Clinical Trial Results:
Evaluation of the effects of chronic treatment with venlafaxine (150 mg) and pregabalin (200 mg) on emotional indices of anxiety and panic induced by breathing carbon dioxide.
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Summary
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EudraCT number |
2008-000971-15 |
Trial protocol |
GB |
Global end of trial date |
26 Aug 2009
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Results information
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Results version number |
v1(current) |
This version publication date |
21 Apr 2019
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First version publication date |
21 Apr 2019
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Other versions |
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Summary report(s) |
Publication |
Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information
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Trial identification
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Sponsor protocol code |
P1V-ANX-CT01-07
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
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Other trial identifiers |
NHS REC reference: 08/H0308/298 | ||
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Sponsors
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Sponsor organisation name |
University of Bristol
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Sponsor organisation address |
One Cathedral Square, Bristol, United Kingdom, BS1 5DD
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Public contact |
Dr Alison Diaper, University of Bristol, alison_diaper@hotmail.com
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Scientific contact |
Dr Alison Diaper, University of Bristol, alison_diaper@hotmail.com
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Paediatric regulatory details
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Is trial part of an agreed paediatric investigation plan (PIP) |
No
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Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial? |
No
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Results analysis stage
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Analysis stage |
Final
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Date of interim/final analysis |
09 Sep 2009
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
26 Aug 2009
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Global end of trial reached? |
Yes
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Global end of trial date |
26 Aug 2009
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Was the trial ended prematurely? |
No
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General information about the trial
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Main objective of the trial |
• To determine whether chronic (3 week) venlafaxine dosing reduces the anxiety symptoms induced by breathing a mixture of air and 7.5% carbon dioxide (CO2).
• To determine whether chronic (3 week) pregabalin dosing reduces the anxiety symptoms induced by breathing a mixture of air and 7.5% CO2.
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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 a Research Ethics Committee (Cambridge 2 Research Ethics Committee), relevant Health Service Trust regulatory approval (University Hospitals Bristol NHS 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.
The study was of no direct benefit to the participants involved.
A medic was on call and available to all participants at all times, and two researchers administered the CO2 inhalations.
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Background therapy |
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Evidence for comparator |
In the present study we will investigate the effects of two drugs prescribed to treat GAD, venlafaxine (Effexor®) and pregabalin (Lyrica®), both of which have different mechanisms of actions to the drugs already tested using the CO2 challenge. As both drugs require several weeks of dosing to be effective in treating GAD, the participants in this study will be given a CO2 challenge after chronic dosing. Consequently, participants will be treated for 3 weeks with either venlafaxine or pregabalin prior to undertaking the CO2 challenge test. Venlafaxine is a bicyclic antidepressant, and is usually categorized as a serotonin-noradrenaline reuptake inhibitor (SNRI), however, it has also been referred to as a serotonin- noradrenaline- dopamine- reuptake inhibitor (Goeringer et al., 2001). It works by blocking the transporter "reuptake" proteins for key neurotransmitters affecting mood, thereby leaving more active neurotransmitter in the synapse. The neurotransmitters principally affected are serotonin and noradrenaline. Additionally, in high doses it weakly inhibits the reuptake of dopamine (Wellington and Perry, 2001). Venlafaxine is well absorbed with at least 92% of an oral dose being absorbed into the systemic circulation. The drug is extensively metabolized in the liver via the cytochrome P450 2D6 (CYP2D6) isoenzyme to O-desmethylvenlafaxine. This metabolite is equally potent as a serotonin-noradrenaline reuptake inhibitor as the parent compound, such that the differences in metabolism between extensive and poor metabolisers are not clinically important. Steady-state concentrations of venlafaxine and its metabolite are attained in the blood within three days and therapeutic effects are usually observed within 3-4 weeks. No accumulation of venlafaxine has been observed during chronic administration in healthy participants. | ||
Actual start date of recruitment |
03 Nov 2008
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
No
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Population of trial subjects
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Number of subjects enrolled per country |
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Country: Number of subjects enrolled |
United Kingdom: 60
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Worldwide total number of subjects |
60
