Cardiovascular Diseases Heart failure caused by Amyloid Cardiomyopathy Transthyretin Amyloid Cardiomyopathy
Conditions
Interventions
Patients will receive the following interventions:
-NI006/placebo dosing
-vital signs and physical examination
-Questionnaires & 6-minute walking test
-MRI or Bone Scintigraphy
-Echocardiography
-cont
Sponsors
Neurimmune AG
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Written informed consent obtained from the subject prior to any trial-related procedure indicating that he/she understands the purpose of and procedures required for the trial and is willing to participate in it 2. Male or female subjects aged >=18 years (and 1.21; late phase imaging: Perugini Grade 2 or 3) and absence of gammopathy (negative serum and urine immunofixation electrophoresis plus normal free light chain serum ratio). If a gammopathy is detected, diagnosis must be established based on tissue biopsy as indicated above 4. Known genotype as follows: a) Known pathogenic TTR mutation for subjects with hereditary ATTR-CM b) Known negative genetic testing for a TTR mutation for subjects with sporadic, WT-ATTR-CM 5. Chronic Heart Failure with all of the following characteristics: a) LVEF >=40% b) Left ventricular wall thickness (LVWT) >=14 mm, measured by echocardiography c) N-terminal pro b-type natriuretic peptide (NT-proBNP) level >=600 pg/mL d) Able to walk >=150 meter in the 6-MWT e) New York Heart Association (NYHA) class III (applicable only for cohort 7) f) No hospitalizations for cardiac disease for at least 30 calendar days prior to screening 6. General health status acceptable for a participation in a clinical trial with a Karnofsky Performance Status >=60% 7. Stable pharmacological treatment of any other chronic condition for at least 30 calendar days prior to screening, with the exclusion of immunomodulatory and immunosuppressive treatments 8. Absolute neutrophil count (ANC) >=1000 cells/mm³, platelet count >=100,000 cells/mm³, and hemoglobin >=10 g/dL 9. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test at screening and must agree to use highly effective physician-approved contraception from screening to 5 months after ending trial participation 10. Males must be surgically sterile or must agree to use highly effective physician-approved contraception throughout of the trial participation, and for 5 months after ending trial participation Inclusion Criteria for OLE2 1.Participation in the OLE in cohorts 1 to 5 with a minimum of one administration of NI006 during OLE 2.Written informed consent for OLE2 obtained from the subject prior to any OLE2-related procedure indicating that he/she understands the purpose of and procedures required for the trial and is willing to participate in it 3.Availability for all scheduled visits 4.WOCBP must have a negative serum pregnancy test at screening and must agree to use highly effective physician-approved contraception from screening to 5 months after ending trial participation 5.Males must be surgically sterile or must agree to
Exclusion criteria
Exclusion criteria: 1. Amyloid light-chain (AL) amyloidosis or any other non ATTR amyloidosis 2. Heart failure corresponding to NYHA class IV 3. Uncontrolled hypertension with systolic pressure >=180 mmHg or diastolic pressure >=110 mmHg confirmed by 3 measurements in supine position recorded with 5 minutes break in between the measurements 4. Hypotension with systolic pressure =6000 pg/mL (NT-proBNP >=8'500 pg/mL applicable only for cohort 7) 6. Heart failure not predominantly caused by ATTR-CM 7. Any severe uncorrected valve disease 8. Chronic liver disease with liver function test abnormalities: a) Alanine transaminase (ALT) and aspartate aminotransferase (AST) > 2.5 × upper limit of normal (ULN) b) Total bilirubin > 2 × ULN 9. Respiratory insufficiency requiring oxygen therapy 10. Renal insufficiency with estimated glomerular filtration rate (eGFR) = 2 years 12. Uncontrolled infection as per Investigator*s judgement 13. Known human immunodeficiency virus (HIV) infection, seropositivity for HIV, hepatitis B and C as well as active hepatitis A 14. Autoimmune disease requiring immunosuppressive/modulating treatment in the last 2 years 15. History of organ transplantation or ventricular assist device (VAD) 16. Polyneuropathy disability (PND) score > IIIA 17. Suspected or known intolerance/allergy to proteins or any components of the investigational medicinal product (IMP) 18. Concomitant immunosuppressant therapy e.g., corticosteroids, prednisone, dexamethasone except as indicated in low dose (i.e., up to 10 mg prednisone or equivalent daily is allowed) for other medical conditions such as inhaled steroid for asthma 19. Use of the following drugs acting on TTR or ATTR: tolcapone, diflunisal, patisiran, inotersen, and long-term doxycycline, in the 30 calendar days prior to signing informed consent form (ICF). Tafamidis is permitted if it is given as standard of care in a stable dose for at least 30 calendar days prior to signing the ICF 20. Participation in another investigational clinical trial or intake of investigational drug within 30 calendar days before signing the ICF 21. Suspected or known drug or alcohol abuse 22. Serious psychiatric or any other medical condition (including laboratory abnormalities), which, in the opinion of the Investigator, makes the subject unsuitable for inclusion and puts the subject at an unacceptable risk 23. Subject is nursing or is considering becoming pregnant during the trial or in the 5 months after ending trial participation 24. Unwillingness or inability to adhere to the trial requirements 25. If subject is in any way dependent on Neurimmune AG or the principal Investigator or if the subject is accommodated in an establishment on judicial or administra
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Primary endpoints: • Number and proportion of treatment emergent adverse events (TEAEs) • Number and proportion of SAEs • Changes in clinical laboratory parameters (continuous parameters) • Change from baseline in cardiac biomarkers • Changes by visit for vital signs • Changes by visit for ECG parameters (continuous parameters) • Summary of echocardiogram results | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary endpoints: • PK parameters for the SAD phase: Maximum observed serum concentration (Cmax), time to maximum observed serum concentration (Tmax), area under the serum concentration-time curve from zero to infinity (AUCinf),serum clearance (CL), apparent volume of distribution during terminal phase (Vz), apparent volume of distribution at steady state (Vss), terminal elimination half-life (t*) • PK parameters for the MAD phase: Cmax, Tmax, area under the serum concentration-time curve from time zero to the end of the dosing interval after the first dose (AUC*), CL, Vz, Vss, t*, accumulation ratio for maximum concentration (RaccCmax), accumulation ratio calculated from AUC (RaccAUC) •PK parameters for the OLE and OLE 2 phase: Minimum observed serum concentration (Ctrough), dose normalized Ctrough, accumulation ratio compared to SAD/MAD calculated from dose-normalized Ctrough Exploratory endpoints: • 6-Minute Walk Test (6-MWT) • Kansas City Cardiomyopathy Questionnaire (KCCQ) • Echocardiography (contractile function [strain], thickness and filling pressure, left ventricular ejection fraction [LVEF]) • Estimation of amyloid load by imaging method in a subset of subjects • Changes in biomarkers • Determination of TTR, free thyroxine (T4), Vitamin A levels and Retinol-binding protein (RBP) • Determination of anti-drug antibody (ADA) response • Immunohistochemistry (IHC) of cardiac or salivary gland biopsies in in a subset of subjects (OPTIONAL) | — |
Countries
Netherlands
Outcome results
None listed