Clinical Trial Results:
Hellenic Anglo Research into Morning Or Night antihypertensive drug deliverY trial.
Summary
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EudraCT number |
2011-004192-37 |
Trial protocol |
GB |
Global end of trial date |
31 Oct 2016
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Results information
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Results version number |
v1(current) |
This version publication date |
14 May 2017
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First version publication date |
14 May 2017
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Other versions |
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 |
CRO1749
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Additional study identifiers
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ISRCTN number |
- | ||
US NCT number |
NCT01669928 | ||
WHO universal trial number (UTN) |
- | ||
Sponsors
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Sponsor organisation name |
Joint Research Compliance Office, Imperial College London
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Sponsor organisation address |
Room 221, Medical school Building, St Mary's Campus, Norfolk Place, London, United Kingdom, W2 1PG
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Public contact |
Professor Neil Poulter, Imperial College London, +44 20 7594 3446, n.poulter@imperial.ac.uk
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Scientific contact |
Professor Neil Poulter, Imperial College London, +44 20 7594 3446, n.poulter@imperial.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 |
11 Apr 2016
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Is this the analysis of the primary completion data? |
Yes
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Primary completion date |
11 Apr 2016
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Global end of trial reached? |
Yes
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Global end of trial date |
31 Oct 2016
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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 detect if there is a 3mm Hg difference in average 24 hour systolic blood pressure when blood pressure lowering medications are taken in the evening compared with same medications taken in the morning.
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Protection of trial subjects |
No measures were required to be put into place as patients were on their usual blood pressure medications with the only change being the time of day (morning or evening) the medication should be taken.
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Background therapy |
All study recruits continued on whatever drug therapy and lifestyle manoeuvres were in place before recruitment into the trial. Recruits were advised to make no changes to these interventions at any stage in the trial other than the timing of drug administration (morning or evening). | ||
Evidence for comparator |
In order to detect a 3 mm Hg difference in mean 24 hour systolic BP (SBP) (between periods when antihypertensive medications are taken in the morning and when taken at night) with 80% power (2-sided), p < 0.05 and an estimated standard deviation (SD) in mean 24 hour SBP of 10 mmHg, 90 patients were needed to complete the trial. Assuming a dropout rate of approximately 10%, 100 patients in total were required to be randomized between the two centres, with 45 patients in each treatment group. | ||
Actual start date of recruitment |
23 Jul 2013
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Long term follow-up planned |
No
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Independent data monitoring committee (IDMC) involvement? |
Yes
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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: 53
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Country: Number of subjects enrolled |
Greece: 50
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Worldwide total number of subjects |
103
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EEA total number of subjects |
103
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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) |
51
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From 65 to 84 years |
52
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85 years and over |
0
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Recruitment
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Recruitment details |
103 patients were recruited to the trial between July 2013 and Jan 2015, across two sites: Peart-Rose Research Unit, Imperial College London, UK and the Outpatient Clinic of 1st Medical Propedeutic Dept. of Internal Medicine, AHEPA Hospital, Aristotle University of Thessaloniki, Greece. The the last patient last visit occurred in July 2015. | |||||||||||||||||||||||||||
Pre-assignment
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Screening details |
Suitable participants were identified at treating hospitals, research departments or the general practices by the study team. Patients were screened if they were on 2 or more stable hypertensive medications for at least 3 months prior to the study and were aged between 18-80 years. | |||||||||||||||||||||||||||
Period 1
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Period 1 title |
Baseline to Crossover
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Is this the baseline period? |
Yes | |||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Morning/Evening | |||||||||||||||||||||||||||
Arm description |
Patients who took their BP medication in the morning (between 06:00 and 11:00) in the first period for 12 weeks and in the evening (between 18:00 and 23:00) in the second period for another 12 weeks. | |||||||||||||||||||||||||||
Arm type |
Sequence | |||||||||||||||||||||||||||
Investigational medicinal product name |
Usual BP medication
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Investigational medicinal product code |
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Other name |
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Pharmaceutical forms |
Tablet, Capsule
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Routes of administration |
Oral use
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Dosage and administration details |
Usual BP medication
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Arm title
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Evening/Morning | |||||||||||||||||||||||||||
Arm description |
Patients who took their BP medication in the evening (between 18:00 and 23:00) in the first period for 12 weeks and in the morning (between 06:00 and 11:00) in the second period for another 12 weeks. | |||||||||||||||||||||||||||
Arm type |
Sequence | |||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Period 2
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Period 2 title |
Crossover to Final Visit
