Clinical Trial Results:
Alternative Treatments of Adult female Urinary Tract Infection: a double blind, placebo controlled,factorial randomised trial of Uva ursi and open pragmatic trial of ibuprofen.
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Summary
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EudraCT number |
2013-003327-11 |
Trial protocol |
GB |
Global end of trial date |
21 Jan 2017
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Results information
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Results version number |
v1(current) |
This version publication date |
03 Feb 2018
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First version publication date |
03 Feb 2018
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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 |
3623
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Additional study identifiers
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ISRCTN number |
ISRCTN43397016 | ||
US NCT number |
- | ||
WHO universal trial number (UTN) |
- | ||
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Sponsors
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Sponsor organisation name |
University of Southampton
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Sponsor organisation address |
University Road, Southampton, United Kingdom, SO17 1BJ
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Public contact |
Catherine Simpson, University of Southampton, 0044 2381205154, ctu@soton.ac.uk
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Scientific contact |
Michael Moore, University of Southampton, 0044 2381205154, mvm198@soton.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 |
31 May 2017
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Is this the analysis of the primary completion data? |
No
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Global end of trial reached? |
Yes
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Global end of trial date |
21 Jan 2017
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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 evaluate whether Uva ursi compared to placebo or the advice to take ibuprofen compared to no advice provide relief from urinary symptoms in adult women with suspected UTI.
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Protection of trial subjects |
Women prepared to accept a delayed antibiotic prescription for their symptoms and who meet the eligibility criteria will be consented for randomisation. All participants will be issued a prescription for delayed antibiotics. This prescription will be used if symptoms worsen or after three to five days if symptoms are not improving (most symptoms should have settled by this time).
EXCLUSION CRITERIA
Known or suspected pregnancy or breast feeding. In women of child bearing age a urine pregnancy test will usually be performed unless not indicated (for instance prior hysterectomy)
Known immunodeficiency state, long term corticosteroids therapy or chemotherapy
Diabetes
Has any of the following (A – F) known contra-indications or cautions to ibuprofen and any as listed in the current SmPC detailed in Appendix 3:
A. Asthmatics sensitive to NSAIDS/ ibuprofen or aspirin
B. Severe heart failure and uncontrolled hypertension
C. Active gastro-intestinal ulceration or bleeding
D. Crohn’s disease or ulcerative colitis
E. Documented poor renal function
F. Chronic kidney disease (Grade 3 – 5)
Currently or within 7 days taken antibiotics
Using a NSAID or Uva ursi preparation and unwilling or unable to discontinue for the study period
Suspected upper urinary tract infection (back pain, fever>38⁰C, systemic illness)
Women for whom immediate antibiotics are otherwise indicated - frequent recurrent infection: >3 UTI episodes in past 12 months
Defect of the blood clotting system
Bladder surgery including cystoscopy in the last four weeks.
Currently taking warfarin
Recruited to another interventional trial in the previous 6 weeks
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Background therapy |
None | ||
Evidence for comparator |
to be added | ||
Actual start date of recruitment |
03 Aug 2015
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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: 382
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Worldwide total number of subjects |
382
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EEA total number of subjects |
382
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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) |
337
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From 65 to 84 years |
45
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85 years and over |
0
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Recruitment
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Recruitment details |
Adult women (18-70) presenting to primary care, with suspected lower urinary tract infection (suspected by GP or nurse practitioner). Subjects were recruited between August 2015 and November 2016 in GP surgeries in England. | ||||||||||||||||||||||||||||||||||||||||
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Pre-assignment
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Screening details |
Adult women with suspected lower urinary infection will be recruited in primary care, GP surgeries, walk-in centres and Out of Hours, by general practitioners or experienced practice nurses. Women prepared to accept a delayed antibiotic prescription for their symptoms and who meet the eligibility criteria will be consented for randomisation. | ||||||||||||||||||||||||||||||||||||||||
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Pre-assignment period milestones
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Number of subjects started |
627 [1] | ||||||||||||||||||||||||||||||||||||||||
Number of subjects completed |
382 | ||||||||||||||||||||||||||||||||||||||||
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Pre-assignment subject non-completion reasons
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Reason: Number of subjects |
Declined to participate: 43 | ||||||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Ineligible: 137 | ||||||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Not enough time: 36 | ||||||||||||||||||||||||||||||||||||||||
Reason: Number of subjects |
Other reasons: 29 | ||||||||||||||||||||||||||||||||||||||||
| 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: 627 subjects were actively screened and for the reasons presented in the table below, 245 did not complete the pre-assignment period. |
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Period 1
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Period 1 title |
Overall Trial (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, Assessor | ||||||||||||||||||||||||||||||||||||||||
Blinding implementation details |
In order to maintain blinding the placebo was approximately matched in colour and flavouring.
