Heart Defects, Congenital
Conditions
Keywords
cyanotic congenital heart disease, shunt palliation, thrombosis, clopidogrel
Brief summary
Contemporary management of cyanotic congenital heart disease includes three stages of surgery. Incidence of shunt thrombosis and death between the two first stages of palliation remains important. The primary objective of the study is to evaluate the efficacy of Clopidogrel 0.2 mg/kg/day for the reduction of all cause mortality and shunt related morbidity in neonates or infants with cyanotic congenital heart disease palliated with a systemic-to-pulmonary artery shunt (e.g. modified Blalock Taussig Shunt \[BTS\]). The secondary objective was to assess the safety of Clopidogrel in the study population.
Detailed description
In this event-driven study, participants were to be randomized and treated as soon as possible after shunt placement. They were then to be treated and followed until the primary endpoint criteria was reached i.e. (shunt thrombosis, the next surgical procedure for correction of the congenital heart disease or death) or one year of age or the common study-end-date, which ever came first. The common study-en-date was defined as the date when it was projected that 172 participants would have reached the primary endpoint criteria.
Interventions
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
TRIPLE (Subject, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
No minimum to 92 Days
Healthy volunteers
No
Inclusion criteria
* Cyanotic congenital heart disease treated by any palliative systemic-to-pulmonary artery shunt.
Exclusion criteria
* Active bleeding or increase risk of bleeding, * Allergy to 2 or more classes of drug, * Unable to receive drug orally or enterically, * Current clinically significant or persistent thrombocytopenia, neutropenia, severe hepatic or renal failure.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants Reaching Primary Endpoint Criteria (First Occurrence of Death / Shunt Thrombosis / Cardiac Procedure < 120 Days Considered of Thrombotic Nature) | Median follow-up of 5.8 months (up to a maximum of 12 months after randomization) | The primary endpoint was the first occurence of any of the following events: Death (including heart transplant); Shunt thrombosis requiring intervention; Hospitalization for bi-directional Glenn procedure or any cardiac related intervention prior to 120 days of age following an event or a shunt narrowing considered to be of thrombotic nature by the blinded adjudication committee. Only the first event was counted. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants According to Bleeding Type/Etiology | From randomization up to 28 days after treatment discontinuation or final follow-up visit, whichever comes first | 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. Participants who had multiple bleedings could be counted several times. |
| Number of Participants With Bleeding Events | From randomization up to 28 days after treatment discontinuation or final follow-up visit, whichever comes first | Bleeding events spanning from signature of the Informed Consent Form up to the last visit were collected as for any Adverse Event. The 'on-treatment' period was defined as the period from randomization up until 28 days after treatment discontinuation or final follow-up visit, whichever came first, and participants who experienced bleeding events during that period were counted. |
Countries
Argentina, Belgium, Brazil, Canada, China, Denmark, Egypt, Finland, France, Germany, Hong Kong, Hungary, India, Israel, Italy, Malaysia, Mexico, Netherlands, Norway, Poland, Portugal, Russia, Singapore, South Africa, South Korea, Spain, Sweden, Taiwan, Thailand, United Kingdom, United States
Participant flow
Recruitment details
Recruitment was initially planned with a minimum of 490 participants anticipating that it would continue until a total of 172 participants reaching primary endpoint criteria is achieved. Finally 906 participants were enrolled and randomized between November 2006 and October 2009 in 134 sites in 31 countries. Actual median follow-up was 5.8 months.
Pre-assignment details
A participant was considered randomized when informed consent had been obtained and there was confirmation of successful allocation of a randomization number through the study treatment allocation system (Interactive Voice Response System).
