- ICH GCP
- Registr klinických studií v USA
- Klinická studie NCT01957059
A Phase I/II Study of BMN053 in Subjects With Duchenne Muscular Dystrophy (DMD)
A Phase I/II, Open-label, Dose Escalating With 48 Week Treatment Study to Assess the Safety and Tolerability, Pharmacokinetics, Pharmacodynamics and Efficacy of BMN053 (Previously Known as PRO053) in Subjects With Duchenne Muscular Dystrophy.
Přehled studie
Postavení
Podmínky
Detailní popis
Typ studie
Zápis (Aktuální)
Fáze
- Fáze 2
- Fáze 1
Kontakty a umístění
Studijní místa
-
-
-
Leuven, Belgie, 3000
- UZ Leuven, Campus Gasthuisberg
-
-
-
-
-
Paris, Francie, 75651
- Institut de Myologie
-
-
-
-
-
Leiden, Holandsko, 2333ZA
- Leids Universitair Medisch Centrum
-
-
-
-
-
Rome, Itálie, 00168
- Policlinico Universitario Agostino Gemelli
-
-
-
-
-
London, Spojené království, WC1n 3JH
- Great Ormond Street Hospital for Children
-
Newcastle, Spojené království, NE1 3BZ
- Institute of Genetic Medicine International Centre for Life
-
-
Kritéria účasti
Kritéria způsobilosti
Věk způsobilý ke studiu
Přijímá zdravé dobrovolníky
Pohlaví způsobilá ke studiu
Popis
Inclusion Criteria:
- Duchenne muscular dystrophy resulting from a mutation correctable by treatment with BMN053 confirmed by a state-of-the-art DNA diagnostic technique covering all DMD gene exons, including but not limited to MLPA (Multiplex Ligation-dependent Probe Amplification), CGH (Comparative Genomic Hybridisation), SCAIP (Single Condition Amplification/Internal Primer) or HRMCA (High-Resolution Melting Curve Analysis).
- Ambulant boys aged at least 5 years on the day of first dosing able to walk for at least 300 metres in the 6 minute walking distance (6MWD) test. In addition, results of the 6MWD test must be within ±30 metres of each other at 2 of 3 pre-treatment visits (screen 1, 2 and baseline) prior to first BMN053 administration.
- Adequate quality for biopsy (confirmed with MRI) of the lateral head of the gastrocnemius muscle. Only under exceptional circumstances will an alternative muscle (preferably brachii) be considered for biopsy and only following discussion between the Principal Investigator and the BioMarin Medical Monitor.
- Life expectancy of at least 3 years after inclusion in the study.
- Glucocorticosteroid use which is stable for at least 3 months prior to first BMN053 administration. Subjects must have been receiving glucocorticosteroids for at least 6 months prior to the first BMN053 administration.
- Willing and able to adhere to the study visit schedule and other protocol requirements.
- Written informed consent signed (by parent(s)/legal guardian and/or the subject, according to the local regulations).
- In France, a subject will be eligible for inclusion in this study only if either affiliated to, or a beneficiary of, a social security category.
- Anticipated adequate vein access for intravenous (IV) infusion.
Exclusion Criteria:
- Current or history of liver disease or impairment.
- Current or history of renal disease or impairment.
- At least two aPTT above upper limit of normal (ULN) within the last month prior to first dose of BMN053.
- Screening platelet count below the lower limit of normal (LLN).
- Acute illness within 4 weeks prior to first dose of BMN053 which may interfere with the study assessments.
- Severe mental retardation and/or behavioural problems which, in the opinion of the Investigator, prohibit participation in this study.
- Severe cardiomyopathy which, in the opinion of the Investigator prohibits participation in this study. If a subject has a left ventricular ejection fraction <45% at screening, the Investigator should discuss inclusion of the subject with the Medical Monitor.
- Expected need for daytime mechanical ventilation within the next year.
- Use of anticoagulants, antithrombotics or antiplatelet agents.
- Use of idebenone or other forms of coenzyme Q10 within 1 month prior to the start of the screening for the study.
- Use of nutritional or herbal supplements which, in the opinion of the Investigator, may influence muscle performance within 1 month prior to first dose of BMN053.
- Use of any other investigational product or participation in another trial with an investigational product, within 6 months prior to the start of the screening for the study.
Studijní plán
Jak je studie koncipována?
Detaily designu
- Primární účel: Léčba
- Přidělení: Nerandomizované
- Intervenční model: Paralelní přiřazení
- Maskování: Žádné (otevřený štítek)
Zbraně a zásahy
Skupina účastníků / Arm |
Intervence / Léčba |
---|---|
Experimentální: Dose escalation phase
In the dose-escalation phase, following screening assessment, two cohorts of three subjects each receive two single doses of BMN 053 in two study periods (i.e., four single doses in total per subject).
In each study period they will receive BMN 053 by IV infusion and by SC injection (separated by one week).
The proposed doses are 1 mg/kg (Cohort 1, study period 1), 3 mg/kg (Cohort 2, study period 1), 6 mg/kg (Cohort 1, study period 2) and 9 mg/kg (Cohort 2, study period 2).
The actual doses may be amended or repeated based on emerging data from previous doses.
|
All doses of BMN053 have been administered as subcutaneous injections.
|
Experimentální: Regimen selection
After completion of the dose-escalation period of Cohort 1, the safety data of the subjects will be reviewed by a DSMB and if no safety concerns these subjects will continue to receive 6 mg/kg BMN053 weekly by SC injection for 48 weeks.