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Arms
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Are arms mutually exclusive |
Yes
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Arm title
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Group 1 | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Herb Uva ursi 1200mg three times a day and advice to take ibuprofen 400mg three times a day. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Uva ursi
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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 |
Herb Uva ursi 1200mg three times a day and advice to take ibuprofen 400mg three times a day.
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Arm title
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Group 2 | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Herb Uva ursi placebo three times a day and advice to take ibuprofen 400mg three times a day. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
No investigational medicinal product assigned in this arm
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Arm title
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Group 3 | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Herb Uva ursi 1200mg three times a day and no advice to take ibuprofen. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
Experimental | ||||||||||||||||||||||||||||||||||||||||
Investigational medicinal product name |
Uva ursi
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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 |
Herb Uva ursi 1200mg three times a day and no advice to take ibuprofen.
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Arm title
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Group 4 | ||||||||||||||||||||||||||||||||||||||||
Arm description |
Herb Uva ursi placebo three times a day and no advice to take ibuprofen. | ||||||||||||||||||||||||||||||||||||||||
Arm type |
No intervention | ||||||||||||||||||||||||||||||||||||||||
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 |
Group 1
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Reporting group description |
Herb Uva ursi 1200mg three times a day and advice to take ibuprofen 400mg three times a day. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 2
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Reporting group description |
Herb Uva ursi placebo three times a day and advice to take ibuprofen 400mg three times a day. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 3
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Reporting group description |
Herb Uva ursi 1200mg three times a day and no advice to take ibuprofen. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 4
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Reporting group description |
Herb Uva ursi placebo three times a day and no advice to take ibuprofen. | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
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End points reporting groups
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Reporting group title |
Group 1
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Reporting group description |
Herb Uva ursi 1200mg three times a day and advice to take ibuprofen 400mg three times a day. | ||
Reporting group title |
Group 2
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Reporting group description |
Herb Uva ursi placebo three times a day and advice to take ibuprofen 400mg three times a day. | ||
Reporting group title |
Group 3
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Reporting group description |
Herb Uva ursi 1200mg three times a day and no advice to take ibuprofen. | ||
Reporting group title |
Group 4
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Reporting group description |
Herb Uva ursi placebo three times a day and no advice to take ibuprofen. | ||
Subject analysis set title |
ITT frequency imputed population B (Uva ursi group)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All patients who were randomised regardless of treatment received, took Uva Ursi (Group 1+3), and their mean frequency symptom (burning, urgency, day time frequency and night time frequency) severity score on days 2-4 was imputed using multiple imputation, if missing.
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Subject analysis set title |
ITT frequency imputed population B (Uva ursi placebo group)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All patients who were randomised regardless of treatment received, took Uva Ursi placebo (Group 2+4), and their mean frequency symptom (burning, urgency, day time frequency and night time frequency) severity score on days 2-4 was imputed using multiple imputation, if missing.
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Subject analysis set title |
ITT frequency imputed population B (Ibuprofen group)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All patients who were randomised regardless of treatment received, were advised to take ibuprofen (Group 1+2), and their mean frequency symptom (burning, urgency, day time frequency and night time frequency) severity score on days 2-4 was imputed using multiple imputation, if missing.
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Subject analysis set title |
ITT frequency imputed population B (No ibuprofen group)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All patients who were randomised regardless of treatment received, were not advised to take ibuprofen (Group 3+4), and their mean frequency symptom (burning, urgency, day time frequency and night time frequency) severity score on days 2-4 was imputed using multiple imputation, if missing.
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Subject analysis set title |
Per-Protocol population E (Uva ursi group)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Per-Protocol population E is formed of the Intention To Treat (ITT) population (all patients that were randomised regardless of treatment received), but excluding the following patients:
Patients who were randomised in treatment groups 1 or 2 and were not recorded as having at least ‘3’ doses of ibuprofen on days 1, 2 and 3, or patients who were randomised in treatment groups 3 or 4 and were recorded as having any use of ibuprofen.
This subject analysis set includes patients who took Uva ursi (Group 1+3) and belong to the per-protocol population E.
