In patients with symptomatic New York Heart Association (NYHA) Class II/III/IV dilated cardiomyopathy (DCM) in which mutations in the gene encoding the lamin A/C protein (LMNA) have been implicated:Primary Objective:* NYHA Class II/III patients only…
ID
Source
Brief title
Condition
- Myocardial disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Endpoint:
* NYHA Class II/III patients only: Change from baseline in 6MWT at Week 24
Secondary outcome
Secondary Endpoints:
1. NYHA Class II/III patients only: Change from baseline in 6MWT at Weeks 4 and
24
2. NYHA Class II/III patients only: Change from baseline in Kansas City
Cardiomyopathy Questionnaire (KCCQ) Physical Limitation (PL) and Total Symptom
Score (TSS) domains at Weeks 12 and 24
3. NYHA Class II/III patients only: Change from baseline in Patient Global
Impression (PGI) scores at Weeks 12 and 24
o Patient Global Impression of Severity (PGI-S)
o Patient Global Impression of Change (PGI-C)
4. NYHA Class II/III patients only: Change from baseline in N terminal
pro-brain natriuretic peptide (NT-proBNP) at Weeks 4, 12 and 24
5. HFS: gedefinieerd als de tijd vanaf randomisatie tot het eerste optreden van
elke gebeurtenis in de samenstelling van overlijden als gevolg van welke
oorzaak dan ook, of verergering hartfalen (HF-gerelateerde
ziekenhuisopname of HF-gerelateerd spoedeisende zorgbezoek).
7. OS
8. Safety as determined by:
o Incidence and severity of adverse events (AEs)
o Changes in clinical safety laboratory tests, vital signs and 12 lead
electrocardiograms (ECGs)
o Incidence and severity of ventricular or atrial arrhythmias detected
clinically using existing implantable cardioverter defibrillator (ICD)/cardiac
resynchronization therapy defibrillator (CRT-D) or other applicable device
interrogations at Weeks 12 and 24
Background summary
Lamins are critical protein components of the nuclear lamina, which lie between
the inner nuclear membrane and the chromatin. They provide structural support
for the cell nucleus, participate in many different nuclear processes,
including chromatin organization, connecting the nucleus to the cytoplasm, gene
transcription and mitosis. Mutations in the gene encoding the lamin A/C protein
(LMNA) cause a variety of human diseases, known collectively as laminopathies.
Dilated cardiomyopathy (DCM), which is also referred to as non-ischemic heart
failure (HF) with reduced ejection fraction (HFrEF), is one of the more common
phenotypes associated with LMNA mutations. Mutations in the LMNA gene are the
second most common cause of familial DCM after those in titin (TTN)
(Hershberger et al 2013) and account for up to 8% of all cases. Patients with
LMNA-related DCM frequently suffer from atrioventricular conduction defects and
have a significantly increased risk of sudden death due to ventricular
arrhythmias (Hershberger et al 2013).
Currently, there is no effective, disease-specific treatment available for
LMNA-related DCM. To date, treatment is limited to conventional therapies for
DCM (angiotensin-converting-enzyme inhibitors or angiotensin 2 receptor
blockers, beta blockers, aldosterone receptor antagonists and diuretics) which
are largely symptomatic and supportive. Progressive deterioration in left
ventricular (LV) function and refractory HF symptoms are often treated with
resynchronization therapy (bi ventricular pacing/ICD). In patients whose
disease continues to progress in spite of aggressive cardiovascular (CV)
management, cardiac transplantation may be considered.
Study objective
In patients with symptomatic New York Heart Association (NYHA) Class II/III/IV
dilated cardiomyopathy (DCM) in which mutations in the gene encoding the lamin
A/C protein (LMNA) have been implicated:
Primary Objective:
* NYHA Class II/III patients only: Evaluate the effect of ARRY 371797
(PF-07265803) on functional capacity (as measured by the 6 minute walk test
[6MWT]) compared to placebo
Secondary Objectives:
* NYHA Class II/III patients only: Evaluate additional measures of efficacy of
ARRY-371797 (PF-07265803) compared to placebo in the randomized period
* Characterize the plasma pharmacokinetics (PK) of ARRY 371797 (PF-07265803)
and metabolites
* Evaluate the impact of ARRY-371797 (PF-07265803) on hospitalization-free
survival (HFS) and overall survival (OS)
* Evaluate the safety of ARRY-371797 (PF-07265803) compared to placebo
Study design
This multinational Phase 3 study will evaluate the efficacy, safety and PK
following treatment with ARRY-371797 (PF-07265803) compared with placebo (1:1
randomization) in at least 120 patients with NYHA functional Class II and III
DCM secondary to LMNA mutations. NYHA functional Class IV patients (up to
approximately 40) will also be enrolled (1:1 randomization) and will be
assessed for overall safety and time from randomization to HF-related
hospitalization or death due to any cause, in addition to PK and efficacy, if
feasible.