3 more treatment-naïve subjects will be entered into this Group.
These 6 subjects will form Group 1 of the Regimen Selection phase who received 6 mg/kg SC.
At the time of this amendment (4) this part of the study has been completed.
Following completion of the dose-escalation study period of Cohort 2 (9 mg/kg), the planned review of the preliminary plasma PK data from the dose-escalation phase showed a relative bioavailability of 50% for BMN053 with SC dosing (50% lower plasma AUC after SC dosing compared to IV dosing).
Taking into consideration the risk of injection site reactions noted with similar compounds when administered SC over longer term, the planned 9 mg/kg BMN053 weekly by SC injection will be discontinued to be replaced by an IV regimen.
|
All doses of BMN053 will be administered as IV infusions. The proposed doses are as follows: • 3 mg/kg All doses of BMN053 will be administered as IV infusions. The proposed doses are as follows: • 4-6 mg/kg |
Experimentální: 48-week Treatment Phase
Thirty additional treatment-naïve subjects will be recruited for the primary evaluation and will receive treatment at the recommended regimen for a total of 48 weeks. Subjects dosed initially in the dose escalation phase and/or the regimen selection phase of the study will not be included in the primary analysis. Following completion of the 2nd study period for Cohort 2, the safety data will be reviewed by the DSMB and in the absence of safety concerns the subjects may enter the 48 week treatment phase and receive 9 mg/kg PRO053 once weekly by SC injection. Three new subjects will enter cohort 2 (i.e. 6 subjects in total at this dose level). After the initial 12 subjects have completed 12 weeks of dosing the dose for the Treatment group (30 new subjects) will be selected based on the totality of the 12-week data from those initial 12 subjects. The initial 12 subjects will also be dosed on the selected dose (i.e. continue on their dose or [down-]titrate). |
All doses of PRO053 will be administered as IV infusions.
The proposed doses will be decided upon completion of the Regimen Selection Phase of Groups 2 and 3
|
Experimentální: Dosing extension
All subjects who have completed the dose escalation and regimen selection phase of the study (N=15), and subjects who have complete the treatment phase of the study who have tolerated the treatment will be offered to continue dosing in the dosing extension with ongoing assessment of efficacy, safety, and tolerability of BMN 053.
Safety, efficacy, PK/PD and biomarker assessments will be performed at scheduled visits; adverse events (AEs) and concomitant medications and therapies will be continuously monitored.
The dose extension phase will provide BMN 053 treatment for 48 weeks.
|
All doses of PRO053 will be administered as IV infusions.
The proposed doses will be decided upon completion of the Regimen Selection Phase of Groups 2 and 3 and the Treatment Phase Group 4.
|
Co je měření studie?
Primární výstupní opatření
Měření výsledku |
Časové okno |
---|---|
Změna od výchozí hodnoty v 6minutovém testu chůze
Časové okno: po 48 týdnech léčebné fáze
|
po 48 týdnech léčebné fáze
|
Sekundární výstupní opatření
Měření výsledku |
Časové okno |
---|---|
Svalová síla
Časové okno: po 48 týdnech léčebné fáze
|
po 48 týdnech léčebné fáze
|
Muscle function
Časové okno: after 48 weeks treatment phase
|
after 48 weeks treatment phase
|
Pulmonary function
Časové okno: after 48 weeks treatment phase
|
after 48 weeks treatment phase
|
Functional outcomes questionnaire
Časové okno: after 48 weeks treatment phase
|
after 48 weeks treatment phase
|
Adverse Events
Časové okno: after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase
|
after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase
|
Safety Laboratory
Časové okno: after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase
|
after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase
|
Cardiac function
Časové okno: after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase
|
after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase
|
Pharmacokinetic parameters at different dose levels
Časové okno: after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase
|
after single intravenous and subcutaneous doses, and after 48 weeks of treatment phase
|
Presence of (BMD-like) dystrophin expression in muscle biopsy
Časové okno: after 48 weeks treatment phase
|
after 48 weeks treatment phase
|
Production of exon skip 53 mRNA in muscle biopsy
Časové okno: after 48 weeks treatment phase
|
after 48 weeks treatment phase
|
Spolupracovníci a vyšetřovatelé
Sponzor
Vyšetřovatelé
- Vrchní vyšetřovatel: V. Straub, Prof., Institute of Genetic Medicine, Newcastle University, UK
Publikace a užitečné odkazy
Užitečné odkazy
Termíny studijních záznamů
Hlavní termíny studia
Začátek studia (Aktuální)
Primární dokončení (Aktuální)
Dokončení studie (Aktuální)
Termíny zápisu do studia
První předloženo
První předloženo, které splnilo kritéria kontroly kvality
První zveřejněno (Odhad)
Aktualizace studijních záznamů
Poslední zveřejněná aktualizace (Aktuální)
Odeslaná poslední aktualizace, která splnila kritéria kontroly kvality
Naposledy ověřeno
Více informací
Termíny související s touto studií
Klíčová slova
Další relevantní podmínky MeSH
Další identifikační čísla studie
- PRO053-CLIN-01
Tyto informace byly beze změn načteny přímo z webu clinicaltrials.gov. Máte-li jakékoli požadavky na změnu, odstranění nebo aktualizaci podrobností studie, kontaktujte prosím register@clinicaltrials.gov. Jakmile bude změna implementována na clinicaltrials.gov, bude automaticky aktualizována i na našem webu .