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| Name | Class |
|---|---|
| Sunnybrook Health Sciences Centre | OTHER |
| McMaster Children's Hospital | OTHER |
| The Rotunda Hospital | OTHER |
| John Hunter Hospital |
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Patent ductus arteriosus (PDA), the most common cardiovascular complication of prematurity, is associated with higher mortality and morbidities in extremely low gestational age neonates (ELGANs, < 27+0 weeks). Ibuprofen and acetaminophen, which act by reducing prostaglandin synthesis, are the most commonly used first and second line agents for PDA treatment across Canada. However, initial treatment failure with monotherapy is a major problem, occurring in >60% ELGANs. Treatment failure is associated with worsening rates of mortality and bronchopulmonary dysplasia (BPD), while early treatment success can achieve rates comparable to neonates without PDA. Treatment failure resulting in prolonged disease exposure is thought to be a major contributor. Recently, combination therapy with acetaminophen and ibuprofen has emerged as a new treatment regime. Acetaminophen exerts anti-prostaglandin effect through a different receptor site than ibuprofen, providing a biological rationale for their synergistic action.
The objective of this study is to evaluate the clinical impact, efficacy and safety of combination regime (Ibuprofen + IV Acetaminophen) for the first treatment course for PDA in ELGANs vs. Ibuprofen alone (current standard treatment).
The study will also evaluate the effects of combination regime vs. ibuprofen alone on neurodevelopmental outcomes at 18-30 months corrected age.
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Combination Therapy | Experimental | Intravenous or enteral ibuprofen, as decided by clinical team, in the standard clinical dose used in participating NICUs (typically, for neonates < 7 days old - 10 mg/kg/dose on day 1, 5 mg/kg/dose q24h on days 2 and 3; for neonates > 7 days old - 20 mg/kg/dose on day 1, 10 mg/kg/dose q24h on days 2 and 3) And study drug (intravenous acetaminophen 15 mg/kg/dose IV q6h for 3 days). |
|
| Standard Clinical Practice - Monotherapy | Placebo Comparator | Intravenous or enteral ibuprofen, as decided by clinical team, in the standard clinical dose used in participating NICUs (typically, for neonates < 7 days old - 10 mg/kg/dose on day 1, 5 mg/kg/dose q24h on days 2 and 3; for neonates > 7 days old - 20 mg/kg/dose on day 1, 10 mg/kg/dose q24h on days 2 and 3) And Placebo [(0.9% saline IV q6h for 3 days).](streamdown:incomplete-link) |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Acetaminophen Injection | Drug | Acetaminophen injection solution 1000 mg/100 mL (10 mg/mL) latex-free plastic bag - dosage for this protocol is 15mg/kg/dose IV four times a day for 3 days |
| Measure | Description | Time Frame |
|---|---|---|
| Composite of pre-discharge mortality or any grade BPD | Need for oxygen or positive pressure respiratory support at 36 weeks postmenstrual age (PMA) | 36 weeks PMA |
| Measure | Description | Time Frame |
|---|---|---|
| PDA treatment success | Defined as PDA closure or becoming insignificant [diameter <1.5 mm] | 6-10 days post treatment initiation |
| Renal or hepatic dysfunction | Renal dysfunction defined as urine output < 1ml/kg/hour for the previous 24 hours or serum creatinine > 100 micromol/L; hepatic dysfunction defined as serum aminotransferase (ALT) > 100 units/L |
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Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Laura Thomas, MSc | Contact | 416-586-4800 | 172060 | laura.thomas@sinaihealth.ca |
| Name | Affiliation | Role |
|---|---|---|
| Amish Jain, MD PhD | MOUNT SINAI HOSPITAL | Principal Investigator |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| John Hunter Hospital | Active, not recruiting | Newcastle | New South Wales | 2300 | Australia | |
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| OTHER_GOV |
| Royal Alexandra Hospital | OTHER |
| Centre de Recheche du Centre Hospitalier Université Laval | OTHER |
| Royal North Shore Hospital | OTHER |
| Prince of Wales Hospital, Shatin, Hong Kong | OTHER |
