Primary:Determine baseline and changes over time in cardiac structure and function in BAG3 associated DCM.Secondary:Assess the progression of prognostic disease biochemical biomarkers in BAG3 associated DCM.
ID
Source
Brief title
Condition
- Myocardial disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Baseline and change over the course of one year follow up time measures of left
ventricular volumes at end systole and diastole including LVEF, LVESVI, LVEDVI
and LVMI using imaging over the course of one year follow up time.
Secondary outcome
Baseline, variance, and correlation of circulating biochemical biomarkers
hsTNI, hsTNT and NT-proBNP to clinical markers of disease severity over the
course of one year follow up time.
Background summary
A ubiquitously expressed protein, BAG3 is predominantly expressed in the heart
where it acts through multiple protein-protein binding domains to couple small
and large heat shock proteins to regulate several different cellular processes
including protein quality control. BAG3 plays a key role in protein quality
control and its loss is related to early and progressive cardiac dysfunction.
BAG3 binds and interacts with a myriad of binding partners to promote protein
processing and avert apoptosis. Through binding to HSP70, HSPB6 and HSPB8, BAG3
regulates cellular protection during hypoxia/reoxygenation. BAG3 binds BCL2 to
inhibit the canonical intrinsic limb of the apoptosis cascade. During cellular
stress
BAG3 mediates autophagy up-regulation via interactions with HSPB9 and HSPA1A.
Animal models of partial deficiencies of BAG3 demonstrate susceptibility to
stress manifesting as myofibrillary disruption, decreased autophagy, increased
apoptosis, and left ventricular dysfunction, whereas complete BAG3 deficiency
results in rapid cardiovascular decline and early mortality in transgenic
animals.
Clinical BAG3 DCM is a rare disorder, occurring in an estimated 2-6% of
patients with DCM accounting for an overall prevalence estimated to occur in 1
out of ~25,000 patients in the United States. BAG3 DCM is thought to be due to
haploinsufficiency based on the functional loss of a single allele and reduced
BAG3 protein expression. Clinically, BAG3 DCM is characterized by an early HF
presentation (80% of genotype-positive patients
manifesting HF by age 40). Asymptomatic middle-aged patients with known
pathologic BAG3 mutations, have a high incidence of developing HF, 26.1% over
~2 years follow-up. Once symptoms develop, BAG3 DCM patients manifest a poor
prognosis, 5.1%/year rate of death or major cardiovascular events (LV device
implantation, heart transplant or SCD or equivalent).
Please refer to protocol section 2.2 for more information
Study objective
Primary:
Determine baseline and changes over time in cardiac structure and function in
BAG3 associated DCM.
Secondary:
Assess the progression of prognostic disease biochemical biomarkers in BAG3
associated DCM.
Study design
This is a prospective, multinational, multicenter, natural history study to
characterize the progression of circulating, imaging, and clinical biomarkers
in BAG3 DCM population over time and the corresponding relationship with the
clinical outcomes. At least 30 and a maximum of approximately 35 participants
with BAG3 DCM and cardiac imaging evidence of left ventricular systolic
dysfunction will be enrolled such that 30 evaluable participants complete the
study at one year of follow-up. These participants will be stratified to Cohort
1 (New York Heart Association [NYHA] Class I to Class III) or Cohort 2 (NYHA
Class IV) according to their NYHA Class at screening and can be initiated
simultaneously. The ratio of the number of participants for Cohort 1 versus
Cohort 2 must be at least 2:1. That is, no more than one-third of the total
number of participants will be in NYHA Class IV and no more than 20% of these
NYHA Class IV participants will be on home inotropic therapy. All study
participants will be followed for survival and disease progression outcomes for
1 year.
Please refer to protocol section 4 for more information
Study burden and risks
Participants may generate a more in-depth description of BAG3 disease
progression which may aid in drug development of future therapies. Considering
the measures taken to minimize risk to participants participating in this
study, the potential risks identified in association with cMRI, blood draws,
CPET, echocardiography are justified by the anticipated benefits that may be
afforded to participants with BAG3 DCM.
Please refer to section "What side effects could you experience", section "What
are the pros and cons if you take part in the study?" and Appendix D "Study
tests, procedures and assessments and associated risk details" in the Subject
Information Sheet and Consent Form for an overview of the risks and side
effects.
East 42nd Street 235
New York NY10017
US
East 42nd Street 235
New York NY10017
US
Listed location countries
Age
Inclusion criteria
1. Participants >=18 years (or the minimum country specific age of consent if
>18) at Visit 1 (Screen 1). Type of Participant and Disease Characteristics: 2.
Participants who are willing and able to comply with all scheduled visits,
laboratory tests, and other study procedures. 3. Documented BAG3 pathogenic or
likely pathogenic mutation interpreted according to the American College of
Medical Genetics Guidelines. 4. NHYA Class I-IV at screening (Stage B-D). 5.
LVEF <=50%, except if LVEF 45-50% and NYHA Class I then NT-proBNP must be >=300
ng/dL. LVEF measurement must be within the last 12 month from Echo or cMRI 6.
Capable of giving signed informed consent for the study as described in
Appendix 1 section 10.1.2, which includes compliance with the requirements and
restrictions listed in the ICD and in this protocol.
Exclusion criteria
1. Acute decompensated HF within 1 month prior to enrollment. 2. Any of the
following within 3 months prior to screening: myocardial infarction (MI),
cardiac surgical procedures (other than for pacemaker/ICD/CRT-defibrillator
[CRTD] implantation), acute coronary syndrome or hospitalization for cardiac
arrhythmia. 3. History of heart transplantation. 4. eGFR <30 mL/min/1.73 m2
(using the CKD-EPI formula). 5. 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 by the medical monitor, other early
stage surgically curatively resected malignancies with greater than a 20%
expected 2 year recurrence rate. 6. Noncardiac condition that limits lifespan
to <1 year. 7. Presence of other form(s) of cardiomyopathy contributing to HF
(eg, inflammatory or infiltrative cardiomyopathy), clinically significant
cardiac anatomic abnormality (eg, LV aneurysm), clinically significant coronary
artery disease (eg, coronary revascularization, exercise induced angina) per
Investigator judgment or uncorrected, hemodynamically significant (ie,
moderate-severe) primary structural valvular disease not due to HF. 8. Any
severe concurrent disease or condition (eg, active systemic infection) that, in
the judgment of the investigator, would make the participant inappropriate for
study participation. 9. Other medical or psychiatric condition including recent
(within the past year) or active suicidal ideation/behaviour or laboratory
abnormality that may increase the risk of study participation or, in the
investigator*s judgment, make the participant inappropriate for the study. 10.
Previous administration with an investigational drug within 30 days (or as
determined by the local requirement). 11. Likelihood, in the investigator*s
opinion, of undergoing cardiac transplantation, left ventricular assist device
(LVAD) or other device implantation, or other cardiac surgery within the next 3
months. 12. No more than 3 first-degree members of the same family. 13.
Investigator site staff or Pfizer employees directly involved in the conduct of
the study, site staff otherwise supervised by the investigator, and their
respective family members.
Design
Recruitment
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 |
|---|---|
| CCMO | NL81632.068.22 |