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Subject analysis set title |
Per-Protocol population E (Uva ursi placebo group)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Per-Protocol population E is formed of the Intention To Treat (ITT) population (all patients that were randomised regardless of treatment received), but excluding the following patients:
Patients who were randomised in treatment groups 1 or 2 and were not recorded as having at least ‘3’ doses of ibuprofen on days 1, 2 and 3, or patients who were randomised in treatment groups 3 or 4 and were recorded as having any use of ibuprofen.
This subject analysis set includes patients who took Uva ursi placebo (Group 2+4) and belong to the per-protocol population E.
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Subject analysis set title |
Per-Protocol population E (Ibuprofen group)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Per-Protocol population E is formed of the Intention To Treat (ITT) population (all patients that were randomised regardless of treatment received), but excluding the following patients:
Patients who were randomised in treatment groups 1 or 2 and were not recorded as having at least ‘3’ doses of ibuprofen on days 1, 2 and 3, or patients who were randomised in treatment groups 3 or 4 and were recorded as having any use of ibuprofen.
This subject analysis set includes patients who were advised to take ibuprofen (Group 1+2) and belong to the per-protocol population E.
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Subject analysis set title |
Per-Protocol population E (No ibuprofen group)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Per-Protocol population E is formed of the Intention To Treat (ITT) population (all patients that were randomised regardless of treatment received), but excluding the following patients:
Patients who were randomised in treatment groups 1 or 2 and were not recorded as having at least ‘3’ doses of ibuprofen on days 1, 2 and 3, or patients who were randomised in treatment groups 3 or 4 and were recorded as having any use of ibuprofen.
This subject analysis set includes patients who were not advised to take ibuprofen (Group 3+4) and belong to the per-protocol population E.
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Subject analysis set title |
Per-Protocol population F (Uva ursi group)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Per-Protocol population F is formed of the Intention To Treat (ITT) population (all patients that were randomised regardless of treatment received), but excluding the following patients:
Patients who were not recorded as having at least ‘3’ doses of Uva ursi on days 1, 2 and 3.
This subject analysis set includes patients who took Uva ursi (Group 1+3) and belong to the per-protocol population F.
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Subject analysis set title |
Per-Protocol population F (Uva ursi placebo group)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Per-Protocol population F is formed of the Intention To Treat (ITT) population (all patients that were randomised regardless of treatment received), but excluding the following patients:
Patients who were not recorded as having at least ‘3’ doses of Uva ursi on days 1, 2 and 3.
This subject analysis set includes patients who took Uva ursi placebo (Group 2+4) and belong to the per-protocol population F.
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Subject analysis set title |
Per-Protocol population F (Ibuprofen group)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Per-Protocol population F is formed of the Intention To Treat (ITT) population (all patients that were randomised regardless of treatment received), but excluding the following patients:
Patients who were not recorded as having at least ‘3’ doses of Uva ursi on days 1, 2 and 3.
This subject analysis set includes patients who were advised to take ibuprofen (Group 1+2) and belong to the per-protocol population F.
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Subject analysis set title |
Per-Protocol population F (No ibuprofen group)
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Subject analysis set type |
Per protocol | ||
Subject analysis set description |
Per-Protocol population F is formed of the Intention To Treat (ITT) population (all patients that were randomised regardless of treatment received), but excluding the following patients:
Patients who were not recorded as having at least ‘3’ doses of Uva ursi on days 1, 2 and 3.
This subject analysis set includes patients who were not advised to take ibuprofen (Group 3+4) and belong to the per-protocol population F.
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Subject analysis set title |
ITT population A (Uva ursi group)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All patients who were randomised regardless of treatment received and took Uva Ursi (Group 1+3).
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Subject analysis set title |
ITT population A (Uva ursi placebo group)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All patients who were randomised regardless of treatment received and took Uva Ursi placebo (Group 2+4).
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Subject analysis set title |
ITT population A (Ibuprofen group)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All patients who were randomised regardless of treatment received and were advised to take Ibuprofen (Group 1+2).
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Subject analysis set title |
ITT population A (No ibuprofen group)
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Subject analysis set type |
Intention-to-treat | ||
Subject analysis set description |
All patients who were randomised regardless of treatment received and were not advised to take Ibuprofen (Group 3+4).
