Overcoming Membrane Transporters to Improve CNS Drug Delivery - Improving Brain Antioxidants After Traumatic Brain Injury (Pro-NAC)
Overcoming Membrane Transporters to Improve CNS Drug Delivery
The overall purpose of this research study is to investigate the safety of pharmacological therapies that may potentially improve pediatric outcomes after traumatic brain injury. Traumatic brain injuries are the leading cause of death and disability among children and young adults.
Hypothesis: Combinational therapy with a membrane transporter and antioxidant are safe after TBI and can overcome barriers to the brain and synergistically improve bioavailability and efficacy the antioxidant content of the body and CNS after TBI.
調査の概要
詳細な説明
Specific Aim: Define the capacity of the combination of probenecid and NAC to safely and synergistically preserve levels of GSH and reduce oxidative stress in children with severe TBI. We will enroll 20 children age 2 to less than 18 years old (less than 216 months) after severe TBI in a randomized, controlled study of administration of the combinational therapy and test if the administration of these drugs is safe and if antioxidant reserve can be preserved within the serum and CSF.
Probenecid (at the same dose that is used as an adjunct to antibiotic therapy) and NAC (at the same dose that is used for acetaminophen-induced liver disease), or vehicles will be given for 3 days. The primary outcomes of the study will be the safety of drug administration and the CSF and serum levels anti-oxidant reserve (AOR), with the presumption that maintaining anti-oxidant levels within the brain may prove neuroprotective. Other secondary outcomes (CSF and serum probenecid, NAC, GSH and phenytoin concentrations) will also be tested. Adverse events occuring during treatment with these drugs after TBI will be monitored by a local Data Safety Monitoring Board.
研究の種類
入学 (実際)
段階
- フェーズ2
- フェーズ 1
連絡先と場所
研究場所
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Pennsylvania
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Pittsburgh、Pennsylvania、アメリカ、15213
- Children's Hospital of Pittsburgh of UPMC
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参加基準
適格基準
就学可能な年齢
健康ボランティアの受け入れ
受講資格のある性別
説明
Inclusion Criteria:
- Children (age 2 - 18 y) with severe TBI (GCS < or = 8) with an externalized ventricular drain placed for measurement of intracranial pressure
Exclusion Criteria:
- Brain dead on admission to ICU
- Pregnancy
- Contraindications to enteral medications
Contraindications to probenecid:
- status epilepticus
- blood dyscrasias
- under 2 years-of-age
- coadministration of salicylates
- renal dysfunction or urate kidney stones
- hypersensitivity to probenecid
- Contraindications to N-acetylcysteine: hypersensitivity to N-acetylcysteine
- Family unwilling to consent
研究計画
研究はどのように設計されていますか？
デザインの詳細
- 主な目的：処理
- 割り当て：ランダム化
- 介入モデル：並列代入
- マスキング：4倍
武器と介入
参加者グループ / アーム |
介入・治療 |
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実験的：Drug
Probenecid and N-acetyl cysteine will be administered at standard doses for the first 4 days after TBI.
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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.
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プラセボコンパレーター：Placebo
Placebos will be prepared for the two experimental drugs and administered at identical time periods.
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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.
他の名前：
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この研究は何を測定していますか？
主要な結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Number of Participants Who Experienced Adverse Events
時間枠：14 days after drug administration
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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 |
14 days after drug administration
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二次結果の測定
結果測定 |
メジャーの説明 |
時間枠 |
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Antioxidant Reserve
時間枠：Within 5 days of injury
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Antioxidant reserves in CSF and serum will be calculated in both treatment arms and compared.
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Within 5 days of injury
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協力者と研究者
スポンサー
協力者
捜査官
- 主任研究者：Michael J Bell, MD、University of Pittsburgh
- スタディディレクター：Robert SB Clark, MD、University of Pittsburgh
出版物と役立つリンク
一般刊行物
- Hagos FT, Empey PE, Wang P, Ma X, Poloyac SM, Bayir H, Kochanek PM, Bell MJ, Clark RSB. Exploratory Application of Neuropharmacometabolomics in Severe Childhood Traumatic Brain Injury. Crit Care Med. 2018 Sep;46(9):1471-1479. doi: 10.1097/CCM.0000000000003203.
- Clark RSB, Empey PE, Bayir H, Rosario BL, Poloyac SM, Kochanek PM, Nolin TD, Au AK, Horvat CM, Wisniewski SR, Bell MJ. Phase I randomized clinical trial of N-acetylcysteine in combination with an adjuvant probenecid for treatment of severe traumatic brain injury in children. PLoS One. 2017 Jul 7;12(7):e0180280. doi: 10.1371/journal.pone.0180280. eCollection 2017.
研究記録日
主要日程の研究
研究開始
一次修了 (実際)
研究の完了 (実際)
試験登録日
最初に提出
QC基準を満たした最初の提出物
最初の投稿 (見積もり)
学習記録の更新
投稿された最後の更新 (見積もり)
QC基準を満たした最後の更新が送信されました
最終確認日
詳しくは
この情報は、Web サイト clinicaltrials.gov から変更なしで直接取得したものです。研究の詳細を変更、削除、または更新するリクエストがある場合は、register@clinicaltrials.gov。 までご連絡ください。 clinicaltrials.gov に変更が加えられるとすぐに、ウェブサイトでも自動的に更新されます。
小児外傷性脳損傷の臨床試験
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