Dose Escalation Study of Intravenous Baclofen in Healthy Adult Volunteers

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

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.

Study Overview

• Status: Completed
• Conditions: Safety and Pharmacokinetics of Intravenous Baclofen
• Intervention / Treatment: Drug: Intravenous baclofen

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 39
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Minnesota
    • Minneapolis, Minnesota, United States, 55455
      • University of Minnesota

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 65 years (ADULT, OLDER_ADULT)
• Accepts Healthy Volunteers: Yes
• Genders Eligible for Study: All

Description

Inclusion Criteria:

1. Males and females between the ages of 18-65.
2. Subjects are capable of giving informed consent.
3. 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.
4. 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:

1. Women who are pregnant.
2. Women who are breastfeeding.
3. Subject has a history of intolerance to IV administration of medication.
4. Subject has a known hypersensitivity to baclofen.
5. Subject has a significant history of cardiac, neurologic, psychiatric, oncologic, endocrine, metabolic, renal or hepatic disease
6. Subject has taken or used any investigational drug or device in the 30 days prior to screening.
7. 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.
8. Subject reveals clinically significant abnormalities on screening laboratory tests.
9. Subject is a non-English speaker, such that ability to ascertain neurological status would require an interpreter.
10. Sleep deprivation (for example. working the night shift the evening prior to the study).

Study Plan

How is the study designed?

Design Details

• Primary Purpose: TREATMENT
• Allocation: NA
• Interventional Model: SINGLE_GROUP
• Masking: NONE

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

EXPERIMENTAL: Intravenous Baclofen; 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

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: University of Minnesota
• Collaborators: Paralyzed Veterans of America Research Foundation
• Investigators: Principal Investigator: Robert L Kriel, MD, University of Minnesota; Principal Investigator: Linda E Krach, MD, University of Minnesota

Study record dates

Study Major Dates

• Study Start: January 1, 2014
• Primary Completion (ACTUAL): June 1, 2014
• Study Completion (ACTUAL): June 1, 2014

Study Registration Dates

• First Submitted: August 14, 2013
• First Submitted That Met QC Criteria: August 22, 2013
• First Posted (ESTIMATE): August 29, 2013

Study Record Updates

• Last Update Posted (ACTUAL): May 7, 2019
• Last Update Submitted That Met QC Criteria: May 3, 2019
• Last Verified: May 1, 2019

More Information

Terms related to this study

• Keywords: tolerability; pharmacokinetics; spasticity; intravenous; interruption; baclofen withdrawal
• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Peripheral Nervous System Agents; GABA Agents; Neuromuscular Agents; Muscle Relaxants, Central; GABA Agonists; GABA-B Receptor Agonists; Baclofen
• Other Study ID Numbers: Baclofen_Dose escalation