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End point title |
Frequency symptom severity on days 2-4 (ITT frequency imputed population B - Uva ursi comparison) | ||||||||||||
End point description |
Mean frequency symptom (burning, urgency, day time frequency and night time frequency) severity score on days 2-4, for the intention to treat population with imputed frequency symptom severity scores on days 2-4 using multiple imputation.
Main comparison: Uva ursi versus Uva ursi placebo.
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End point type |
Primary
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End point timeframe |
Across days 2-4 after the start of the treatment (day 1 represents the start of the treatment).
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Statistical analysis title |
Analysis of covariance | ||||||||||||
Statistical analysis description |
ANCOVA model: Mean frequency symptom severity score on days 2-4 = intercept + uva ursi treatment group + ibuprofen treatment group + mean frequency symptom severity score at baseline + age.
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Comparison groups |
ITT frequency imputed population B (Uva ursi group) v ITT frequency imputed population B (Uva ursi placebo group)
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Number of subjects included in analysis |
382
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Analysis specification |
Pre-specified
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Analysis type |
superiority | ||||||||||||
P-value |
= 0.661 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Least squares means difference | ||||||||||||
Point estimate |
-0.06
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Confidence interval |
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level |
95% | ||||||||||||
sides |
2-sided
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lower limit |
-0.33 | ||||||||||||
upper limit |
0.21 | ||||||||||||
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End point title |
Frequency symptom severity on days 2-4 (ITT frequency imputed population B - Ibuprofen comparison) | ||||||||||||
End point description |
Mean frequency symptom (burning, urgency, day time frequency and night time frequency) severity score on days 2-4, for the intention to treat population with imputed frequency symptom severity scores on days 2-4 using multiple imputation.
Main comparison: Advice to take ibuprofen versus no advice to take ibuprofen.
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End point type |
Primary
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||||||||||||
End point timeframe |
Across days 2-4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of covariance | ||||||||||||
Statistical analysis description |
ANCOVA model: Mean frequency symptom severity score on days 2-4 = intercept + uva ursi treatment group + ibuprofen treatment group + mean frequency symptom severity score at baseline + age.
|
||||||||||||
Comparison groups |
ITT frequency imputed population B (Ibuprofen group) v ITT frequency imputed population B (No ibuprofen group)
|
||||||||||||
Number of subjects included in analysis |
382
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.951 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Least squares means difference | ||||||||||||
Point estimate |
-0.01
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.27 | ||||||||||||
upper limit |
0.26 | ||||||||||||
|
|||||||||||||
End point title |
Frequency symptom severity on days 2-4 (Per-Protocol population E - Uva ursi comparison) | ||||||||||||
End point description |
Mean frequency symptom (burning, urgency, day time frequency and night time frequency) severity score on days 2-4, for the per-protocol ibuprofen related population E.
Main comparison: Uva ursi versus Uva ursi placebo.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Across days 2-4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of covariance | ||||||||||||
Statistical analysis description |
ANCOVA model: Mean frequency symptom severity score on days 2-4 = intercept + uva ursi treatment group + ibuprofen treatment group + mean frequency symptom severity score at baseline + age.
|
||||||||||||
Comparison groups |
Per-Protocol population E (Uva ursi group) v Per-Protocol population E (Uva ursi placebo group)
|
||||||||||||
Number of subjects included in analysis |
171
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.805 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Least squares means difference | ||||||||||||
Point estimate |
0.04
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.28 | ||||||||||||
upper limit |
0.36 | ||||||||||||
|
|||||||||||||
End point title |
Frequency symptom severity on days 2-4 (Per-Protocol population E - Ibuprofen comparison) | ||||||||||||
End point description |
Mean frequency symptom (burning, urgency, day time frequency and night time frequency) severity score on days 2-4, for the per-protocol ibuprofen related population E.
Main comparison: Advice to take ibuprofen versus no advice to take ibuprofen.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Across days 2-4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of covariance | ||||||||||||
Statistical analysis description |
ANCOVA model: Mean frequency symptom severity score on days 2-4 = intercept + uva ursi treatment group + ibuprofen treatment group + mean frequency symptom severity score at baseline + age.
|
||||||||||||
Comparison groups |
Per-Protocol population E (Ibuprofen group) v Per-Protocol population E (No ibuprofen group)
|
||||||||||||
Number of subjects included in analysis |
171
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.69 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Least squares means difference | ||||||||||||
Point estimate |
0.07
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.27 | ||||||||||||
upper limit |
0.41 | ||||||||||||
|
|||||||||||||
End point title |
Frequency symptom severity on days 2-4 (Per-Protocol population F - Uva ursi comparison) | ||||||||||||
End point description |
Mean frequency symptom (burning, urgency, day time frequency and night time frequency) severity score on days 2-4, for the per-protocol uva ursi related population F.
