Trattamento di pazienti affetti da emofilia A con inibitori del FVIII (MOTIVATE)
TRATTAMENTO MODERNO DEI PAZIENTI CON EMOFILIA POSITIVI PER INIBITORI A - Uno studio osservazionale internazionale
This is a non-interventional, multicenter, observational, international study in male persons with haemophilia A who have developed inhibitors to any replacement coagulation factor VIII (FVIII) product. The purpose of the study is to capture different approaches in the management of persons with haemophilia A and FVIII inhibitors, document current immune tolerance induction approaches, and evaluate the efficacy and safety of immune tolerance induction, including the combination of FVIII and emicizumab. Patients will be assigned to 1 of 3 groups based on the treatments they receive, and may switch to another group if their treatment is changed. Participants will be followed after a maximum observational period of 5 years.
Panoramica dello studio
Stato
Condizioni
Descrizione dettagliata
This study will capture different approaches in the management of persons with haemophilia A (HA) and inhibitors. HA is a serious blood coagulation disorder caused by a deficiency in FVIII that results in a failure to produce FVIII in sufficient quantities to achieve satisfactory haemostasis. Patients with HA are predisposed to recurrent bleeds into joints and soft tissues that culminate in debilitating arthropathy and long-term morbidity. HA can be effectively treated with replacement FVIII concentrates, obtained by fractionation of human plasma (pdFVIII) or using recombinant technology (rFVIII). In patients receiving FVIII replacement therapy, inhibitors can develop that neutralise the effect of treatment. Inhibitors develop in ~35% of patients who have not been previously exposed to FVIII treatment and ~1% of patients who have undergone previous FVIII treatment. Inhibitor development has major adverse implications on bleeding rates, morbidity, mortality and quality of life.
Immune tolerance induction (ITI), which involves prolonged treatment with plasma-derived (pdFVIII) or recombinant FVIII (rFVIII), is the only clinically proven strategy for eradication of inhibitors and is recommended as the primary treatment option in European and US guidelines. Bypassing agents (activated recombinant factor VII [rFVIIa] and activated prothrombin complex concentrate [aPCC]) are used to manage bleeding episodes (BEs) and for prophylaxis or in surgical settings in patients with FVIII inhibitors. The bispecific factor IX (FIX) and factor X (FX) monoclonal antibody emicizumab was approved in the US in November 2017, and in Europe in February 2018.
The overall objective of this study is to capture different approaches in the management of participants with HA and inhibitors, document current ITI approaches, and evaluate efficacy and safety of ITI, including the combination of FVIII and emicizumab. Patients will be assigned to 1 of 3 groups based on the treatments they receive:
- Group 1 receives ITI with Nuwiq, octanate, or wilate, with aPCC or rFVIIa administered as needed
- Group 2 receives ITI with Nuwiq, octanate, or wilate, in combination with emicizumab, with aPCC or rFVIIa administered as needed
- Group 3 receives routine prophylaxis with emicizumab, aPCC or rFVIIa without ITI
Tipo di studio
Iscrizione (Stimato)
Contatti e Sedi
Contatto studio
- Nome: Carmen Escuriola-Ettingshausen, MD
- Numero di telefono: +4961059638909
- Email: carmen.escuriola@hzrm.de
Backup dei contatti dello studio
- Nome: Robert Sidonio, MD, MSc
- Numero di telefono: 404-785-1637
- Email: robert.sidonio.jr@emory.edu
Luoghi di studio
-
-
-
Mörfelden-Walldorf, Germania, 64546
- Reclutamento
- HZRM Hämophilie-Zentrum Rhein Main
-
Contatto:
- Carmen Escuriola-Ettingshausen, MD
- Numero di telefono: +4961059638909
- Email: carmen.escuriola@hzrm.de
-
Investigatore principale:
- Carmen Escuriola-Ettingshausen, MD
-
-
-
-
Georgia
-
Atlanta, Georgia, Stati Uniti, 30329
- Reclutamento
- Arthur M. Blank Hospital
-
Investigatore principale:
- Robert Sidonio, MD, MSc
-
Contatto:
- Robert Sidonio, MD, MSc
- Numero di telefono: 404-785-1637
- Email: robert.sidonio.jr@emory.edu
-
-
Criteri di partecipazione
Criteri di ammissibilità
Età idonea allo studio
- Bambino
- Adulto
- Adulto più anziano
Accetta volontari sani
Sessi ammissibili allo studio
Metodo di campionamento
Popolazione di studio
The study population includes males with haemophilia A who have delveloped inhibitors to any FVIII product. Participants starting treatment after study inclusion will have all data recorded prospectively while those who have already started treatment can enter if detailed retrospective documentation is available. Participants will be observed for a maximum of 5 years.
