Clinical Trial Results:
A proof of concept study in allergic rhinitis, to evaluate the differential effects of doxazosin between single and chronic dosing on nasal airway calibre
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Summary
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EudraCT number |
2012-005035-85 |
Trial protocol |
GB |
Global end of trial date |
02 Jun 2015
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Results information
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Results version number |
v1(current) |
This version publication date |
01 Jun 2016
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First version publication date |
01 Jun 2016
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Other versions |
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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 |
2012RC14
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01946035 | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
Tayside Medical Sciences Centre on behalf of the University of Dundee & NHS Tayside
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Sponsor organisation address |
Residency Block, Level 3, Ninewells Hospital, George Pirie Way, Dundee, United Kingdom, DD1 9SY
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Public contact |
Prof Brian Lipworth, Scottish Centre for Respiratory Research , 44 01382383188, b.j.lipworth@dundee.ac.uk
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Scientific contact |
Prof Brian Lipworth, Scottish Centre for Respiratory Research, 44 01382383188, b.j.lipworth@dundee.ac.uk
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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 |
18 Dec 2015
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
02 Jun 2015
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Global end of trial reached? |
Yes
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Global end of trial date |
02 Jun 2015
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Was the trial ended prematurely? |
Yes
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General information about the trial
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Main objective of the trial |
What are the effects of chronic alpha blocker use on nasal blockage in patients with allergic rhinitis(allergic inflammation of the nose)?
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Protection of trial subjects |
Subjects were recruited from a database of volunteers who had agreed to be contacted with regard to participating in departmental research. Subjects received a written information sheet (PIS) with details of trial requirements, and had this for at least 24 hours before attending for a screening visit. They were encouraged to discuss the possibility of participation with study staff and others.
Informed consent was obtained before any protocol-specific procedures were carried out. Subjects were given every opportunity to clarify points they did not understand, and ask for more information. It was emphasized that the subject could withdraw consent to participate at any time without loss of benefits to which they otherwise would be entitled. The Chief Investigator could also withdraw a participant at any point if they felt it would be unsafe or inappropriate for the subject to continue. An informed consent form was signed and dated by the subject and the person taking consent, and the volunteer received a copy.
Subjects were only selected if they met the pre-determined inclusion criteria.
Medical history and concomitant medications were reviewed by a medically qualified person to confirm it was safe for the subject to receive the study drug. A physical examination was conducted before randomisation. A screening blood sample was taken at the screening with tests appropriate to the risk of the study. Blood pressure was taken at each visit.
Participants received an emergency mobile phone number, carried by a study doctor 24 hours a day, to contact if they experienced any problems.
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Background therapy |
Antihistamines and / or intranasal corticosteroids were withheld for 7 days prior to the first study visit, and were not permitted for the duration of the study. If required, participants were given sodium cromoglycate 2% nasal spray if required for relief of symptoms on demand. | ||
Evidence for comparator |
Current management guidelines for allergic rhinitis advocate the use of nasal corticosteroids and antihistamines as first line therapy. However, despite such treatment, there is an unmet need with many patients remaining symptomatic in terms of persistent nasal blockage. Alpha-receptor agonists such as oxymetazoline are available without prescription and provide effective acute decongestant relief, mediated by direct venoconstriction of the nasal sinusoids and by vasoconstriction of afferent arterioles and arteriovenous shunts, leading to a reduction in blood flow to the sinusoids. However, their repeated use is associated with a rapid tachyphylaxis of response due alpha-receptor down-regulation and G protein uncoupling, resulting in desensitization of response. In addition to tachyphylaxis of the vasoconstrictor response, there is also an associated increase in nasal airway hyper-reactivity and rebound worsening of nasal congestion, resulting in the so-called syndrome of rhinitis medicamentosa. Hence, alpha-agonists are only recommended for decongestant use on a temporary short-term basis in patients with allergic rhinitis, for example to aide nasal breathing during an acute viral episode. These data have in turn led to a novel paradoxical pharmacological hypothesis, namely that chronic dosing with a selective alpha-1 receptor antagonist doxazosin might be beneficial in allergic rhinitis by producing alpha-1 receptor up-regulation and associated resensitization of alpha-receptor-mediated responsiveness. Doxazosin exhibits strong inverse agonist activity at the alpha-1 receptor and may therefore be able to inhibit constitutive unliganded receptor activity in addition to its antagonist activity by inhibiting the receptor when activated by ligand. The presence of inverse agonist activity also appears to be related to the propensity for inducing up-regulation of alpha-1. | ||
