Heart Defects, Congenital
Conditions
Keywords
cyanotic congenital heart disease, shunt palliation, thrombosis, clopidogrel
Brief summary
This study is the extension of the CLARINET study \[NCT00396877 -EFC5314\] in neonates or infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary artery shunt. The primary objective was to assess the safety up to 18 months of age of the extended use of Clopidogrel 0.2 mg/kg/day in patients for whom the shunt was still in place at one year of age. The secondary objective was to assess the efficacy on the occurrence of shunt thrombosis requiring intervention or any death.
Detailed description
Patients remained in the treatment group to which they were originally allocated for the CLARINET study and continued blindly their treatment (0.2 mg/kg/day of clopidogrel or placebo) up to the occurrence of shunt thrombosis, next surgical procedure for correction of the congenital heart disease, death, or 18 months of age, whichever came first. The maximum treatment duration were 6 months.
Interventions
DRUGClopidogrel
Form: reconstituted solution using Clopidogrel powder Route: oral or enteric Frequency: once daily Dose: daily dose adjusted for weight
DRUGplacebo
Form: reconstituted solution using matching placebo powder Route: oral or enteric Frequency: once daily Dose: daily dose adjusted for weight
Sponsors
Bristol-Myers Squibb
Sanofi
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
DOUBLE (Subject, Investigator)
Eligibility
Sex/Gender
ALL
Age
12 Months to No maximum
Healthy volunteers
No
Inclusion criteria
* Patients randomized in the CLARINET study, * Still receiving the study drug, * Palliative systemic-to-pulmonary artery shunt still in place at 1 year of age, * Investigator's decision to continue based on his/her judgment of the expected benefit / risk of continuing treatment with study drug, * Signed informed consent to participate in the long-term safety study.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Bleeding Events | Up to a maximum of 6 months | All bleeding events experienced during the study period were collected as for any Adverse Event. The 'on-treatment' period was defined as the period from inclusion in the extension study up to 28 days after treatment discontinuation, and participants who experienced bleeding events during that period were counted. |
| Number of Participants According to Bleeding Type/Etiology | Up to a maximum of 6 months | For all reported bleeding events, the type and the etiology of the bleeding event were collected. Participants who experienced bleeding events during the 'on-treatment period' were counted by bleeding type and etiology. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Shunt Thrombosis Requiring Intervention or Deaths | Up to a maximum of 6 months | Outcome events, shunt thrombosis requiring intervention or death, experienced during the study period were recorded. Participants were counted excluding the events that occured after the participant's protocol study end (occurrence of shunt thrombosis, next surgical procedure for correction of the congenital heart disease, death, or 18 months of age, whichever came first). |
Countries
Brazil, France, Germany, Hungary, India, Italy, Malaysia, Mexico, Poland, Portugal, Russia, Spain, Taiwan, United Kingdom, United States
Participant flow
Recruitment details
49 participants were enrolled between January 2009 and January 2010 in 25 sites in 15 countries (7 countries involved in CLARINET study were not selected as the delay in obtaining IRB/IEC and Health Authorities approvals would prevent recruitment and/or no patient would be recruited as the second surgery is always performed before 1 year of age).
Participants by arm
| Arm | Count |
|---|---|
| Placebo 0.2 mL/kg/day matching placebo solution once daily | 23 |
| Clopidogrel 0.2 mg/kg/Day 0.2 mL/kg/day Clopidogrel reconstituted solution at 1mg/mL once daily | 26 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Parent(s)/guardian(s)'s request | 0 | 1 |
Baseline characteristics
| Characteristic | Total | Clopidogrel 0.2 mg/kg/Day | Placebo |
|---|---|---|---|
| Age at shunt palliation | 19.4 days STANDARD_DEVIATION 22.3 | 13.7 days STANDARD_DEVIATION 12.7 | 25.7 days STANDARD_DEVIATION 28.7 |
| Age Continuous at inclusion | 368.0 days STANDARD_DEVIATION 3.5 | 368.0 days STANDARD_DEVIATION 2.7 | 368.1 days STANDARD_DEVIATION 4.2 |
| Age Continuous at randomization in CLARINET study | 38.8 days STANDARD_DEVIATION 23.8 | 33.1 days STANDARD_DEVIATION 20.5 | 45.2 days STANDARD_DEVIATION 26.1 |
| Height at inclusion | 70.8 centimeters (cm) STANDARD_DEVIATION 7.8 | 70.0 centimeters (cm) STANDARD_DEVIATION 10.4 | 71.8 centimeters (cm) STANDARD_DEVIATION 2.8 |
| Region of Enrollment Brazil | 6 participants | 2 participants | 4 participants |
| Region of Enrollment France | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Germany | 3 participants | 3 participants | 0 participants |
| Region of Enrollment Hungary | 3 participants | 1 participants | 2 participants |
| Region of Enrollment India | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Italy | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Malaysia | 2 participants | 1 participants | 1 participants |
| Region of Enrollment Mexico | 10 participants | 4 participants | 6 participants |
| Region of Enrollment Poland | 2 participants | 1 participants | 1 participants |
| Region of Enrollment Portugal | 4 participants | 1 participants | 3 participants |
