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Effects of GABA Modulator AZD7325 on Cortical Excitability

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ClinicalTrials.gov Identifier: NCT02135198
Recruitment Status : Completed
First Posted : May 9, 2014
Last Update Posted : August 28, 2015
Sponsor:
Information provided by (Responsible Party):
University College, London

Brief Summary:

GABA (gamma-aminobutyric acid) is the main inhibitory compound in the human brain. Drugs that enhance its effects by binding on GABA receptors (e.g., benzodiazepines) are used to treat various diseases such as epilepsy, insomnia, anxiety or movement disorders. However, the use of these medications is often compromised due to their side effects, like sedation, cognitive impairment, and addiction.

Many of these side effects have been linked to a particular type of GABA receptor (GABA A alpha 1). Therefore, effort is being made to develop drugs that do not act on this receptor, but maintain their beneficial properties by acting on other types of GABA receptors. AZD7325 is a drug that selectively acts on GABA A alpha 2 and A alpha 3 receptors, but not A alpha 1. It has been tested in more than 700 people and so far proved to be generally well tolerated. Positron emission tomography (PET) study in humans demonstrated that AZD7325 binds to GABA A receptors in the brain after a single dose. Early clinical studies have shown that it has less sedative and cognitive adverse events as compared with a benzodiazepine lorazepam.

In this study, we will investigate its effects on short interval intracortical inhibition (SICI). SICI is neurophysiological marker of inhibitory processes in the motor cortex. It is obtained non-invasively by using transcranial magnetic stimulation (TMS). In TMS, magnetic impulses applied over the scalp that in turn induce a current in a small area of the brain. If applied over the motor areas of the brain, impulses result in muscle twitch that is recorded with surface electrodes. SICI is enhanced by certain drugs like benzodiazepines that act on GABA A alpha 1,2,3, and 5 receptor subtypes, but not by zolpidem acting solely on alpha 1 subtype. Because GABA A alpha 5 receptor subtype is less common in the cortex, it has been concluded that the drug effects on SICI are related to GABA A alpha 2 and alpha 3 receptors.

If AZD7325 proves to enhance SICI in healthy volunteers, this would create the grounds for the use of this medication to treat certain neurological disorders in which SICI has been found to be impaired (e.g., dystonia).


Condition or disease Intervention/treatment Phase
Healthy Drug: 2 mg AZD7325 Drug: 10 mg AZD7325 Drug: Placebo Phase 1

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 12 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double (Participant, Investigator)
Primary Purpose: Basic Science
Official Title: A Phase I Single Site, Single Dose, Randomised, Double-blind, Placebo Controlled 3-way Cross-over Biomarker Study Investigating the Effect of the GABA Modulator AZD7325 on Short Interval Intracortical Inhibition (SICI) in Healthy Volunteers
Study Start Date : September 2014
Actual Primary Completion Date : August 2015
Actual Study Completion Date : August 2015

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: 2 mg AZD7325
2 mg AZD7325 in orange capsule, Size 0, single oral dose
Drug: 2 mg AZD7325
A single 2 mg oral dose of AZD7325

Drug: 10 mg AZD7325
A single 10 mg oral dose of AZD7325

Drug: Placebo
A single oral dose

Experimental: 10 mg AZD7325
10 mg AZD7325 in orange capsule, Size 0, singe oral dose
Drug: 2 mg AZD7325
A single 2 mg oral dose of AZD7325

Drug: 10 mg AZD7325
A single 10 mg oral dose of AZD7325

Drug: Placebo
A single oral dose

Placebo Comparator: Placebo
10 mg Microcrystalline cellulose in orange capsule, Size 0, single oral dose
Drug: 2 mg AZD7325
A single 2 mg oral dose of AZD7325

Drug: 10 mg AZD7325
A single 10 mg oral dose of AZD7325

Drug: Placebo
A single oral dose




Primary Outcome Measures :
  1. Change in conventional measure of percentage short interval intracortical inhibition (SICI) at an interstimulus interval (ISI) of 2.5 ms and conditioning stimulus intensity of 70 percent of resting motor threshold [ Time Frame: baseline at 1, 2, and 8 hours after the study medication. ]

