First-in-Human Study of NI006 in Patients With Amyloid Transthyretin Cardiomyopathy

NCT04360434 | Completed Phase 1

• 2 other identifiers: NI006-1012019-001932-80
• Study Type: interventional
• Target: 46
• Locations: 4 countries
• Sites: 6

Brief Summary

A phase 1, randomized, placebo-controlled, double-blind, dose escalation trial combining single-ascending dose and multiple-ascending dose phases of NI006 or placebo, followed by an open-label extension phase in subjects with Amyloid Transthyretin Cardiomyopathy (ATTR-CM).

Conditions

Amyloid Transthyretin Cardiomyopathy

Keywords

ATTR; Transthyretin; Amyloidosis; Cardiomyopathy; ATTR-CM

Outcome Measures

Primary Outcomes (3)

• Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters, vital signs, electrocardiogram and echocardiogram

  Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters (hematology, clinical chemistry, immunology, urinalysis), vital signs, electrocardiogram and echocardiogram

  4 months

• Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters, vital signs, electrocardiogram and echocardiogram

  Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters (hematology, clinical chemistry, immunology, urinalysis), vital signs, electrocardiogram and echocardiogram

  12 months

• Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters, vital signs, electrocardiogram and echocardiogram

  Number and proportion of treatment emergent adverse events and serious adverse events and clinically significant changes in laboratory parameters (hematology, clinical chemistry, immunology, urinalysis), vital signs, electrocardiogram and echocardiogram

  additional up to 10 months

Secondary Outcomes (14)

• NI006 pharmacokinetic profile and parameters - Cmax

  4 months

• NI006 pharmacokinetic profile and parameters - Tmax

  4 months

• NI006 pharmacokinetic profile and parameters - AUCinf

  1 month

• NI006 pharmacokinetic profile and parameters - CL

  4 months

• NI006 pharmacokinetic profile and parameters - Vz

  4 months

Other Outcomes (6)

• Exploratory - Efficacy of multiple doses of NI006 on 6-Minute Walk Test (6-MWT)

  4 and 12 months

• Exploratory - Efficacy of multiple doses of NI006 on patient questionnaire outcome

  4 and 12 months

• Exploratory - Efficacy of multiple doses of NI006 on amyloid load

  4 and 12 months

Study Arms (2)

NI006

EXPERIMENTAL

Dose escalation in up to 6 dose cohorts. Subjects will be administered a single dose of NI006 in the SAD, multiple doses of NI006 in the MAD and OLE phases.

Drug: NI006

Placebo

PLACEBO COMPARATOR

Subjects will be administered a single dose of placebo in the SAD phase and multiple doses of placebo in the MAD phase. In the OLE phase, all subjects will be administered multiple doses of NI006.

Drug: Placebo

Interventions

NI006 DRUG

NI006 will be administered intravenously

NI006

Placebo DRUG

Formulation buffer of NI006, matching volume of NI006 doses will be administered intravenously

Placebo

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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
• Male or female subjects aged ≥18 years (and \< 85 years only for cohort 7) at the time of obtaining informed consent and with confirmed availability for the scheduled trial visits
• Confirmed ATTR-Cardiomyopathy diagnosis established by:
• Polarizing light microscopy of green birefringent material in Congo red-stained tissue specimens and confirmed diagnosis of ATTR amyloidosis by IHC or mass spectrometry OR
• positive bone scintigraphy using either DPD, HMDP or PYP, with cardiac signal intensity indicative of ATTR-Cardiomyopathy (early phase imaging: cardiac mediastinum ratio \> 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
• Known genotype as follows:
• Known pathogenic TTR mutation for subjects with hereditary ATTR- Cardiomyopathy
• Known negative genetic testing for a TTR mutation for subjects with sporadic, WT- ATTR-Cardiomyopathy
• Chronic Heart Failure with all of the following characteristics:
• LVEF ≥40%
• LVWT ≥14 mm, measured by echocardiography
• NT-proBNP level ≥600 pg/mL
• Able to walk ≥150 meter in the 6-MWT
• NYHA class III (applicable only for cohort 7)
• No hospitalizations for cardiac disease for at least 30 calendar days prior to screening

You may not qualify if:

• Amyloid light-chain amyloidosis or any other non ATTR amyloidosis
• Heart failure corresponding to NYHA class IV
• 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
• Hypotension with systolic pressure ≤ 90 mmHg or diastolic pressure ≤ 60 mmHg confirmed by 3 measurements in supine position recorded with 5 minutes break in between the measurements
• NT-proBNP ≥6'000 pg/mL (NT-proBNP ≥8'500 pg/mL applicable only for cohort 7)
• Heart failure not predominantly caused by ATTR-Cardiomyopathy
• Any severe uncorrected valve disease
• Chronic liver disease with liver function test abnormalities:
• ALT and AST \> 2.5 × ULN
• Total bilirubin \> 2 × ULN
• Respiratory insufficiency requiring oxygen therapy
• Renal insufficiency with eGFR \< 30 mL/min/1.73 m2 using the CKD-EPI equation
• Active malignancy with exception of the following:
• Adequately treated basal cell carcinoma
• Squamous cell carcinoma of the skin

Sponsors & Collaborators

• Neurimmune AG: lead

Study Sites (6)

Hôpital Henri Mondor

Créteil, 94000, France

Location

CHU de Rennes - Hôpital Pontchaillou

Rennes, 35033, France

Location

CHU Toulouse - Hôpital Rangueil

Toulouse, 31059, France

Location

Universitätsklinikum Heidelberg

Heidelberg, 69120, Germany

Location

University Medical Center Groningen

Groningen, 9713, Netherlands

Location

Hospital Universitario Puerta de Hierro Majadahonda

Majadahonda, 28222, Spain

Location

Related Publications (1)

• Garcia-Pavia P, Aus dem Siepen F, Donal E, Lairez O, van der Meer P, Kristen AV, Mercuri MF, Michalon A, Frost RJA, Grimm J, Nitsch RM, Hock C, Kahr PC, Damy T. Phase 1 Trial of Antibody NI006 for Depletion of Cardiac Transthyretin Amyloid. N Engl J Med. 2023 Jul 20;389(3):239-250. doi: 10.1056/NEJMoa2303765. Epub 2023 May 20.

  PMID: 37212440 DERIVED

MeSH Terms

Conditions

Amyloidosis; Cardiomyopathies

Condition Hierarchy (Ancestors)

Proteostasis Deficiencies; Metabolic Diseases; Nutritional and Metabolic Diseases; Heart Diseases; Cardiovascular Diseases

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: QUADRUPLE
• Who Masked: PARTICIPANT, CARE PROVIDER, INVESTIGATOR, OUTCOMES ASSESSOR
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: March 11, 2020
• First Posted: April 24, 2020
• Study Start: February 10, 2020
• Primary Completion: July 26, 2023
• Study Completion: July 26, 2023
• Last Updated: November 3, 2023

Record last verified: 2023-11

Locations

NL (1); DE (1); ES (1); FR (3)