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 dysfuction |
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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 |
To evaluate the efficacy of NEOD001 plus standard of care vs. placebo plus standard of care when administered intravenously in subjects with AL amyloidosis by assessing time to all- cause mortality or cardiac hospitalization |
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E.2.2 | Secondary objectives of the trial |
In subjects with AL amyloidosis, comparing NEOD001 plus standard of care vs. placebo plus standard of care: • To evaluate the cardiac response rate as assessed by NT-proBNP • To evaluate time to cardiac mortality or cardiac hospitalization • To evaluate cardiac functional response using the 6 Minute Walk Test (6MWT) • To evaluate general health-related quality of life using the Short Form 36 questionnaire (SF-36) • To evaluate cardiac-specific quality of life using the Kansas City Cardiomyopathy Questionnaire (KCCQ) • To evaluate the renal response rate using established criteria (Palladini 2014) • To evaluate the hepatic response rate according to consensus criteria (Comenzo 2012) |
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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. Aged ≥ 18 years 2. Newly diagnosed and AL amyloidosis treatment naïve 3. Bone marrow consistent with plasma cell dyscrasia within 42 days prior to Month 1-Day 1 4. Confirmed diagnosis of 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 immunohistochemistry OR mass spectroscopy of AL amyloidosis 5. Confirmed diagnosis of AL amyloidosis by mass spectrometry of tissue biopsy 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 6. 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 • Echocardiogram demonstrating a mean left ventricular wall thickness > 12 mm in the absence of other cardiac cause to explain wall thickening (such as hypertension or cardiac valvular disease) • NT-proBNP ≥ 650 pg/mL in the absence of renal failure or atrial fibrillation with an uncontrolled ventricular rate 7. Planned first-line chemotherapy contains bortezomib administered weekly and SC 8. Adequate bone marrow reserve, hepatic and renal function, as demonstrated by: absolute neutrophil count (ANC) ≥ 1.0 x10^9/L • platelet count ≥ 75 x 10^9/L • hemoglobin ≥ 9 g/dL • total bilirubin ≤ 2 x upper limit of normal (ULN) • aspartate aminotransferase (AST) / serum glutamic oxaloacetic transaminase (SGOT) ≤ 3 x ULN • alanine aminotransferase (ALT) / serum glutamic pyruvic transaminase (SGPT) ≤ 3 x ULN • alkaline phosphatase (ALP) ≤ 5 x ULN (except for patients with hepatomegaly and isozymes specific to liver, rather than bone) • estimated glomerular filtration rate (eGFR) ≥ 30 mL/min 9. Seated systolic blood pressure 90-180 mmHg 10. Distance walked during 6MWT is ≥30 meters and ≤550 meters 11. Women of childbearing potential (WOCBP) must have two negative pregnancy tests during Screening, the second within 24 hours prior to the first administration of study drug and must agree to use physician-approved contraception from Screening to 30 days following the last study drug administration 12. Male subjects must be surgically sterile or must agree to use physician-approved contraception from Screening to 30 days following the last study drug administration 13. Ability to understand and willingness to sign an informed consent form prior to initiation of any study procedures |
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E.4 | Principal exclusion criteria |
Subjects must meet none of the following criteria: 1. Non-AL amyloidosis 2. NT-proBNP > 8,500 pg/mL 3. Meets the International Myeloma Working Group (IMWG) definition of Multiple Myeloma (see Appendix 11) *Note that subjects who meet the IMWG definition of symptomatic multiple myeloma with signs and/or symptoms attributable only to associated amyloidosis and who do not otherwise meet the criteria for diagnosis of smoldering myeloma are potentially eligible upon approval of the Sponsor. 4. Subject is eligible for and plans to undergo ASCT 5. 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 6. Myocardial infarction, uncontrolled angina, severe uncontrolled ventricular arrhythmias, or electrocardiographic evidence of acute ischemia, within 6 months prior to the Month 1-Day 1 Visit 7. Severe valvular stenosis (e.g. aortic or mitral stenosis with a valve area <1.0 cm2) or severe congenital heart disease 8. ECG evidence of acute ischemia or active conduction system abnormalities with the exception of any of the following: • First degree 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 Prior to randomization, any ECG screening abnormalities must be noted as “not clinically significant” by the Investigator 9. Peripheral neuropathy assessed as National Cancer Institute-Common Terminology Criteria for Adverse Events ( NCI-CTCAE) Grade 2 with pain, Grade 3 or Grade 4 10. Subject is receiving oral or IV antibiotics, antifungals or antivirals within 1 week of Month 1-Day 1 with the exception of prophylactic oral agents 11. Prior treatment with hematopoietic growth factors, transfusions of blood or blood products within 1 week of Month 1-Day 1 12. Prior radiotherapy within 4 weeks of Month 1-Day 1 13. Major surgery within 4 weeks of Month 1-Day 1 or planned major surgery during the study 14. 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 15. History of Grade ≥ 3 infusion-associated AEs or hypersensitivity to another monoclonal antibody, or known hypersensitivity to diphenhydramine (or an equivalent H1 antihistamine) or acetaminophen (or its equivalent, paracetamol) 16. Uncontrolled, active human immunodeficiency virus (HIV), Hepatitis B or Hepatitis C infection 17. Prior treatment with NEOD001 18. Treatment with another investigational agent within 30 days of Month 1-Day 1 19. Women who are pregnant or lactating 20. 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 |
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E.5 End points |
E.5.1 | Primary end point(s) |
Time to all-cause mortality or cardiac hospitalization |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
As adjudicated by the CEC |
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E.5.2 | Secondary end point(s) |
• NT-proBNP • Time to cardiac mortality or cardiac hospitalization • 6MWT • SF-36 • KCCQ • Renal best response • Hepatic best response |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
• NT-proBNP best response from baseline to Month 9 • Time to cardiac mortality or cardiac hospitalization as adjudicated by the CEC • Change from baseline to Month 9 in the 6MWT • Change from baseline to Month 9 in the SF-36 • Change from baseline to Month 9 in the KCCQ • Renal best response from baseline to Month 9 (Palladini 2014) • Hepatic best response from baseline to Month 9 (Comenzo 2012) |
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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 | 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 | 10 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 25 |
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 |
Australia |
Austria |
Belgium |
Canada |
Czech Republic |
France |
Germany |
Greece |
Israel |
Italy |
Netherlands |
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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The study will end when approximately 156 primary endpoint events have occurred and EOS visits have been completed for all subjects who remain on study at that time. Events are defined as deaths due to any cause, or cardiac hospitalizations as adjudicated by the CEC |
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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 | 3 |
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 | 3 |
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 |