The Effect of Methenamine Hippurate to Reduce Antibiotic Prescribing Due to New Episodes of Urinary Tract Infections (UTI) in Elderly Women With Recurrent UTI - a Triple- Blinded, Randomized Placebo-controlled Phase IV Study
Phase: PHASE4
Conditions: Recurrent Urinary Tract Infection
Sponsor: University of Oslo

 CLINICAL STUDY PROTOCOL 
 
 
 
 
 
 
 
The effect of methenamine hippurate to reduce antibiotic 
prescribing due to new episodes of urinary tract infections 
(UTI) in elderly women with recurrent UTI – a triple-blinded, 
randomized placebo-controlled phase IV study 
 
 
Study Code: 
ImpresU WP3 (Improving rational prescribing for UTI in frail elderly Work 
Package 3) 
EudraCT Number: 
2018-002235-15  
Version Number: 
Version 11.1 
Date: 
7th July 2021 
 
 
Sponsor: 
University of Oslo 
Principal investigator(s): 
Sigurd Høye  
 
 
 
 
 
 
 
 
 
 
 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
2 (35) 
 
SYNOPSIS 
 
Title: The effect of methenamine hippurate to reduce antibiotic prescribing due to new episodes of 
urinary tract infections (UTI) in elderly women with recurrent UTI – a triple-blinded, randomized 
placebo-controlled phase IV study 
 
EudraCT Number: 
2018-002235-15 
 
Indication: Recurrent UTI in elderly women is a major driver of antibiotic prescription.  
 
Rational for conducting the study: There is a need for a large well-conducted randomised 
controlled trial (RCT) to clarify both the safety and preventive effect of methenamine hippurate for 
longer term use. 
 
Primary objective: The primary objective of this study is to investigate if taking methenamine 
hippurate reduce the need for antibiotic usage due to recurrent UTI (measured as the number of 
courses of antibiotics). 
 
Secondary objectives: 
 
to investigate if methenamine hippurate will have a prolonged effect on antibiotic usage even 
after discontinuation 
 
to investigate if taking methenamine hippurate reduces the incidence of UTI 
 
to investigate if methenamine hippurate can reduce severity of UTI symptoms 
 
to investigate if methenamine hippurate can reduce duration of UTI episodes 
 
to investigate if number of complications such as pyelonephritis and hospital admission for 
UTI differ between methenamine hippurate and placebo 
 
To investigate if phylogenetic subgroups of E. Coli found at inclusion is an effect modifier in 
the above outcomes. 
 
Study design: Blinded randomised controlled phase IV trial where patients are randomised to 
active intervention (methenamine hippurate) or controls (placebo).  
 
Study population: Women aged ≥70 years with recurrent UTIs in community dwellings.  
 
Number of patients: 400. 
 
Inclusion criteria:  
 
woman 
 
age ≥70 years 
 
recurrent UTIs defined as ≥3 episodes of antibiotic treated acute cystitis (acute symptoms 
specific/related to the urinary tract) during the last twelve months or ≥2 episodes during the 
last 6 months 
 
able and willing to comply with all trial requirements  
 
able and willing to give informed consent 

Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1 
Date: 
7th July 2021 
3 (35) 
Exclusion criteria: 

the patient has taken methenamine hippurate within the last 12 months

the patient is allergic to methenamine hippurate

the patient is having current antibiotic prophylaxis for UTI

the patient has a urinary catheter (chronic indwelling catheters as well as intermittent
urinary catheterisation)

the patient has known severe chronic renal failure or estimated creatinine glomerular
filtration rate ≤30 ml/min (known = registered in GP clinical records)

the patient has a known condition or treatment associated with significant impaired
immunity (e.g. long-term oral steroids, chemotherapy, or immune disorder) (known =
registered in GP clinical records)

the patient has a known severe hepatic impairment (known = registered in GP clinical
records)

the patient is suffering from severe dehydration

the patient has gout

the patient has a need for long term use of antacids such as magnesium hydroxide,
magnesium carbonate, aluminium hydroxide

the patient has a life expectancy estimated by a clinician to be less than six months

the patient has been involved in, including completion of, follow-up procedures, in another
clinical trial of an investigational medicinal product in the last 90 days

the patient suffers from incontinence too severe to be able to provide a voided urine
specimen

the patient is participating in ImpresU Work Package 2

the patient is suffering from significant known abnormal renal tract anatomy/physiology (i.e.
single kidney, persistent urinary tract stone disease, severe vesicoureteral reflux) or
neuropathic bladder disorders

lactose intolerance.
Premature termination of the study 
The difference between groups in SAEs deemed to be linked to possible treatment with 
methenamine hippurate will be continuously monitored without breaking the code. The study will be 
terminated in case there are significantly more SAEs within one of the groups during the trial.  
Investigational product, dosage and administration: Methenamine hippurate 1 gram or placebo 
per os morning and evening day 1-180. 
Primary outcome variables and examinations: Number of UTI courses during day 2-180 
Study period: 1 November 2019 to 31 December 2022. 

Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1 
Date: 
7th July 2021 
5 (35) 
Signature Principal Investigator the Netherlands
Date (day-month-year)
Theo Verheij 
Printed name of Principal Investigator the Netherlands
Signature Principal Investigator Poland
Date (day-month-year)
Maciek Godycki-Cwirko 
Printed name of Principal Investigator Poland

Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1 
Date: 
7th July 2021 
6 (35) 
CONTACT DETAILS
Role 
Name 
Address 
Phone 
Fax 
E-mail 
Sponsor 
University 
of Oslo 
PO Box 
1130, 
Blindern, 
0318 Oslo, 
Norway 
+47 
228506
50 
Mette.brekke@medisin.uio
.no 
Chief 
Investigator 
Sigurd 
Høye 
PO Box 
1130, 
Blindern, 
0318 Oslo, 
Norway 
+47 
22844603 
+47 
228506
50 
Sigurd.hoye@medisin. 
uio.no 
Principal 
Investigator 
Sweden 
Pär-Daniel 
Sundvall 
Research 
and 
Development 
Primary 
Health Care, 
Region 
Västra 
Götaland, 
Research 
and 
Development 
Centre Södra 
Älvsborg 
Sweden, 
Sven 
Eriksonsplats
en 4, SE-503 
38 Borås 
+46 
722506196 
par-
daniel.sundvall@vgregion.
se 
Principal 
Investigator 
the 
Netherlands 
Theo 
Verheij 
Universitair 
Medisch 
Centrum 
Utrecht, 
Julius Center, 
Heidelbergla
an100, 
3584CX, 
Utrecht, 
the 
Netherlands,  
T.J.M.Verheij@umcutrecht
.nl  

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
7 (35) 
 
 
Principal 
Investigator 
Poland 
 Maciek 
Godycki-
Cwirko 
Medical 
University of 
Lodz, Centre 
for Family 
and 
community 
Medicine, 
Ulica 
Kopcinskiego 
20, 90-153 
Lodz,  
Phone +48 
42 679 55 46, 
Fax +48  
42 678 6041 
 
maciej.godycki-
cwirko@umed.lodz.pl 
 
 
 
 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
8 (35) 
 
TABLE OF CONTENTS 
1. 
Introduction ...........................................................................................................................11 
1.1. 
Background ..........................................................................................................................11 
1.2. 
Rationale for conducting this study ......................................................................................11 
1.3. 
Risk/Benefit evaluation ........................................................................................................11 
2. 
Study Objectives and Endpoints ..........................................................................................12 
3. 
Study Design and Procedures .............................................................................................14 
3.1. 
Overall study design and flow chart .....................................................................................14 
3.2. 
Rationale for study design ...................................................................................................14 
3.3. 
Table 1. Study visits .............................................................................................................15 
3.4. 
Study assessments ..............................................................................................................15 
4. 
Study Population ..................................................................................................................17 
4.1. 
Inclusion criteria ...................................................................................................................17 
4.2. 
Exclusion criteria ..................................................................................................................17 
4.3. 
Subject enrolment and randomization .................................................................................18 
4.4. 
Discontinuation and withdrawal of subjects .........................................................................18 
4.4.1. 
Withdrawal of subjects .........................................................................................................18 
4.4.2. 
Premature termination of the study .....................................................................................19 
5. 
Study Treatments .................................................................................................................19 
5.1. 
Identity of investigational medicinal products ......................................................................19 
5.1.1. 
Doses and length of treatment. ............................................................................................20 
5.1.2. 
Labelling ...............................................................................................................................20 
5.1.3. 
Storage and handling ...........................................................................................................20 
5.1.4. 
Drug accountability and treatment compliance ...................................................................20 
5.1.5. 
Destruction ...........................................................................................................................20 
5.2. 
Blinding .................................................................................................................................21 
5.4 Concomitant medication ..............................................................................................................21 
6. 
Study Measurements and Variables ....................................................................................22 
6.1. 
Primary variable ...................................................................................................................22 
6.2. 
Secondary variable(s) ..........................................................................................................22 
6.3. 
Safety variable(s) .................................................................................................................22 
6.4. 
Biological sampling procedures ...........................................................................................22 
6.4.1. 
Handling, storage and destruction of biological samples ....................................................22 
6.4.2. 
Total volume of blood per patient ........................................................................................23 
6.4.3. 
Biobank ................................................................................................................................23 
7. 
Safety ...................................................................................................................................23 
7.1. 
Reference Safety Information ..............................................................................................23 
7.2. 
Definitions .............................................................................................................................24 
7.2.1. 
Adverse Event (AE)..............................................................................................................24 
7.2.2. 
Adverse Drug Reaction (ADR) .............................................................................................24 
7.2.3. 
Serious Adverse Event (SAE) ..............................................................................................25 
7.2.4. 
Suspected unexpected serious adverse reaction (SUSAR) ...............................................25 
7.3. 
Reporting ..............................................................................................................................25 
7.3.1. 
Adverse Event (AE)..............................................................................................................25 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
9 (35) 
 