Main comparison: Uva ursi versus uva ursi placebo.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Across days 2-4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of covariance | ||||||||||||
Statistical analysis description |
ANCOVA model: Mean frequency symptom severity score on days 2-4 = intercept + uva ursi treatment group + ibuprofen treatment group + mean frequency symptom severity score at baseline + age.
|
||||||||||||
Comparison groups |
Per-Protocol population F (Uva ursi group) v Per-Protocol population F (Uva ursi placebo group)
|
||||||||||||
Number of subjects included in analysis |
209
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.407 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Least squares means difference | ||||||||||||
Point estimate |
-0.12
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.4 | ||||||||||||
upper limit |
0.16 | ||||||||||||
|
|||||||||||||
End point title |
Frequency symptom severity on days 2-4 (Per-Protocol population F - Ibuprofen comparison) | ||||||||||||
End point description |
Mean frequency symptom (burning, urgency, day time frequency and night time frequency) severity score on days 2-4, for the per-protocol uva ursi related population F.
Main comparison: Advice to take ibuprofen versus no advice to take ibuprofen.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Across days 2-4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of covariance | ||||||||||||
Statistical analysis description |
ANCOVA model: Mean frequency symptom severity score on days 2-4 = intercept + uva ursi treatment group + ibuprofen treatment group + mean frequency symptom severity score at baseline + age.
|
||||||||||||
Comparison groups |
Per-Protocol population F (Ibuprofen group) v Per-Protocol population F (No ibuprofen group)
|
||||||||||||
Number of subjects included in analysis |
209
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.73 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Least squares means difference | ||||||||||||
Point estimate |
-0.05
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.34 | ||||||||||||
upper limit |
0.24 | ||||||||||||
|
||||||||||
End point title |
Antibiotic use during week 1 and week 2 (ITT population A - Uva ursi comparison) | |||||||||
End point description |
Indicator of use of antibiotics as recorded in the symptom diary during weeks 1-2.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Across days 1-14 after the start of the treatment (day 1 represents the start of the treatment).
|
|||||||||
|
||||||||||
Statistical analysis title |
Logistic regression | |||||||||
Statistical analysis description |
Logistic regression model on the antibiotic use during week 1 and week 2 adjusting for age (Uva ursi comparison).
|
|||||||||
Comparison groups |
ITT population A (Uva ursi group) v ITT population A (Uva ursi placebo group)
|
|||||||||
Number of subjects included in analysis |
276
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
P-value |
= 0.293 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
0.59
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.22 | |||||||||
upper limit |
1.58 | |||||||||
|
||||||||||
End point title |
Antibiotic use during week 1 and week 2 (ITT population A - Ibuprofen comparison) | |||||||||
End point description |
Indicator of use of antibiotics as recorded in the symptom diary during weeks 1-2.
|
|||||||||
End point type |
Secondary
|
|||||||||
End point timeframe |
Across days 1-14 after the start of treatment (day 1 represents the start of the treatment).
|
|||||||||
|
||||||||||
Statistical analysis title |
Logistic regression | |||||||||
Statistical analysis description |
Logistic regression model on the antibiotic use during week 1 and week 2 adjusting for age (Ibuprofen comparison).
|
|||||||||
Comparison groups |
ITT population A (Ibuprofen group) v ITT population A (No ibuprofen group)
|
|||||||||
Number of subjects included in analysis |
276
|
|||||||||
Analysis specification |
Pre-specified
|
|||||||||
Analysis type |
superiority | |||||||||
P-value |
= 0.009 | |||||||||
Method |
Regression, Logistic | |||||||||
Parameter type |
Odds ratio (OR) | |||||||||
Point estimate |
0.27
|
|||||||||
Confidence interval |
||||||||||
level |
95% | |||||||||
sides |
2-sided
|
|||||||||
lower limit |
0.1 | |||||||||
upper limit |
0.72 | |||||||||
|
|||||||||||||
End point title |
Frequency symptom severity on days 2-4 adjusting for antibiotic use up to day 4 (ITT frequency imputed population B - Uva ursi comparison) | ||||||||||||
End point description |
Mean frequency symptom (burning, urgency, day time frequency and night time frequency) severity score on days 2-4, for the intention to treat population with imputed frequency symptom severity scores on days 2-4 using multiple imputation, adjusting for antibiotic use up to day 4 after the start of the treatment.