The study will be conducted in 2 parts: a randomized, double-blind treatment
period for at least 24 weeks, followed by an ARRY 371797 (PF-07265803)
open-label treatment period. During the randomized, double-blind period,
patients, Investigators, site personnel and the Sponsor personnel directly
involved with the conduct of the study will remain blinded to assigned
treatment, except for regulatory reporting requirements. Study drug treatment
received in the randomized period will remain blinded for all patients until
the database is frozen/locked, the primary analysis is performed (after all
patients have the opportunity to be followed for at least 24 weeks), and a
mature evaluation of HF-related hospitalization and all-cause mortality has
been completed, after which treatments will be unblinded and patients receiving
placebo may initiate treatment with ARRY 371797 (PF-07265803) provided
eligibility criteria are met. The end of the study is reached when all patients
in the open-label treatment period have had the opportunity to be followed for
at least 24 weeks in the open-label period of the study or have discontinued
from the study, whichever comes first. Patients who remain on treatment at the
end of the study and who may, in the opinion of the Investigator, derive
benefit from continued treatment with ARRY-371797 (PF-07265803) will be
provided the opportunity to continue treatment with ARRY-371797 (PF-07265803).
An independent Data Monitoring Committee (DMC) will review safety, PK and
efficacy data at regular intervals. A study Steering Committee (SC) will be
involved in oversight of the study and will ensure transparent management of
the study according to the protocol. A Clinical Events Committee (CEC) will be
utilized to adjudicate causes for hospitalizations.
For NYHA Class II/III patients, a central laboratory will be used for analyses
of ECGs, echocardiograms (ECHO), NT-proBNP and safety laboratory assessments.
For NYHA Class IV patients who are not able to attend post-baseline clinic
visits, local laboratories may be used.
One formal interim efficacy analysis for futility will be performed on the Week
12 6MWT data after the first 30 randomized NYHA Class II/III patients have
completed the Week 12 assessment or have discontinued from the study prior to
Week 12.
Intervention
Patients will be randomized (1:1) to the following groups:
* ARRY-371797: 400 mg BID (4 × 100 mg tablets, BID)
(800 mg total daily dose)
* Matching placebo: 4 tablets BID (8 tablets daily)
Placebo and active drug tablets will be identical in appearance during the
double-blind treatment period to maintain the study blind.
If a patient has safety or tolerability issues at 4 tablets BID (ARRY 371797
[400 mg BID] or placebo), study drug may be reduced to 2 tablets BID (ARRY
371797 [200 mg BID] or placebo) as described in this protocol. If a patient has
tolerability issues at 2 tablets BID (ARRY-371797 [200 mg BID] or placebo),
study drug may be further reduced to 1 tablet BID (ARRY 371797 [100 mg BID] or
placebo) as described in this protocol.
If study drug is not well tolerated at any dose level, treatment will be
permanently discontinued for that patient.
Study burden and risks
More than 500 adults, both healthy subjects and patients, have taken the study
drugs, ARRY-371797 (PF-07265803). Side effects considered associated with
ARRY-371797 in studies where patients (more than 300) have received at least 1
dose of ARRY-371797 (PF-07265803) (the study drug) are as follows:
Most common side effects (occur more than 10% of the time):
* Mouth inflammation that may be associated with ulcerations of the mouth
mucous membranes.
Less common side effects (occur 1 to 20% of the time):
* Headache
* Nausea
* Vomiting
* Diarrhea
* Increased phosphokinase
Placebo
If the patients are receiving placebo there is a possibility that symptoms of
their disease may return or get worse.
Blood Samples: The risks of taking blood may include fainting, pain and/or
bruising. Rarely, there may be a small blood clot or infection at the site of
the needle puncture.