7.3.2. 
Adverse Drug Reaction (ADR) .............................................................................................25 
7.3.3. 
Serious Adverse Event (SAE) ..............................................................................................25 
7.3.4. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) ............................................26 
7.3.5. 
Annual Safety Report ...........................................................................................................27 
8. 
Statistics ...............................................................................................................................27 
8.1. 
Sample size calculation .......................................................................................................27 
8.2. 
Statistical analysis ................................................................................................................27 
9. 
Data Management ................................................................................................................29 
9.1. 
Recording of data .................................................................................................................29 
9.1.1. 
Source data ..........................................................................................................................30 
9.2. 
Data storage and management ...........................................................................................30 
10. 
Quality Control and Quality Assurance ................................................................................30 
10.1. 
Monitoring .............................................................................................................................30 
10.2. 
Audits and inspections .........................................................................................................31 
10.3. 
Data safety monitoring committee .......................................................................................31 
11. 
Ethics ....................................................................................................................................31 
11.1. 
Ethics committee ..................................................................................................................31 
11.2. 
Informed consent .................................................................................................................32 
11.3. 
Subject data protection ........................................................................................................32 
11.4. 
Insurances ............................................................................................................................32 
12. 
Protocol Deviations and Amendments ................................................................................32 
13. 
Report and publications .......................................................................................................33 
14. 
Study Timetable ...................................................................................................................33 
14.1. 
Study Period .........................................................................................................................33 
14.2. 
Definition of “End of study”...................................................................................................33 
15. 
List of References ................................................................................................................33 
 
 
LIST OF APPENDICES 
 
1. Farmasøytisk/kjemisk dokumentasjon for Hiprex, Kragerø tablettproduksjon A/S. 
2. SmPC Hiprex, Meda. 
3. Etikettforslag norsk 
4. Patient reported outcome 
5. Safety reporting flow-chart 
6. EMA-akkreditering 
7. Mail Legemiddelansvarsforsikring 
8. Legemiddelansv.forsikring Kragerø tabl.prod. 
 
 
 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
10 (35) 
 
LIST OF ABBREVIATIONS  
 
Abbreviation 
Explanation 
ADR 
Adverse Drug Reaction 
AE 
Adverse Event 
AMR 
Antimicrobial Resistance 
CA 
Competent Authority 
EC 
Ethics Committee  
(e)CRF  
(electronic) Case Report Form  
EDC 
Electronic Data Capture 
GCP 
Good Clinical Practice 
GP 
General Practitioner 
ICF 
Informed Consent Form 
IMP 
Investigational Medicinal Product 
ImpresU 
Improving rational prescribing for UTI in frail elderly 
ISF 
Investigator Study File 
OOH 
Out Of Hours Service 
PI 
Principal Investigator 
PRO 
Patient Reported Outcome (PRO) 
RCT 
Randomised Controlled Trial 
RO 
Research Online 
SAE 
Serious Adverse Event  
SAR 
Serious Adverse drug Reaction 
SmPC 
Summary of Product Characteristics 
SUSAR 
Suspected Unexpected Serious Adverse Reactions  
UTI 
Urinary Tract Infection 
WP 
Work Package  

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
11 (35) 
 
1. 
INTRODUCTION  
1.1. 
Background 
Recurrent urinary tract infection (UTI) in elderly women is a major driver of antibiotic prescription 
(1-9). Hence, the question of feasible and appropriate preventive measures are important issues in 
this field. Methenamine hippurate is frequently prescribed in Norway and Sweden as prophylaxis 
for recurrent UTI (9). Methenamine hippurate is hardly used outside of Scandinavia. Methenamine 
hippurate acts via the production of formaldehyde from hexamine, which in turn acts as a 
bacteriostatic agent, therefore methenamine hippurate is not defined as an antibiotic. According to 
a Cochrane review 2012 the rates of adverse events for preventing UTI was low (10). Although this 
review showed methenamine hippurate might be effective in preventing UTI in the short term, there 
is a need for large well-conducted randomised controlled trial (RCT) to clarify both the safety and 
effectivity of preventive methenamine hippurate for longer term use (11-16). This is particularly 
important for longer term use for people without neuropathic bladder disorders (10). A Norwegian 
longitudinal observational study including women aged 50-80 years with recurrent UTI indicated a 
significant and large reduction of more than 50% in antibiotic prescriptions for UTI after start of 
prophylactic methenamine hippurate (Gjelstad, personal communication). This further strengthens 
the need for an RCT of methenamine hippurate as prophylaxis for recurrent UTI.  
 
Escherichia coli (E. coli) is a part of the human gastrointestinal microbiota (17). Uropathogenic 
E.coli from fecal reservoirs are the predominant causative microbes in uncomplicated UTIs (18-20). 
Previous studies have shown that strains of E.coli can be divided into phylogenetic subgroups (A, 
B1, B2, C, D, E and F), and that subgroup B2 and D represents the most virulent types and are 
associated with extra-intestinal infections (21-23).  
We aim to investigate whether the phylogenetic subgroups of E.coli present in the urine cultures at 
inclusion can have a modifying role on the preventive effect of Methenamine hippurate in this 
study. If feasible, we will also investigate whether or not subsequent episodes of acute UTIs in 
elderly women with recurrent UTI are caused by E.coli of the same phylotype.   
1.2. 
Rationale for conducting this study 
Existing knowledge suggests that methenamine hippurate is a safe drug with few and mild side 
effects and with the potential to significantly reduce antibiotic usage for women with recurrent UTIs. 
Methenamine hippurate has been on the market for a long time but has never been tested to 
prevent recurrent UTIs in larger RCTs with long time follow-up. Hence, this must be proven in a 
large randomised trial before recommending large scale use of this drug (10). 
1.3. 
Risk/Benefit evaluation 
Potential benefits from IMP: 
 
decreased total use of UTI antibiotics 
 
reduced antibiotic pressure on gut microbiota in the population and possibly reduced 
antimicrobial resistance (AMR) in the population  
 
decreased number of UTIs 
 
increased quality of life. 
 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
12 (35) 
 
Potential risks from IMP: 
 
polypharmacy, many patients have a large number of regular medication, and 
methenamine hippurate will be a new one for six months  
 
simultaneous intake of sulphonamide antibiotics can increase risk of crystalluria. Therefore 
methenamine hippurate will temporarily be paused if the participant gets a course of 
sulphonamide antibiotics. There are no other known clinical relevant interactions between 
methenamine hippurate and other pharmaceuticals. 
 
Anticipated adverse drug reactions in the study: 
Methenamine hippurate is well tolerated and adverse effects are rare and generally mild (10). 
Possible side effects might be minor gastrointestinal upsets, dysuria (seldom), abdominal 
cramps, anorexia, rash and stomatitis (10). The trial team will be available on telephone for 
urgent cases during the whole study period. This will be solved for each country. 
 
Risk/benefit rationale: 
 
The benefit of the study is potentially great for elderly women with recurrent UTI resulting in 
fewer UTI episodes, reduced antibiotic usage and therefore also reducing the risk of AMR. 
 
The risk of the study is considered to be very small. 
 
In summary the benefits greatly outweigh the potential small risks. This will be evaluated and 
confirmed by relevant ECs before commencing the trial. 
    
