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Clinical Trial Results:
Further development of a new model of GAD: The effect of a clinically effective and non−effective dose of lorazepam on CO2 induced anxiety

Summary
EudraCT number	2006-001085-17
Trial protocol	GB
Global end of trial date	29 Aug 2008

Results information
Results version number	v1(current)
This version publication date	21 Apr 2019
First version publication date	21 Apr 2019
Other versions
Summary report(s)	Publication

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

P1V-S01-03-06

ISRCTN number

US NCT number

WHO universal trial number (UTN)

Sponsor organisation name

University of Bristol

Sponsor organisation address

Queens Road, Bristol, United Kingdom, BS8 1QU

Public contact

Dr Alison Diaper, University of Bristol, alison_diaper@hotmail.com

Scientific contact

Dr Alison Diaper, University of Bristol, alison_diaper@hotmail.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

29 Aug 2008

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

29 Aug 2008

Was the trial ended prematurely?

Main objective of the trial

A human model of GAD will be useful to investigate how GAD symptoms occur, and to test potential medications in healthy volunteers and in patients. To be effective, any potential model needs to reliably reproduce anxiety in healthy people and the degree of anxiety provoked should be repeatable and measurable. In addition the effects of known anxiolytics should mirror those in patients. We have developed a possible model of GAD using the inhalation of increased levels of carbon dioxide (7.5% CO2) for 20 minutes (Bailey et, al 2005). In healthy volunteers, this challenge induces anxiety and increases blood pressure and heart rate. To further validate the 7.5% CO2 challenge as a model of GAD, it is essential to know whether the dose of lorazepam required to alleviate anxiety is similar between subjects in the model and patients with GAD. This model could then be used to test the effectiveness of potential medications on GAD and stress.

Protection of trial subjects

The Psychopharmacology Unit is experienced in managing and conducting human research in patient and healthy volunteer populations. Experience with the effects of inhaling 7.5% CO2 has been obtained from research completed over the last 8 years, using the procedure on hundreds of subjects. The study was performed in accordance with ICH Good Clinical Practice, with approval from the Local Research Ethics Committee (Central and South Bristol Research Ethics Committee), relevant Health Service Trust regulatory approval (United Bristol Healthcare Trust), and the Medicines and Healthcare products Regulatory Agency (MHRA). Approval in writing was received prior to starting the study. Aspects of the Data Protection Act were adhered to. The case report forms were completed and stored appropriately. Data held on the computer were anonymised. Volunteers were recruited using advertisements approved for that reason by the Ethics Committee. After initial contact, the subjects received the Participant Information Sheet and were given at least 48 hours to read it and consider the implications of their participation in the study. They were given the time to raise any questions with the investigators prior to making the decision to participate. Each subject was then asked to give their written informed consent after one of the investigators had explained the nature, purpose and risks of the study, by signing the Informed Consent Forms. A letter was sent to the subjects’ general practitioners informing them of their patients’ participation in the trial. Emergency out-of-hours contact telephone numbers for study medic were given to all participants, and adverse events were recorded during and after test days.

Background therapy

The inhalation of carbon dioxide (CO2) has a lengthy history in psychiatry. The technique of inhaling a low concentration (5-7.5%) of CO2 for 15 or 20 minutes was developed by Gorman et al. (1984) who used 5% CO2 as a control gas for an experiment in which patients with panic disorder were asked to hyperventilate. However, more patients panicked in the CO2 group than the hyperventilation group. This discovery that the inhalation of 5% CO2 produces panic in patients with panic disorder, but not in subjects without anxiety, has been replicated and validated and is a well recognised experimental model. In patients with panic disorder, the anxiety resulting from a CO2 challenge has been shown to be sensitive to treatment with acute and chronic alprazolam (Sanderson et al., 1994; Woods et al., 1986). Although much of the published literature on CO2-induced anxiety has focussed on panic anxiety in patients with panic disorder, recent interest has focussed away from the idea that only patients with panic disorder are sensitive to the effects of CO2. We have recently reported that the inhalation of 7.5% CO2 for 20 minutes in healthy subjects produces an increase in blood pressure and heart rate, and increased feelings of anxiety, fear and tension (Bailey et al., 2005). These results suggest that the inhalation of 7.5% CO2 produces a state that is more like generalized anxiety rather than panic. Also, recent studies by us, and others, have reported that the inhalation of 35% CO2 activates the stress response system in healthy volunteers (Argyropoulos et al., 2002; Kaye et al., 2004; van Duinen et al., 2005).

Evidence for comparator

Bailey et al. (2005) have postulated that the state produced by inhalation of 7.5% CO2 is more like that seen in a state of generalised anxiety, rather than a panic attack. This hypothesis was further explored using two proven anxiolytic therapies for GAD: a benzodiazepine (lorazepam) and a selective serotonin reuptake inhibitor (SSRI; paroxetine; Bailey et al., 2007). Benzodiazepine agonists effectively treat acute anxiety, whereas SSRls are commonly used for longer periods to treat both panic and generalised anxiety disorder. New research has shown that drugs acting on the GABAA receptor may be effective in attenuating 7.5% CO2-induced anxiety more than other anxiolytics (Bailey et al., 2009). It is unclear if these drug effects on the CO2 challenge are general or dose-dependent. This study was therefore conducted to determine the dose-¬related effects of 0.5mg (considered not clinically effective) and 2.0mg (clinically effective) of the benzodiazepine lorazepam on anxiety induced by inhalation of 7.5% CO2 for 20 minutes.

Actual start date of recruitment

09 May 2008

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

United Kingdom: 18

Worldwide total number of subjects

EEA total number of subjects

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

From 65 to 84 years

85 years and over

Subject disposition

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Recruitment details

Subjects were recruited using existing databases at the Psychopharmacology Unit, University of Bristol (UoB), via advertisements on the UoB careers website, and posters around the UoB.

Screening details

99 participants made contact, 89 PISs sent out, 43 screened by telephone (basic information about smoking and drinking habits, estimated height and weight, and illnesses/medications), 37 invited for screening. Screen fails included: taking part in another drugs study, worried about side effects, history or family history of psychiatric problems.

Number of subjects started

99 ^[1]