| Region of Enrollment Russian Federation | 1 participants | 0 participants | 1 participants |
| Region of Enrollment Spain | 2 participants | 2 participants | 0 participants |
| Region of Enrollment Taiwan | 9 participants | 5 participants | 4 participants |
| Region of Enrollment United Kingdom | 3 participants | 2 participants | 1 participants |
| Region of Enrollment United States | 1 participants | 1 participants | 0 participants |
| Sex: Female, Male Female | 24 Participants | 14 Participants | 10 Participants |
| Sex: Female, Male Male | 25 Participants | 12 Participants | 13 Participants |
| Shunt on cardiopulmonary bypass No | 42 participants | 21 participants | 21 participants |
| Shunt on cardiopulmonary bypass Yes | 7 participants | 5 participants | 2 participants |
| Type of initial shunt palliation Central shunt | 4 participants | 3 participants | 1 participants |
| Type of initial shunt palliation Modified Blalock Taussig Shunt with Norwood | 1 participants | 1 participants | 0 participants |
| Type of initial shunt palliation Modified Blalock Taussig Shunt without Norwood | 38 participants | 20 participants | 18 participants |
| Type of initial shunt palliation Sano procedure with Norwood | 0 participants | 0 participants | 0 participants |
| Type of initial shunt palliation Sano procedure without Norwood | 2 participants | 1 participants | 1 participants |
| Type of initial shunt palliation Stent of ductus arteriosus | 4 participants | 1 participants | 3 participants |
| Weight at inclusion | 8.0 kilograms (kg) STANDARD_DEVIATION 1.2 | 8.1 kilograms (kg) STANDARD_DEVIATION 1.2 | 7.9 kilograms (kg) STANDARD_DEVIATION 1.1 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 23 | 17 / 26 |
| serious Total, serious adverse events | 3 / 23 | 6 / 26 |
Outcome results
Primary
Number of Participants According to Bleeding Type/Etiology
For all reported bleeding events, the type and the etiology of the bleeding event were collected. Participants who experienced bleeding events during the 'on-treatment period' were counted by bleeding type and etiology.
Time frame: Up to a maximum of 6 months
Population: The analysis was performed on the same population as previously (i.e. ITT population).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants According to Bleeding Type/Etiology | Puncture (vascular access site) | 0 participants |
| Placebo | Number of Participants According to Bleeding Type/Etiology | Spontaneous | 0 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants According to Bleeding Type/Etiology | Puncture (vascular access site) | 1 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants According to Bleeding Type/Etiology | Spontaneous | 1 participants |
Primary
Number of Participants With Bleeding Events
All bleeding events experienced during the study period were collected as for any Adverse Event. The 'on-treatment' period was defined as the period from inclusion in the extension study up to 28 days after treatment discontinuation, and participants who experienced bleeding events during that period were counted.
Time frame: Up to a maximum of 6 months
Population: The analysis was performed on the Intent-to-treat (ITT) population that consisted of all included participants. Participants were analyzed in the treatment arm allocated at randomization into the CLARINET study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Bleeding Events | Any bleeding event | 0 participants |
| Placebo | Number of Participants With Bleeding Events | - Serious | 0 participants |
| Placebo | Number of Participants With Bleeding Events | - Serious with an outcome of death | 0 participants |
| Placebo | Number of Participants With Bleeding Events | - Leading to permanent treatment discontinuation | 0 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants With Bleeding Events | - Leading to permanent treatment discontinuation | 0 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants With Bleeding Events | Any bleeding event | 2 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants With Bleeding Events | - Serious with an outcome of death | 0 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants With Bleeding Events | - Serious | 0 participants |
Secondary
Number of Participants With Shunt Thrombosis Requiring Intervention or Deaths
Outcome events, shunt thrombosis requiring intervention or death, experienced during the study period were recorded. Participants were counted excluding the events that occured after the participant's protocol study end (occurrence of shunt thrombosis, next surgical procedure for correction of the congenital heart disease, death, or 18 months of age, whichever came first).
Time frame: Up to a maximum of 6 months
Population: The analysis was performed on the Intent-to-treat (ITT) population that consisted of all included participants. Participants were analyzed in the treatment arm allocated at randomization into the CLARINET study.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Shunt Thrombosis Requiring Intervention or Deaths | shunt thrombosis requiring intervention | 0 participants |
| Placebo | Number of Participants With Shunt Thrombosis Requiring Intervention or Deaths | death | 1 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants With Shunt Thrombosis Requiring Intervention or Deaths | shunt thrombosis requiring intervention | 0 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants With Shunt Thrombosis Requiring Intervention or Deaths | death | 0 participants |