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Overcoming Membrane Transporters to Improve CNS Drug Delivery - Improving Brain Antioxidants After Traumatic Brain Injury (Pro-NAC)

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ClinicalTrials.gov Identifier: NCT01322009
Recruitment Status : Completed
First Posted : March 24, 2011
Results First Posted : August 15, 2016
Last Update Posted : August 15, 2016
Sponsor:
Collaborators:
National Institutes of Health (NIH)
National Institute of Neurological Disorders and Stroke (NINDS)
Information provided by (Responsible Party):
Robert Clark, MD, University of Pittsburgh

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor);   Primary Purpose: Treatment
Condition Pediatric Traumatic Brain Injury
Interventions Drug: Probenecid and N-acetyl cysteine
Drug: Placebo
Enrollment 14
Recruitment Details 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.
Pre-assignment Details  
Arm/Group Title Drug Placebo
Hide Arm/Group Description

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.

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.

Period Title: Overall Study
Started 7 7
Completed 7 4
Not Completed 0 3
Reason Not Completed
Death             0             1
Adverse Event             0             1
ng tube discontinued             0             1
Arm/Group Title Drug Placebo Total
Hide Arm/Group Description

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.

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 of all reporting groups
Overall Number of Baseline Participants 7 7 14
Hide Baseline Analysis Population Description
[Not Specified]
Age, Categorical  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 14 participants
<=18 years
7
 100.0%
7
 100.0%
14
 100.0%
Between 18 and 65 years
0
   0.0%
0
   0.0%
0
   0.0%
>=65 years
0
   0.0%
0
   0.0%
0
   0.0%
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 7 participants 7 participants 14 participants
8.6  (4.9) 9.7  (5.7) 9.1  (5.1)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 7 participants 7 participants 14 participants
Female
1
  14.3%
3
  42.9%
4
  28.6%
Male
6
  85.7%
4
  57.1%
10
  71.4%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United States Number Analyzed 7 participants 7 participants 14 participants
7 7 14
1.Primary Outcome
Title Number of Participants Who Experienced Adverse Events
Hide Description

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

Time Frame 14 days after drug administration
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Drug Placebo
Hide Arm/Group Description:

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.

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 Number of Participants Analyzed 7 7
Measure Type: Number
Unit of Measure: participants
0 2
2.Secondary Outcome
Title Antioxidant Reserve
Hide Description Antioxidant reserves in CSF and serum will be calculated in both treatment arms and compared.
Time Frame Within 5 days of injury
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Drug Placebo
Hide Arm/Group Description:

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.

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 Number of Participants Analyzed 7 7
Mean (Standard Error)
Unit of Measure: reactive oxygen species scavenged
751  (85) 735  (117)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Drug, Placebo
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value >0.05
Comments [Not Specified]
Method ANOVA
Comments Analysis run over study period but data entered only for the 6 h time point
Time Frame [Not Specified]
Adverse Event Reporting Description [Not Specified]
 
Arm/Group Title Drug Placebo
Hide Arm/Group Description

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.

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.

All-Cause Mortality
Drug Placebo
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--      --/--    
Show Serious Adverse Events Hide Serious Adverse Events
Drug Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/7 (0.00%)      1/7 (14.29%)    
Nervous system disorders     
death  0/7 (0.00%)  0 1/7 (14.29%)  1
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Drug Placebo
Affected / at Risk (%) # Events Affected / at Risk (%) # Events
Total   0/7 (0.00%)      1/7 (14.29%)    
Skin and subcutaneous tissue disorders     
rash  0/7 (0.00%)  0 1/7 (14.29%)  1
Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Robert Clark
Organization: University of Pittsburgh
Phone: 412-692-7260
Responsible Party: Robert Clark, MD, University of Pittsburgh
ClinicalTrials.gov Identifier: NCT01322009     History of Changes
Other Study ID Numbers: NS069247
1R01NS069247-01 ( U.S. NIH Grant/Contract )
First Submitted: March 22, 2011
First Posted: March 24, 2011
Results First Submitted: May 19, 2016
Results First Posted: August 15, 2016
Last Update Posted: August 15, 2016