Heart Failure
Conditions
Keywords
Heart Failure (HF), Single photon emission computer tomography scan (SPECT), Implantable cardioverter defibrillator (ICD), Left Ventricular ejection fraction (LVEF), New York Health Association (NYHA), Metaiodobenzylguanidine (mIBG), 123I-iobenguane, Heart-to-mediastinal ratio (H/M), ADMIRE-ICD (AdreView Myocardial Imaging for Risk Evaluation - Implantable Cardioverter Defibrillator, All-cause mortality, Cardiac mortality
Brief summary
This is an event-driven Phase IIIb, multicentre, randomised, clinical study to demonstrate the efficacy of AdreView™ imaging for appropriately guiding the decision of implantable cardioverter defibrillator (ICD) implantation, in New York Health Association (NYHA) class II and III heart failure participants with 25%\<=left ventricular ejection fraction (LVEF)\<=35%, and in particular, for identifying participants who are at low risk for sudden cardiac death and who would not benefit, or may suffer harm, from implantation of an ICD device.
Interventions
DRUGIobenguane I -123 Injection
Iobenguane I-123 Injection, AdreView. All participants scheduled for an Iobenguane I-123 Injection, AdreView scan.
DEVICEImplantable Cardioverter Defibrillator
In the Iobenguane I-123 Injection group, participants with H/M ratio less or equal to 1.6 underwent ICD device implantation, while those with H/M ratio greater than or equal to 1.6 did not undergo ICD implantation.
DRUGThyroid blocking
Participants received a thyroid blocking agent before the Iobenguane I-123 Injection, AdreView, scan unless medically not indicated, according to local practice.
Sponsors
Advanced Clinical, LLC
TFS
H2O Clinical LLC
AG Mednet Inc.
ICON CEAC
ICON Clinical
ABX CRO
TransPerfect
GE Healthcare
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Participants \>=18 years of age at the time dated informed consent was obtained. * Female participants must be pre-menarchal, surgically sterile (had a documented bilateral oophorectomy and/or documented hysterectomy), postmenopausal (cessation of menses for more than 1 year), non-lactating, or, if of childbearing potential, a serum or urine pregnancy test with the results known prior to AdreView (Iobenguane I-123 Injection) administration) was negative. * Participants willing and able to comply with all study procedures and a signed and dated informed consent was obtained before any study-procedure was carried out. * Heart failure NYHA class II or III for symptoms, participants with ischemic or non-ischemic heart disease, eligible for ICD implantation as per each site's standard of practice. * Non-ischemic dilated cardiomyopathy or ischemic heart disease of at least 3 months duration receiving guideline-directed optimal medical therapy. * 25%≤LVEF≤35%, performed within 3 months before or at time of enrollment, as measured by radionuclide ventriculography, or electrocardiogram \[ECG\]-gated SPECT myocardial perfusion imaging \[MPI\], or magnetic resonance imaging \[MR\], computed tomography \[CT\], or 3D or 2D echocardiography \[Simpson's or multidisc method only, M-mode echocardiography was not accepted\]. In case LVEF measurement was performed within 3 months before enrollment, measurement should be performed at least 40 days after a hospitalization for HF or acute coronary syndrome (including myocardial infarction), and to be valid, method of measurement should be in accordance with the protocol and the imaging exam should be made available to the Sponsor in digital format. In case several valid LVEF measurements are available, the closest to enrollment will be used for inclusion determination. * Clinically stable heart failure in the medical judgment of the investigator (i.e. no significant changes in medication, no worsening of symptoms, no unscheduled visits to the doctor's office) for the past 30 days and no hospitalization for heart failure or acute coronary syndrome (including myocardial infarction) in the past 40 days. * Reasonable expectation of meaningful survival for at least 1 year.
