HealthyPhase 1NCT02135198
Effects of GABA Modulator AZD7325 on Cortical Excitability
A Phase 1 study testing 2 mg AZD7325 and 10 mg AZD7325 in people with Healthy, run by University College, London at 1 site in United Kingdom.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 55 years, men onlyHealthy volunteers can take part
- Conditions the study is for
- Healthy
- What is being tested?
- 2 mg AZD7325 and 10 mg AZD7325
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 12 participants
- Where
- 1 siteUnited Kingdom
- Study dates
- Sep 2014to Aug 2015
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 55 years
- Men only
- Healthy volunteers accepted
- Adult
Who may be able to join
- 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
Who cannot join
- 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
Show all 13Show fewer
- 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
Trial locations and contacts
1 site in 1 country.
United Kingdom1 site
National Hospital for Neurology and Neurosurgery, UCLH NHS Foundation Trust
London, WC1N 3BG
About this study
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
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.
Read more
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).
- Conditions
- Healthy
- Being tested
- 2 mg AZD7325, 10 mg AZD7325, Placebo
- Keywords
- GABA modulator, AZD7325, Short interval intracortical inhibition, volunteers
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
2 mg AZD7325Drug
A single 2 mg oral dose of AZD7325
10 mg AZD7325Drug
A single 10 mg oral dose of AZD7325
PlaceboDrug
A single oral dose
| Study group | Role | What they receive |
|---|---|---|
| 2 mg AZD7325 | Experimental | 2 mg AZD7325 in orange capsule, Size 0, single oral dose Receives: Drug: 2 mg AZD7325; Drug: 10 mg AZD7325; Drug: Placebo |
| 10 mg AZD7325 | Experimental | 10 mg AZD7325 in orange capsule, Size 0, singe oral dose Receives: Drug: 2 mg AZD7325; Drug: 10 mg AZD7325; Drug: Placebo |
| Placebo | Placebo comparator | 10 mg Microcrystalline cellulose in orange capsule, Size 0, single oral dose Receives: Drug: 2 mg AZD7325; Drug: 10 mg AZD7325; Drug: Placebo |
What is being measured
The primary outcome is the main question the study is designed to answer.
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
Measured: baseline at 1, 2, and 8 hours after the study medication.
Secondary outcomes (3)
Change in the variables of kinematic analysis of circle drawing
Measured: baseline at 1, 2, and 8 hours after the study medication
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)
Measured: baseline at 1, 2, and 8 hours after the study medication
Safety and tolerability of a single dose of AZD7325 by assessment of adverse events, vital signs, physical examination, ECG, and laboratory variables
Measured: 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
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted9 May 2014 (estimated)
- Study startSep 2014
- Primary completionAug 2015
- Study completionAug 2015
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for HealthyStudies of the same condition, open and under way.
- More trials run by University College, LondonThe sponsor's other registered studies.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind
- Who is masked
- Participant, Investigator
- Enrolment
- 12 participants (actual)
Sponsor and investigators
- Lead sponsor
- University College, London
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Martin Koltzenburg, Prof, Principal investigator, Institute of Neurology, University College London
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02135198
- Sponsor's protocol ID
- 13/0231
- Other IDs
- 2013-005472-17
- Status last verified
- Apr 2015
- First submitted
- 15 Apr 2014
- Last updated
- 28 Aug 2015
- Results posted
- No
- Data monitoring committee
- Yes
Study at a glance
From the registry record, last updated by the sponsor on 28 Aug 2015. Recruitment status is as the sponsor reported it: confirm with the study team.
- 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
- ClinicalTrials.gov ID
- NCT02135198
- Acronym / sponsor ID
- 13/0231
- Conditions
- Healthy
- Keywords
- GABA modulator, AZD7325, Short interval intracortical inhibition, volunteers
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 12 participants (actual)
- Lead sponsor
- University College, LondonUniversity, hospital or other
- Study start
- Sep 2014
- Primary completion
- Aug 2015 (actual)
- Study completion
- Aug 2015 (actual)
- First posted
- 9 May 2014 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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).
Study design
- Primary purpose
- Basic science
- Allocation
- Randomised
- Intervention model
- Crossover
- Masking
- Double blind (participant, investigator)
- Number of arms
- 3
| Arm | Type | Receives |
|---|---|---|
| 2 mg AZD7325 | Experimental | Drug: 2 mg AZD7325, Drug: 10 mg AZD7325, Drug: Placebo2 mg AZD7325 in orange capsule, Size 0, single oral dose |
| 10 mg AZD7325 | Experimental | Drug: 2 mg AZD7325, Drug: 10 mg AZD7325, Drug: Placebo10 mg AZD7325 in orange capsule, Size 0, singe oral dose |
| Placebo | Placebo comparator | Drug: 2 mg AZD7325, Drug: 10 mg AZD7325, Drug: Placebo10 mg Microcrystalline cellulose in orange capsule, Size 0, single oral dose |
Who may qualify
- Ages
- 18 to 55 years
- Sex
- Male only
- Healthy volunteers
- Accepted
- Age groups
- Adult
Key inclusion criteria (6 listed)
- 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
Key exclusion criteria (13 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| 2 mg AZD7325A single 2 mg oral dose of AZD7325 | Drug | 10 mg AZD7325, 2 mg AZD7325, Placebo |
| 10 mg AZD7325A single 10 mg oral dose of AZD7325 | Drug | 10 mg AZD7325, 2 mg AZD7325, Placebo |
| PlaceboA single oral dose | Drug | 10 mg AZD7325, 2 mg AZD7325, Placebo |
Primary outcome
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.
3 secondary outcomes
Change in the variables of kinematic analysis of circle drawing
Time frame: baseline at 1, 2, and 8 hours after the study medication
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
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
Results and safety
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 28 Aug 2015.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Martin Koltzenburg, Prof principal investigator
Institute of Neurology, University College London
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing 2 mg AZD7325 and 10 mg AZD7325 in people with Healthy, run by University College, London at 1 site in United Kingdom.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 6 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 28 Aug 2015. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
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.). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 28 Aug 2015.