E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Haemophilia A Haemophilia A with inhibitors |
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E.1.1.1 | Medical condition in easily understood language |
Haemophilia A Haemophilia A with inhibitors |
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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 | 20.0 |
E.1.2 | Level | LLT |
E.1.2 | Classification code | 10018938 |
E.1.2 | Term | Haemophilia A (Factor VIII) |
E.1.2 | System Organ Class | 100000004850 |
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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 | 10053751 |
E.1.2 | Term | Hemophilia A with anti factor VIII |
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 confirm the haemostatic effect of Mim8 as bleeding prophylaxis for adults and adolescents with haemophilia A with or without inhibitors. This will be done by: • Demonstrating superiority in number of bleeding episodes when treated with Mim8 once-weekly versus no prophylaxis for participants on no prophylaxis treatment prior to enrolment (Comparing Arm 1 and Arm 2 main treatment period) • Demonstrating non-inferiority in number of bleeding episodes when treated with either Mim8 once-weekly or once-monthly versus treatment with coagulation factor prophylaxis during run-in for participants on prophylaxis treatment prior to enrolment (Comparing Arm 3 and Arm 4 run-in with main treatment period). |
Patvirtinti kraujavimams profilaktikai skiriamo Mim8 hemostazinį poveikį tyrime dalyvaujantiems suaugusiesiems ir paaugliams, sergantiems hemofilija A, kuriems yra arba nėra nustatyta inhibitorių.
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E.2.2 | Secondary objectives of the trial |
1. To investigate safety of Mim8 prophylaxis in adults and adolescents with haemophilia A with or without FVIII inhibitors. 2. To evaluate the consumption of factor product per bleed treatment (number of injections) after Mim8 prophylaxis in adults and adolescents with haemophilia A with or without inhibitors. 3. To evaluate the development of anti-Mim8 antibodies after Mim8 prophylaxis in adults and adolescents with haemophilia A with or without inhibitors. 4. To evaluate treatment burden after Mim8 prophylaxis in adults and adolescents with haemophilia A with or without inhibitors. 5. To evaluate aspects of patient’s physical functioning after Mim8 prophylaxis in adults and adolescents with haemophilia A with or without inhibitors. 6. To evaluate joint pain intensity after Mim8 prophylaxis in adults and adolescents with haemophilia A with or without inhibitors. |
Ištirti profilaktikai skiriamo Mim8 saugumą suaugusiesiems ir paaugliams, sergantiems hemofilija A, kuriems yra arba nėra nustatyta FVIII inhibitorių. Įvertinti krešėjimo faktoriaus koncentrato suvartojimą kiekvieno kraujavimo atvejo gydymo metu (injekcijų skaičių) po Mim8 skyrimo profilaktikai suaugusiesiems ir paaugliams, sergantiems hemofilija A, kuriems yra arba nėra nustatyta inhibitorių. Įvertinti antikūnų prieš Mim8 susidarymą po Mim8 skyrimo profilaktikai suaugusiesiems ir paaugliams, sergantiems hemofilija A, kuriems yra arba nėra nustatyta inhibitorių.
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Informed consent obtained before any study-related activities. Study-related activities are any procedures that are carried out as part of the study, including activities to determine suitability for the study 2. Male or female participants with diagnosis of congenital haemophilia A of any severity based on medical records 3. Participants has been prescribed treatment with factor VIII concentrates or bypassing agent in the last 26 weeks prior to screening 4. Age above or equal to 12 years at the time of signing informed consent. 5. Body weight greater than or equal to 30 kg 6. Applicable to participants treated with on-demand/no prophylaxis prior to enrolment: ≥5 bleeds in the last 26 weeks prior to screening visit, for which factor VIII concentrates or bypassing agent has been prescribed 7. Applicable to participants with FVIII activity greater than or equal to 1% who are on prophylactic treatment: greater than or equal to 1 bleed in the last 26 weeks prior to screening visit, for which factor VIII concentrates or bypassing agent has been prescribed 8. Willingness and ability to comply with scheduled visits and study procedures, including the completion of diary and patient-reported outcomes questionnaires |
1. Informuoto asmens sutikimo gavimas prieš bet kokių su tyrimu susijusių veiksmų atlikimą. Su tyrimu susiję veiksmai – tai bet kokios tyrimo tikslais atliekamos procedūros, įskaitant veiksmus tinkamumui dalyvauti tyrime nustatyti. 2. Vyras arba moteris su bet kokio sunkumo įgimtos hemofilijos A diagnoze, remiantis medicinine dokumentacija. 3. Dalyviai , kuriems per paskutines 26 savaites iki atrankos buvo paskirtas gydymas VIII faktoriaus koncentratu arba krešėjimo sistemą apeinančiu preparatu arba nustatytas tokio gydymo poreikis. 4. Amžius nuo 12 metų imtinai informuoto asmens sutikimo pasirašymo metu. 5. Kūno svoris ≥ 30 kg. 6. Taikoma tyrimo dalyviams, kuriems buvo taikymas gydymas pagal poreikį / nebuvo taikomas profilaktinis gydymas: ≥ 5 kraujavimo atvejai per paskutines 26 savaites iki atrankos vizito, kuriems buvo paskirti VIII faktoriaus koncentratai arba krešėjimo sistemą apeinantys preparatai 7. Taikoma tyrimo dalyviams, kurių FVIII aktyvumas yra ≥1% ir kurie gydomi profilaktiškai: ≥ 1 kraujavimo atvejai per paskutines 26 savaites iki atrankos vizito, kuriems buvo paskirti VIII faktoriaus koncentratai arba krešėjimo sistemą apeinantys preparatai. 8. Pasirengimas ir gebėjimas dalyvauti planiniuose vizituose ir tyrimo procedūrose, įskaitant dienyno ir pacientų nurodomų baigčių klausimynų pildymą.