2. 
STUDY OBJECTIVES AND ENDPOINTS 
The primary objective of this study is to investigate if taking methenamine hippurate reduce the 
need for antibiotic usage due to recurrent UTI (measured as number of antibiotic courses). The 
remaining objectives are considered secondary. Pyelonephritis, hospitalization and death will be 
registered as safety endpoints in the study. 
 
Objectives 
Outcome Measures / variables / 
endpoints 
Time point(s) of 
evaluation of 
this outcome 
measure (if 
applicable) 
Primary Objective 
 
 
1 
The primary objective of this 
study is to investigate if 
taking methenamine 
hippurate reduces the need 
for antibiotic usage due to 
recurrent UTI (measured as 
number of antibiotic courses). 
Number of UTI antibiotic treatments 
during the six months of treatment. If 
the participant receives >1 antibiotic 
course for UTI without symptom relief it 
is regarded as one episode and counted 
as one antibiotic treatment. If there has 
been an asymptomatic period of at least 
14 days in-between two UTI antibiotic 
After six months 
of treatment. 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
13 (35) 
 
courses, this is regarded as a new 
antibiotic treatment. 
Secondary Objectives 
 
 
2a 
To investigate if 
methenamine hippurate will 
have a prolonged effect on 
antibiotic usage even after 
discontinuation. 
Number of UTI antibiotic treatments 
during the six months following 
completion of treatment. If the 
participant receives >1 antibiotic course 
for UTI without symptom relief it is 
regarded as one episode and counted 
as one antibiotic treatment. If there has 
been an asymptomatic period of at least 
14 days in-between two UTI antibiotic 
courses, this is regarded as a new 
antibiotic treatment. 
Six months after 
completing (12 
months after 
commencing) 
treatment. 
2b To investigate if taking 
methenamine hippurate 
reduces the incidence of UTI. 
Number of UTIs (acute symptoms 
specific/related to the urinary tract) 
during the six months of treatment. If 
the participant has had >1 UTI episode 
without symptom relief it is regarded as 
one episode. If there has been an 
asymptomatic period of at least 14 days 
in-between two UTI episodes, this is 
regarded as a new episode. 
After six months 
of treatment. 
2c 
To investigate if 
methenamine hippurate can 
reduce severity of UTI 
symptoms. 
Registration of symptom severity when 
initiating treatment for UTI. 
After six months 
of treatment. 
2d To investigate if 
methenamine hippurate can 
reduce duration of UTI 
episodes. 
Registration of number of days of 
symptoms during UTI episodes. 
After six months 
of treatment. 
2e 
To investigate if number of 
complications such as 
pyelonephritis and hospital 
admission for UTI differ 
between methenamine 
hippurate and placebo. 
Registration of number of pyelonephritis 
and hospital admission for UTI. 
Six and 12 
months after 
commencing 
treatment. 
2f 
To investigate if phylogenetic 
subgroups of E. coli found at 
inclusion is an effect modifier 
in the above outcomes. 
 
(see above) 
(see above) 
 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
14 (35) 
 
3. 
STUDY DESIGN AND PROCEDURES 
3.1. 
Overall study design and flow chart 
Study design: Blinded randomised controlled phase IV trial where patients are randomised to 
active intervention (methenamine hippurate) or controls (placebo). 
Setting and study population: Women aged ≥70 years with recurrent UTIs in primary care. A 
total of 400 patients will be randomized in this trial, with approximately 100 patients in each of the 
participating countries; Norway, Sweden, Poland and the Netherlands.  
 
Diagram 1. Schematic diagram of procedures: 
 
Visit/ 
Telephone 
contact  
Visit 1 
Screening and 
randomization (®) 
Telephone 
follow-up in  
case of acute 
UTI episode(s)  
End of 
treatment 
End of  
study 
Day(s) 
 
1 
 
2-360 
 
180 
 
360 
Methenamine 
hippurate 
(N=200) 
 
Placebo 
(N=200) 
 
 
3.2. 
Rationale for study design 
This is a triple blinded RCT in women aged ≥70 years with recurrent UTIs, defined as ≥3 episodes 
of antibiotic treated acute cystitis (acute symptoms specific/related to the urinary tract) during the 
last twelve months or ≥2 episodes during the last six months. 
 
The trial will be triple blinded in order to avoid bias by the patient, the doctor or the person doing 
statistical analysis. As methenamine hippurate is a prophylactic treatment six months of therapy is 
necessary. To be able to evaluate if there is a prolonged effect of treatment another six months 
follow-up is necessary.   
 
The effect of methenamine hippurate is dependent on acidic urine. The hippurate component work 
as acidifying the urine in patients. We will register urine pH for all patients in the study and see if 
this has a modifying effect on the results. We will not use lack of acidic urine as an exclusion 
criterion. 
 
Potential effect modifiers to be registered in CRF and adjusted for in the analysis:  
R

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
15 (35) 
 
 
patient’s age 
 
urine acidity (pH) 
 
number of antibiotic courses for UTIs in the 12 months preceding inclusion in the study 
 
presence of urease/stone-producing bacteria in urine culture day 1 such as proteus, some 
klebsiella species, Morganella morganii, Corynebacterium urealyticum and providencia 
 
use of local oestrogen 
 
patient has diabetes mellitus 
 
obesity defines as BMI ≥30 
 
presence of known abnormality of the urogenital tract 
 
if the patient is sexually active 
 
if the patient previously have experienced kidney stone. 
 
 
3.3. 
Table 1. Study visits 
 
 
Visit 1 
Screening 
and 
randomisation 
Telephone 
follow-up in 
case of acute 
UTI 
episode(s) 
Telephone 
follow-up 
every 30 days 
in all patients  
Telephone contact 
by end of treatment 
Telephone 
contact by 
end of 
study 
Day(s) 
1 
2-360 
2-180 
180 
360 
Informed consent 
X 
 
 
 
 
Demography, level of care 
X 
 
 
 
 
Medical history 
X 
 
 
 
 
Physical examination***  
X 
 
 
 
 
 Dipstick urinalysis and      
urine culture 
X 
X 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
Randomisation 
X 
 
 
 
 
Patient Reported Outcome 
 
X 
X 
X 
X 
Concomitant medication** 
X 
 
 
 
 
Serious Adverse Events 
 
X 
X 
X 
X* 
 * In case of SAE present and not resolved by day 360, this will be followed until resolution. 
** After visit 1 concomitant medication will only be registered in case of SAE, otherwise not. 
*** If needed to determine eligibility or complete baseline data. 
 
3.4. 
Study assessments 
 
Visit 1 – Screening, inclusion and randomisation 
Visit 1 (screening and inclusion) is performed by a trial team member or specially trained local 
investigators at primary health care centres. Before screening, the Investigator will provide 
thorough oral and written information about the study to the subject. The subject will be given the 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
16 (35) 
 
opportunity to ask questions and be given sufficient time to consider participation. Subject who 
agree to participate will give signed and dated informed consent prior to any study-related activity.   
The investigator will keep a subject screening log and a subject enrolment log. 
The patients will when possible be found through a screening procedure of each GPs (General 
Practitioners) Electronic Patient Record, finding patients who had at least 3 courses of UTI 
antibiotics last year. Otherwise eligible patients will be identified through doctors and nurses in 
clinical work with frail elderly. Only patients fulfilling the inclusion criteria and consenting to 
participate will be included. Demography and level of care will be registered. Medical history 
including current medication, risk factors for recurrent UTI such as urinary bladder dysfunction (e.g. 
overactive bladder), diabetes mellitus, obesity (BMI >30), local treatment with oestrogen, sexual 
activity or abnormality of the urogenital tract. A voided urine specimen will be collected and dipstick 
urinalysis regarding pH, nitrite and leukocyte esterase will be performed as well as a urine culture, 
also asking for ureas-producing bacteria. In case of growth of pure cultures of E. coli in the 
inclusion urine culture, we will freeze the isolates of E.coli and send them to the department of 
clinical microbiology at Sahlgrenska University Hospital in Sweden for analysis of phylogenetic 
subgroups according to published protocols using PCR-technique.    
 
If the patient presents with symptoms of an acute UTI or are on antibiotic treatment for a UTI at the 
inclusion visit, the infection is handled by regular health services (GP or out of Hours (OOH) 
service). The patient will wait until 2 weeks after finishing treatment for the UTI before the 
researcher completes the inclusion and takes the baseline urine sample. The treatment with IMP 
will start the day after the completed inclusion of the patient. The current UTI should be registered 
at the baseline form as a UTI prior to inclusion in the study. The same procedure will be followed if 
the patient is on prophylactic treatment with UTI antibiotics, but is willing to stop the prophylactic 
treatment to enter the study. A note of the actions taken will be written in the comments section in 
the baseline CRF by the responsible researcher. 
 