Actual start date of recruitment |
04 Sep 2013
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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: 40
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Worldwide total number of subjects |
40
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EEA total number of subjects |
40
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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) |
37
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From 65 to 84 years |
3
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85 years and over |
0
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Recruitment
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Recruitment details |
Subjects were recruited from September 2013 until April 2015. A total of 15 subjects completed the study. | ||||||||||||||||||
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Pre-assignment
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Screening details |
Subjects were assessed at screening against pre-defined inclusion and exclusion criteria. Eligible subjects entered a 1-3 week run-in period. | ||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
40 | ||||||||||||||||||
Intermediate milestone: Number of subjects |
Screening Visit: 40
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Intermediate milestone: Number of subjects |
Run-In Period: 18
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Number of subjects completed |
17 [1] | ||||||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Did not meet inclusion criteria: 22 | ||||||||||||||||||
Reason: Number of subjects |
Adverse event, non-fatal: 1 | ||||||||||||||||||
| Notes [1] - The number of subjects reported to be in the pre-assignment period is not consistent with the number starting period 1. It is expected that the number completing the pre-assignment period are also present in the arms in period 1. Justification: The number of subjects who started the pre-assignment period (40) is the number of subjects screened into the study. 17 subjects completed the pre-assignment period and were randomised into the study. Of these 17 subjects, 15 completed both arms of the cross-over trial and were able to be analysed. There are thus 15 subjects in the arms in Period 1. |
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Period 1
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Period 1 title |
Randomised Treatment (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 |
Blinding was performed under the direct supervision of the affiliated NHS Tayside Clinical Trials Pharmacist, Ninewells Hospital, Dundee. This was GCP compliant with a clear audit trail. Participants were allocated randomised treatment chronologically as they entered the trial. The IMP was double-blinded so that neither the study team nor participants knew whether the treatment was active or placebo at any given point.
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Arms
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Are arms mutually exclusive |
No
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Arm title
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Doxazosin | ||||||||||||||||||
Arm description |
Subjects randomized to prolonged released Doxazosin (Cardozin XL) 4mg once daily in the evening for 3 - 5 weeks. There was a 1- to 3- week run-in and washout period in between randomized treatments. Baseline measures after run-in and washout were performed at visits 2 of 6, while single-dose effects were measured at visits 3 of 7 and chronic dose effects at visits 4 of 8 (at 12 h post-dose). At each of these visits, an oxymetazoline dose-response curve was also performed. At visits 5 of 9 after the last dose, a bolus histamine challenge was performed along with subsequent recovery in response oxymetazoline (at 36 h post-dose). Cross-over design - Participants received both IMPs (participated in both arms) during the course of the study. | ||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||
Investigational medicinal product name |
Doxazosin
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Investigational medicinal product code |
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Other name |
Cardozin XL
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Doxazosin 4mg was taken once daily for 3 - 5 weeks.
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Arm title
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Placebo | ||||||||||||||||||
Arm description |
Subjects randomized to identical (over-encapsulated) placebo once daily in the evening for 3 - 5 weeks. There was a 1- to 3- week run-in and washout period in between randomized treatments. Baseline measures after run-in and washout were performed at visits 2 of 6, while single-dose effects were measured at visits 3 of 7 and chronic dose effects at visits 4 of 8 (at 12 h post-dose). At each of these visits, an oxymetazoline dose-response curve was also performed. At visits 5 of 9 after the last dose, a bolus histamine challenge was performed along with subsequent recovery in response oxymetazoline (at 36 h post-dose). | ||||||||||||||||||
Arm type |
Placebo | ||||||||||||||||||
Investigational medicinal product name |
Placebo
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Placebo was taken once daily for 3 - 5 weeks.