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E.4 | Principal exclusion criteria |
1. Previous participation in this study. Participation is defined as signed informed consent
2. Participation (i.e., signed informed consent) in any interventional clinical study with receipt of the last dose within 6 months (or 5 half-lives of the investigational medicinal product, whichever is shorter) before planned randomisation.
3. Exposure to non-factor haemostatic products for bleeding prophylaxis within 6 months (or 5 half-lives of the medicinal product, whichever is shorter) before planned randomisation, for participants not included in the run-in.
4. Female who is pregnant, breast-feeding or intends to become pregnant or is of child-bearing potential and not using a highly effective contraceptive method (highly effective contraceptive measures as defined in Section 10.4 or as required by local regulation or practice). Breast feeding is allowed only during the run-in period.
5. Any disorder, except for conditions associated with haemophilia A, which in the investigator’s opinion might jeopardise participant’s safety or compliance with the protocol.
6. Known or suspected hypersensitivity to trial product(s), any constituents of the product or to related products.
7. Receipt of gene therapy at any given time point.
8. Ongoing or planned immune tolerance induction (ITI) therapy.
9. Major surgery planned to take place after screening.
10. Known congenital or acquired coagulation disorders other than haemophilia A.
11. Hepatic dysfunction defined as AST and/or ALT greater than 3 times the upper limit combined with total bilirubin greater than 1.5 times the upper limit measured at screening.
12. Renal impairment defined as estimated Glomerular Filtration Rate (eGFR) less than or equal to 30 ml/min/1.73 m2 for serum creatinine measured at screening.
13. Previous or current thromboembolic disease or events (with the exception of previous catheter-associated thrombosis for which anti-thrombotic treatment is not currently ongoing) or risk of thromboembolic disease, as evaluated by investigator.
14. Mental incapacity, unwillingness to cooperate, or a language barrier precluding adequate understanding and cooperation.
15. Other conditions (e.g., autoimmune disease) or laboratory abnormality that may increase risk of bleeding or thrombosis as evaluated by the investigator. |
1. Ankstesnis dalyvavimas šiame tyrime. Dalyvavimas apibrėžiamas kaip pasirašytas informuoto asmens sutikimas. 2. Dalyvavimas ( pvz. pasirašyta sutikimo forma) bet kokiame interveniciniame klinikiniame tyrime gavus paskutinę dozę 6 mėnesių laikotarpiu (arba 5 atitinkamo tiriamojo vaistinio preparato pusėjimo trukmes atitinkančiu laikotarpiu, atsižvelgiant, kuris laikotarpis trumpesnis) iki planuojamos randomizacijos. 3. Faktorių neturinčių hemostatinių preparatų poveikis kraujavimo profilaktikai per 6 mėnesius (arba 5 vaistinio preparato pusinės eliminacijos periodus, atsižvelgiant į tai, kuris laikotarpis yra trumpesnis) prieš planuojamą pirmąją dozę dalyviams, neįtrauktiems į parengiamąjį etapą. 4. Nėščios, krūtimi maitinančios arba pastoti ketinančios moterys, taip pat vaisingo amžiaus moterys, nenaudojančios itin veiksmingo kontracepcijos metodo (10.4 skyriuje apibrėžtų arba remiantis vietoje galiojančiais reikalavimais ar praktika nustatytų itin veiksmingų kontracepcijos priemonių). Maitinimas krūtimi leistinas tik parengiamojo etapo metu. 5. Bet koks sutrikimas, išskyrus su hemofilija A susijusias būkles, kuris, tyrėjo nuomone, gali kelti grėsmę tyrimo dalyvio saugumui arba protokolo reikalavimų laikymuisi. 6. Žinomas arba įtariamas padidėjęs jautrumas tyrimo laikotarpiu skiriamam tiriamajam preparatui (-ams), jo (jų) sudedamosioms dalims arba panašiems preparatams. 7. Genų terapijos taikymas bet kuriuo metu 8. Taikoma arba planuojama taikyti imuninės tolerancijos indukcijos (ITI) terapija. 9. Planuojama didelės apimties operacija, laikotarpiu po atrankos. Žr. didelės apimties operacijos apibrėžimą Protokolo 6–7 lentelėje. 