 
All data related to inclusion visit including trial name, study-ID and informed consent will be 
documented in the medical record of the patient.  
 
 
Telephone follow-up in case of acute UTI episode(s) 
Any episodes of acute UTI during the follow-up period (day 2-360) will be handled by regular health 
services (GP or out of Hours (OOH) service). Participants are informed at inclusion (Visit 1) to 
contact the trial team in case of any UTI-related health care contacts during the follow-up period. 
The study team will follow up each UTI episode until resolved with registration of relevant data by 
telephone contact and by ordering copies of medical records regarding the UTI episode including 
laboratory results regarding urinary dipsticks and urine culture.  
 
Following data will be collected in case of acute UTI episode(s) during day 2-360 (telephone follow-
up and from medical record): 
 
confirmation and registration of UTI symptoms (acute symptoms specific/related to the 
urinary tract), registration of symptom severity when initiating treatment for UTI. This will be 
measured by a scale 0-6 (no symptoms to worst possible) for each of the three cardinal 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
17 (35) 
 
symptoms and general condition, Patient Reported Outcome (PRO) – grading of 
symptoms, see appendix 
 
UTI antibiotic treatment (name of drug, dosage and duration) 
 
registration of any pyelonephritis and hospital admission for UTI 
 
ordering copies of medical records regarding the UTI episode including laboratory tests 
performed by regular health service (dipstick urinalysis regarding nitrite and leukocyte 
esterase and urine culture) 
 
SAEs, whereas relationship with IMP cannot be excluded. 
 
In case of an episode of UTI all clinically relevant data have already been recorded in the patient’s 
medical record by the physician, therefore these telephone follow-ups will only be recorded in the 
CRF. In case of SAE this will be recorded in the medical record.    
 
Telephone contacts every 30 days during the first six months as well as day 360 
During telephone contacts every 30 days during the first six months as well as day 360 registration 
of any symptoms and side effects from the trial medication will be recorded as well as SAEs, 
whereas relationship with IMP cannot be excluded. Participants will be asked if they have forgotten 
to contact the study team in case of any UTI-related health care contacts. If so, the study team will 
follow up these UTI episode(s) with registration of relevant data as described above. 
In case of new UTI not recorded, we will record PRO using the scale. In case of an episode of UTI 
all clinically relevant data have already been recorded in the patient’s medical record by the 
physician, therefore these telephone follow-ups will only be recorded in the CRF. In case of SAE 
this will be recorded in the medical record. By the end of the project period, the study team will 
contact the patients’ GP, and ask the GP to go through the patients’ records during the project 
period in order to validate the number of UTI episodes. 
 
 
4. 
STUDY POPULATION 
4.1. 
Inclusion criteria 
 
woman 
 
age ≥70 years 
 
recurrent UTIs defined as ≥3 episodes of antibiotic treated acute cystitis (acute symptoms 
specific/related to the urinary tract) during the last twelve months or ≥2 episodes during the 
last 6 months 
 
able and willing to comply with all trial requirements  
 
able and willing to give informed consent. 
 
4.2. 
 Exclusion criteria 
 
the patient has taken methenamine hippurate within the last 12 months  
 
the patient is allergic to methenamine hippurate   
 
the patient is having current antibiotic prophylaxis for UTI 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
18 (35) 
 
 
the patient has a urinary catheter (chronic indwelling catheters as well as intermittent 
urinary catheterisation) 
 
the patient has known severe chronic renal failure or estimated creatinine glomerular 
filtration rate ≤30 ml/min (known = registered in GP’ clinical records) 
 
the patient has a known condition or treatment associated with significant impaired 
immunity (e.g. long-term oral steroids, chemotherapy, or immune disorder) (known = 
registered in GP clinical records) 
 
the patient has a known severe hepatic impairment (known = registered in GP clinical 
records) 
 
the patient is suffering from severe dehydration 
 
the patient has shown signs of gout 
 
the patient has a need for long term use of antacids such as magnesium hydroxide, 
magnesium carbonate, aluminium hydroxide  
 
the patient has a life expectancy estimated by a clinician to be less than six months 
 
the patient has been involved in, including completion of, follow-up procedures, in another 
clinical trial of an investigational medicinal product in the last 90 days 
 
the patient suffers from incontinence too severe to be able to provide a voided urine 
specimen 
 
the patient is participating in ImpresU Work Package 2 
 
the patient is suffering from significant known abnormal renal tract anatomy/physiology (i.e. 
single kidney, persistent urinary tract stone disease, severe vesicoureteral reflux) or 
neuropathic bladder disorders   
 
the patient has lactose intolerance. 
4.3. 
Subject enrolment and randomization 
Included participants will be randomised strictly sequentially, as subjects are eligible for 
randomisation. If a subject discontinues from the study, the subject number will not be re-used, and 
the subject will not be allowed to re-enter the study.  
 
Four sets of 100 random numbers each, one for each participating country, will be created using 
Research Randomizer. A block randomisation will be performed (the block size is concealed to 
prevent functional unblinding). The outcome will be transferred to a separate Excel spreadsheet for 
each country where each row, representing one patient, is sequentially numbered. Norway will 
have the numbers 1-100, Sweden 101-200, the Netherlands 201-300 and Poland 301-400. Each 
country will follow their randomisation list strictly sequentially. The inclusion will stop when a total of 
400 participants are included in the study.   
4.4. 
Discontinuation and withdrawal of subjects 
4.4.1. 
Withdrawal of subjects 
Subjects are free to discontinue their participation in the study at any time without prejudice to further 
treatment. In either case, serious adverse events where relation to IMP cannot be excluded, will be 
followed up. Other reasons for discontinuing a subject are incorrect enrolment and subjects lost to 
follow-up. 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
19 (35) 
 
 
Any subject fulfilling any of the pre-defined exclusion criteria will be withdrawn from the study: 
 
participating patients withdrawing their consent, subjects are free to discontinue their 
participation in the study at any time without prejudice to further treatment 
 
participating patients developing allergic reactions or any other SAE possibly due to 
methenamine hippurate 
 
participating patients requiring long term use of alkalizing substances (such as antacids) 
during the first six months when taking IMP as alkalizing substances reduces the effect of 
methenamine hippurate and should be avoided 
 
participating patients developing serious illness making it impossible for them to continue 
taking the study tablets. 
 
Simultaneous intake of sulphonamide antibiotics can increase risk of crystalluria. Therefore, 
methenamine hippurate will temporarily be paused if the participant is prescribed a course of 
sulphonamide antibiotics, but will continue with IMP after that. 
 
Participating patients developing clinically significant dehydration will not receive IMP until clinically 
resolved dehydration, but will continue with IMP after that.  
 
Those patients who have to prematurely stop taking the IMP, except for patients’ withdrawing their 
consent, will be followed up in the same framework of the study and in the same way as 
participants receiving IMP. 
 
4.4.2. 
Premature termination of the study 
The difference between groups in SAEs deemed to be linked to methenamine hippurate will be 
continuously monitored (appendix 5). The study will be terminated if there is a significant difference 
between the two trial arms regarding SAE, SAR and SUSAR probably or definitely related to the 
trial medication or UTI. This will be done by comparing the two groups without breaking the code. 
The code will be broken if the difference between groups in these adverse effects are statistically 
significant (p<0.05). The study will be prematurely terminated if the statistical difference is to the 
disadvantage of active IMP. SAE, SAR and SUSAR possibly related to the trial medication or UTI 
will be registered but not used for decision making for eventual premature termination of the study. 
The investigator will promptly inform the participants, the Ethics Committee (EC) and other relevant 
regulatory authorities according to national regulations providing a detailed written explanation. 
 
5. 
STUDY TREATMENTS 
5.1. 
Identity of investigational medicinal products 
IMP will be provided by the pharmaceutical company Mylan A/S who will send the IMP and 
corresponding placebo to Kragerø Tablettproduksjon AS (see attachment), who will be responsible 
for packing and labelling of boxes according to the randomisation list. Kragerø Tablettproduksjon 
AS will deliver IMP to a designated pharmacy in each country which in turn will distribute IMP to 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
20 (35) 
 
participating sites. The IMP will be handed out consecutively to participants for six months use 
(four boxes with 90 tablets each), in accordance with the randomisation list. 
 