Exclusion criteria
* Participants with existing ICD or participant having an indication of ICD implantation for secondary prevention of sudden cardiac death. * Hospitalization for HF or for acute coronary syndrome in the previous 40 days. * Participants where a cardiac resynchronisation therapy (CRT) was planned or indicated. * Other indication for placement of device (sustained ventricular tachycardia, resuscitated sudden death, need for atrioventricular pacing). * NYHA class I or class IV symptoms at the time of study entry. * Participants with chronic renal insufficiency defined as serum creatinine ≥ 3 mg/dl (or ≥ 265.2 µmol/L). * American College of College-American Heart Association (ACC-AHA) class III or class IV (unstable) angina. * Known or suspected hypersensitivity/allergy to Iobenguane or to any of the excipients an Adreview (Iobenguane I-131 injection). * Participant who was pregnant or plans to become pregnant within 2 weeks after AdreView (Iobenguane I-123 Injection) administration. * Participant who had used any medication in the 2 weeks before AdreView (Iobenguane I-123 Injection) that could interfere with the test: e.g. but not limited to amitriptyline or derivatives, imipramine or derivatives, other antidepressants or drugs known or suspected to inhibit the norepinephrine transporter, antihypertensives that deplete norepinephrine stores or inhibit reuptake, sympathomimetic amines or cocaine. * Participants that had a medical condition that could interfere with the AdreView test (e.g. but not limited to left ventricular assist device (LVAD), or prior heart transplant). * Participants who participated in a clinical study involving a drug or device within 30 days prior to study entry and participants participating in any other clinical study. * Participants having serious non-cardiac medical condition associated with significant elevation of plasma catecholamines, including pheochromocytoma. * Participants with a clinical diagnosis of (or being treated for) Parkinson's disease or Multiple System Atrophy. * The participant had participated in a research study using ionizing radiation in the previous 12 months. * Participants previously randomized in this study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| All-cause Mortality | From randomization until the end of the follow-up period (median 304 days) | All-cause mortality included all reported deaths of participants during the study due to any cause. Percentage of participants who died due to any cause were reported. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Participants With Cardiac Death | From randomization until the end of the follow-up period (median 304 days) | Cardiac death composed of sudden cardiac death, death due to cardiac arrhythmia, death due to heart failure, and death due to other cardiovascular causes. |
| Percentage of Participants With Hospitalization for Cardiovascular Cause | From randomization until the end of the follow-up period (median 304 days) | Percentage of participants who were hospitalized for cardiovascular cause were reported. |
| Percentage of Participants With All-Cause Hospitalization | From randomization until the end of the follow-up period (median 304 days) | Percentage of participants with all-cause hospitalization were reported. |
| Percentage of Participants With Events of Complications of Device: H/M >=1.6 in Full Analysis Set | From randomization until the end of the follow-up period (median 304 days) | Composite of the percentage of participants with events of hospitalization or death related to major complications of device implantation (i.e., need for thoracotomy, pericardiocentesis, or vascular surgery), complications of long-term device therapy (i.e., infection not leading to hospitalization, lead and/or generator removal/replacement, inappropriate shocks, explanation), and combined as 'complications of device' for participants with H/M \>=1.6. Participants who were alive at time of database lock (DBL) were censored at the last known-alive date. |
| Percentage of Participants With Syncope | From randomization until the end of the follow-up period (median 304 days) | Percentage of participants with Syncope were reported. Participants who were alive at time of DBL were censored at the last known-alive date by date of DBL. |
| Percentage of Participants With Implantable Cardioverter Defibrillator (ICD) Implantation | From randomization until the end of the follow-up period (median 304 days) | Percentage of participants with ICD implantation were reported. |
| Percentage of Participants With Events of Complications of Device | From randomization until the end of the follow-up period (median 304 days) | Composite of the percentage of participants with events of hospitalization or death related to major complications of device implantation (i.e., need for thoracotomy, pericardiocentesis, or vascular surgery), complications of long-term device therapy (i.e., infection not leading to hospitalization, lead and/or generator removal/replacement, inappropriate shocks, explanation), and combined as 'complications of device'. |
| Percentage of Participants With Events (Composite of the Occurrence of Resuscitated Life-Threatening Ventricular Tachycardia, Unstable Ventricular Tachyarrhythmias, Sudden Cardiac Death [SCD] and Resuscitated Cardiac Arrest) | From randomization until the end of the follow-up period (median 304 days) | Percentage of participants with composite events i.e occurrence of resuscitated life-threatening ventricular tachycardia, unstable ventricular tachy-arrhythmias, SCD and resuscitated cardiac arrest were reported. Participants who were alive at time of database lock (DBL) were censored at the last known-alive date. |
Countries
Canada, Czechia, France, Germany, Hungary, Italy, Netherlands, Poland, Spain, United States
Participant flow
Recruitment details
The Study was conducted at 70 centers in United States of America, Canada and Europe between 30 December 2015 and 04 May 2018. A total of 395 participants were enrolled in study, of which 52 were screen failures mainly due to exclusion criteria met.
Pre-assignment details
Out of 343 participants, 321 participants with 25% \<=left ventricular ejection fraction (LVEF) \<=35% were randomized in a 1:1 ratio to the AdreView™ group or Standard of Care (SoC) group stratified by enrolling center via an interactive web response system and 22 participants were not randomized but included in safety analysis set.
