Heart Failure
Conditions
Keywords
heart failure, pediatric, LCZ696, sacubitril/valsartan, open-label study, angiotensin receptor neprilysin inhibitor, PANORAMA-HF
Brief summary
The purpose of this study was to evaluate long-term safety and tolerability and to provide post-trial access to sacubitril/valsartan to eligible participants who successfully completed CLCZ696B2319 (PANORAMA-HF) core study Part 2 as per protocol.
Detailed description
This was a multicenter, open-label long-term extension study for participants who successfully completed PANORAMA-HF core study Part 2 of the trial or who discontinued study drug treatment early in Part 2 due to the implementation of Urgent safety measure (USM) of PANORAMA-HF core study. Provided that they fulfilled the protocol requirements, these patients were eligible to participate in the OLE. Depending on when and where the participant was enrolled, the duration of the study was of a minimum of 1 year, or until receipt of local marketing authorization and commercial availability, or reaching the maximum limit allowed by local regulations, or until Dec-2023, whichever occurred first.
Interventions
DRUGsacubitril/valsartan
Target dose 3.1 mg/kg bid Formulations: Tablets (50, 100, 200 mg) Granules \[12.5 mg (4 granules), 31.25 mg (10 granules), in capsules\] Liquid (1 mg/ml, 4 mg/ml, prepared from tablets)
Sponsors
Novartis Pharmaceuticals
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to 18 Years
Healthy volunteers
No
Inclusion criteria
* Signed informed consent * On study drug at PANORAMA-HF Part 2 EOS visit. Does not have any significant safety issue
Exclusion criteria
* Subject only participated in PANORAMA-HF Part 1 or was a SF in PANORAMA-HF or permanently discontinued study drug in PANORMA-HF Part 2 * Use of investigational drugs within 5 half-lives of enrollment or within 30 days (longer duration); with the exception of PANORAMA-HF study drug (requires \>/=36-hour washout before baseline visit) * History of hypersensitivity or allergy to study treatment, its excipients or drugs of similar chemical class, ACEIs, ARBs, or NEP inhibitor and known/suspected contraindications to sacubitril/valsartan * Renal vascular hypertension (including renal artery stenosis) * Significant renal estimated glomerular filtration rate disorder (eGFR calculated using modified Schwartz formula \<30% mean GFR for age); hepatic disorder (serum aspartate aminotransferase or alanine aminotransferase \> 3 times upper limit of normal); gastrointestinal disorder or biliary disorder * History of angioedema * Parents or legal guardians of subject who do not give consent or allow the child to give assent, or inability of patient or parents/legal guardians to follow instructions or comply with follow-up procedures * Any medical condition(s) that may put the patient at risk in the investigator's opinion or that the investigator deems unsuitable for the study * Other protocol defined inclusion/
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Adverse Events | to end of study, up to 4,5 years | Number of participants with at least one Adverse Events (AEs) |
| Number of Participants With Serious Adverse Events | to end of study, up to 4.5 years | Number of participants with at least one Serious Adverse Events (SAEs) |
| Duration of Drug Exposure | Up to 4.5 years | Median duration of exposure to sacubitril/valsartan (including temporary interruptions) |
Countries
Argentina, Austria, Bulgaria, Canada, Croatia, Czechia, Finland, France, Germany, Hungary, India, Israel, Italy, Japan, Lebanon, Poland, Portugal, Russia, Singapore, South Africa, South Korea, Spain, Switzerland, Taiwan, Thailand, Turkey (Türkiye), United States
Participant flow
Recruitment details
79 centers in 27 countries: Korea, Republic of(4), United States(15), Bulgaria(1), Italy(7), Thailand(2), Poland(2), Japan(8), Singapore(2), Israel(1), Turkey(3), Taiwan(2), South Africa(1), Portugal(3), Lebanon(2), Canada(2), Switzerland(1), Czech Republic(1), Croatia(1), Argentina(1), Hungary(1), India(4), Germany(5), France(1), Austria(1), Spain(5), Russia(2), Finland(1)
Pre-assignment details
A 36-hour washout after the last dose of study medication taken in the PANORAMA-HF core study (Visit 416) was required for all participants before starting Open Label Extension study medication.
Participants by arm
| Arm | Count |
|---|---|
| Age Group 1 Patients 6 years and older receiving open label sacubitril/valsartan 3.1 mg/kg bid | 130 |
| Age Group 2 Patients 1 year to \< 6 years receiving open label sacubitril/valsartan 3.1 mg/kg bid | 85 |
| Total | 215 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Adverse Event | 16 | 1 |
| Overall Study | Death | 6 | 4 |
| Overall Study | Guardian decision | 4 | 1 |
| Overall Study | Lost to Follow-up | 1 | 0 |
| Overall Study | No treatment was received | 0 | 1 |
| Overall Study | Other | 1 | 0 |
| Overall Study | Participant decision | 2 | 0 |
| Overall Study | Physician Decision | 8 | 5 |
Baseline characteristics
| Characteristic | Age Group 2 | Total | Age Group 1 |
|---|---|---|---|
| Age, Continuous | 2.94 Years STANDARD_DEVIATION 1.149 | 8.92 Years STANDARD_DEVIATION 5.747 | 12.83 Years STANDARD_DEVIATION 3.864 |
| Race/Ethnicity, Customized American Indian or Alaska Native | 0 Participants | 2 Participants | 2 Participants |
| Race/Ethnicity, Customized Asian | 23 Participants | 47 Participants | 24 Participants |
| Race/Ethnicity, Customized Black or African American | 10 Participants | 29 Participants | 19 Participants |
| Race/Ethnicity, Customized Multiple | 4 Participants | 4 Participants | 0 Participants |
| Race/Ethnicity, Customized Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race/Ethnicity, Customized Unknown | 6 Participants | 13 Participants | 7 Participants |
| Race/Ethnicity, Customized White | 41 Participants | 119 Participants | 78 Participants |
| Sex: Female, Male Female | 49 Participants | 109 Participants | 60 Participants |
| Sex: Female, Male Male | 36 Participants | 106 Participants | 70 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | 7 / 130 | 4 / 85 | 11 / 215 |
| other Total, other adverse events | 90 / 130 | 60 / 85 | 150 / 215 |
| serious Total, serious adverse events | 59 / 130 | 25 / 85 | 84 / 215 |
Outcome results
Primary
Duration of Drug Exposure
Median duration of exposure to sacubitril/valsartan (including temporary interruptions)
Time frame: Up to 4.5 years
Population: Safety Set (SAF): All participants who received at least one dose of open-label study treatment during the extension open-label study.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Age Group 1 | Duration of Drug Exposure | 894 Days |
| Age Group 2 | Duration of Drug Exposure | 951 Days |
Primary
Number of Participants With Adverse Events
Number of participants with at least one Adverse Events (AEs)
Time frame: to end of study, up to 4,5 years
Population: Safety Set (SAF): All participants who received at least one dose of open-label study treatment during the extension open-label study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Age Group 1 | Number of Participants With Adverse Events | 111 Participants |
| Age Group 2 | Number of Participants With Adverse Events | 78 Participants |
Primary
Number of Participants With Serious Adverse Events
Number of participants with at least one Serious Adverse Events (SAEs)
Time frame: to end of study, up to 4.5 years
Population: Safety Set (SAF): All participants who received at least one dose of open-label study treatment during the extension open-label study.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Age Group 1 | Number of Participants With Serious Adverse Events | 59 Participants |
| Age Group 2 | Number of Participants With Serious Adverse Events | 25 Participants |