participant and/or caregiver preference for emicizumab compared with previous FVIII regimen, as assessed through use of the Emicizumab Preference Survey (EmiPref) at month 6
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1 stato articolare nel corso del tempo sulla base dell’analisi HEAD-US, prestando attenzione al punteggio relativo alla sinovite 2 stato clinico delle articolazioni nel corso del tempo sulla base del punteggio HJHS v2.1, escludendo la valutazione della deambulazione 3 stato articolare allo screening e amese 36 sulla base dell’analisi IPSG; con RM 4 numero e percentuale delle articolazioni patologiche, con o senza sanguinamento persistente, nel corso del tempo 5 numero di sanguinamenti delle articolazioni bersaglio nel corso del tempo (articolazioni in cui si sono manifestati = 3 sanguinamenti nella stessa articolazione nelle ultime 24 sett.); 6 HRQoL valutata mediante CATCH nel corso del tempo 7 variazione del livello di attività fisica nel corso dello studio, misurata mediante Fitbit 8 variazione del conteggio dei passi giornalieri, dei minuti attivi, dei MET, della MVPA; in base alla classificazione del Fitbit e tipo di attività fisica 9 variazione del tempo e del grado di intensità dell’attività fisica svolta, misurata mediante IPAQ-SF 10 numero di tutti i sanguinamenti, trattati, spontanei, articolari, articolari trattati e nelle articolazioni bersaglio nel corso del tempo, valutato mediante BMQ 11 preferenza del paz. e/o del caregiver per emicizumab rispetto al regime precedente con FVIII, valutata mediante EmiPref al mese 6. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
1-2. At Screening (Day -28 to Day -1), Months 6, 12, 24 and 36 3. At Screening (Day -28 to Day -1) and Month 36 4. At Months 6, 12, 24 and 36 5. Up to 36 months 6. At Baseline (Day 1), Months 3, 6, 12, 18, 24, and 36 7-8. Until Month 36 9. At Baseline (Day 1), Months 3, 6, 12, 18, 24, and 36 10. Until Month 36 11. At Month 6
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1-2. Allo screening (dal giorno -28 al giorno -1), mesi 6, 12, 24 e 36 3. Allo screening (dal giorno -28 al giorno -1) e al mese 36 4. Ai mesi 6, 12, 24 e 36 5. Fino a 36 mesi 6. Al basale (giorno 1), mesi 3, 6, 12, 18, 24 e 36 7-8. Fino al mese 36 9. Al basale (giorno 1), mesi 3, 6, 12, 18, 24 e 36 10. Fino al mese 36 11. Al mese 6 |
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E.5.2 | Secondary end point(s) |
1. Incidence and severity of adverse events, with severity determined according to World Health Organization (WHO) toxicity scale 2. Incidence of thromboembolic events 3. Incidence of thrombotic microangiopathy 4. Incidence of severe hypersensitivity, anaphylaxis, and anaphylactoid events 5. Incidence and severity of injection-site reactions 6. Prevalence of anti-drug antibodies (ADAs) against emicizumab at baseline and incidence of ADAs against emicizumab during the study 7. Number and proportion of participants who develop anti-FVIII inhibitors (titer >=0.6 BU/mL) at specified timepoints
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1 incidenza e gravità degli eventi avversi, con la gravità determinata secondo la scala di classificazione della tossicità dell’Organizzazione Mondiale della Sanità (OMS); 2 incidenza di eventi tromboembolici; 3 incidenza di microangiopatia trombotica (TMA); 4 incidenza di eventi gravi di ipersensibilità, di anafilassi e anafilattoidi; 5 incidenza e gravità delle reazioni nel sito di iniezione. 6 prevalenza di anticorpi antifarmaco (Anti-Drug Antibody, ADA) al basale e incidenza di ADA durante lo studio; 7 numero e percentuale di partecipanti che sviluppano inibitori anti-FVIII (titolo = 0,6 UB/mL) in momenti temporali specificati. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1-5. Until 24 weeks (Safety Follow-up) after the final dose of emicizumab 6. At Baseline (Day 1), Months 6, 12, 24 and 36 7. Up to 36 months
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1-5. Fino a 24 settimane (follow-up di sicurezza) dopo la dose finale di emicizumab 6. Al basale (giorno 1), mesi 6, 12, 24 e 36 7. Fino a 36 mesi |
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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 | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | Yes |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
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) | No |
E.7.4 | Therapeutic use (Phase IV) | Yes |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | Yes |
E.8.1.7.1 | Other trial design description |
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E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 1 |
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 | 4 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 27 |
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 |
Brazil |
Canada |
Germany |
Hungary |
Ireland |
Italy |
Morocco |
Russian Federation |
Turkey |
United Kingdom |
United States |
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E.8.7 | Trial 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
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 0 |
E.8.9.2 | In all countries concerned by the trial years | 3 |
E.8.9.2 | In all countries concerned by the trial months | 0 |
E.8.9.2 | In all countries concerned by the trial days | 0 |