Participants by arm
| Arm | Count |
|---|---|
| AdreView™ Participants received 1 intravenous injection of 10 mCi (370 MBq) of AdreView™ (Iobenguane I-123 Injection). Participants with AdreView™ Heart-to-Mediastinal ratio (H/M) \<1.6 underwent Implantable Cardioverter Defibrillator (ICD) device implantation and H/M \>= 1.6 continued to receive GDMT according to clinical standard practice. | 164 |
| Standard of Care Participants received 1 intravenous injection of 10 mCi (370 MBq) of AdreView™ (Iobenguane I-123 Injection) and underwent ICD implantation and were followed up in accordance with internationally accepted HF guidelines. | 157 |
| Total | 321 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 3 |
| Overall Study | Other than specified above | 5 | 6 |
| Overall Study | Study termination by Sponsor | 150 | 142 |
| Overall Study | Withdrawal by Subject | 7 | 6 |
Baseline characteristics
| Characteristic | Standard of Care | Total | AdreView™ |
|---|---|---|---|
| Age, Continuous | 62.1 years STANDARD_DEVIATION 10.05 | 63.1 years STANDARD_DEVIATION 9.76 | 64.1 years STANDARD_DEVIATION 9.4 |
| Ethnicity (NIH/OMB) Hispanic or Latino | 9 Participants | 26 Participants | 17 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 140 Participants | 282 Participants | 142 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 8 Participants | 13 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 3 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 9 Participants | 19 Participants | 10 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 8 Participants | 13 Participants | 5 Participants |
| Race (NIH/OMB) White | 137 Participants | 286 Participants | 149 Participants |
| Sex: Female, Male Female | 22 Participants | 57 Participants | 35 Participants |
| Sex: Female, Male Male | 135 Participants | 264 Participants | 129 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 6 / 164 | 5 / 157 | 11 / 343 |
| other Total, other adverse events | 0 / 164 | 0 / 157 | 0 / 343 |
| serious Total, serious adverse events | 65 / 164 | 62 / 157 | 127 / 343 |
Outcome results
Primary
All-cause Mortality
All-cause mortality included all reported deaths of participants during the study due to any cause. Percentage of participants who died due to any cause were reported.
Time frame: From randomization until the end of the follow-up period (median 304 days)
Population: Analysis was performed on full analysis set (FAS) that was defined as participants included in the safety analysis set who were randomised to the AdreView™ group or the SoC group.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AdreView™ | All-cause Mortality | 3.0 percentage of participants |
| Standard of Care | All-cause Mortality | 3.2 percentage of participants |
Comparison: Analysis was performed using the Cox proportional hazards model stratified by country, with method of treatment guidance (SoC vs AdreView™ group) as the only covariate.p-value: 0.845995% CI: [0.295, 3.719]Log Rank
Secondary
Percentage of Participants With All-Cause Hospitalization
Percentage of participants with all-cause hospitalization were reported.
Time frame: From randomization until the end of the follow-up period (median 304 days)
Population: Analysis was performed on FAS population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AdreView™ | Percentage of Participants With All-Cause Hospitalization | 17.1 percentage of participants |
| Standard of Care | Percentage of Participants With All-Cause Hospitalization | 22.3 percentage of participants |
Secondary
Percentage of Participants With Cardiac Death
Cardiac death composed of sudden cardiac death, death due to cardiac arrhythmia, death due to heart failure, and death due to other cardiovascular causes.
Time frame: From randomization until the end of the follow-up period (median 304 days)
Population: Analysis was performed on FAS population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AdreView™ | Percentage of Participants With Cardiac Death | 1.2 percentage of participants |
| Standard of Care | Percentage of Participants With Cardiac Death | 0.6 percentage of participants |
Secondary
Percentage of Participants With Events (Composite of the Occurrence of Resuscitated Life-Threatening Ventricular Tachycardia, Unstable Ventricular Tachyarrhythmias, Sudden Cardiac Death [SCD] and Resuscitated Cardiac Arrest)
Percentage of participants with composite events i.e occurrence of resuscitated life-threatening ventricular tachycardia, unstable ventricular tachy-arrhythmias, SCD and resuscitated cardiac arrest were reported. Participants who were alive at time of database lock (DBL) were censored at the last known-alive date.