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Is this the baseline period? |
No | |||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Morning/Evening | |||||||||||||||||||||||||||
Arm description |
Patients who took their BP medication in the morning (between 06:00 and 11:00) in the first period for 12 weeks and in the evening (between 18:00 and 23:00) in the second period for another 12 weeks. | |||||||||||||||||||||||||||
Arm type |
Sequence | |||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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Evening/Morning | |||||||||||||||||||||||||||
Arm description |
Patients who took their BP medication in the evening (between 18:00 and 23:00) in the first period for 12 weeks and in the morning (between 06:00 and 11:00) in the second period for another 12 weeks. | |||||||||||||||||||||||||||
Arm type |
Sequence | |||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Period 3
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Period 3 title |
At Final visit
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Is this the baseline period? |
No | |||||||||||||||||||||||||||
Allocation method |
Not applicable
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Blinding used |
Not blinded | |||||||||||||||||||||||||||
Arms
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Are arms mutually exclusive |
No
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Arm title
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Morning | |||||||||||||||||||||||||||
Arm description |
Result for the morning admission. | |||||||||||||||||||||||||||
Arm type |
Morning | |||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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Evening | |||||||||||||||||||||||||||
Arm description |
Results for evening admission | |||||||||||||||||||||||||||
Arm type |
Evening | |||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Baseline characteristics reporting groups
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Reporting group title |
Morning/Evening
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Reporting group description |
Patients who took their BP medication in the morning (between 06:00 and 11:00) in the first period for 12 weeks and in the evening (between 18:00 and 23:00) in the second period for another 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Evening/Morning
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Reporting group description |
Patients who took their BP medication in the evening (between 18:00 and 23:00) in the first period for 12 weeks and in the morning (between 06:00 and 11:00) in the second period for another 12 weeks. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Morning/Evening
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Reporting group description |
Patients who took their BP medication in the morning (between 06:00 and 11:00) in the first period for 12 weeks and in the evening (between 18:00 and 23:00) in the second period for another 12 weeks. | ||
Reporting group title |
Evening/Morning
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Reporting group description |
Patients who took their BP medication in the evening (between 18:00 and 23:00) in the first period for 12 weeks and in the morning (between 06:00 and 11:00) in the second period for another 12 weeks. | ||
Reporting group title |
Morning/Evening
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Reporting group description |
Patients who took their BP medication in the morning (between 06:00 and 11:00) in the first period for 12 weeks and in the evening (between 18:00 and 23:00) in the second period for another 12 weeks. | ||
Reporting group title |
Evening/Morning
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Reporting group description |
Patients who took their BP medication in the evening (between 18:00 and 23:00) in the first period for 12 weeks and in the morning (between 06:00 and 11:00) in the second period for another 12 weeks. | ||
Reporting group title |
Morning
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Reporting group description |
Result for the morning admission. | ||
Reporting group title |
Evening
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Reporting group description |
Results for evening admission |
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End point title |
24 hour ABPM - mean systolic BP | |||||||||
End point description |
24 hour ABPM - mean systolic BP
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End point type |
Primary
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End point timeframe |
24 hours
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Statistical analysis title |
Regression adjusted | |||||||||
Statistical analysis description |
Includes 95 patients who had ABPMs at baseline, crossover and final visits.
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Comparison groups |
Morning v Evening
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Number of subjects included in analysis |
190
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
Method |
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Parameter type |
Mean difference (final values) | |||||||||
Point estimate |
0.11
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-3.2 | |||||||||
upper limit |
3.42 | |||||||||
Statistical analysis title |
Observed difference [1] | |||||||||
Statistical analysis description |
95 patients who completed ABPMs at baseline, crossover and final visits were included in this analysis.
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Comparison groups |
Morning v Evening
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Number of subjects included in analysis |
190
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
Method |
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Parameter type |
Mean difference (final values) | |||||||||
Point estimate |
0.1
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
0 | |||||||||
upper limit |
- | |||||||||
Notes [1] - A low or upper value for the confidence interval may be missing. Values for both the lower and upper limit are expected to be provided with a 2-sided confidence interval. Justification: The outcome is a difference and it is not specific to one group or the other but it makes sense to enter the observed values for the two groups. These are not estimates but exact numbers so there is no related confidence interval. |
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End point title |
24 hour ABPM - mean diastolic BP | |||||||||
End point description |
24 hour ABPM - mean diastolic BP
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End point type |
Primary
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End point timeframe |
24 hours
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Statistical analysis title |
Regression adjusted | |||||||||
Statistical analysis description |
Includes 95 patients who had ABPMs at baseline, crossover and final visits.