Descrizione
Inclusion Criteria:
- Male persons with haemophilia A, of any severity, who have a historical inhibitor titer ≥ 0.6 BU/mL, including those who have failed previous immune tolerance induction (ITI) attempt(s)
- Persons undergoing ITI with Nuwiq, octanate, or wilateor undergoing ITI with Nuwiq®, octanate® or wilate® and receiving prophylactic therapy with emicizumab, activated prothrombin complex concentrate (aPCC), or activated recombinant factor VII (rFVIIa)
- Participants or participants' parent(s)/legal guardian(s) must be capable of giving signed informed consent and be able to understand the trial documents
Exclusion Criteria:
- Participants are excluded from the trial if any coagulation disorder other than haemophilia A is diagnosed
- Partly retrospective patients will be excluded if detailed documentation on treatment, all bleeding episodes, inhibitor titers, and FVIII levels is not available for the retrospective period
Piano di studio
Come è strutturato lo studio?
Dettagli di progettazione
- Modelli osservazionali: COHORT
- Prospettive temporali: PROSPECTIVE
Coorti e interventi
Gruppo / Coorte |
Intervento / Trattamento |
|---|---|
|
Group 1: ITI with Nuwiq, octanate, or wilate
Participants receiving immune tolerance induction with either Nuwiq, octanate, or wilate. As needed, aPCC/rFVIIa will be administered to treat bleeding episodes or during surgery and for prophylaxis. |
Nuwiq is a recombinant FVIII concentrate from a human cell line. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information. Octanate is a high-purity human Factor VIII / von Willebrand Factor (VWF) concentrate. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information. Wilate is a high-purity human von Willebrand Factor (VWF)/Factor VIII concentrate. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information. Recombinant factor VIIa (rFVIIa) is a blood factor VII manufactured using recombinant technology. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information.
Altri nomi:
Activated prothrombin complex concentrate (aPCC) is an anti-inhibitor coagulant complex acting on multiple pathways to facilitate coagulation. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information.
Altri nomi:
|
|
Group 2: ITI with Nuwiq, octanate, or wilate with emicizumab
Participants receiving immune tolerance induction with either Nuwiq, octanate, or wilate, in combination with emicizumab prophylaxis. As needed, aPCC/rFVIIa will be administered to treat bleeding episodes or during surgery. |
Nuwiq is a recombinant FVIII concentrate from a human cell line. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information. Octanate is a high-purity human Factor VIII / von Willebrand Factor (VWF) concentrate. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information. Wilate is a high-purity human von Willebrand Factor (VWF)/Factor VIII concentrate. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information. Recombinant factor VIIa (rFVIIa) is a blood factor VII manufactured using recombinant technology. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information.
Altri nomi:
Activated prothrombin complex concentrate (aPCC) is an anti-inhibitor coagulant complex acting on multiple pathways to facilitate coagulation. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information.
Altri nomi:
Emicizumab is a therapeutic antibody which brings activated factor IX and factor X together It is administered via subcutaneous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information.
Altri nomi:
|
|
Group 3: Prophylaxis with emicizumab, aPCC, or rFVIIa
Participants receiving routine prophylaxis with emicizumab, aPCC, or rFVIIa without immune tolerance induction. On-demand aPCC/rFVIIa can be used as needed to treat bleeding episodes or during surgery. |
Recombinant factor VIIa (rFVIIa) is a blood factor VII manufactured using recombinant technology. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information.