Kragerø Tablettproduksjon AS will create 200 sets of boxes containing methenamine hippurate 
and 200 sets of boxes containing placebo (lactose). The boxes will have identical labelling (see 
attachment). Only patient ID on the label will be linked to the randomisation list, telling which 
medication the patient has received. 
Boxes with active substance consist of tablets with the active substance methenamine hippurate 1 
gram. This is equivalent to the standard recommended dose of methenamine hippurate as 
presented in Summary of Product Characteristics (SmPC) (attachment). Boxes with placebo drug 
will contain the equivalent dose of lactose. 
5.1.1. 
Doses and length of treatment. 
Participants will be instructed to take one study tablet morning and evening for 180 days. This 
corresponds to a daily dose of 2 g methenamine hippurate or placebo daily. The dosage is 
according to SPC for preventive treatment. The length of treatment is line with previous studies 
which have used 6-12 months as length of treatment (13-16, 24-25). This is also in line with clinical 
practice, and we have chosen 6 months to maximise compliance in this vulnerable patient group.  
5.1.2. 
Labelling 
The acquisition, labelling, Qualified Person release and delivery of the methenamine hippurate will 
be performed by Kragerø Tablettproduksjon AS. The boxes will be labelled according to example 
(attachment) with corresponding labels for each country in local language. 
5.1.3. 
Storage and handling 
One pharmacy/medical distributor will be designated to be responsible for sending out the 
medication to the relevant sites in each country. The medication will be stored at each site in a 
locked cupboard in a secure access room. The sealed code envelopes will be kept together with 
the IMP in a locked cupboard. The monitor will check if any unauthorised code breaks has been 
performed during the study. IMPs will be stored according to storage instructions and local 
requirements with a controlled temperature not exceeding 30 degrees Celsius. Each study site will 
sign for sending out the IMP to the patient. Each study site will keep accountability logs and temp 
logs. 
5.1.4. 
Drug accountability and treatment compliance 
Any remaining non-used IMP will be gathered by a study nurse/phd-student by the end of 180 days 
of the trial and will be stored at the study site. The monitor will count remaining IMP and control 
treatment compliance and report this. Finally, the non-used IMP will be sent to the designated 
pharmacy for destruction. An accountability log will be made for each patient, including the batch 
number. 
5.1.5. 
Destruction 
Destruction of IMP will be performed at the designated pharmacy as stated above. Current 
medication taken by participants will be registered at inclusion. As interaction with other 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
21 (35) 
 
medications are limited, there is no necessity to register changes in ongoing medication during the 
trial period with the exception of prescribed UTI antibiotics, sulphonamide antibiotics, alkalizing 
substances (such as antacids), or in case of SAE report.  
5.2. 
Blinding 
Boxes are to be handed out sequentially to each participating patient following the number on the 
boxes, 4 identical boxes with 90 tablets in each box, in total 360 tablets. No information on the 
boxes reveals if the content is active drug or placebo. The electronic version of the Excel files (one 
for each country) will be available for the monitor in order to assist with emergency unblinding 
when needed. The staffs involved in these procedures are not to disclose this information to 
anyone else until all statistical analysis is done. One exception is if there is an SAE and it is 
deemed important to break the code.  
 
Kragerø Tablettproduksjon AS will produce 400 identical sets of boxes labelled either “ImpresU 
study drug – number ZZZ” or “ImpresU study drug – number ZZZ” (ZZZ is a sequential number 
from 1-400). Patients, GPs meeting patients, pharmacists dispensing drugs, the investigators and 
persons involved in statistical analysis will not be aware of group allocation until all statistical 
analyses are done (triple blind). 
 
 
5.3       Breaking the blinding in an emergency situation  
The study code should only be broken for valid medical or safety reasons e.g. in the case of a 
severe adverse event where it is necessary for the treating physician to know which treatment the 
patient is receiving. There will be one sealed opaque envelope for each medication ID available, at 
the study sites, containing information of active substance or placebo regarding IMP. These 
envelopes will be stored together with the IMP. The treating physician contacts the coordinating 
centre or the PI via phone numbers available on patient/physician information cards regarding the 
study medication. On these cards, there will also be an emergency number provided by the 
Sponsor to be able to reach the code break envelope/list in emergency situations. The 
coordinating centre (or the Sponsor) provides the treating physician with the information as 
requested. On receipt of the treatment allocation details, the treating physician deals with the 
participant’s medical emergency as appropriate. The PI documents the breaking of the code and 
the reasons for doing so on the CRF and in the site file. The PI notifies the Sponsor as soon as 
possible following the code break detailing the necessity of the code break.  
 
5.4 Concomitant medication 
Medications considered necessary for the patient’s safety and well-being may be given at the 
discretion of the investigators unless not specified in the exclusion criteria. Concomitant medication 
will be recorded in the Case Report Form (CRF) at inclusion. As interaction with other medication is 
limited, there is no necessity to register changes in routine medication during the trial period with the 
exception of prescribed UTI antibiotics or in case of SAE report. In case of severe dehydration, or 
treatment with sulphonamide antibiotics the participant should temporarily pause IMP. Alkalizing 
substances (such as antacids) reduces the effect of methenamine hippurate and should be avoided. 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
22 (35) 
 
Hence, patients requiring long term use of antacids will not be included, or withdrawn if there will be 
a need for long term use of alkalizing substances during the first six months when taking IMP. 
 
   
6. 
STUDY MEASUREMENTS AND VARIABLES 
 
number of UTI antibiotic treatments (name of drug, dosage and duration) during day 2-360 
 
number of UTIs (acute symptoms specific/related to the urinary tract) during day 2-360 
 
registration of symptoms and severity when initiating treatment for UTI. This will be 
measured by a scale 0-6 (no symptoms to worst possible) for each of the three cardinal 
symptoms and general condition.  
 
registration of number of pyelonephritis and hospital admission for UTI 
 
laboratory tests at Visit 1: urine culture and dipstick urinalysis regarding pH, nitrite and 
leukocyte esterase  
 
laboratory tests ordered by the ordinary clinician in case of episodes of UTI during the study 
period (urinary dipsticks regarding nitrite and leukocyte esterase and urine culture) 
 
level of care: general practice, residential home care or nursing home 
 
SAEs, whereas relationship with IMP cannot be excluded.   
6.1. 
Primary variable 
(See section “2 Study Objectives and Endpoints”). 
6.2. 
Secondary variable(s) 
(See section “2 Study Objectives and Endpoints”). 
6.3. 
Safety variable(s) 
Pyelonephritis, hospitalization and death will be registered as safety endpoints. Methenamine 
hippurate has a well-documented safety profile and is a commonly used medication in primary care 
settings in Scandinavia. Therefore, non-serious adverse events (AE) will not be recorded in this 
study. All SAEs, whereas relationship with IMP cannot be excluded, occurring during the study 
period are recorded and reported according to guidelines in each country. 
 
6.4. 
Biological sampling procedures 
6.4.1. 
Handling, storage and destruction of biological samples 
A urine specimen will be taken at the inclusion for culture and dipstick urinalysis regarding pH, 
nitrite and leukocyte esterase. The urine specimen will be destroyed after this.  
 
In case of growth of pure cultures of E. coli in the inclusion urine culture, we will freeze the isolates 
of E.coli and send them to the department of clinical microbiology at Sahlgrenska University 
Hospital in Sweden for analysis of phylogenetic subgroups according to published protocols using 
PCR-technique.    
 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
23 (35) 
 
Any episodes of acute UTI during the follow-up period (day 2-360) will be handled by regular health 
services (primary health care centres, OOH services or hospitals). The study team will order copies 
of medical records from acute UTI episodes including laboratory results regarding urinary dipsticks 
and urine culture. If feasible, we will also send pure culture E. coli isolates for phylogenetic typing 
as previously described.  
 
6.4.2. 
Total volume of blood per patient 
No blood tests will be taken in this study.  
 
6.4.3. 
Biobank 
The urine specimen taken at the inclusion visit for analysis of a urine dipstick and culture will not be 
registered in a biobank (if not required in national guidelines), as the urine specimen will be 
destroyed immediately after analysis. We will freeze isolates of E.coli from the inclusion urine 
culture, and if possible from some of the cultures taken during subsequent episodes of acute UTIs.  
Bacteria is not regarded human material and does not need a biobank registration.  
 