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Baseline characteristics reporting groups [1]
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Reporting group title |
Randomised Treatment
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Reporting group description |
Inclusion Criteria: Physician-based diagnosis of mild allergic rhinitis, at least one positive skin prick test to a panel of common aeroallergens, at least a 20L/min and 20% reversibility in PNIF during DRF to oxymetaozoline using a diluent (baseline) followed by cumulative doses of 25 mcg, 50 mcg, and 100 mcg (sum of both nostrils) at 15-min intervals, able to withhold nasal steroids and antihistamines for the duration of the study. Exclusion Criteria: Deviated nasal septum (>50%), obstructive inferior turbinate hypertrophy, obstructive adenoidal hypertrophy, nasal polyposis, systolic blood pressure less than 100 mmHg, taking vasodilators which might interact with doxazosin to adversely lower blood pressure. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| Notes [1] - The number of subjects reported to be in the baseline period is not equal to the worldwide number of subjects enrolled in the trial. It is expected that these numbers will be the same. Justification: The worldwide number enrolled is the number of subjects screened into the study (40). The number of subjects in the baseline period is the number who were then randomised into the study (17). Of these 17 subjects, 15 completed both arms of the cross-over trial and were able to be analysed. |
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Subject analysis sets
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Subject analysis set title |
Completed Subjects
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Subject analysis set type |
Per protocol | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Subject analysis set description |
Inclusion Criteria: Diagnosis of mild allergic rhinitis, at least one positive skin prick test to a panel of common aeroallergens. At least a 20 L/min and 20% reversibility in PNIF during a DRC to oxymetazoline using a diluent (baseline) followed by cumulative doses of 25 mcg, 50 mcg and 100 mcg (sum of both nostrils) at 15 minute intervals. Able to withhold nasal steroid and anti-histamines for the duration of the study.
Exclusion Criteria: Deviated Nasal Septum (>50%), obstructive inferior turbinate hyeprtrophy, obstructive adenoidal hypertrophy, or nasal polyposis. Systolic blood pressure less than 100 mmHg. Taking any vasodilators which might interact with doxazosin to adversely lower blood pressure.
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End points reporting groups
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Reporting group title |
Doxazosin
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Reporting group description |
Subjects randomized to prolonged released Doxazosin (Cardozin XL) 4mg once daily in the evening for 3 - 5 weeks. There was a 1- to 3- week run-in and washout period in between randomized treatments. Baseline measures after run-in and washout were performed at visits 2 of 6, while single-dose effects were measured at visits 3 of 7 and chronic dose effects at visits 4 of 8 (at 12 h post-dose). At each of these visits, an oxymetazoline dose-response curve was also performed. At visits 5 of 9 after the last dose, a bolus histamine challenge was performed along with subsequent recovery in response oxymetazoline (at 36 h post-dose). Cross-over design - Participants received both IMPs (participated in both arms) during the course of the study. | ||
Reporting group title |
Placebo
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Reporting group description |
Subjects randomized to identical (over-encapsulated) placebo once daily in the evening for 3 - 5 weeks. There was a 1- to 3- week run-in and washout period in between randomized treatments. Baseline measures after run-in and washout were performed at visits 2 of 6, while single-dose effects were measured at visits 3 of 7 and chronic dose effects at visits 4 of 8 (at 12 h post-dose). At each of these visits, an oxymetazoline dose-response curve was also performed. At visits 5 of 9 after the last dose, a bolus histamine challenge was performed along with subsequent recovery in response oxymetazoline (at 36 h post-dose). | ||
Subject analysis set title |
Completed Subjects
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Inclusion Criteria: Diagnosis of mild allergic rhinitis, at least one positive skin prick test to a panel of common aeroallergens. At least a 20 L/min and 20% reversibility in PNIF during a DRC to oxymetazoline using a diluent (baseline) followed by cumulative doses of 25 mcg, 50 mcg and 100 mcg (sum of both nostrils) at 15 minute intervals. Able to withhold nasal steroid and anti-histamines for the duration of the study.