Main comparison: Uva ursi versus Uva ursi placebo.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Across days 2-4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of covariance | ||||||||||||
Statistical analysis description |
ANCOVA model: Mean frequency symptom severity score on days 2-4 = intercept + uva ursi treatment group + ibuprofen treatment group + mean frequency symptom severity score at baseline + age + indicator of use of antibiotics up to day 4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
Comparison groups |
ITT frequency imputed population B (Uva ursi placebo group) v ITT frequency imputed population B (Uva ursi group)
|
||||||||||||
Number of subjects included in analysis |
382
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.704 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Least squares means difference | ||||||||||||
Point estimate |
-0.05
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.32 | ||||||||||||
upper limit |
0.21 | ||||||||||||
|
|||||||||||||
End point title |
Frequency symptom severity on days 2-4 adjusting for antibiotic use up to day 4 (ITT frequency imputed population B - Ibuprofen comparison) | ||||||||||||
End point description |
Mean frequency symptom (burning, urgency, day time frequency and night time frequency) severity score on days 2-4, for the intention to treat population with imputed frequency symptom severity scores on days 2-4 using multiple imputation, adjusting for antibiotic use up to day 4 after the start of the treatment.
Main comparison: Advice to take ibuprofen versus No advice to take ibuprofen.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Across days 2-4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of covariance | ||||||||||||
Statistical analysis description |
ANCOVA model: Mean frequency symptom severity score on days 2-4 = intercept + uva ursi treatment group + ibuprofen treatment group + mean frequency symptom severity score at baseline + age + indicator of use of antibiotics up to day 4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
Comparison groups |
ITT frequency imputed population B (Ibuprofen group) v ITT frequency imputed population B (No ibuprofen group)
|
||||||||||||
Number of subjects included in analysis |
382
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.791 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Least squares means difference | ||||||||||||
Point estimate |
0.04
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.24 | ||||||||||||
upper limit |
0.31 | ||||||||||||
|
|||||||||||||
End point title |
Frequency symptom severity on days 2-4 adjusting for antibiotic use up to day 4 (Per-Protocol population E - Uva ursi comparison) | ||||||||||||
End point description |
Mean frequency symptom (burning, urgency, day time frequency and night time frequency) severity score on days 2-4, for the per-protocol ibuprofen related population E, adjusting for antibiotic use up to day 4 after the start of the treatment.
Main comparison: Uva ursi versus Uva ursi placebo.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Across days 2-4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of covariance | ||||||||||||
Statistical analysis description |
ANCOVA model: Mean frequency symptom severity score on days 2-4 = intercept + uva ursi treatment group + ibuprofen treatment group + mean frequency symptom severity score at baseline + age + indicator of use of antibiotics up to day 4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
Comparison groups |
Per-Protocol population E (Uva ursi group) v Per-Protocol population E (Uva ursi placebo group)
|
||||||||||||
Number of subjects included in analysis |
161
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.819 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Least squares means difference | ||||||||||||
Point estimate |
0.04
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.28 | ||||||||||||
upper limit |
0.36 | ||||||||||||
|
|||||||||||||
End point title |
Frequency symptom severity on days 2-4 adjusting for antibiotic use up to day 4 (Per-Protocol population E - Ibuprofen comparison) | ||||||||||||
End point description |
Mean frequency symptom (burning, urgency, day time frequency and night time frequency) severity score on days 2-4, for the per-protocol ibuprofen related population E, adjusting for antibiotic use up to day 4 after the start of the treatment.
Main comparison: Advice to take ibuprofen versus No advice to take ibuprofen.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Across days 2-4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of covariance | ||||||||||||
Statistical analysis description |
ANCOVA model: Mean frequency symptom severity score on days 2-4 = intercept + uva ursi treatment group + ibuprofen treatment group + mean frequency symptom severity score at baseline + age + indicator of use of antibiotics up to day 4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
Comparison groups |
Per-Protocol population E (Ibuprofen group) v Per-Protocol population E (No ibuprofen group)
|
||||||||||||
Number of subjects included in analysis |
161
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.486 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Least squares means difference | ||||||||||||
Point estimate |
0.12
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.22 | ||||||||||||
upper limit |
0.47 | ||||||||||||
|
|||||||||||||
End point title |
Frequency symptom severity on days 2-4 adjusting for antibiotic use up to day 4 (Per-Protocol population F - Uva ursi comparison) | ||||||||||||
End point description |
Mean frequency symptom (burning, urgency, day time frequency and night time frequency) severity score on days 2-4, for the per-protocol uva ursi related population F, adjusting for antibiotic use up to day 4 after the start of the treatment.