Secondary Outcome Measures :
  1. Change in the variables of kinematic analysis of circle drawing [ Time Frame: baseline at 1, 2, and 8 hours after the study medication ]
  2. Change in the rating on a 0-100 mm Visual Analogue Scale (VAS) of degree of sedation and the score of Symbol Digit Modalities Test (SDMT) [ Time Frame: baseline at 1, 2, and 8 hours after the study medication ]
  3. Safety and tolerability of a single dose of AZD7325 by assessment of adverse events, vital signs, physical examination, ECG, and laboratory variables [ Time Frame: 4 times ( before each dose and 48-96 hours after the last dose of study medication). Adverse events also at follow-up telephone call within a week after the last dose of study medication ]

Other Outcome Measures:
  1. The change in the area under the curve of short interval intracortical inhibition (SICI) slope recruitment using conditioning stimulus intensities of 50, 60, 70, and 80 percent of resting motor threshold [ Time Frame: baseline at 1, 2, and 8 hours after the study medication ]


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Ages Eligible for Study:   18 Years to 55 Years   (Adult)
Sexes Eligible for Study:   Male
Accepts Healthy Volunteers:   Yes
Criteria

Inclusion Criteria:

  • Male adults aged 18 to 55 years (extremes are included)
  • A body weight resulting in a body mass index (BMI) of 18 - 30 kg/m2 (extremes included) using the formula BMI = body-weight [in kg] / body-height [in m]2
  • Able and willing to sign the Informed Consent Form prior to screening evaluations
  • History of good physical and mental health as determined by history taking and laboratory examinations, ECG, blood pressure and heart rate recordings as judged by the investigator
  • Willing not to consume alcohol or to smoke or chew tobacco on days of assessments
  • Subjects must be willing to avoid unprotected sex or donating sperm until 3 weeks after drug administration

Exclusion Criteria:

  • History of sensitivity/idiosyncrasy to AZD7325 or chemically related compounds or excipients which may be employed in the study or to any other drug used in the past
  • Subject has taken systemically any potent or moderate CYP3A4 or CYP2C9 inhibitor, 1 month prior to screening (topical or inhaled are permitted) such as: aprepitant, barbiturates, carbamazepine, clarithromycin, erythromycin, cyclosporine, diltiazem, efavirenz, fluconazole, HIV protease inhibitors, glucocorticoids, itraconazole (oral/IV), ketoconazole, nefazodone, nevirapine, phenytoin, pioglitazone, primidone, rifabutin, rifampicin, telithromycin, St. John's wort, verapamil
  • Use of any prescription drug within two weeks prior to the first dosing, except for topical medication without systemic exposure
  • Clinically relevant history or presence of any medical disorder, potentially interfering with this trial
  • Clinically relevant abnormal laboratory, ECG, HR or BP at screening as judged by the investigator
  • History of or current abuse of drugs (including prescription medication) or alcohol or solvents
  • Smoking in excess of 5 cigarettes per day or the equivalent within 28 days prior to the first study day
  • Smoking or chewing of tobacco or consuming of alcohol 24 hours before and on the days of assessment
  • Subject is family member or in the employment line management of study personnel
  • Subject's partner is planning pregnancy within 3 months of last dosing
  • Participation in an investigational medicinal product (IMP) intervention trial within last month or more than four in the previous 12 months
  • Abnormal SICI response, kinematic analysis of circle drawing, SDMT, VAS outside 95% confidence interval of normal at screening visit
  • Contraindications for TMS

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02135198


Locations
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United Kingdom
National Hospital for Neurology and Neurosurgery, UCLH NHS Foundation Trust
London, United Kingdom, WC1N 3BG
Sponsors and Collaborators
University College, London
Investigators
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Principal Investigator: Martin Koltzenburg, Prof Institute of Neurology, University College London
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Responsible Party: University College, London
ClinicalTrials.gov Identifier: NCT02135198    
Other Study ID Numbers: 13/0231
2013-005472-17 ( EudraCT Number )
First Posted: May 9, 2014    Key Record Dates
Last Update Posted: August 28, 2015
Last Verified: April 2015
Keywords provided by University College, London:
GABA modulator
AZD7325
Short interval intracortical inhibition
volunteers