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EEA total number of subjects |
60
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Number of subjects enrolled per age group |
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In utero |
0
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Preterm newborn - gestational age < 37 wk |
0
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Newborns (0-27 days) |
0
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Infants and toddlers (28 days-23 months) |
0
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Children (2-11 years) |
0
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Adolescents (12-17 years) |
0
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Adults (18-64 years) |
60
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From 65 to 84 years |
0
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85 years and over |
0
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Recruitment
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Recruitment details |
All respondents to the advertising underwent an initial telephone screening and sent a PIS. Those interested in participating attended for a screening visit to assess eligibility, and give informed to consent to participate if suitable. Participants then attended a baseline visit before for randomisation. | ||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Physical examination, blood exam (biochemistry and haematology), height/weight/blood pressure, neuropsychiatric interview, ECG, alcohol breath test, pregnancy test, urinalysis and urine drugs of abuse test. | ||||||||||||||||||||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
79 [1] | ||||||||||||||||||||||||||||||||||||
Intermediate milestone: Number of subjects |
Screening: 79
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Number of subjects completed |
60 | ||||||||||||||||||||||||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Not eligible: 19 | ||||||||||||||||||||||||||||||||||||
| Notes [1] - The number of subjects reported to have started the pre-assignment period are not the same as the worldwide number enrolled in the trial. It is expected that these numbers will be the same. Justification: Subjects were found not eligible for the study at screening period. |
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Period 1
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Period 1 title |
Randomisation (overall period)
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Is this the baseline period? |
Yes | ||||||||||||||||||||||||||||||||||||
Allocation method |
Randomised - controlled
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Blinding used |
Double blind | ||||||||||||||||||||||||||||||||||||
Roles blinded |
Subject, Investigator, Monitor, Data analyst | ||||||||||||||||||||||||||||||||||||
Blinding implementation details |
Participants were randomised to placebo (study arm A) or one of two active drugs (study arms B or C). Study drugs and randomisations were provided by Bilcare GCS (Europe) Ltd. Participants were allocated at random to one of the study arms below in the ratio 1:1:1, in blocks of 6. Both the venlafaxine and pregabalin tablets were over-encapsulated to give the same appearance as that of the red placebo capsule.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Placebo | ||||||||||||||||||||||||||||||||||||
Arm description |
Placebo | ||||||||||||||||||||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
DB size AA-el Swedish orange capsules
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Two capsules per day.
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Arm title
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Venlafaxine | ||||||||||||||||||||||||||||||||||||
Arm description |
Venlafaxine | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Venlafaxine
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Investigational medicinal product code |
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Other name |
Venlafaxine 37.5mg tablets (Efexor, Wyeth)
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
75mg on days 0-2, 112.5mg on days 3-6, 150mg on days 7-21, 75mg on days 22-24 and 37.5mg on days 25-26. Dose one capsule twice a day, morning and evening.
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Arm title
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Pregabalin | ||||||||||||||||||||||||||||||||||||
Arm description |
Pregabalin | ||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Pregabalin
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Investigational medicinal product code |
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Other name |
Pregabalin 50mg capsules (Lyrica, Pfizer)
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
100mg on days 0-6, 200mg on days 7-21, 100mg on days 22-24 and 50mg on days 25-26. Dose one capsule taken twice a day, morning and evening.
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Baseline characteristics reporting groups
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Reporting group title |
Randomisation
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo | ||
Reporting group title |
Venlafaxine
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Reporting group description |
Venlafaxine | ||
Reporting group title |
Pregabalin
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Reporting group description |
Pregabalin | ||
Subject analysis set title |
All subjects
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Subject analysis set type |
Full analysis | ||
Subject analysis set description |
n=54 completers
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End point title |
Panic Symptom Inventory | ||||||||||||||||
End point description |
The Panic Symptom Inventory (PSI) was used to rate panic anxiety and the associated symptoms of autonomic arousal, with the option of rating 0 = not at all, 1 = slight, 2 = moderate, 3= severe, 4 = very severe. The PSI was adapted from Clark and Hemsley (1982), and lists 34 items and has been used in studies of panic provocation (Nutt et al., 1990; Bell et al., 2002) and previous CO2 studies (Argyropoulos et al., 2002, Bailey et al., 2005).
