A global trial to determine the effectiveness and safety of ION-682884 in patients with Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Ionis Pharmaceuticals Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Cardiovascular Diseases [C14]

Trial duration

29 Jun 2020 → ongoing

Decision date (initial)

2024-09-29

Transition trial

Yes

Low-intervention

No

Rare-disease indication

Yes

Vulnerable population

Yes

Funding sources

Ionis Pharmaceuticals Inc.

External identifiers

EU CT number

2024-514434-20-00

EudraCT number

2019-002835-27

WHO UTN

U1111-1311-9891

ClinicalTrials.gov

NCT04136171

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety

To evaluate the effect of treatment with ION-682884 compared to placebo up to Week 140 on the composite endpoint of cardiovascular (CV) death and recurrent CV clinical events in patients with ATTR-CM receiving available standard of care (SoC)

Secondary objectives 8

1. Change From Baseline in the 6-minute Walk Test (6MWT) Distance at Week 140
2. Change From Baseline in the Kansas City Cardiomyopathy Questionnaire (KCCQ) Scores at Week 140
3. Recurrent CV Clinical Events up to Week 140
4. All-Cause Mortality up to Week 160
5. All-Cause Mortality up to Week 140
6. Primary endpoint in subgroup of patients treated with tafamidis at Baseline
7. CV Mortality up to Week 160
8. CV Mortality up to Week 140

Conditions and MedDRA coding

Transthyretin-Mediated Amyloid Cardiomyopathy (ATTR-CM)

Study design 3 periods

Regulatory references

Plan to share IPD

Yes

IPD plan description

Ionis may share anonymized individual participant data, aggregated clinical data, and other types of data that support the results in this study. Data requests from qualified researchers will be considered once all three of the following criteria are met: (1) 12 months from marketing approval of the study drug in both the United States and European Union; (2) 18 months from conclusion of the study; and (3) 6 months from publication of study article. Access would be via a secure environment and is contingent upon approval of a research proposal and entry into an appropriate data use agreement. Requests to access data can be submitted via the website https://vivli.org/ourmember/ionis/

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 5

1. Females must be non-pregnant and non-lactating, and either surgically sterile or post-menopausal or abstinent. If engaged in sexual relations of child-bearing potential, agree to use 1 highly effective contraceptive method
2. Males must be surgically sterile or, abstinent or, if engaged in sexual relations with a woman of child-bearing potential, the participant or the participant's non-pregnant female partner must be using a highly effective contraceptive method
3. Amyloid deposits in cardiac or non-cardiac tissue confirmed by Congo Red (or equivalent) staining OR technetium scintigraphy (99mTc -3,3- diphosphono-1,2- propanodicarboxylic acid [DPD-Tc], 99m Tc- pyrophosphate [PYP-Tc], or 99mTc-hydroxymethylene-diphosphonate [HMDP-Tc]) with Grade 2 or 3 cardiac uptake in the absence of abnormal light chains ratio, centrally confirmed
4. End-diastolic interventricular septum thickness of > 12 mm on Screening echocardiogram
5. New York Heart Association (NYHA) class I-III

Exclusion criteria 6

1. Acute coronary syndrome, unstable angina, stroke, transient ischemic attack (TIA), coronary revascularization, cardiac device implantation, cardiac valve repair, or major surgery within 3 months of Screening
2. Cardiomyopathy not primarily caused by ATTR-CM, for example, cardiomyopathy due to hypertension, valvular heart disease, or ischemic heart disease
3. Monoclonal gammopathy of undetermined significance (MGUS) and/or alterations in immunoglobulin free light chain (FLC) ratio, unless fat, bone marrow, or heart biopsy confirming the absence of light chain and the presence of TTR protein by mass spectrometry or immunoelectron microscopy. For patients with CKD and without presence of monoclonal protein in blood and urine, the acceptable FLC ratio is 0.26-2.25. Results different from that may be discussed with local hematologist, Investigator and Medical Monitor if the risks associated with the biopsy outweigh the benefits
4. Prior liver or heart transplant, and/or Left Ventricular Assist Device (LVAD) or anticipated liver transplant or LVAD within 1 year after randomization
5. Current or previous treatment with Tegsedi™ (inotersen) or Onpattro™ (patisiran) or other oligonucleotide or RNA therapeutic (including siRNA; does not apply to COVID-19 mRNA vaccinations)
6. Current treatment with diflunisal, doxycycline, with or without ursodeoxycholic acid, and/or non-dihydropyridine calcium-channel blocker (e.g.,verapamil, diltiazem). Patients receiving any of these agents must respect a Wash-out Period of 14 days before randomization.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 5

1. Composite endpoint of CV-death and recurrent CV clinical events comparing the 2 study arms up to Week 140. Cardiovascular clinical events include: 1. Hospitalization for myocardial infarction (MI)
2. Hospitalization for HF
3. Hospitalization for arrhythmia
4. Hospitalization for stroke/Transient Ischemic Attack TIA
5. HF urgent visits to ED/ER or HF clinics requiring administration of intravenous (IV) diuretics for improvement.

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 1

Placebo 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Ionis Pharmaceuticals Inc.

Sponsor organisation

Ionis Pharmaceuticals Inc.

Address

2855 Gazelle Court

City

Carlsbad

Postcode

92010-6670

Country

United States

Scientific contact point

Organisation

Ionis Pharmaceuticals Inc.

Contact name

Global Regulatory Affairs

Public contact point

Organisation

Ionis Pharmaceuticals Inc.

Contact name

Global Regulatory Affairs

Third parties 22

Locations

12 EU/EEA countries · 40 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 111 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

6 submissions — initial application plus substantial / non-substantial modifications