 
7. 
SAFETY 
7.1. 
Reference Safety Information 
Anticipated adverse drug reactions in the study: 
 
 
Methenamine hippurate is well tolerated and adverse effects are generally mild (10) 
 
According to SPC: 
 
Gastrointestinal disorders  
o Uncommon: gastric irritation, irritation of the bladder, nausea, vomiting 
o Not known: diarrhoea, abdominal pain 
 
Skin and subcutaneous disorders  
o Uncommon: Rash, pruritus 
 
Alkalizing substances (such as antacids) reduces the effect of methenamine hippurate and 
should be avoided. Hence, patients requiring long term use of antacids will not be included 
or withdrawn if there will be a need for long term treatment with alkalizing substances when 
taking IMP during the first six months. 
 
Simultaneous intake of sulphonamide antibiotics can increase risk of crystalluria. Therefore, 
methenamine hippurate will temporarily be paused if the participant is prescribed a course 
of sulphonamide antibiotics. 
 
Except for those described above, there are no other known clinically relevant interactions 
between methenamine hippurate and other pharmaceuticals 
 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
24 (35) 
 
7.2. 
Definitions 
7.2.1. 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical investigation subject 
administered a medicinal product and which does not necessarily have a causal relationship with 
this treatment. An AE can therefore be any unfavourable and unintended sign (including an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of a 
medicinal (investigational) product, whether or not related to the medicinal (investigational) 
product. 
 
Causality 
The investigator is responsible for determining whether there is a causal relationship between an 
AE and the use of a medicinal product.  
 
AEs are categorized either as unrelated, possibly related or related, as defined below: 
 
Unrelated: the AE is not reasonable in relation to the use of the medicinal product, or 
another cause can itself explain the occurrence of the event. 
 
Possibly related: the AE may be explained by the medicinal product and the onset is 
reasonable in relation to the use of the medicinal product, however there is insufficient 
information to determine the likelihood of this possibility. 
 
Related: the AE is most likely explained by the medicinal product and the onset is 
reasonable in relation to the use of the medicinal product. 
 
Severity 
In addition to assessing the relationship of the administration of the investigational product(s) to 
adverse events, an assessment is required of the intensity (severity) of the event. The following 
over-all classifications should be used: 
 
 
Mild: An adverse event which is relatively mild and transient in nature, but can be an 
annoyance, and does not interfere with normal activities.  
 
Moderate: An adverse event which may be uncomfortable but is not hazardous to health. It 
may be sufficiently discomforting to interfere with normal activities but does not completely 
prevent them. 
 
Severe: An adverse event which is incapacitating and/or it is a hazard to the subject. 
 
7.2.2. 
Adverse Drug Reaction (ADR) 
Regarding marketed medicinal products: A response to a drug which is noxious and unintended 
and which occurs at doses normally used in man for prophylaxis, diagnosis, or therapy of diseases 
or for modification of physiological function. 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
25 (35) 
 
7.2.3. 
Serious Adverse Event (SAE) 
Any untoward medical occurrence that at any dose: 
 
results in death, 
 
is life-threatening, 
 
requires inpatient hospitalization or prolongation of existing hospitalization, 
 
results in persistent or significant disability/incapacity, or 
 
is a congenital anomaly/birth defect. 
 
Medical and scientific judgement should be exercised in deciding whether an event is “serious” and 
if expected reported is appropriate in other situations, such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization, but may jeopardize the 
subject or may require intervention to prevent one of the other outcomes listed in the definition 
above. These should also usually be considered SAEs. 
7.2.4. 
Suspected unexpected serious adverse reaction (SUSAR) 
A SUSAR is a serious adverse reaction of which nature or severity is not consistent with the 
applicable product information (e.g., Investigator's Brochure for an unapproved investigational 
product or package insert/summary of product characteristics for an approved product). 
7.3. 
Reporting 
7.3.1. 
Adverse Event (AE) 
Methenamine hippurate has a well-documented safety profile and is a commonly used medication 
in primary care settings in Scandinavia. As a result of this no non-serious adverse events will be 
recorded in this study. All SAEs, whereas relationship with IMP cannot be excluded, occurring 
during the study period are recorded as detailed in Section 7.3.3 Reporting Procedures for Serious 
Adverse Events. 
 
It will be left to the Investigator’s clinical judgment to decide whether or not a symptom or side 
effect is of sufficient severity to require the participant’s removal from treatment. A participant may 
also voluntarily withdraw from treatment due to what the participant perceives as an intolerable 
symptom or side effect. 
 
7.3.2. 
Adverse Drug Reaction (ADR) 
Methenamine hippurate has a well-documented safety profile and is a commonly used medication 
in primary care settings in Scandinavia. Therefore, non-serious AE will not be recorded in this 
study.  
7.3.3. 
Serious Adverse Event (SAE) 
All SAEs that is life threatening or results in death must be reported using the SAE Report Form by 
the person who has discovered the SAE or nominated delegate. The SAE form will be 
electronically submitted to the sponsor or delegate within 24 hours of the site study team becoming 
aware of the event.  

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
26 (35) 
 
 
SAEs requiring inpatient hospitalization or prolongation of existing hospitalization and AEs resulting 
in persistent or significant disability/incapacity will not be reported if being expected events in a frail 
elderly population (e.g. hip fracture, heart failure, ischemic heart disease). If these SAEs are 
related to UTI (e.g. pyelonephritis) they must be reported using the SAE Report Form by the 
person who has discovered the SAE or nominated delegate. If relationship with IMP cannot be 
excluded these SAEs are possibly, probably or definitely related to the trial medication. If so these 
adverse events must be reported as SAR (Serious Adverse drug Reaction) if expected and 
included in SmPC or as SUSAR (Suspected Unexpected Serious Adverse Reaction) if unexpected 
and not included in SmPC. SUSAR is further described in 7.3.4. The reason why only reporting 
these when relationship to IMP cannot be excluded: Methenamine hippurate is a well-known and 
widely used drug in Scandinavia with few and mild side effects which has been clinically used 
since many decades. There is no reason to expect any previously unknown AE and SAE to occur 
in this trial. Judgement whether related to UTI or the trial medication will be done by the PI of each 
country.     
 
SAEs consisting of a congenital anomaly or birth defect is not relevant in this trial as all participants 
are women aged ≥70 years. 
 
Please find safety reporting flow-chart in appendix 5.  
  
 
SAEs will be registered throughout the studied period. In case of SAE present and not resolved by 
day 360, this SAE will be followed until resolution. 
 
 
The sponsor or delegate will perform an initial check of the report, request any additional 
information, and ensure it is reviewed by the PI or other delegated personnel for relatedness and 
expectedness as soon as possible considering the reporting time for a potential SUSAR according 
to the relevant competent authority. Additional and further requested information (follow-up or 
corrections to the original case) will be detailed on a new SAE Report Form and submitted to the 
sponsor or delegate. See safety reporting flowchart in appendix 5. If the event has not resolved by 
day 360 the SAE will be reviewed again to see if resolution has occurred. If the event is considered 
“resolved” or “resolving” no further follow-up is required. If not, the event must be followed up until 
such a time point.  
 
7.3.4. 
Suspected Unexpected Serious Adverse Reaction (SUSAR) 
All SUSARs will be reported by the Sponsor or delegate to the relevant Competent Authority (CA) 
(EudraVigilance database) and to the Ethics Committee and other parties as applicable. For fatal 
and life-threatening SUSARs, this will be done no later than seven calendar days after the Sponsor 
or delegate is first aware of the reaction. Any additional relevant information will be reported within 
eight calendar days of the initial report. All other SUSARs will be reported within 15 calendar days. 
 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
27 (35) 
 
This study is an investigator initiated non-commercial study where the PI lacks the ability to report 
directly into the European database of side effects (EudraVigilance) and we therefore ask CA for 
help. SUSAR is reported via CIOMS-form.  
 
7.3.5. 
Annual Safety Report 
A safety report will be completed by the Sponsor once a year and sent to the relevant CA and the 
EC. The document will define the time period reported and summarize all occurred serious events 
(SAEs and SUSARs). The safety report should also always include a summary assessment of the 
safety of subjects that are still included in the trial and whether the benefit-risk assessment 
changed since the study was approved. 
8. 
STATISTICS 
8.1. 
Sample size calculation 
The sample size calculation is made for the primary objective described in section “2 Study 
Objectives and Endpoints”. 
 
We assume these selected older individuals will have an average of two courses of 
antibiotics for suspected UTI every six months (4). 
 
We assume a 25% reduction of antibiotic prescriptions during the first six-month period 
after introduction of methenamine hippurate. Hence the intervention group would have an 
average of 1.5 while the control group is assumed to remain around 2.0. We assume the 
standard deviation in each group to be 1.5. This will result in an effect size of 0.33 (small 
effect). We decided a smaller effect size would not be worth looking for. 
 