Participants by arm
| Arm | Count |
|---|---|
| Placebo | 439 |
| Clopidogrel 0.2 mg/kg/Day | 467 |
| Total | 906 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 2 | 1 |
| Overall Study | Parent(s)/guardian(s)'s request | 4 | 7 |
Baseline characteristics
| Characteristic | Total | Placebo | Clopidogrel 0.2 mg/kg/Day |
|---|---|---|---|
| Age at shunt palliation | 16.1 days STANDARD_DEVIATION 18.7 | 16.0 days STANDARD_DEVIATION 18.7 | 16.2 days STANDARD_DEVIATION 18.6 |
| Age, Continuous | 36.1 days STANDARD_DEVIATION 22.4 | 36.0 days STANDARD_DEVIATION 22.5 | 36.1 days STANDARD_DEVIATION 22.3 |
| Age, Customized 30 (<) - 92 days | 445 participants | 216 participants | 229 participants |
| Age, Customized ≤ 30 days | 461 participants | 223 participants | 238 participants |
| Height | 51.6 Centimeters (cm) STANDARD_DEVIATION 4.5 | 51.8 Centimeters (cm) STANDARD_DEVIATION 4.6 | 51.4 Centimeters (cm) STANDARD_DEVIATION 4.4 |
| Region of Enrollment Argentina | 52 participants | 24 participants | 28 participants |
| Region of Enrollment Belgium | 21 participants | 9 participants | 12 participants |
| Region of Enrollment Brazil | 65 participants | 31 participants | 34 participants |
| Region of Enrollment Canada | 11 participants | 5 participants | 6 participants |
| Region of Enrollment China | 21 participants | 10 participants | 11 participants |
| Region of Enrollment Denmark | 6 participants | 3 participants | 3 participants |
| Region of Enrollment Egypt | 10 participants | 4 participants | 6 participants |
| Region of Enrollment Finland | 3 participants | 2 participants | 1 participants |
| Region of Enrollment France | 21 participants | 11 participants | 10 participants |
| Region of Enrollment Germany | 113 participants | 54 participants | 59 participants |
| Region of Enrollment Hong Kong | 1 participants | 1 participants | 0 participants |
| Region of Enrollment Hungary | 18 participants | 9 participants | 9 participants |
| Region of Enrollment India | 47 participants | 20 participants | 27 participants |
| Region of Enrollment Israel | 7 participants | 3 participants | 4 participants |
| Region of Enrollment Italy | 39 participants | 20 participants | 19 participants |
| Region of Enrollment Korea, Republic of | 5 participants | 3 participants | 2 participants |
| Region of Enrollment Malaysia | 9 participants | 5 participants | 4 participants |
| Region of Enrollment Mexico | 69 participants | 32 participants | 37 participants |
| Region of Enrollment Netherlands | 6 participants | 2 participants | 4 participants |
| Region of Enrollment Norway | 16 participants | 8 participants | 8 participants |
| Region of Enrollment Poland | 10 participants | 3 participants | 7 participants |
| Region of Enrollment Portugal | 20 participants | 10 participants | 10 participants |
| Region of Enrollment Russian Federation | 28 participants | 13 participants | 15 participants |
| Region of Enrollment Singapore | 4 participants | 2 participants | 2 participants |
| Region of Enrollment South Africa | 26 participants | 13 participants | 13 participants |
| Region of Enrollment Spain | 30 participants | 16 participants | 14 participants |
| Region of Enrollment Sweden | 11 participants | 6 participants | 5 participants |
| Region of Enrollment Taiwan | 22 participants | 12 participants | 10 participants |
| Region of Enrollment Thailand | 5 participants | 2 participants | 3 participants |
| Region of Enrollment United Kingdom | 32 participants | 16 participants | 16 participants |
| Region of Enrollment United States | 178 participants | 90 participants | 88 participants |
| Sex: Female, Male Female | 383 Participants | 185 Participants | 198 Participants |
| Sex: Female, Male Male | 523 Participants | 254 Participants | 269 Participants |
| Shunt on cardiopulmonary bypass No | 535 participants | 262 participants | 273 participants |
| Shunt on cardiopulmonary bypass Yes | 371 participants | 177 participants | 194 participants |
| Time from shunt palliation to randomization 1 (<) to 2 weeks | 231 participants | 105 participants | 126 participants |
| Time from shunt palliation to randomization ≤ 1 week | 229 participants | 116 participants | 113 participants |
| Time from shunt palliation to randomization 2 (<) to 4 weeks | 236 participants | 117 participants | 119 participants |
| Time from shunt palliation to randomization > 4 weeks | 210 participants | 101 participants | 109 participants |
| Type of systemic-to-pulmonary artery shunt palliation Central shunt | 78 participants | 38 participants | 40 participants |
| Type of systemic-to-pulmonary artery shunt palliation Modified Blalock Taussig Shunt with Norwood | 113 participants | 51 participants | 62 participants |
| Type of systemic-to-pulmonary artery shunt palliation Modified Blalock Taussig Shunt without Norwood | 509 participants | 252 participants | 257 participants |
| Type of systemic-to-pulmonary artery shunt palliation Not applicable | 1 participants | 0 participants | 1 participants |
| Type of systemic-to-pulmonary artery shunt palliation Sano procedure with Norwood | 114 participants | 54 participants | 60 participants |
| Type of systemic-to-pulmonary artery shunt palliation Sano procedure without Norwood | 7 participants | 2 participants | 5 participants |
| Type of systemic-to-pulmonary artery shunt palliation Stent of ductus arteriosus | 84 participants | 42 participants | 42 participants |
| Weight | 3.5 kilograms (kg) STANDARD_DEVIATION 0.7 | 3.5 kilograms (kg) STANDARD_DEVIATION 0.7 | 3.4 kilograms (kg) STANDARD_DEVIATION 0.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 96 / 436 | 107 / 464 |
| serious Total, serious adverse events | 196 / 436 | 234 / 464 |
Outcome results
Primary
Number of Participants Reaching Primary Endpoint Criteria (First Occurrence of Death / Shunt Thrombosis / Cardiac Procedure < 120 Days Considered of Thrombotic Nature)
The primary endpoint was the first occurence of any of the following events: Death (including heart transplant); Shunt thrombosis requiring intervention; Hospitalization for bi-directional Glenn procedure or any cardiac related intervention prior to 120 days of age following an event or a shunt narrowing considered to be of thrombotic nature by the blinded adjudication committee. Only the first event was counted.
