E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Light chain (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 | 18.1 |
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 |
The objective of this study is to determine the efficacy and safety of NEOD001 versus placebo in subjects with AL amyloidosis who have persistent cardiac dysfunction. |
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E.2.2 | Secondary objectives of the trial |
• Change from baseline to Month 12 in the Physical Component Score of the Short Form-36 (SF-36)
• Change from baseline to Month 12 in the 6-minute walk test (6MWT)
• For renal-evaluable subjects, renal best response from baseline to Month 12
• For subjects with peripheral neuropathy, change from baseline to Month 12 in their Neuropathy Impairment Score–Lower Limbs (NIS-LL) score
• For subjects with painful peripheral neuropathy, change from baseline to Month 12 in their VASPI score
• Change from baseline to Month 12 in the Kansas City Cardiomyopathy Questionnaire (KCCQ)
• Progression free survival (combined cardiac and renal progression) at Month 12
• Assessment of the safety and tolerability of NEOD001 as assessed by vital signs, duration of therapy |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Subjects must meet all of the following criteria:
1. Age ≥18 years
2. Confirmed diagnosis of systemic AL amyloidosis by the following:
• Histochemical diagnosis of amyloidosis determined by polarizing light microscopy of green birefringent material in Congo red-stained tissue specimens OR characteristic electron microscopy appearance
AND
• Confirmatory electron microscopy immunohistochemistry OR mass spectroscopy of AL amyloidosis
3. Confirmed diagnosis of AL amyloidosis by mass spectrometry of tissue biopsy (if archival tissue is not available, a biopsy is required) if the subject meets any of the following:
• Is black or African American
• Is over 75 years of age with concurrent monoclonal gammopathy
• Has a history of familial amyloidosis and has concurrent monoclonal gammopathy
4. Cardiac involvement as defined by ALL of the following:
• Past documented or presently noted clinical signs and symptoms supportive of a diagnosis of heart failure in the setting of a confirmed diagnosis of AL amyloidosis in the absence of an alternative explanation for heart failure
• Either an endomyocardial biopsy consistent with AL amyloidosis OR an echocardiogram demonstrating a mean left ventricular wall thickness in diastole >12 mm in the absence of other causes (e.g., severe hypertension, aortic stenosis) which would adequately explain the degree of wall thickening
• NT-proBNP ≥650 pg/mL in the absence of renal failure defined by an eGFR <30 mL/min/1.73 m2 or atrial fibrillation with an uncontrolled ventricular rate, as defined by >110 beats per minute
5. NT-proBNP <5000 pg/mL
6. Received at least one prior systemic chemotherapeutic regimen, which may include stem cell transplant, for AL amyloidosis
7. Achieved at least a partial hematologic response to a previous therapy resulting in a stable hematologic condition not currently requiring additional active treatment against the PCD component of their AL disease
8. Adequate bone marrow reserve, hepatic and renal function, as demonstrated by:
• Absolute neutrophil count (ANC) ≥1.0 x109/L
• Platelet count ≥75 × 109/L
• Hemoglobin ≥9 g/dL
• Total bilirubin ≤2 × upper limit of normal (ULN)
• Aspartate aminotransferase (AST) ≤3 × ULN
• Alanine aminotransferase (ALT) ≤3 × ULN
• Estimated glomerular filtration rate (eGFR) ≥30 mL/min/1.73 m2 as estimated by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation
9. Systolic blood pressure (BP) 90-180 mmHg
10. Distance walked during 6MWT is >100 meters and <600 meters
11. Women of childbearing potential (WOCBP) must have 2 negative pregnancy tests during Screening, the second within 24 hours prior to the first administration of study drug and must agree to use highly effective physician-approved contraception from Screening to 90 days following the last study drug administration
12. Male subjects must be surgically sterile or must agree to use highly effective physician-approved contraception from Screening to 90 days following the last study drug administration
13. Ability to understand and willingness to sign an ICF prior to initiation of any study procedures |
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E.4 | Principal exclusion criteria |
Subjects must not meet any of the following criteria:
1. Diagnosis of non-AL amyloidosis
2. Meets the International Myeloma Working Group (IMWG) definition of Multiple Myeloma
3. Symptomatic orthostatic hypotension that in the medical judgment of the Investigator would interfere with subject’s ability to safely receive treatment or complete study assessments
4. Myocardial infarction, uncontrolled angina, uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia, within 6 months prior to the Month 1-Day 1 Visit
5. Severe valvular stenosis (e.g. aortic or mitral stenosis with a valve area <1.0 cm2) or severe congenital heart disease
6. ECG evidence of acute ischemia or active conduction system abnormalities with the exception of any of the following:
• First degree atrioventricular (AV) block
• Second degree AV block Type 1 (Mobitz Type 1/Wenckebach type)
• Right or left bundle branch block
• Atrial fibrillation with a controlled ventricular rate
Note: Prior to randomization, any ECG screening abnormalities must be reviewed and designated as either “clinically significant” or “not clinically significant” by the Investigator
7. Has not recovered (i.e., equivalent to a CTCAE Grade 1 [mild] or better) from the clinically significant toxic effects of prior anticancer therapy. Exception: subjects with prior bortezomib treatment may have CTCAE Grade 2 neuropathy.