Time frame: From randomization until the end of the follow-up period (median 304 days)
Population: Analysis was performed on FAS population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AdreView™ | Percentage of Participants With Events (Composite of the Occurrence of Resuscitated Life-Threatening Ventricular Tachycardia, Unstable Ventricular Tachyarrhythmias, Sudden Cardiac Death [SCD] and Resuscitated Cardiac Arrest) | 1.2 percentage of participants |
| Standard of Care | Percentage of Participants With Events (Composite of the Occurrence of Resuscitated Life-Threatening Ventricular Tachycardia, Unstable Ventricular Tachyarrhythmias, Sudden Cardiac Death [SCD] and Resuscitated Cardiac Arrest) | 2.5 percentage of participants |
Secondary
Percentage of Participants With Events of Complications of Device
Composite of the percentage of participants with events of hospitalization or death related to major complications of device implantation (i.e., need for thoracotomy, pericardiocentesis, or vascular surgery), complications of long-term device therapy (i.e., infection not leading to hospitalization, lead and/or generator removal/replacement, inappropriate shocks, explanation), and combined as 'complications of device'.
Time frame: From randomization until the end of the follow-up period (median 304 days)
Population: Analysis was performed on FAS population.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AdreView™ | Percentage of Participants With Events of Complications of Device | Hospitalization/death | 4.9 percentage of participants |
| AdreView™ | Percentage of Participants With Events of Complications of Device | Complications of long-term device therapy | 4.3 percentage of participants |
| AdreView™ | Percentage of Participants With Events of Complications of Device | Complications of device | 5.5 percentage of participants |
| Standard of Care | Percentage of Participants With Events of Complications of Device | Hospitalization/death | 3.8 percentage of participants |
| Standard of Care | Percentage of Participants With Events of Complications of Device | Complications of long-term device therapy | 6.4 percentage of participants |
| Standard of Care | Percentage of Participants With Events of Complications of Device | Complications of device | 6.4 percentage of participants |
Secondary
Percentage of Participants With Events of Complications of Device: H/M >=1.6 in Full Analysis Set
Composite of the percentage of participants with events of hospitalization or death related to major complications of device implantation (i.e., need for thoracotomy, pericardiocentesis, or vascular surgery), complications of long-term device therapy (i.e., infection not leading to hospitalization, lead and/or generator removal/replacement, inappropriate shocks, explanation), and combined as 'complications of device' for participants with H/M \>=1.6. Participants who were alive at time of database lock (DBL) were censored at the last known-alive date.
Time frame: From randomization until the end of the follow-up period (median 304 days)
Population: Analysis was performed on FAS population. Here, overall number of participants analyzed = participants with H/M \>=1.6.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| AdreView™ | Percentage of Participants With Events of Complications of Device: H/M >=1.6 in Full Analysis Set | Hospitalization/death | 3.8 percentage of participants |
| AdreView™ | Percentage of Participants With Events of Complications of Device: H/M >=1.6 in Full Analysis Set | Complications of long-term device therapy | 3.8 percentage of participants |
| AdreView™ | Percentage of Participants With Events of Complications of Device: H/M >=1.6 in Full Analysis Set | Complications of device | 3.8 percentage of participants |
| Standard of Care | Percentage of Participants With Events of Complications of Device: H/M >=1.6 in Full Analysis Set | Hospitalization/death | 0 percentage of participants |
| Standard of Care | Percentage of Participants With Events of Complications of Device: H/M >=1.6 in Full Analysis Set | Complications of long-term device therapy | 15.0 percentage of participants |
| Standard of Care | Percentage of Participants With Events of Complications of Device: H/M >=1.6 in Full Analysis Set | Complications of device | 15.0 percentage of participants |
Secondary
Percentage of Participants With Hospitalization for Cardiovascular Cause
Percentage of participants who were hospitalized for cardiovascular cause were reported.
Time frame: From randomization until the end of the follow-up period (median 304 days)
Population: Analysis was performed on FAS population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AdreView™ | Percentage of Participants With Hospitalization for Cardiovascular Cause | 7.3 percentage of participants |
| Standard of Care | Percentage of Participants With Hospitalization for Cardiovascular Cause | 7.6 percentage of participants |
Secondary
Percentage of Participants With Implantable Cardioverter Defibrillator (ICD) Implantation
Percentage of participants with ICD implantation were reported.
Time frame: From randomization until the end of the follow-up period (median 304 days)
Population: Analysis was performed on FAS population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AdreView™ | Percentage of Participants With Implantable Cardioverter Defibrillator (ICD) Implantation | 73.2 percentage of participants |
| Standard of Care | Percentage of Participants With Implantable Cardioverter Defibrillator (ICD) Implantation | 81.5 percentage of participants |
Secondary
Percentage of Participants With Syncope
Percentage of participants with Syncope were reported. Participants who were alive at time of DBL were censored at the last known-alive date by date of DBL.
Time frame: From randomization until the end of the follow-up period (median 304 days)
Population: Analysis was performed on FAS population.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| AdreView™ | Percentage of Participants With Syncope | 2.4 percentage of participants |
| Standard of Care | Percentage of Participants With Syncope | 0 percentage of participants |