This study has been transitioned to CTIS with ID 2024-515092-36-00 check the CTIS register for the current data. Primary• To assess safety and tolerability of acoramidis in participants with symptomatic transthyretin amyloid cardiomyopathy (ATTR-CM)…
ID
Source
Brief title
Condition
- Cardiac disorders, signs and symptoms NEC
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
• Safety parameters to be assessed: treatment- emergent serious adverse events
(SAEs) and adverse events (AEs), AEs leading to treatment discontinuation,
abnormal physical examination findings of clinical relevance, abnormal vital
signs of clinical relevance, abnormal electrocardiogram (ECG) parameters of
clinical relevance, and changes in clinical safety laboratory parameters of
clinical relevance
Secondary outcome
• All-cause mortality and CV mortality
• Change from Baseline in distance walked during the 6MWT (6MWD)
• Change from Baseline in KCCQ Overall Summary Score (KCCQ-OS)
• CV-related hospitalization
• Change from baseline in TTR level (an in vivo measure of TTR stabilization)
• TTR stabilization measured in established ex vivo assays (FPE and Western
blot) in the PK-PD substudy
Background summary
Acoramidis is a potent and selective stabilizer of transthyretin (TTR) that is
being developed by Eidos Therapeutics, Inc. for the treatment of TTR
amyloidosis (ATTR), a progressive, fatal disease in which deposition of amyloid
derived from either variant or wild-type TTR causes severe organ damage and
dysfunction.
Clinically, ATTR presents as either a cardiomyopathy (ATTR-CM), an
infiltrative, restrictive cardiomyopathy characterized by progressive left and
right heart failure, or as a peripheral polyneuropathy (ATTR-PN), a
length-dependent neurodegenerative disease affecting sensorimotor and autonomic
functions.
Variant ATTR-CM (ATTRv-CM) and ATTR-PN (formerly referred to as familial
amyloid polyneuropathy [FAP]) are driven by pathogenic point mutations in the
TTR gene; over 140 such mutations have been described. In addition, older
individuals may develop ATTR derived from wild-type TTR (ATTRwt). In ATTRwt,
the major organ involved is the heart (ATTRwt-CM), although carpal tunnel
syndrome and tendon involvement are common, and may also involve the peripheral
nervous system.
Destabilization, misfolding, and aggregation of TTR lead to the deposition of
TTR amyloid and tissue damage. Several small molecules have been shown to bind
to and stabilize TTR, potentially preventing the initiating event in
amyloidogenesis. Eidos* therapeutic hypothesis is that a highly effective TTR
stabilizer will halt or slow ATTR disease progression in ATTR-CM (both variant
ATTR [ATTRv] and ATTRwt) and ATTR-PN.
Acoramidis is a potent, highly selective, small-molecule TTR stabilizer. It has
demonstrated the ability to stabilize TTR in vivo following oral dosing to
nonhuman mammals, in healthy volunteers and participants with ATTR-CM.
Study objective
This study has been transitioned to CTIS with ID 2024-515092-36-00 check the CTIS register for the current data.
Primary
• To assess safety and tolerability of acoramidis in participants with
symptomatic transthyretin amyloid cardiomyopathy (ATTR-CM)
Secondary
• To evaluate the effect of acoramidis on all-cause mortality (ACM) and
cardiovascular (CV) mortality
• To evaluate the effect of acoramidis on the 6- minute walk test (6MWT)
• To evaluate the effect of acoramidis on health- related quality of life (QoL)
Kansas City Cardiomyopathy Questionnaire (KCCQ)
• To evaluate the effect of acoramidis on the frequency of CV-related
hospitalization (CVH)
• To assess the pharmacodynamic (PD) effects of acoramidis as assessed by
o circulating TTR concentration as an in vivo biomarker of stabilization and
o established ex vivo assays of TTR stabilization
Study design
The primary objective of this prospective, multi-center, open-label study is to
evaluate the long-term safety and tolerability of acoramidis in patients with
an established diagnosis of ATTR-CM and heart failure who are concomitantly
treated with currently recommended heart failure therapies. Secondary efficacy
and PD objectives will be assessed. Exploratory objectives may also be
assessed.
All participants who complete 30 months of blinded study treatment and the
Month 30 assessments of the double-blind treatment period of the Phase 3
ATTRibute-CM trial (AG10-301) may be eligible to participate in this Open Label
Extension (OLE) study of acoramidis. The Day 1 visit in Study AG10-304 may be
the same as the Month 30 visit in Study AG10-301. Under these circumstances,
the last dose of Investigational Medicinal Product (IMP) in Study AG10-301
(either blinded acoramidis or matching placebo) will be the night before the
day of the Month 30 visit. The first dose of open-label acoramidis in Study
AG10-304 will be during the Study AG10-304 Day 1 visit after baseline
assessments have been completed.