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Comparison groups |
Morning v Evening
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Number of subjects included in analysis |
190
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Analysis specification |
Pre-specified
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Analysis type |
superiority | |||||||||
Method |
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Parameter type |
Mean difference (final values) | |||||||||
Point estimate |
0.77
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Confidence interval |
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level |
95% | |||||||||
sides |
2-sided
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lower limit |
-1.38 | |||||||||
upper limit |
2.91 |
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Adverse events information [1]
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Timeframe for reporting adverse events |
23rd July 2013 (date first patient enrolled) to 15th July 2015 (28 days after last patient, last visit).
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Assessment type |
Systematic | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary used for adverse event reporting
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Dictionary name |
MedDRA | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
19.0
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Reporting groups
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Reporting group title |
Morning/Evening
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Evening/Morning
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Reporting group description |
- | |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Notes [1] - There are no non-serious adverse events recorded for these results. It is expected that there will be at least one non-serious adverse event reported. Justification: No non-serious adverse events were reported, only one three serious adverse events were reported in the trial. |
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Frequency threshold for reporting non-serious adverse events: 0.05% | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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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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18 Jul 2012 |
Substantial amendment. Minor administrative changes to the trial protocol and patient information sheet. Submission of letter of invitation to participant and patient diary card for Ethics approval. |
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25 Sep 2012 |
Minor amendment. Administrative changes made to the GP letter regarding patient participation to provide information on which randomisation arm the patient has been allocated and to provide further detail of the current medication the patient is taking. |
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19 Oct 2012 |
Minor amendment. Administrative changes to the trial protocol, patient information sheet and consent form to clarify inconsistencies regarding ABPM measurement timings. |
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02 Jul 2013 |
Substantial amendment. Following sections of the protocol changed:
1) Secondary outcome
Clarification that occurrence of side effects is based self reported serious adverse events to maintain
consistency with the adverse events reporting section which already states this.
2) and 3) Inclusion and Exclusion Criteria
Reduction of the lower accepted Diastolic Blood Pressure to 65 mmHg (instead of 75) to enhance the
generalisability of the findings as our clinic database has shown this better reflects the current patient population in
the clinic and therefore the population under study.
4) Treatment Schedule
Further details added to the protocol and patient information sheet to clarify the questions asked and data that will be collected.
5) Sponsor
Sponsor contact change from Lucy Parker to Nabila Youssouf. NB the Sponsor did not change. |
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23 Apr 2014 |
Minor and substantial amendments.
SUBSTANTIAL AMENDMENT TO MHRA AND ETHICS
Change in the inclusion criteria that previously included 'Caucasian patients [white and of European origin]
aged 18-80 years' to now state 'Any patients aged 18-80 years'. This was to enhance the generalisability of the
findings as the clinic database has shown this better reflects the current patient population in the clinic and
therefore the population under study.
MINOR AMENDMENT TO MHRA AND ETHICS
In the previous amendment we informed of a change in Sponsor contact details but the details were not changed on the protocol in error, so this was been corrected in version 5 of the protocol.
SUBSTANTIAL AMENDMENT TO ETHICS ONLY
1) Questionnaire designed to be given to patients at the end of the study to gain their feedback on preference for time of day for taking medication. We have attached the questionnaire for review (to ethics only)
2) Intended to contact patients who have taken part in other studies and consented to being contacted for future studies. Drafted letter and questionnaire for review (to ethics only) |
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19 Dec 2014 |
Minor amendments:
1) Sponsor contact details
The contact person for the Sponsor changed and updated on version 6 of the protocol
2) Correction of typo On page 9, section 4.1 of the protocol which still referred to patients recruited being Caucasian. This was changed in the last substantial amendment in the inclusion/exclusion criteria on the protocol
but was missed from this section in error so was now deleted
3) Change in distribution of patient recruitment. The previous version of the protocol stated that an equal number of patients will be recruited at each of the two sites for the study. As recruitment was slower at one site, recruitment would not be equal between sites and this was changed in the protocol accordingly. NB was NOT a change to the number of patients to be recruited. |
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11 Feb 2015 |
Minor amendment. Updated sponsor details on the protocol version 7. |
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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 |