Pragmatic, multicenter, double-blinded, placebo controlled, parallel, two-armed, superiority randomized trial comparing two treatment regimens for the first treatment course of PDA in ELGANs
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Double-blinded
| Ibuprofen 20 mg/mL oral suspension or Ibuprofen lysine 10 mg/mL injection solution (Neoprofen) | Drug | Ibuprofen is not a study drug - standard of care in participating NICUs in the standard clinical dose for neonates (typically, for neonates < 7 days old - 10 mg/kg/dose on day 1, 5 mg/kg/dose q24h on days 2 and 3; for neonates > 7 days old - 20 mg/kg/dose on day 1, 10 mg/kg/dose q24h on days 2 and 3) |
|
| Sodium chloride 0.9% injection | Other | Placebo- IV q6h for 3 days |
|
| Occurring within 7 days of treatment initiation |
| Further exposure to pharmacological PDA treatments | As per units' standard practice (not part of study procedures) | From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization |
| Procedure for PDA closure | Surgical closure for PDA | From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization |
| Mortality | Death during initial tertiary NICU stay | From date of randomization until date of death (assessed up to a maximum of 250 days after randomization) |
| Severity of BPD at 36 weeks PDM using Jensen's criteria | Grade 1, nasal cannula ≤2 L/min; grade 2, nasal cannula >2 L/min or noninvasive positive airway pressure; grade 3, invasive mechanical ventilation | At 36 weeks PDM |
| NEC ≥ stage 2A | NEC ≥ stage 2A during NICU stay | From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization |
| Duration (days) of invasive or non-invasive respiratory support | Days of invasive or non invasive support during NICU say | From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization |
| Need for diuretic use | Diuretic use for BPD treatment | From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization |
| Need for systemic steroids | Use for BPD treatment | From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization |
| Sepsis | Diagnosis of sepsis during NICU stay | From date of randomization until death, discharge home or discharge to a community hospital (whichever comes first) assessed up to a maximum of 250 days after randomization |
| Royal North Shore Hospital |
| Recruiting |
| St Leonards |
| New South Wales |
| 2065 |
| Australia |
|
| Royal Alexandra Hospital | Recruiting | Edmonton | Ontario | T5H 3V9 | Canada |
|
| McMaster Children's Hospital | Recruiting | Hamilton | Ontario | L8N 3Z5 | Canada |
|
| Sunnybrook Health Sciences Centre | Recruiting | Toronto | Ontario | M4N 3M5 | Canada |
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| Mount Sinai Hospital | Recruiting | Toronto | Ontario | M5G 1X5 | Canada |
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| Centre Hospitalier de l'Université Laval | Not yet recruiting | Québec | Quebec | G1V 4G2 | Canada |
|
| Prince of Wales Hospital | Not yet recruiting | Shatin | NT | Hong Kong |
|
| The Rotunda Hospital | Active, not recruiting | Dublin | Ireland |
| ID | Term |
|---|---|
| D004374 | Ductus Arteriosus, Patent |
| ID | Term |
|---|---|
| D006330 | Heart Defects, Congenital |
| D018376 | Cardiovascular Abnormalities |
| D002318 | Cardiovascular Diseases |
| D006331 | Heart Diseases |
| D000013 | Congenital Abnormalities |
| D009358 | Congenital, Hereditary, and Neonatal Diseases and Abnormalities |
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| ID | Term |
|---|---|
| D000082 | Acetaminophen |
| D007052 | Ibuprofen |
| D013535 | Suspensions |
| D012965 | Sodium Chloride |
| ID | Term |
|---|---|
| D000083 | Acetanilides |
| D000813 | Anilides |
| D000577 | Amides |
| D009930 | Organic Chemicals |
| D000814 | Aniline Compounds |
| D000588 | Amines |
| D010666 | Phenylpropionates |
| D000146 | Acids, Carbocyclic |
| D002264 | Carboxylic Acids |
| D003102 | Colloids |
| D045424 | Complex Mixtures |
| D004304 | Dosage Forms |
| D004364 | Pharmaceutical Preparations |
| D002712 | Chlorides |
| D006851 | Hydrochloric Acid |
| D017606 | Chlorine Compounds |
| D007287 | Inorganic Chemicals |
| D017670 | Sodium Compounds |
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