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End point type |
Primary
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End point timeframe |
Measured before and after each CO2 inhalation
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| Notes [1] - 1 dropout replaced, therefore 18 in analysis. [2] - 5 drop outs replaced, therefore 18 in analysis. |
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Statistical analysis title |
Paired t test | ||||||||||||||||
Statistical analysis description |
Paired t tests for placebo and venlafaxine, placebo and pregabalin, and venlafaxine and pregabalin showed the following results. At the Peak-Air time point, PSI scores on venlafaxine were significantly higher than on pregabalin (t=2.549, df=34, p<0.05). At the Peak-35% CO2 time point, PSI scores on venlafaxine were significantly higher than on pregabalin (t=2.235, df=34, p<0.05).
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Comparison groups |
Venlafaxine v Placebo v Pregabalin
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Number of subjects included in analysis |
54
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Analysis specification |
Pre-specified
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Analysis type |
equivalence | ||||||||||||||||
P-value |
< 0.05 [3] | ||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||
Confidence interval |
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| Notes [3] - At the Peak-35% CO2 time point, PSI scores on venlafaxine were significantly higher than on pregabalin (t=2.235, df=34, p<0.05). |
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End point title |
Generalised Anxiety Disorder Inventory (GAD-C) | ||||||||||||||||
End point description |
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End point type |
Primary
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End point timeframe |
Before and after each CO2 inhalation
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| Notes [4] - 1 dropout replaced, therefore 18 included in final analysis [5] - 5 dropouts replaced, therefore 18 included in final analysis |
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Statistical analysis title |
Paired t test | ||||||||||||||||
Statistical analysis description |
At the Peak Air time point, GAD-C scores on placebo were significantly higher than on pregabalin (t=2.059, df=28.4, p<0.05, and scores on venlafaxine were also significantly higher than on pregabalin (t=2.230, df=26.9, p<0.05). At the Peak 35% CO2 time point, GAD-C scores on venlafaxine were significantly higher than on pregabalin (t=2.145, df=34, p<0.05).
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Comparison groups |
Venlafaxine v Pregabalin v Placebo
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Number of subjects included in analysis |
54
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Analysis specification |
Post-hoc
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Analysis type |
equivalence | ||||||||||||||||
P-value |
< 0.05 [6] | ||||||||||||||||
Method |
t-test, 2-sided | ||||||||||||||||
Confidence interval |
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| Notes [6] - At the Peak 35% CO2 time point, GAD-C scores on venlafaxine were significantly higher than on pregabalin (t=2.145, df=34, p<0.05). |
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Adverse events information
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Timeframe for reporting adverse events |
From signing of informed consent form until last subject last visit (follow-up).
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
12.1
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Reporting groups
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Reporting group title |
Placebo
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Reporting group description |
Placebo | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Venlafaxine
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Reporting group description |
Venlafaxine | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Pregabalin
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Reporting group description |
Pregabalin | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 0% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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Substantial protocol amendments (globally) |
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| Were there any global substantial amendments to the protocol? Yes | |||
Date |
Amendment |
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24 Apr 2008 |
Contact list - Changed Site Management Organisation to Funder
Section 13.2.2 Serious Adverse Events (SAEs) - Removed the need to report SAEs to P1vital (funder)
Section 18.2 On-Site Audits – Removed the need to inform P1vital (funder) |
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28 Apr 2009 |
• Change to inclusion/exclusion criteria.
Currently the inclusion/exclusion criteria states that all resting blood pressure at screening should be between 100-140 mmHg systolic and 60-90 mmHg diastolic. Because of this tight range, we are excluding many fit participants with blood pressures outside of this range, when they are otherwise suitable for inclusion. We wish to add a statement to the inclusion/exclusion criteria which would mean that blood pressure results outside of this range should be subject to the judgment of the study physician as to the clinical significance of the results. If the study physician felt any out-of-range results were not clinically significant or relevant to the study, then s/he could then pass the participant fit to enter the study.
As all participants will only be included on the study if deemed suitable by the study physician, there will be no additional risk to participants. The benefit of this amendment will be the inclusion of suitable participants who would otherwise fail screening unnecessarily. There will be no consequences to participants already on the trial, and no change to the evaluation of results. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? No | |||
Limitations and caveats |
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| Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data. | |||
| None reported | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/22516666 |
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