10. Žinomi įgimti arba įgyti krešėjimo sutrikimai, išskyrus hemofiliją A. 11. Kepenų funkcijos sutrikimas, apibrėžiamas kaip AST ir (arba) ALT kiekis, > 3 kartus viršijantis viršutinę ribą, kartu su bendro bilirubino kiekiu, > 1,5 karto viršijančiu viršutinę ribą, vertinant atrankos metu. 12. Inkstų funkcijos pablogėjimas, apibrėžiamas kaip apskaičiuotasis glomerulų filtracijos greitis (aGFG) ≤ 30 ml/min/1.73 m2, remiantis atrankos metu nustatytu kreatinino kiekiu serume. 13. Tromboembolinė liga arba reiškiniaia anamnezėje arba šiuo metu (išskyrus su kateteriu susijusią trombozę anamnezėje, dėl kurios šiuo metu netaikomas antitrombozinis gydymas) arba tromboembolinės ligos rizika tyrėjo vertinimu. 14. Neveiksnumas dėl psichikos sutrikimo, nenoras bendradarbiauti arba kalbos barjeras, kliudantis tinkamai suprasti ir bendradarbiauti. 15. Kitos būklės (pavyzdžiui, autoimuninė liga) arba laboratoriniais tyrimais nustatyta patologija, dėl kurių gali būti didesnė kraujavimo arba trombozės rizika tyrėjo vertinimu.
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E.5 End points |
E.5.1 | Primary end point(s) |
Number of treated bleeds |
Gydytų kraujavimo atvejų skaičius |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
- No prophylaxis treatment (Arms 1, 2a and 2b): From randomisation (week 0) to end of main (week 26) - Prophylaxis treatment (Arms 3 and 4): From initiation of run-in (26-52 weeks prior to week 0) to week 0 and from randomisation (week 0) to end of main (week 26) |
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E.5.2 | Secondary end point(s) |
1. Number of injection site reactions 2. Occurrence of antiMim8 antibodies 3. Number of treated spontaneous bleeds 4. Number of treated joint bleeds 5. Number of treated traumatic bleeds 6. Number of treated target joint bleeds 7. Consumption of factor product per bleed treatment (number of injections) 8. Change in physical function domain of paediatric quality of life inventory (PEDS-QL) 9. Change in participant’s treatment burden using the haemophilia treatment experience measure (Hemo-TEM) 10. Change in participant’s joint pain score using Joint Pain Rating Scale |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. All participants receiving Mim8 (Arms 2a, 2b, 3 and 4): From randomisation (week 0) to end of main (week 26) 2. All participants receiving Mim8 (Arms 2a, 2b, 3 and 4): From randomisation (week 0) to end of extension (week 52) 3. – 7.: - No prophylaxis treatment (Arms 1, 2a and 2b): From randomisation (week 0) to end of main (week 26) - Prophylaxis treatment (Arms 3 and 4): From initiation of run-in (26-52 weeks prior to week 0) to week 0 and from randomisation (week 0) to end of main (week 26) 8. – 10.: All participants (Arms 1, 2a, 2b, 3 and 4): From randomisation (week 0) to the end of the main part (week 26) |
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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) | 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 | Yes |
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 |
Intra-individual (within-patient) comparison |
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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 | Yes |
E.8.2.3.1 | Comparator description |
Different treatment regimen of Mim8 |
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E.8.2.4 | Number of treatment arms in the trial | 5 |
E.8.3 |
The trial involves single site in the Member State concerned
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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 | 51 |
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 | No |
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 |
China |
India |
Israel |
Japan |
Korea, Republic of |
Malaysia |
Saudi Arabia |
South Africa |
Taiwan |
United States |
European Union |
Switzerland |
Russian Federation |
Turkey |
United Kingdom |
Serbia |
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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
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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 | 2 |
E.8.9.1 | In the Member State concerned months | 3 |
E.8.9.1 | In the Member State concerned days | 30 |
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 | 30 |