8. Received any of the following within the specified time frame prior to the Month 1-Day 1 Visit:
• Oral or intravenous antibiotics, antifungals, or antivirals within 1 week, with the exception of prophylactic oral agents
• Hematopoietic growth factors, transfusions of blood or blood products within 1 week
• Chemotherapy, radiotherapy, or other plasma cell directed therapy within 6 months
• ASCT within 12 months
• Major surgery within 4 weeks or planned major surgery during the study
• Any other investigational agent within 4 weeks
• Prior treatment with NEOD001, 11-1F4, anti-serum amyloid P antibody, or other investigational treatment directed at amyloid
9. Active malignancy with the exception of any of the following:
• Adequately treated basal cell carcinoma, squamous cell carcinoma, or in situ cervical cancer
• Adequately treated Stage I cancer from which the subject is currently in remission and has been in remission for ≥2 years
• Stage I prostate cancer that does not require treatment
• Any other cancer from which the subject has been disease-free for ≥2 years
10. History of Grade ≥3 infusion-related AEs or hypersensitivity to another monoclonal antibody
11. Known prior allergic or infusion reaction to any of the study drug excipients
12. Uncontrolled bacterial, viral, fungal, HIV, hepatitis B, or hepatitis C infection
13. Women who are breastfeeding
14. Any condition which could interfere with, or the treatment for which might interfere with, the conduct of the study or which would, in the opinion of the Investigator, unacceptably increase the subject’s risk by participating in the study
15. Unable or unwilling to adhere to the study-specified procedures and restrictions
16. Subject is under legal custodianship |
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E.5 End points |
E.5.1 | Primary end point(s) |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
NT-proBNP best response from baseline to Month 12 |
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E.5.2 | Secondary end point(s) |
• SF-36
• 6MWT
• Renal best response
• Peripheral neuropathy score
• KCCQ
• Progression free survival (combined cardiac and renal progression)
• Assessment of the safety and tolerability of NEOD001 as assessed by vital signs |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• Change from baseline to Month 12 in the Physical Component Score of the SF-36
• Change from baseline to Month 12 in the 6MWT
• For renal-evaluable subjects, renal best response from baseline to Month 12
• For subjects with peripheral neuropathy, change from baseline to Month 12 in their NIS-LL score
• For subjects with painful peripheral neuropathy, change from baseline to Month 12 in their VASPI score
• Change from baseline to Month 12 in the KCCQ
• Progression free survival (combined cardiac and renal progression) at Month 12
• Assessment of the safety and tolerability of NEOD001 as assessed by vital signs, duration of therapy, 12-lead ECGs, routine laboratory assessments, and frequency and severity of AEs as assessed by CTCAE grade
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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 | Yes |
E.6.7 | Pharmacodynamic | Yes |
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) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
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 | Yes |
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
| Yes |
E.8.4 | The trial involves multiple sites in the Member State concerned | No |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 15 |
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 |
France |
Germany |
Greece |
Italy |
Spain |
United Kingdom |
United States |
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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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LVLS
The study will end when the last subject completes 12 months of study treatment and the 30-day safety follow-up period (i.e., EOS Visit). After completing 12 months of treatment and the EOS Visit, a subject may be considered for entry into an open-label extension study, during which subjects will receive active treatment and may receive concurrent chemotherapy. |
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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 | 6 |
E.8.9.1 | In the Member State concerned days | 0 |
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 | 6 |
E.8.9.2 | In all countries concerned by the trial days | 0 |