Main comparison: Uva ursi versus uva ursi placebo.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Across days 2-4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of covariance | ||||||||||||
Statistical analysis description |
ANCOVA model: Mean frequency symptom severity score on days 2-4 = intercept + uva ursi treatment group + ibuprofen treatment group + mean frequency symptom severity score at baseline + age + indicator of use of antibiotics up to day 4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
Comparison groups |
Per-Protocol population F (Uva ursi group) v Per-Protocol population F (Uva ursi placebo group)
|
||||||||||||
Number of subjects included in analysis |
202
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.559 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Least squares means difference | ||||||||||||
Point estimate |
-0.08
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.36 | ||||||||||||
upper limit |
0.2 | ||||||||||||
|
|||||||||||||
End point title |
Frequency symptom severity on days 2-4 adjusting for antibiotic use up to day 4 (Per-Protocol population F - Ibuprofen comparison) | ||||||||||||
End point description |
Mean frequency symptom (burning, urgency, day time frequency and night time frequency) severity score on days 2-4, for the per-protocol uva ursi related population F, adjusting for antibiotic use up to day 4 after the start of the treatment.
Main comparison: Advice to take ibuprofen versus No advice to take ibuprofen.
|
||||||||||||
End point type |
Secondary
|
||||||||||||
End point timeframe |
Across days 2-4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
|
|||||||||||||
Statistical analysis title |
Analysis of covariance | ||||||||||||
Statistical analysis description |
ANCOVA model: Mean frequency symptom severity score on days 2-4 = intercept + uva ursi treatment group + ibuprofen treatment group + mean frequency symptom severity score at baseline + age + indicator of use of antibiotics up to day 4 after the start of the treatment (day 1 represents the start of the treatment).
|
||||||||||||
Comparison groups |
Per-Protocol population F (No ibuprofen group) v Per-Protocol population F (Ibuprofen group)
|
||||||||||||
Number of subjects included in analysis |
202
|
||||||||||||
Analysis specification |
Pre-specified
|
||||||||||||
Analysis type |
superiority | ||||||||||||
P-value |
= 0.878 | ||||||||||||
Method |
ANCOVA | ||||||||||||
Parameter type |
Least squares means difference | ||||||||||||
Point estimate |
0.02
|
||||||||||||
Confidence interval |
|||||||||||||
level |
95% | ||||||||||||
sides |
2-sided
|
||||||||||||
lower limit |
-0.26 | ||||||||||||
upper limit |
0.31 | ||||||||||||
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Adverse events information
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Timeframe for reporting adverse events |
All adverse events, for patients randomised into the trial, should be reported from the time the patient signs the informed consent form until four weeks after randomisation.
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Adverse event reporting additional description |
Adverse events presenting to the participants GP will be notified by the practitioner.
In addition participants will carry a study card which highlights the need to notify their own doctor regarding adverse events. As a final check all participants will be asked to consent to a medical notes review which will take place three months after study re
|
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Assessment type |
Systematic | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Dictionary used for adverse event reporting
|
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Dictionary name |
CTCAE | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Dictionary version |
4
|
||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
|
Reporting groups
|
|||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
Reporting group title |
Group 1: Uva ursi + Advice to take ibuprofen
|
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Reporting group description |
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Reporting group title |
Group 2: Uva ursi placebo + Advice to take ibuprofen
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Reporting group description |
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Reporting group title |
Group 3: Uva ursi + No advice to take ibuprofen
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Reporting group description |
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Reporting group title |
Group 4: Uva ursi placebo + No advice to take ibuprofen
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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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16 Jan 2015 |
Protocol updated (v2)
- Informed Consent Forms for the Main Trial amended to include consent to have a pregnancy test if required and to provide a urine sample for microbial culture.
- Patient Information Sheets for the Main Trial amended to clarify how participant contact details will be securely stored.
- Trial Participant Treatment Card amended to include telephone number for the Southampton Clinical Trials Unit.
- Qualitative Research GP Invitation Letter – this is a new document.