Altri nomi:
Activated prothrombin complex concentrate (aPCC) is an anti-inhibitor coagulant complex acting on multiple pathways to facilitate coagulation. It is administered via intravenous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information.
Altri nomi:
Emicizumab is a therapeutic antibody which brings activated factor IX and factor X together It is administered via subcutaneous injection at a dosage determined by the investigator's discretion, in consideration of the participants' clinical condition and prescribing information.
Altri nomi:
|
Cosa sta misurando lo studio?
Misure di risultato primarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
|
Proportion of participants achieving inhibitor titer < 0.6 Bethesda units (BU)/mL L for at least 2 consecutive measurements
Lasso di tempo: Up to 5 years
|
The proportion of participants in Groups 1 and 2 achieving inhibitor titer < 0.6 Bethesda units (BU)/mL L for at least 2 consecutive measurements will be determined. FVIII inhibitor titer is measured at baseline and throughout the study, according to standard of care. |
Up to 5 years
|
|
Proportion of participants achieving FVIII recovery ≥ 66% of the predefined reference value of 1.5% IU/kg body weight (Groups 1 and 2)
Lasso di tempo: Up to 5 years
|
The proportion of participants in Groups 1 and 2 achieving FVIII recovery ≥ 66% of the predefined reference value of 1.5% IU/kg body weight will be determined. Once inhibitor has become negative (< 0.6 BU/mL), FVIII plasma levels are measured prior to and approximately 15 to 30 minutes after FVIII to evaluate FVIII recovery. |
Up to 5 years
|
|
Proportion of participants achieving FVIII half-life ≥ 6 h (Groups 1 and 2)
Lasso di tempo: Up to 5 years
|
The proportion of participants in Groups 1 and 2 achieving FVIII half-life ≥ 6 h will be determined. Once inhibitor has become negative (< 0.6 BU/mL), FVIII plasma levels are measured prior to and at 15-30 minutes and 2, 4, 8-12, and 24 hours after administration of the immune tolerance induction (or prophylactic FVIII) to evaluate half-life; when FVIII trough levels are > 1% during regular prophylaxis, half-life can be evaluated from fewer samples or using a population pharmacokinetic model. |
Up to 5 years
|
|
Annualized bleeding rate
Lasso di tempo: Up to 5 years
|
Annualized rate of all bleeding episodes will be reported and compared between all 3 study groups. |
Up to 5 years
|
Misure di risultato secondarie
Misura del risultato |
Misura Descrizione |
Lasso di tempo |
|---|---|---|
|
Time to achieve immune tolerance induction outcome
Lasso di tempo: Up to 5 years
|
The time it takes to achieve immune tolerance induction will be assessed in Groups 1 and 2. Immune tolerance induction success is defined as inhibitor titer < 0.6 BU/mL for at least 2 consecutive measurements, FVIII recovery ≥ 66% of the predefined reference value of 1.5% IU/kg body weight, and half-life of FVIII ≥ 6 h. |
Up to 5 years
|
|
Frequency of emicizumab, aPCC, and rFVIIa use during immune tolerance induction
Lasso di tempo: Up to 5 years
|
The number of times that participants in Groups 1 and 2 used emicizumab, aPCC, and rFVIIa during immune tolerance induction will be reported. |
Up to 5 years
|
|
Rate of FVIII inhibitor relapse
Lasso di tempo: Up to 5 years
|
Rate of FVIII inhibitor relapses for participants in Groups 1 and 2 during an observational follow-up period in participants who have achieved complete immune tolerance induction success. Relapse is defined as inhibitor titer ≥ 0.6 BU/mL on ≥ 2 consecutive occurrences during the observational follow-up period after having achieved complete success and a prophylactic dose of ≤ 50 IU FVIII/kg every other day. |
Up to 5 years
|
|
Frequency of bleeding episodes
Lasso di tempo: Up to 5 years
|