We assume the level of significance being 0.05, the power to be 0.80 and that a two tailed 
test is explored. 
 
We use Student’s t-test as the statistical analysis but also calculate for Mann-Whitneys test 
(to be used if the outcome variable is not normally distributed). The planned statistical 
method to be used will be multivariate linear regression. Student’s t-test and Mann-
Whitneys test are used as surrogate methods to estimate sample size. 
 
Under the assumptions given above an effective sample size of 286 patients (143+143) is required 
if t-test can be used. However, if Mann-Whitney’s test is required we need 298 (149+149) patients. 
To achieve an effective sample size of at least 298 after considering a 25% loss to follow-up we 
aim to include at least 397 patients. We will aim to include 400 patients. 
 
8.2. 
Statistical analysis 
It is the intention to adjust all analysis for the following confounding variables obtained at visit 1 
 
patient’s age 
 
urine acidity (pH) 
 
number of antibiotic courses for UTIs in the 12 months preceding inclusion in the study 
 
presence of urease/stone-producing bacteria in urine culture day 1 such as proteus, some 
klebsiella species, Morganella morganii, Corynebacterium urealyticum and providencia 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
28 (35) 
 
 
use of local oestrogen 
 
patient has diabetes mellitus 
 
obesity defines as BMI ≥30 
 
presence of known mild abnormality of the urogenital tract 
 
if the patient is sexually active. 
 
If the patient previously have experienced urinary tract stone 
 
Phylogenetic subtype of pure cultures of E.coli in the urine culture at inclusion will be analysed in a 
separate analysis if the number of cultures available for typing are not too small. 
 
The statistical calculation relates to the study objectives described in section “2 Study Objectives 
and Endpoints”: 
1 
Standard linear regression will be used where number of UTI antibiotic treatments will be the 
dependent variable. Group allocation together with the confounding variables above will be 
independent variables. The dependent variable will be transformed using a rank 
transformation in case it is not normally distributed. A p-value will be delivered but no useful 
effect size if a rank transformation is used.  
2a Will be analysed using the same statistical approach as objective 1 above. 
2b Will be analysed using the same statistical approach as objective 1 above. Number of UTIs 
will be the dependent variable. 
2c The outcome variable is measured at first day of a UTI using a six grade ordinal scale. The 
median value from all UTIs will be used if the patient has more than one episode of UTI. The 
dependent variable will be transformed using a rank transformation. It will be analysed using 
linear regression using the same covariates as when analysing objective 1. This will deliver a 
p-value but no useful effect size. 
2d Will be analysed using the same statistical approach as objective 1 above. Number of days 
with symptoms will be the dependent variable. 
2e Will be analysed using the same statistical approach as objective 1 above. Number of severe 
events such as pyelonephritis or hospital admission will be the dependent variable. 
2f    Phylogenetic subtype of pure cultures of E.coli in the inclusion urine culture at inclusion will be 
analysed in a separate statistical analysis if the number of cultures available for typing are at 
least 60 patients. All statistical above will be redone adding phylotype as an extra independent 
variable. Purely descriptive statistics will be presented in case the number is below 60. 
 
Intention to treat analysis and missing data 
The primary statistical analysis is intention to treat. Patients leaving the study completing only a 
part of the first six months will contribute with data up until they leave the study. Their data will be 
recalculated as if they had participated all six months. Patients leaving during the second six 
months period will also contribute with data as above. Patients leaving the study before the second 
six-month period commence will have their value for this period set to be the median value for both 
groups. 
 
Complete case analysis 
A complete case analysis will also be made where only patients having a complete data set will be 
included. 
 
Per protocol analysis 
A per protocol analysis will not be made. 
 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
29 (35) 
 
 
9. 
DATA MANAGEMENT  
9.1. 
Recording of data 
The investigator will ensure that all data collected in the study are recorded in a timely manner 
according to any instructions provided. An electronic Case Report Form (eCRF) will be used for 
data collection. The investigator will ensure that the data are recorded and that any corrections in 
the CRF as specified in the study protocol and in accordance with the instructions provided. The 
investigator ensures the accuracy, completeness and timeliness of the data recorded.  
 
Research Online (RO) is an electronic data capture (EDC) system that will be used for data 
collection. Web-based case report forms (eCRF) are implemented into the system to facilitate the 
study specific data collection. These forms can easily be accessed by all standard web browsers. 
The baseline CRF at inclusion, telephone follow-up in case of acute UTI episode(s), telephone 
contact by end of treatment, telephone contact by end of study and SAE Forms will be entered 
onto this system. Some sites may choose to first register data in a paper version of the CRF that 
will later be entered into the eCRF by the coordinating centre. The investigator will sign the 
completed CRF. A copy of a completed paper CRF will be archived at the study site. The original 
paper CRF will be archived at the coordinating centre in each country. 
 
Multiple validation and range checks will be programmed in the eCRF to assure complete and 
high-quality data. Data that does not comply with these rules or ranges will generate a query that 
must be resolved immediately or at a later stage. Electronic workflows will employ multiple skip and 
jump rules to ensure that only information that is applicable to the patient will appear. After the data 
of the last subject is entered, the clean file will be produced and thereafter the database will be 
closed and data made available for further analysis and publication purposes.  
 
RO meets all requirements according to GCP standards for electronic data entry with respect to 
safeguarding data integrity and data security regulations. Users will have role-based access to the 
system by logging in using their personal username and password. The system will log all data 
entry steps with timestamps and user information. The role-based access to the system will avoid 
unauthorised data access and prevents users from performing actions that they do not have 
authorisation for.  
 
Project management of the study is facilitated by the integrated real live study progress reports. 
RO data traffic over the Internet is encrypted using secured data communication protocols. 
Dedicated databases and web servers are hosted in a secure data centre, the database 
(PostgreSQL) is backed up on a daily basis.  
 
Participants will be identified by a unique trial specific number and/or code in any database. The 
name and any other identifying detail will not be included in any trial data electronic file, only within 
a separate password protected administration database. 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
30 (35) 
 
9.1.1. 
Source data 
The investigator must maintain source documents for each subject in the study. A source data 
verification log will be included in the Investigator Study File (ISF). The investigator must ensure 
that all source documents are accessible for monitoring. 
 
Source documents are original documents, data, and records from which participants’ CRF data 
are obtained. These include, but are not limited to, general practice and hospital medical records.  
CRF entries will be considered source data if the CRF is the site of the original recording (e.g. 
there is no other written or electronic record of data). In this study the CRF will be used as the 
source document for the documentation of inclusion and exclusion criteria, and baseline 
assessment information (visit 1), which will include, but not be limited to, comorbidities (see point 
3.4. study assessment visit 1) and severity of UTI-symptoms.  
 
All documents will be stored safely in confidential conditions. On all study-specific documents, 
other than the signed consent and contact details form, the participant will be referred to by the 
study participant ID, not by name. Requested reports from medical records and laboratory results 
will be entered into CRF.  
9.2. 
Data storage and management 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. All source data including informed consent, a copy of the completed 
CRF, original protocol with amendments and the final report will be stored at the coordinating 
centres for a minimum period of fifteen years after termination of the trial, in accordance with 
country specific regulation/law. 
 
Staff designated by the Sponsor will review the data entered into the CRFs by investigational staff 
for completeness and accuracy and instruct the site personnel to make any required corrections or 
additions. Queries are issued electronically. Designated investigator site staff is required to 
respond to the query and confirm or correct the data. 
 
At the conclusion of the study, the occurrence of any protocol deviations will be determined. After 
these actions have been completed and the database has been declared to be complete and 
accurate, it will be locked and available for data analysis.  
 
Direct access will be granted to authorised representatives from the Sponsor, host institution and 
the regulatory authorities to permit trial-related monitoring, audits and inspections. 
 
10. 
QUALITY CONTROL AND QUALITY ASSURANCE 
10.1. 
Monitoring 
A study monitor will be appointed by the sponsor. The monitor will be appropriately trained and 
informed about the nature of the study, subject written information, GCP and applicable regulatory 
requirements. The monitor’s qualifications will be documented. Monitor Hege Øvergaard will 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
31 (35) 
 
monitor the study in all 4 countries, and separate agreements between monitor and PI in each 
country will be made.  
 
