Dose Escalation Study of Intravenous Baclofen in Healthy Adult Volunteers

Study Overview
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Brief Summary
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The objective of this study is to determine safety and characterize pharmacokinetics of higher doses of intravenous baclofen in healthy subjects. Thirty-six healthy adults received a single dose of PO baclofen (10mg, 15mg or 20mg) and a 10-minute infusion of IV baclofen (7.5mg, 11.5mg or 15mg respectively) with a minimum 48-hour wash out period. Twelve subjects also received a 60-minute infusion of 15mg IV baclofen following an additional 48-hour wash out period. The pharmacokinetic and tolerability information gained from this study will support the development of further studies to assess the use of IV baclofen to prevent or treat baclofen withdrawal syndrome.

Detailed Description
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This randomized, open-label, dose escalation, crossover study was conducted at a contract clinical research facility. Three single doses were evaluated using three cohorts (N=12 per cohort). Study doses were as follows: cohort 1 - 7.5mg IV and 10mg PO, cohort 2 - 11.5mg IV and 15mg PO, and cohort 3 - 15mg IV and 20mg PO. The IV baclofen doses for this trial were based on a 75% bioavailability observed in a previous low dose study.16 The oral formulation of the study drug used in this trial was 10mg baclofen tablet (Teva Pharmaceutical Industries Ltd.) and is commercially available. The intravenous formulation was 2mg/mL solution manufactured by Aptuit LLC. for this study. IV infusions were administered over 10 minutes. In addition, cohort 3 received 15mg over a 60-minute infusion. There was a minimum 48-hour washout period between doses. Initially, 3 subjects received study drug at a given dose, after assessing the safety and tolerance of baclofen the additional 9 subjects received study drug.

Official Title
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Prevention of Baclofen Withdrawal Syndrome: Dose Escalation Study of Intravenous Baclofen in Healthy Adult Volunteers

Conditions
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Safety and Pharmacokinetics of Intravenous Baclofen

Intervention / Treatment
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* Drug: Intravenous baclofen


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females between the ages of 18-65. Subjects are capable of giving informed consent. Female subjects must be post-menopausal for at least 1 year, or surgically incapable of bearing children, or practicing at least one or more of the following methods of contraception for three months prior to, and during the study: hormonal, intrauterine device (IUD), or barrier method in combination with a spermicide. Subject should be medication free, other than hormonal birth control, for 48 hours before through 24 hours after study drug administration. If the need for medication is identified during this time period, it will be discussed with and approved by the PI. Exclusion Criteria: Women who are pregnant. Women who are breastfeeding. Subject has a history of intolerance to IV administration of medication. Subject has a known hypersensitivity to baclofen. Subject has a significant history of cardiac, neurologic, psychiatric, oncologic, endocrine, metabolic, renal or hepatic disease Subject has taken or used any investigational drug or device in the 30 days prior to screening. Subject has taken either prescribed or over the counter medication for 48 hours prior to baclofen administration on either of the study days, other than hormonal birth control. Subject reveals clinically significant abnormalities on screening laboratory tests. Subject is a non-English speaker, such that ability to ascertain neurological status would require an interpreter. Sleep deprivation (for example. working the night shift the evening prior to the study).

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 65 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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Accepts Healthy Volunteers

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Intravenous Baclofen<br>Three single doses were evaluated using three cohorts (N=12 per cohort). Subjects received single doses of baclofen: 7.5, 11.5 or 15mg 10-minute intravenous infusion administered over 10 minutes by an infusion pump and 10, 15, or 20mg taken orally with a 48-hour washout phase between oral and intravenous arms of the study. Initially, 3 subjects received study drug at a given dose, after assessing the safety and tolerance of baclofen the additional 9 subjects received study drug. | Drug: Intravenous baclofen<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety assessments | Blood Pressure & Pulse: Recorded every 5 minutes immediately prior to, and during the IV infusion, then every 15 minutes for 1 hour, then every hour for 12 hours. Assessment of sedation / sleepiness: Subjects will be assessed by using the sleepiness scale prior to drug administration then every 30 minutes for four hours after drug administration. Ataxia and nystagmus: Measured using the following rating scale and definitions of ataxia and nystagmus. 0=none, 1=mild, 2=severe Ataxia: For those who are ambulatory, this will be assessed by gait. Ratings will be: mild-unsteady with tandem gait testing, but able to perform without assistance severe-unable to perform gait testing without assistance. For non-ambulatory subjects, ataxia will be assessed by finger to nose and finger pursuit maneuvers. Nystagmus: mild-present on extreme gaze; severe-present on midline gaze | Upto 24 hours following drug administration | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Concentration(Cmax) | Cmax: Cmax is the maximum baclofen concentration observed | Upto 24 hours following drug administration | 
| AUC(0-inf) | AUC(0-inf): Area under the plasma concentration-versus-time curve from time zero to infinity | Upto 24 hours after drug administration | 
| Plasma Decay Half-life (T1/2) | Plasma Decay Half-life(T1/2): Plasma decay half-life is the time measured for the plasma concentration to decrease by one half | Up to 24 hours after drug administration | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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baclofen withdrawal, interruption, spasticity, pharmacokinetics, tolerability, intravenous