- Symptom Diary by Recall – this is a new document.
- Symptom Diary by Recall Guidelines – this is a new document.
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24 Apr 2015 |
Protocol updated (v3)
- Modified trial design replacing ibuprofen/placebo with 'advice to take ibuprofen/no advice'. This resulted in changes to the trial titles (full and simplified); primary and secondary objectives; the method of statistical analysis and sample size.
- Patient Pack Instruction Cards have been designed to be included in the patient packs to instruct the clinician to advise the participant to take ibuprofen or to give no recommendation.
- The IMP labels have been amended in line with the new trial design.
- The Investigator Brochure for Uva ursi has been changed to remove all reference to ibuprofen and NuPharm laboratories and to document that Essential Nutrition will be responsible for packaging, labelling and distribution of the Patient Packs.
- The IMPDs for Uva ursi and placebo have been updated to include the 6 and 9 month stability data and the proposed shelf life for Uva ursi capsules is 21 months based on the 9 month real-time stability data.
- The protocol and study documents have been amended in line with the new trial design and all references to ibuprofen have been removed from patient facing documents. Amended study documents include: ICFs (4), PISs (4), GP notification letter, Trial Participant Treatment Card, Clinic Poster, Qualitative Research Invitation Letters (2), Participant Diary.
- The participant focus group discussions have been removed.
- The recording of AR/AEs restricted to those judged to be possibly related to the study - medical areas/symptoms specified.
- Participant Urine Collection Instruction Sheet - this is a new document.
- Some minor changes to the text of the protocol and trial documents for clarification purposes or to correct typographical and grammatical errors. New logos for SCTU and the trial added where appropriate.
- Changes to the DMEC membership.
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24 Mar 2016 |
Protocol updated (v4)
- Version 3 of the protocol stated incorrectly in the Trial Synopsis that Uva ursi should be taken 4 times a day instead of 3 times a day. In the main body of the protocol the dosage regimen is specified correctly. This was a typographical error but as the Trial Synopsis is the first point of reference to the IMP in the protocol it was considered a significant error.
- Patient Information Sheet for the Main Trial amended to
a) clarify why a pregnancy test is being carried out.
b) include that if participant falls pregnant whilst taking the IMP they will need to be followed up by their GP until the outcome of their pregnancy is known
c) correct grammatical error - Uva Ursi changed to Uva ursi through out
- Patient Information Sheet for the Main Trial + Day 4 Urine Collection amended as above for PIS for the Main Trial.
- Participant Diary amended by merging the treatment tables on p7 & p9 to collect information more accurately as to when participants took any other treatments. The same data is being collected but in a different format. Some minor changes have been made to the text and order of the diary to correct typographical and grammatical errors or for clarification purposes.
- Addition of 5 new sites: NHS West Sussex PCT; NHS Surrey PCT; NHS East Sussex Downs & Welad PCT; NHS Brighton and Hove City PCT; NHS Hastings and Rother PCT
- Approval of letters to participants following a serious protocol and GCP breach where formal written consent, as detailed in Section 7.2.1 of the protocol, has not been taken from 18 participants taking part in the Qualitative Interviews.
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19 May 2016 |
Protocol updated (v5) [REJECTED BY MHRA - SEE V6 RESUBMISSION]
- IMPDs updated with 18 month stability data to give shelf life of 30 months.
- Increased sample size from 328 to 376 and extended recruitment period to 30/09/16.
- Protocol amended to clarify that GPs and nurse prescribers (NP) can be interviewed as part of the qualitative research study; to clarify that these interviews can take place over the phone; to specify the number of GP/NPs that will be interviewed and to clarify the consent process for both patient and GP/NP interviews.
- PIS updated to include explanation why participants should consult their GP immediately if they develop symptoms of a kidney infection and to clarify that they will be contacted by the research team if after 3 weeks they have not returned their diary or there is key information missing.
- Participant Diary amended to explain that participants will receive a £5 voucher when they have returned a fully completed diary.
- The list of staff conducting specified research procedures has been extended to include HCAs and CTAs. |
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28 Jul 2016 |
Protocol updated (v6)
Resubmission of v5 of the protocol with the following change as requested by the MHRA:
- Exclusion criterion "Recruited to another interventional randomised control trial in previous 4 weeks" amended to " Recruited to another interventional trial in previous 6 weeks".
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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. | |||
Online references |
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| http://www.ncbi.nlm.nih.gov/pubmed/28886751 |
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