Frequency of all bleeding episodes (BEs), including all treated BEs, all spontaneous BEs, all joint BEs, and target joint BEs over time (≥ 3 bleeds in the same joint within 24 weeks) will be compared between study groups. |
Up to 5 years
|
|
Severity of bleeding episodes
Lasso di tempo: Up to 5 years
|
Severity of all bleeding episodes (BEs), including all treated BEs, all spontaneous BEs, all joint BEs, and target joint BEs over time (≥ 3 bleeds in the same joint within 24 weeks) will be compared between study groups. Assessment of BE severity will be defined as:
|
Up to 5 years
|
|
Number of infusions required to control bleeding episodes
Lasso di tempo: Up to 5 years
|
The number of infusions required to control bleeding episodes will be compared between study groups. |
Up to 5 years
|
|
Frequency of bleeding with surgical procedures
Lasso di tempo: Up to 5 years
|
The frequency of bleeding during and after surgical procedures will be compared between study groups. |
Up to 5 years
|
|
Severity of bleeding with surgical procedures
Lasso di tempo: Up to 5 years
|
The severity of bleeding during and after surgical procedures will be compared between study groups. The severity of bleeding during surgery will be defined as:
|
Up to 5 years
|
|
Proportion of participants experiencing adverse drug reactions
Lasso di tempo: Up to 5 years
|
The proportion of participants experiencing adverse drug reactions will be compared between study groups. |
Up to 5 years
|
|
Number of thrombotic events
Lasso di tempo: Up to 5 years
|
The number of thrombotic events will be compared between study groups. |
Up to 5 years
|
|
Treatment costs
Lasso di tempo: Up to 5 years
|
The cost (in dollars) of treatment will be compared between study groups. |
Up to 5 years
|
Collaboratori e investigatori
Sponsor
Collaboratori
Investigatori
- Investigatore principale: Robert Sidonio, MD, MSc, Emory University
Pubblicazioni e link utili
Studiare le date dei record
Studia le date principali
Inizio studio (Effettivo)
Completamento primario (Stimato)
Completamento dello studio (Stimato)
Date di iscrizione allo studio
Primo inviato
Primo inviato che soddisfa i criteri di controllo qualità
Primo Inserito (Effettivo)
Aggiornamenti dei record di studio
Ultimo aggiornamento pubblicato (Effettivo)
Ultimo aggiornamento inviato che soddisfa i criteri QC
Ultimo verificato
Maggiori informazioni
Termini relativi a questo studio
Parole chiave
Termini MeSH pertinenti aggiuntivi
- Malattie genetiche, congenite
- Disturbi della coagulazione del sangue
- Disturbi emorragici
- Disturbi della coagulazione del sangue, ereditari
- Disturbi delle proteine della coagulazione
- Malattie e anomalie congenite, ereditarie e neonatali
- Malattie emiche e linfatiche
- Emofilia A
- Malattie ematologiche
- Aminoacidi, peptidi e proteine
- Proteine
- Fattori biologici
- Proteine del sangue
- Fattori di coagulazione del sangue
- Precursori proteici
- Fattore VIII
- emicizumab
- Fattore von Willebrand
- FVIIA ricombinante
- complesso coagulante anti-inibitore
Altri numeri di identificazione dello studio
- IRB00113316
- 2025P011192 (Altro identificatore: Emory IRB)
Piano per i dati dei singoli partecipanti (IPD)
Hai intenzione di condividere i dati dei singoli partecipanti (IPD)?
Informazioni su farmaci e dispositivi, documenti di studio
Studia un prodotto farmaceutico regolamentato dalla FDA degli Stati Uniti
Studia un dispositivo regolamentato dalla FDA degli Stati Uniti
Queste informazioni sono state recuperate direttamente dal sito web clinicaltrials.gov senza alcuna modifica. In caso di richieste di modifica, rimozione o aggiornamento dei dettagli dello studio, contattare register@clinicaltrials.gov. Non appena verrà implementata una modifica su clinicaltrials.gov, questa verrà aggiornata automaticamente anche sul nostro sito web .