E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Postoperative neonatal cardiac subjects who are undergoing surgery for placement of systemic-to pulmonary artery palliative shunts (e.g., Blalock-Taussig or central shunt), right ventricle to pulmonary artery palliative shunts, or ductus arteriosus stents who are at risk of thrombotic events after repair of structural congenital heart disease. |
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E.1.1.1 | Medical condition in easily understood language |
Newborn subjects from 0-28 days of age who are at risk of developing thrombosis following surgery for repair of structural congenital heart disease. |
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E.1.1.2 | Therapeutic area | Diseases [C] - Cardiovascular Diseases [C14] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | No |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
- To assess the safety and PK / PD profile in this dose finding study of Cangrelor in this neonatal population. - To determine the plasma concentrations of Cangrelor and its primary metabolite, AR-C69712, during administration and after cessation of the infusion in neonates. - To determine the PD of Cangrelor at various doses in neonates as assessed by light transmittance aggregometry (LTA) (primary)and microfluidic flow chamber (exploratory). - To assess recovery of platelet function in neonates by LTA after cessation of the infusion. - To determine the appropriate dose(s) to evaluate in future safety and efficacy trials in neonates. - To evaluate the safety of Cangrelor in neonatal subjects by evaluating adverse events (AEs), serious adverse events (SAEs) and Adverse Events of special interest (AESIs). |
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E.2.2 | Secondary objectives of the trial |
To assess recovery of platelet function in neonates by microfluidic flow chamber (exploratory) after cessation of the infusion. |
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
1. Males and females with congenital heart disease, and ranging in age from birth through 28 days of life; 2. Postoperative neonatal cardiac subjects with placement of systemic - to - pulmonary artery palliative shunts, right ventricle to pulmonary artery palliative shunts, or ductus arteriosus stents who are at risk of thrombotic events after repair for structural congenital heart disease; 3. Written informed consent from a parent/legal guardian; 4. Life expectancy of at least 15 days at study entry. |
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E.4 | Principal exclusion criteria |
1. History of intracerebral bleed (confirmed by an ultrasound [US] of the head prior to surgery and post-operatively prior to administration of cangrelor), or cerebral arteriovenous malformation, or any prior bleed with neurological deficit; 2. Gastrointestinal or urinary bleeding; 3. Cerebrovascular accident or any cerebrovascular accident with a residual neurological deficit; 4. Known congenital or acquired bleeding or clotting disorder; 5. Weight less than 2.5 kg (at the time the patient is being considered for enrollment and at the time cangrelor is to be administered); 6. Adjusted gestational age less than 37 weeks (at the time the patient is being considered for enrollment); 7. Platelet count less than 100,000 cells/μL (at the time the patient is being considered for enrollment and at the time the cangrelor is to be administered); 8. Chest and/or mediastinal tube total fluid volume output of greater than 3 mL/kg/hr at the time cangrelor is to be administered; 9. Subjects with evidence of severe hepatic or renal impairment (AST or ALT greater than three times normal for age or total bilirubin greater than 20 mg/dL; creatinine greater than 2 times the normal upper limit); 10. Known allergy to Cangrelor or known sensitivity to any component of Cangrelor; 11. Any condition that in the opinion of the investigator would constitute a contraindication to participation in the study or cause inability to comply with the study requirements (e.g. no central venous line available for collecting PK/PD samples); 12. Participation in another investigational therapeutic drug or investigational therapeutic device trial within 30 days of starting study; 13. Subjects who have been receiving warfarin (Coumadin®) therapy. |
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E.5 End points |
E.5.1 | Primary end point(s) |
- Determination of total plasma concentrations of Cangrelor and its primary metabolite, AR-C69712, during administration and after cessation of the infusion in neonates; - Proportion of subjects in each cohort who achieve ≥90% inhibition of maximal and final platelet aggregation as measured by LTA using 5 μM and 20 μM ADP in platelet rich plasma; - Individual recovery of platelet function in neonates after cessation of the infusion; - Determination of the appropriate dose(s) to evaluate in future safety and efficacy trials in neonates through the combination of dose, safety, and PK (clearance of parent and metabolite); - Assessment of the safety of Cangrelor in neonatal subjects by evaluating adverse events (AEs), serious adverse events (SAEs) and advetse events of special interest (AEISs). |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
PK Analysis: At 30, 45 and 55 minutes during the Cangrelor infusion, and at 5, 10 and 30 minutes after completion of the infusion.
PD Analysis: At baseline (approximately 15 to 60 minutes before the start of the Cangrelor infusion), approximately 15 minutes before the completion of the Cangrelor infusion, and at 60 minutes after the Cangrelor infusion is completed.
Safety: From beginning of study drug infusion to Day 3 follow-up visit. |
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E.5.2 | Secondary end point(s) |
Exploratory Endpoint included: Evaluation of platelet aggregation and recovery of platelet function after cessation of the Cangrelor infusion in whole blood from neonates, as measured by microfluidic flow chamber. |
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
At 30, 45 and 55 minutes during the Cangrelor infusion, and at 5, 10 and 30 minutes after completion of the infusion. |
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | No |
E.6.4 | Safety | Yes |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | Yes |
E.6.7 | Pharmacodynamic | Yes |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | Yes |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | Yes |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | Yes |
E.7.1.3.1 | Other trial type description |
Dose finding study of Cangrelor in neonatal population. |
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E.7.2 | Therapeutic exploratory (Phase II) | No |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | No |
E.8.1.1 | Randomised | No |
E.8.1.2 | Open | Yes |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | No |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | No |
E.8.2.3 | Other | No |
E.8.3 |
Will this trial be conducted at a single site globally?
| No |
E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
E.8.6 Trial involving sites outside the EEA |
E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
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E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.2 | In all countries concerned by the trial years | 2 |
E.8.9.2 | In all countries concerned by the trial months | 24 |
E.8.9.2 | In all countries concerned by the trial days | 0 |