Time frame: Median follow-up of 5.8 months (up to a maximum of 12 months after randomization)
Population: The analysis was performed on the intent-to-treat (ITT) population (i.e. all randomized participants irrespective of whether or not the participant actually received study drug or the participant's compliance with the study protocol). Participants were included in the treatment group to which they were originally allocated.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants Reaching Primary Endpoint Criteria (First Occurrence of Death / Shunt Thrombosis / Cardiac Procedure < 120 Days Considered of Thrombotic Nature) | Death / Shunt Thrombosis / Cardiac Procedure | 90 participants |
| Placebo | Number of Participants Reaching Primary Endpoint Criteria (First Occurrence of Death / Shunt Thrombosis / Cardiac Procedure < 120 Days Considered of Thrombotic Nature) | - Death | 60 participants |
| Placebo | Number of Participants Reaching Primary Endpoint Criteria (First Occurrence of Death / Shunt Thrombosis / Cardiac Procedure < 120 Days Considered of Thrombotic Nature) | - Shunt thrombosis | 21 participants |
| Placebo | Number of Participants Reaching Primary Endpoint Criteria (First Occurrence of Death / Shunt Thrombosis / Cardiac Procedure < 120 Days Considered of Thrombotic Nature) | - Cardiac procedure <120 days of thrombotic nature | 9 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants Reaching Primary Endpoint Criteria (First Occurrence of Death / Shunt Thrombosis / Cardiac Procedure < 120 Days Considered of Thrombotic Nature) | - Cardiac procedure <120 days of thrombotic nature | 12 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants Reaching Primary Endpoint Criteria (First Occurrence of Death / Shunt Thrombosis / Cardiac Procedure < 120 Days Considered of Thrombotic Nature) | Death / Shunt Thrombosis / Cardiac Procedure | 89 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants Reaching Primary Endpoint Criteria (First Occurrence of Death / Shunt Thrombosis / Cardiac Procedure < 120 Days Considered of Thrombotic Nature) | - Shunt thrombosis | 26 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants Reaching Primary Endpoint Criteria (First Occurrence of Death / Shunt Thrombosis / Cardiac Procedure < 120 Days Considered of Thrombotic Nature) | - Death | 51 participants |
Comparison: Due to the limited knowledge in this population, 3 interim analyses were performed at approximatively 40%, 60%, 80% and 100% of of the maximum number of 172 required primary efficacy events to evaluate the effect of Clopidogrel on the primary endpoint with the potential to end the trial in case of a clear efficacy advantage for Clopidogrel.~The study was designed with 80% power and an overall type I error rate of 5%.p-value: 0.43495% CI: [-19.2, 33.6]Log Rank
Secondary
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. Participants who had multiple bleedings could be counted several times.
Time frame: From randomization up to 28 days after treatment discontinuation or final follow-up visit, whichever comes first
Population: The analysis was performed on the same population as previously (i.e. exposed population).
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants According to Bleeding Type/Etiology | Spontaneous | 60 participants |
| Placebo | Number of Participants According to Bleeding Type/Etiology | Post-traumatic | 6 participants |
| Placebo | Number of Participants According to Bleeding Type/Etiology | Puncture (vascular access site) | 19 participants |
| Placebo | Number of Participants According to Bleeding Type/Etiology | Surgical | 10 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants According to Bleeding Type/Etiology | Surgical | 17 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants According to Bleeding Type/Etiology | Spontaneous | 56 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants According to Bleeding Type/Etiology | Puncture (vascular access site) | 9 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants According to Bleeding Type/Etiology | Post-traumatic | 11 participants |
Secondary
Number of Participants With Bleeding Events
Bleeding events spanning from signature of the Informed Consent Form up to the last visit were collected as for any Adverse Event. The 'on-treatment' period was defined as the period from randomization up until 28 days after treatment discontinuation or final follow-up visit, whichever came first, and participants who experienced bleeding events during that period were counted.
Time frame: From randomization up to 28 days after treatment discontinuation or final follow-up visit, whichever comes first
Population: The analysis was performed on the exposed population (i.e. all randomized participants who received at least one dose of study drug regardless of the amount of treatment received). Participants were included in the treatment group according to the treatment received.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Placebo | Number of Participants With Bleeding Events | Any bleeding event | 88 participants |
| Placebo | Number of Participants With Bleeding Events | - Serious | 32 participants |
| Placebo | Number of Participants With Bleeding Events | - Serious with an outcome of death | 1 participants |
| Placebo | Number of Participants With Bleeding Events | - Leading to permanent treatment discontinuation | 9 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants With Bleeding Events | - Leading to permanent treatment discontinuation | 9 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants With Bleeding Events | Any bleeding event | 87 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants With Bleeding Events | - Serious with an outcome of death | 1 participants |
| Clopidogrel 0.2 mg/kg/Day | Number of Participants With Bleeding Events | - Serious | 30 participants |