Exclusion Criteria: Deviated Nasal Septum (>50%), obstructive inferior turbinate hyeprtrophy, obstructive adenoidal hypertrophy, or nasal polyposis. Systolic blood pressure less than 100 mmHg. Taking any vasodilators which might interact with doxazosin to adversely lower blood pressure.
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End point title |
PNIF | ||||||||||||||||||
End point description |
Peak nasal inspiratory flow
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End point type |
Primary
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End point timeframe |
Timeframe started at the first visit of the treatment period (acute dosing) and extended 3 - 5 weeks until the last visit of the treatment period (chronic dosing).
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Statistical analysis title |
ANOVA | ||||||||||||||||||
Statistical analysis description |
The study was powered at 80% to detect a minimal
important difference of 5 L/min [25] (within-subject SD
7 L/min) in the primary end-point of PNIF with an
alpha error of 0.05 (two tailed). Baseline values after
run-in and washout were compared paired Student’s ttests.
An overall repeated-measures analysis of variance
(ANOVA) was applied to evaluate visit-based effects for
PNIF and other secondary outcomes, followed by paired
Student’s t-tests to compare different time-points. An
overall
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Comparison groups |
Doxazosin v Placebo
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Number of subjects included in analysis |
30
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||||||||
P-value |
≤ 0.05 | ||||||||||||||||||
Method |
ANOVA | ||||||||||||||||||
Confidence interval |
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level |
95% | ||||||||||||||||||
sides |
2-sided
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lower limit |
- | ||||||||||||||||||
upper limit |
- | ||||||||||||||||||
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End point title |
VAS | ||||||||||||||||||
End point description |
Visual Analogue Scale (0-10)
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End point type |
Secondary
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End point timeframe |
3-5 weeks
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Nasal Blockage Score | ||||||||||||||||||
End point description |
Symptom score, range 0-3
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End point type |
Secondary
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End point timeframe |
3-5 weeks
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Overall TNS4 | ||||||||||||||||||
End point description |
Symptom score 0-12
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End point type |
Secondary
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End point timeframe |
3-5 weeks
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Supine Heart Rate | ||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
3-5 weeks
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Erect Heart Rate | ||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
3-5 weeks
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Supine Systolic BP | ||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
3-5 weeks
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Erect Systolic BP | ||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
3-5 weeks
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Supine Diastolic BP | ||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
3-5 weeks
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
Erect Diastolic BP | ||||||||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
3-5 weeks
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| No statistical analyses for this end point | |||||||||||||||||||
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End point title |
change in Mini-RQLQ Scores | ||||||||||||
End point description |
compared to baseline
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End point type |
Secondary
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End point timeframe |
3-5 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Nasal NO | ||||||||||||
End point description |
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End point type |
Secondary
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End point timeframe |
3-5 weeks
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| No statistical analyses for this end point | |||||||||||||
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End point title |
Oxymetazoline DRC | ||||||||||||
End point description |
dose response curve comparing single vs chronic dosing
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End point type |
Secondary
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End point timeframe |
3-5 weeks
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| No statistical analyses for this end point | |||||||||||||
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Adverse events information
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Timeframe for reporting adverse events |
All AEs and SAEs were recorded from the time a participant consented to join the study until the last study visit.
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Adverse event reporting additional description |
Subjects were asked about the occurrence of AEs at each study visit and received training on how to record AEs and concomitant medications. All AEs were recorded on subject-specific logs in the CRFs.
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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 |
18
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Reporting groups
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Reporting group title |
Completed Subjects
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Reporting group description |
- | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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| Frequency threshold for reporting non-serious adverse events: 5% | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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08 Jan 2014 |
REC Amendment (AM01)
Amendment to notify REC of changes made in response to MHRA's grounds for non-acceptance and right to amend request during initial application process.
MHRA Amendment (AM01)
Amendment to notify MHRA of temporary halt of the study pending REC approval of AM01. |
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09 Apr 2014 |
REC Amendment (AM02)
Amendment to restart the study following a temporary halt.
MHRA Amendment (AM02)
Amendment to restart the study following a temporary halt. |
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Interruptions (globally) |
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| Were there any global interruptions to the trial? Yes | |||||||
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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/26741127 |
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