Currently, tafamidis is approved for the treatment of ATTR-CM in some regions.
Participants are not allowed to be treated with tafamidis or any other
ATTR-CM-specific approved or investigational treatment, or therapies used
off-label or as non-prescription supplements for ATTR-CM at any time during the
study. If participants choose treatment with an alternative treatment as
described above, they will be asked to discontinue acoramidis and complete an
End of Treatment (EoT) form, and they may be asked to discontinue/withdraw from
the study. If a participant discontinues/withdraws from the study, the
participant will be asked to complete an early termination visit and a safety
follow-up visit.
Participants are not permitted to participate in another interventional
clinical trial (except Study AG10-301) within 30 days prior to dosing and
throughout Study AG10-304. Participants who choose to participate in another
interventional clinical trial will be asked to withdraw from acoramidis and
complete an EoT form, and they may be asked to discontinue/withdraw from the
study. If a participant discontinues/withdraws from the study, the participant
will be asked to complete an early termination visit and a safety follow-up
visit. Participation in observational and/or registry studies should be
discussed with the Medical Monitor.
If a participant chooses to withdraw from acoramidis, the participant will be
asked to complete an EoT form, and they may be asked to discontinue/withdraw
from the study. If a participant discontinues/withdraws from the study, the
participant will be asked to complete an early termination visit and a safety
follow-up visit (in a clinic or AE collection by phone, if the participant
refuses a visit to the clinic) 30 days after the last dose of acoramidis.
Vital status (alive, death, heart transplant, receiving cardiac mechanical
assist device [CMAD]) will be collected yearly until Month 60, either via
direct contact or through public records. Unless precluded by governing law or
regulation, consent for determination of vital status through public records
may not be withdrawn.
Information on AEs and concomitant medications will be collected throughout the
study. The safety and conduct of the study will be monitored by an independent
Data Monitoring Committee (DMC).
Intervention
Test Product, Dosage, and Mode of Administration: 712 mg acoramidis (equivalent
to 800 mg acoramidis HCl), BID, by mouth
Study burden and risks
See ICF section 7.0
1800 Owens Street Suite C-1200
San Francisco CA 94158
US
1800 Owens Street Suite C-1200
San Francisco CA 94158
US
Listed location countries
Age
Inclusion criteria
To be eligible to participate in this OLE study, participants must meet all the
following criteria:
1. Completed 30 months of the blinded study treatment in Study AG10-301 and the
Study AG10-301 Month 30 visit including assessments and procedures.
2. Have the ability to understand and sign a written informed consent form,
which must be obtained prior to initiation of study procedures.
3. Female participants of childbearing potential who engage in heterosexual
intercourse must agree to use a highly effective method of contraception
beginning with enrollment and continuing for 30 days after the last dose of
acoramidis. Female participants using oral contraceptives must agree to use an
additional birth control method. While not considered highly effective, a
double-barrier method is acceptable. A male participant who is sexually active
with a female of childbearing potential and has not had a vasectomy must agree
to use a double-barrier method of birth control.
Exclusion criteria
Participants who meet any of the following criteria at the Day 1 visit will not
be eligible to participate in the study:
1. Has hemodynamic instability, that in the judgment of the Investigator, would
pose too great a risk for participation in the study.
2. Has had a heart and/or liver transplant within the year prior to Day 1.
3. Has had implantation of a cardiac mechanical assist device (CMAD).
4. Has confirmed diagnosis of light-chain (AL) amyloidosis at any time during
Study AG10-301.
5. Is on dialysis or has a degree of renal impairment that in the opinion of
the Investigator might jeopardize the participant*s safety, increase their risk
from participation, or interfere with the study.
6. Known hypersensitivity to acoramidis, its metabolites, or formulation
excipients.
7. At the end of Study AG10-301 or at Day 1 of Study AG10-304 (or any time
during the study), participant is on prohibited medication.
8. Females who are pregnant or breastfeeding. A negative urine pregnancy test
at the Day 1 visit and at each study visit are required for female participants
of childbearing potential.
9. In the judgment of the Investigator or Medical Monitor, has any clinically
important ongoing medical condition or laboratory abnormality or condition that
might jeopardize the participant*s safety, increase their risk from
participation, or interfere with the study.
10. Participation in another interventional clinical trial (with the exception
of Study AG10-301) within 30 days prior to dosing. Participation in
observational and/or registry studies should be discussed with the Medical
Monitor.
11. Has any condition that in the opinion of the Investigator or Medical
Monitor would preclude compliance with the study protocol such as a history of
substance abuse, alcoholism, or a psychiatric condition.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-515092-36-00 |
| EudraCT | EUCTR2020-005643-22-NL |
| CCMO | NL81127.056.22 |