Trial Outcomes & Findings for Overcoming Membrane Transporters to Improve CNS Drug Delivery - Improving Brain Antioxidants After Traumatic Brain Injury (NCT NCT01322009)

NCT ID: NCT01322009

Last Updated: 2016-08-15

Results Overview

The number of patients experiencing one or more of the following adverse events: Acute renal failure Anaphylaxis Acute respiratory distress syndrome Intracranial infection/abscess Arrhythmia, atrial Arrhythmia, ventricular Bradycardia Cardiac arrest Catheter positive culture Cerebrospinal fluid leak Decubitis Deep vein thrombosis Diabetes Insipidus Emesis Extraaxial hematoma Gastrointestinal bleed Gastritis Hematuria Hemorrhage, other Hemoperitonium Hemothorax Hepatitis Hydrocephalus Hypotension Hypoxemia Infection, other Intraparenchymal hemorrhage Intraventricular hemorrhage Meningitis/ventriculitis Multiorgan dysfunction syndrome Myocardial ischemia Pancreatitis Pericarditis Peritonitis Pneumothorax Pulmonary edema Pulmonary embolism Respiratory arrest Seizures Sepsis Syndrome of inappropriate antidiuretic hormone Transtentorial herniation Withdrawal of Life Support Other SAE causing re-hospitalization Other SAE

• Recruitment status: COMPLETED
• Study phase: PHASE1/PHASE2
• Target enrollment: 14 participants
• Primary outcome timeframe: 14 days after drug administration
• Results posted on: 2016-08-15

Participant Flow

Children 2-18 years-of-age after severe TBI (Glasgow Coma Scale [GCS] score ≤8) recruited from November 2011-September 2013 at a single, tertiary Children's Hospital.

Participant milestones

Measure	Drug Probenecid and N-acetyl cysteine will be administered at standard doses for the first 4 days after TBI. Probenecid and N-acetyl cysteine: After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days or to receive placebos.	Placebo Placebos will be prepared for the two experimental drugs and administered at identical time periods. Placebo: After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days. Placebo contents include equal volumes and dosing regimens of lactose powder (for opacity) suspended in Ora-Plus and normal saline.
Overall Study STARTED	7	7
Overall Study COMPLETED	7	4
Overall Study NOT COMPLETED	0	3

Reasons for withdrawal

Measure	Drug Probenecid and N-acetyl cysteine will be administered at standard doses for the first 4 days after TBI. Probenecid and N-acetyl cysteine: After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days or to receive placebos.	Placebo Placebos will be prepared for the two experimental drugs and administered at identical time periods. Placebo: After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days. Placebo contents include equal volumes and dosing regimens of lactose powder (for opacity) suspended in Ora-Plus and normal saline.
Overall Study Death	0	1
Overall Study Adverse Event	0	1
Overall Study ng tube discontinued	0	1

Baseline Characteristics

Overcoming Membrane Transporters to Improve CNS Drug Delivery - Improving Brain Antioxidants After Traumatic Brain Injury

Baseline characteristics by cohort

Measure	Drug n=7 Participants Probenecid and N-acetyl cysteine will be administered at standard doses for the first 4 days after TBI. Probenecid and N-acetyl cysteine: After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days or to receive placebos.	Placebo n=7 Participants Placebos will be prepared for the two experimental drugs and administered at identical time periods. Placebo: After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days. Placebo contents include equal volumes and dosing regimens of lactose powder (for opacity) suspended in Ora-Plus and normal saline.	Total n=14 Participants Total of all reporting groups
Age, Categorical <=18 years	7 Participants n=5 Participants	7 Participants n=7 Participants	14 Participants n=5 Participants
Age, Categorical Between 18 and 65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Categorical >=65 years	0 Participants n=5 Participants	0 Participants n=7 Participants	0 Participants n=5 Participants
Age, Continuous	8.6 years STANDARD_DEVIATION 4.9 • n=5 Participants	9.7 years STANDARD_DEVIATION 5.7 • n=7 Participants	9.1 years STANDARD_DEVIATION 5.1 • n=5 Participants
Sex: Female, Male Female	1 Participants n=5 Participants	3 Participants n=7 Participants	4 Participants n=5 Participants
Sex: Female, Male Male	6 Participants n=5 Participants	4 Participants n=7 Participants	10 Participants n=5 Participants
Region of Enrollment United States	7 participants n=5 Participants	7 participants n=7 Participants	14 participants n=5 Participants

