E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
AL amyloidosis involves a hematologic disorder caused by clonal plasma cells that produce misfolded immunoglobulin light chains. Overproduction of misfolded light chains results in both soluble, aggregated forms of light chains and insoluble, fibrillar deposits of abnormal AL protein (amyloid), in the tissues and organs. This can cause a range of symptoms and organ dysfunction including cardiac, renal, and hepatic dysfunction, gastrointestinal involvement and neuropathy and macroglossia |
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E.1.1.1 | Medical condition in easily understood language |
Light chain (AL) amyloidosis is a blood disorder, which causes progressive organ damage as a result of the misfolding of proteins. This disease can produce a range of symptoms and organ dysfunction |
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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 | PT |
E.1.2 | Classification code | 10036673 |
E.1.2 | Term | Primary amyloidosis |
E.1.2 | System Organ Class | 10021428 - Immune system disorders |
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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 |
Double-blind Phase To evaluate the efficacy of birtamimab plus standard of care compared to placebo plus standard of care when administered intravenously in Mayo Stage IV subjects with AL amyloidosis by assessing time to all-cause mortality.
Open-label Extension Phase • To evaluate the long-term safety of birtamimab plus standard of care in Mayo Stage IV subjects with AL amyloidosis |
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E.2.2 | Secondary objectives of the trial |
To evaluate birtamimab plus standard of care compared to placebo plus standard of care on the following: • Change from baseline to Month 9 in the 6-Minute Walk Test (6MWT) distance • Change from baseline to Month 9 in health-related quality of life using the Short Form-36 questionnaire Version 2 (SF-36v2) |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1.Aged ≥18 years and legal age of consent according to local regulations 2.Newly diagnosed and AL amyloidosis treatment naive with cardiac involvement 3.Confirmed diagnosis of AL amyloidosis 4.Confirmed Mayo Stage IV AL Amyloidosis as defined by NT-proBNP ≥1800 pg/mL and Troponin-T >0.025 ng/mL or high sensitivity cardiac troponin T ≥40 ng/L and dFLC ≥18 mg/dL 5.Planned first-line chemotherapy contains bortezomib administered subcutaneously weekly
A comprehensive list of inclusion criteria can be found in the protocol.
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E.4 | Principal exclusion criteria |
1.Non-AL amyloidosis 2.NT-proBNP >8500 pg/mL 3.Meets the International Myeloma Working Group (IMWG) definition of multiple myeloma except for malignancy biomarker of involved/and uninvolved serum free light chain ratio ≥100 4.Subject is eligible for and plans to undergo ASCT or organ transplant during the study 5.Myocardial infarction, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or ECG evidence of acute ischemia, within 6 months prior to the Month 1-Day 1 Visit 6.Severe valvular stenosis (e.g., aortic or mitral stenosis with a valve area <1.0 cm2) or severe congenital heart disease 7.ECG evidence of acute ischemia or active conduction system abnormalities 8.Prior treatment with hematopoietic growth factors, transfusions of blood or blood products within 1 week of Month 1-Day 1 9.Prior radiotherapy within 4 weeks of Month 1-Day 1 10.Prior treatment with plasma cell-directed chemotherapy, birtamimab, daratumumab, 11-1F4, anti-serum amyloid P antibody, doxycycline for amyloid, or other investigational treatment directed at amyloid 11.Waldenström's macroglobulinemia and/or immunoglobulin M monoclonal gammopathy
A comprehensive list of exclusion criteria can be found in the protocol.
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to all-cause mortality during the Double-blind Phase
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
Time from the first dose of study drug until death or end of the Double-blind Phase over 9 months
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E.5.2 | Secondary end point(s) |
•Change from baseline to Month 9 of the Double-blind Phase in the 6MWT distance (meters) •Change from baseline to Month 9 of the Double-blind Phase in the Physical Component Summary (PCS) score of the SF-36v2
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
From baseline until Month 9 of the Double-blind Phase |
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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 | Yes |
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 | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
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 | 2 |
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 65 |
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 |
Taiwan |
Australia |
Canada |
Israel |
Japan |
Korea, Republic of |
United Kingdom |
United States |
Austria |
Belgium |
Czechia |
Denmark |
France |
Germany |
Greece |
Hungary |
Ireland |
Italy |
Netherlands |
Poland |
Portugal |
Spain |
Türkiye |
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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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The Double-blind Phase of the study will end when a protocol defined number of primary endpoint events have occurred and EOT Visits have been completed for all subjects who remain in the Double-blind Phase at that time. The end of the study is defined as the date when the last subject last visit occurs in the OLE Phase. |
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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 | 4 |
E.8.9.1 | In the Member State concerned months | 0 |
E.8.9.1 | In the Member State concerned days | 1 |
E.8.9.2 | In all countries concerned by the trial years | 5 |
E.8.9.2 | In all countries concerned by the trial months | 9 |
E.8.9.2 | In all countries concerned by the trial days | 0 |