Echocardiogram:. There have been rare occurrences (1-2%) of transient headache,
back pain, flushing or nausea reported and very rare (1 in 10,000) serious
allergic reactions.
Electrocardiogram: The patient will have electrodes placed on his/her chest,
arms, and legs. They may have some hair shaved so the electrodes will stick to
your skin. The electrodes are attached to wires which are attached to the ECG
machine. During the test the patient will need to lie still while the machine
records their heart*s activity. The patient should not talk during the test.
Six (6) minute walk test: The patients may experience symptoms such as fatigue,
shortness of breath, leg cramps, chest pain, sweating, or other symptoms
associated with this exercise.
Walnut Street 3200
Boulder CO80301
NL
Walnut Street 3200
Boulder CO80301
NL
Listed location countries
Age
Inclusion criteria
* Provide a signed and dated informed consent document prior to initiation of
any study-related procedures. Patients under guardianship or partial
guardianship will be eligible unless prohibited by local laws or by
local/central ethic committees
* Age * 18 years at time of informed consent
* Patients with symptomatic lamin A/C protein (LMNA)-related cardiomyopathy
Class II/III/ or Class IV defined as:
o Gene positive for a pathogenic, likely pathogenic or VUS mutation in the LMNA
gene as determined by an accredited clinical laboratory
o NYHA functional class II or III that has been stable for at least 2 months.
o Evidence of cardiac impairment as determined by LVEF*50%
* Patient will have an implantable cardioverter defibrillator/cardiac
resynchronization therapy defibrillator (ICD/CRT-D). ICD implanted at least 4
weeks prior to initiation of study treatment or CRT-D initiated at least 6
months prior to initiation of study intervention and defibrilation function
activated at least 4 weeks prior to initiation of study intervention. Devices
must have activated pacing capabilities or a separate pacemaker must be present.
* Class II/III patients must have objective functional impairment evidenced by
a reduction in 6-minute walk test (6MWT);
* Stable medical and/or device therapy consistent with American Heart
Association (AHA) / American College of Cardiology (ACC) or European Society of
Cardiology (ESC) guidelines
* Patients must meet acceptable hematology, hepatic and renal laboratory values
as specified within 35 days prior to Day 1
Exclusion criteria
* Presence of other form(s) of cardiomyopathy contributing to HF (e.g.,
inflammatory or infiltrative cardiomyopathy) or clinically significant cardiac
anatomic abnormality (e.g., LV aneurysm), clinically significant coronary
artery disease (e.g., coronary revascularization, exercise-induced angina) or
uncorrected, hemodynamically significant (i.e., moderate-severe) primary
structural valvular disease not due to HR, per investigator judgment
* Currently receiving or deemed at high risk of requiring chronic renal
replacement therapy (e.g., hemodialysis or peritoneal dialysis) within 6 months.
* Treatment with any investigational agent(s) for HF within 35 days prior to
Day 1.
* Malignancy that is active or has been diagnosed within 3 years prior to
screening, except surgically curatively resected in situ malignancies or
surgically cured early breast cancer, prostate cancer, skin cancer (basal cell
carcinoma, squamous cell carcinoma) thyroid cancer or cervical cancer, or,
with prior review of the Medical Monitor, other earlystage surgically
curatively resected malignancies with less than a 20% expected 2-year
recurrence rate.
* Non-cardiac condition that limits lifespan to < 1 year.
* Serum positive for hepatitis B surface antigen, viremic hepatitis C, or human
immunodeficiency virus (HIV) at screening.
* Pregnancy or breastfeeding, or patients who plan to become pregnant during
the duration of the trial
* Patients with an underlying condition that may impact the ability of the
6MWT to reflect changes in cardiovascular function such as: an orthopedic
condition that limits walking abilities (e.g. severe arthritis), significant
musculoskeletal pathology, significant chronic obstructive pulmonary disease
(COPD) that limits exercise tolerance or any other condition that according to
the Investigator's assessment significantly limits a patient's performance on
the 6MWT independently from the patient's cardiomyopathy.
* Documented hypersensitivity/allergy or clinically significant intolerance to
any component of drug product.
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 |
|---|---|
| EudraCT | EUCTR2017-004310-25-NL |
| CCMO | NL65694.100.18 |