PRIMARY outcome

Timeframe: 14 days after drug administration

The number of patients experiencing one or more of the following adverse events:

Acute renal failure Anaphylaxis Acute respiratory distress syndrome Intracranial infection/abscess Arrhythmia, atrial Arrhythmia, ventricular Bradycardia Cardiac arrest Catheter positive culture Cerebrospinal fluid leak Decubitis Deep vein thrombosis Diabetes Insipidus Emesis Extraaxial hematoma Gastrointestinal bleed Gastritis Hematuria Hemorrhage, other Hemoperitonium Hemothorax Hepatitis Hydrocephalus Hypotension Hypoxemia Infection, other Intraparenchymal hemorrhage Intraventricular hemorrhage Meningitis/ventriculitis Multiorgan dysfunction syndrome Myocardial ischemia Pancreatitis Pericarditis Peritonitis Pneumothorax Pulmonary edema Pulmonary embolism Respiratory arrest Seizures Sepsis Syndrome of inappropriate antidiuretic hormone Transtentorial herniation Withdrawal of Life Support Other SAE causing re-hospitalization Other SAE

Outcome measures

Measure	Drug n=7 Participants Probenecid and N-acetyl cysteine will be administered at standard doses for the first 4 days after TBI. Probenecid and N-acetyl cysteine: After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days or to receive placebos.	Placebo n=7 Participants Placebos will be prepared for the two experimental drugs and administered at identical time periods. Placebo: After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days. Placebo contents include equal volumes and dosing regimens of lactose powder (for opacity) suspended in Ora-Plus and normal saline.
Number of Participants Who Experienced Adverse Events	0 participants	2 participants

SECONDARY outcome

Timeframe: Within 5 days of injury

Antioxidant reserves in CSF and serum will be calculated in both treatment arms and compared.

Outcome measures

Measure	Drug n=7 Participants Probenecid and N-acetyl cysteine will be administered at standard doses for the first 4 days after TBI. Probenecid and N-acetyl cysteine: After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days or to receive placebos.	Placebo n=7 Participants Placebos will be prepared for the two experimental drugs and administered at identical time periods. Placebo: After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days. Placebo contents include equal volumes and dosing regimens of lactose powder (for opacity) suspended in Ora-Plus and normal saline.
Antioxidant Reserve	751 reactive oxygen species scavenged Standard Error 85	735 reactive oxygen species scavenged Standard Error 117

Adverse Events

Drug

Serious events: 0 serious events

Other events: 0 other events

Deaths: 0 deaths

Placebo

Serious events: 1 serious events

Other events: 1 other events

Deaths: 0 deaths

Serious adverse events

Measure	Drug n=7 participants at risk Probenecid and N-acetyl cysteine will be administered at standard doses for the first 4 days after TBI. Probenecid and N-acetyl cysteine: After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days or to receive placebos.	Placebo n=7 participants at risk Placebos will be prepared for the two experimental drugs and administered at identical time periods. Placebo: After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days. Placebo contents include equal volumes and dosing regimens of lactose powder (for opacity) suspended in Ora-Plus and normal saline.
Nervous system disorders death	0.00% 0/7	14.3% 1/7 • Number of events 1

Other adverse events

Measure	Drug n=7 participants at risk Probenecid and N-acetyl cysteine will be administered at standard doses for the first 4 days after TBI. Probenecid and N-acetyl cysteine: After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days or to receive placebos.	Placebo n=7 participants at risk Placebos will be prepared for the two experimental drugs and administered at identical time periods. Placebo: After obtaining written parental consent, patients will be randomized by the use of a blind envelope system to one of the following: to receive probenecid (initial: 25 mg/kg/dose; maintenance: 10mg/kg/dose 4 x per day for 11 doses) and NAC (initial: 140mg/kg/dose; maintenance: 70mg/kg/dose 6 x per day for 17 doses) or the placebo via nasogastric (NG) or orogastric (OG) tube for 3 days. Placebo contents include equal volumes and dosing regimens of lactose powder (for opacity) suspended in Ora-Plus and normal saline.
Skin and subcutaneous tissue disorders rash	0.00% 0/7	14.3% 1/7 • Number of events 1

Additional Information

Robert Clark

University of Pittsburgh

Phone: 412-692-7260

Email: clarkrs@ccm.upmc.edu

Results disclosure agreements

• Principal investigator is a sponsor employee
• Publication restrictions are in place