The quality control of this study will have a risk-based approach. The monitor will have regular 
contacts with the clinic to verify informed consents of participating subjects, to confirm that facilities 
remain acceptable, that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the CRFs, to verify inclusion/exclusion criteria, study main endpoints, check 
SAE reporting and that therapy accountability is being carried out. The investigator should ensure 
that all persons assisting with the trial are adequately informed and trained about the protocol, the 
investigational product(s) and their trial related duties and functions. The monitor will check that 
training has been performed and that this is documented. The monitor will also ensure source data 
verification (comparison of the data in the CRF with the medical records and other source data). 
The monitor must have direct access to source data. The extent of monitoring will be defined in a 
monitoring plan.  
 
10.2. 
Audits and inspections 
Authorized representatives of the sponsor, a Competent Authority or an Ethics Committee may 
perform audits or inspection at the centre, including source data verification. The investigator must 
ensure that all source documents are accessible for auditing and inspection. The purpose of an 
audit or inspection is to systematically and independently examine all study-related activities and 
documents, to determine whether these activities were conducted, and data were recorded, 
analysed and accurately reported according to the protocol, Good Clinical Practice (GCP) and any 
applicable regulatory requirements.  
 
10.3. 
Data safety monitoring committee 
A data safety monitoring committee will be established and will consist of 3 external researchers 
with experience from clinical trials on UTI infections in primary care. They will meet every 6 months 
during the trial to ensure data safety. For premature termination of the study, see 4.2.2. 
11. 
ETHICS 
The study will be performed in accordance with the protocol, with the latest version of the 
Declaration of Helsinki, with Good Clinical Practice (ICH-GCP E6(R2) and applicable regulatory 
requirements.   
11.1. 
Ethics committee 
The final study protocol, including the final version of the Informed Consent Form and other 
information given to subjects e.g. advertisements, must be approved or given a favourable opinion 
in writing by an Ethics Committee (EC) as appropriate. The Principal Investigator is responsible for 
informing the EC of any amendment to the protocol, in accordance with local requirements. 
Progress reports and notifications of any serious and unexpected adverse drug reactions will be 
provided to the EC according to local regulations and guidelines.  

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
32 (35) 
 
11.2. 
Informed consent 
The Principal Investigator at each centre will ensure that the subject is given full and adequate oral 
and written information about the nature, purpose and possible risks and benefits of the study. 
Subjects must also be notified that they are free to discontinue from the study at any time. The 
subject should be given the opportunity to ask questions and allowed time to consider the 
information provided. 
 
The subject’s signed and dated informed consent must be obtained before conducting any 
procedure specifically for the study. The monitor(s), the auditor(s), and the CA(s) will be granted 
direct access to the subject’s original medical records for verification of clinical trial procedures 
and/or data, without violating the confidentiality of the subject, to the extent permitted by the 
applicable laws and regulations and that, by signing a written informed consent form, the subject or 
the subject’s legally acceptable representative is authorizing such access. 
 
The original signed Informed Consent Form (ICF) must be stored in the Investigator’s Study File. A 
copy of the signed ICF must be given to the subject.  
 
The EC must approve modifications that lead to a revised ICF before the revised form is used.  
11.3. 
Subject data protection  
The ICF will incorporate wording that complies with relevant data protection and privacy legislation. 
Pursuant to this wording, subjects will authorize the collection, use and disclosure of their study 
data by the investigator and by those persons who need that information for the purposes of the 
study. 
 
The ICF will explain that study data will be stored in a computer database, maintaining 
confidentiality in accordance with national data legislation. All data computer processed by the 
sponsor will be identified by ImpresU WP3/Subject ID/Initials. 
 
The ICF will also explain that for data verification purposes, authorized representatives of the 
sponsor, a regulatory authority or an EC may require direct access to parts of the hospital or 
practice records relevant to the study, including subjects’ medical history.   
11.4. 
Insurances 
The Norwegian study subjects are covered by Legemiddelansvarsforsikringen.  
The Swedish study subjects are covered by Svenska Läkemedelsförsäkringen, LFF Service AB. 
The Dutch study subjects are covered by CNA Insurance Company (Europe) S.A. 
The Polish study subjects are covered by Towarzystwo Ubezpieczeń i Reasekuracji „WARTA”. 
12. 
PROTOCOL DEVIATIONS AND AMENDMENTS 
Modifications to the signed protocol are only possible through approved protocol amendments and 
with the agreement of all responsible persons. Details of non-substantial amendments are to be 
clearly noted in the amended protocol. 
 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
33 (35) 
 
A change that concerns; a new trial site, new principal investigator and or a new informed consent 
form should only be submitted to the concerned EC. 
In case of a substantial protocol amendment (e.g. change of; main purpose of the trial, 
primary/secondary variable, measurement of primary variable, investigational product, or dosing), 
the concerned EC and CA must be informed and should be asked for its opinion/approval prior 
implementation of amended protocol, as to whether a full re-evaluation of the ethical aspects of the 
study is necessary by the committee. This will be fully documented. 
 
The Investigator must not implement any deviation from, or change to the protocol, without 
discussion with, and agreement by the Sponsor and prior review and documented 
approval/favourable opinion of the amendment from the relevant EC and CA, except where it is 
necessary to eliminate an immediate hazard to study subjects, or where the change(s) involves 
only logistical or administrative aspects of the study (e.g. change in monitor(s), change of 
telephone numbers). 
13. 
REPORT AND PUBLICATIONS 
After completion of the study, the results will be analysed and a clinical study report will be 
prepared. Within one year after the end of the study, the sponsor will submit a study report with the 
results of the study, including any publications/abstracts of the study, to the accredited EC and the 
CA. In addition, upon study completion and finalization of the study report the results of this trial will 
be either submitted for publication and/or posted in a publicly accessible database of clinical trial 
results.   
14. 
STUDY TIMETABLE 
 
14.1. 
Study Period 
Subject enrolment is estimated to start by November 1st 2019, subject enrolment is estimated to 
stop on December 31st of 2020 and last subject last visit is estimated to be on December 31st  
2021. 
14.2. 
Definition of “End of study” 
Data collection will stop when the target number of participants are included. The study ends when 
the last follow up is made for all included participants. Hence, the study may formally end before 
results are accepted for publication. The sponsor will notify the concerned EC and the CA of the 
end of the study within a period of 90 days.  
 
 
15. 
LIST OF REFERENCES 
1. Colgan R, Williams M: Diagnosis and treatment of acute uncomplicated cystitis. Am Fam 
Physician. 2011, 84 (7): 771-776. 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
34 (35) 
 
2. Davis C, Rantell A.Lower urinary tract infections in women.Br J Nurs. 2017 May 
11;26(9):S12-S19. doi: 10.12968/bjon.2017.26.9.S12. 
3. Barclay J, Veeratterapillay R, Harding C.Non-antibiotic options for recurrent urinary tract 
infections in women.BMJ. 2017 Nov 23;359:j5193. doi: 10.1136/bmj.j5193.   
4. Aydin A, Ahmed K, Zaman I, Khan MS, Dasgupta P. Recurrent urinary tract infections in 
women. Int Urogynecol J. 2015 Jun;26(6):795-804. doi: 10.1007/s00192-014-2569-5. Epub 
2014 Nov 20.  
5. Geerlings SE, Beerepoot MA, Prins JM.Prevention of recurrent urinary tract infections in 
women: antimicrobial and nonantimicrobial strategies.Infect Dis Clin North Am. 2014 
Mar;28(1):135-47 
6. van Buul, L. W., van der Steen, J. T., Veenhuizen, R. B., Achterberg, W. P., Schellevis, F. 
G., Essink, R. T., ... & Hertogh, C. M. (2012). Antibiotic use and resistance in long term 
care facilities. Journal of the American Medical Directors Association, 13(6), 568-e1. 
7. van Buul, L. W., Veenhuizen, R. B., Achterberg, W. P., Schellevis, F. G., Essink, R. T., de 
Greeff, S. C., ... & Hertogh, C. M. (2015). Antibiotic prescribing in Dutch nursing homes: 
how appropriate is it?. Journal of the American Medical Directors Association, 16(3), 229-
237. 
8. Sundvall, P. D., Stuart, B., Davis, M., Roderick, P., & Moore, M. (2015). Antibiotic use in the 
care home setting: a retrospective cohort study analysing routine data. BMC geriatrics, 
15(1), 71 
9. Alberg T, Holen Ø, Blix HS, Lindbæk M, Bentele H, Eriksen HM.Antibiotic use and 
infections in nursing homes.Tidsskr Nor Laegeforen. 2017 Mar 7;137(5):357-361. doi: 
10.4045/tidsskr.16.0621  
10. Lee BS, Bhuta T, Simpson JM, Craig JC: Methenamine hippurate for preventing urinary tract 
infections. The Cochrane database of systematic reviews 2012, 10:CD003265. 
11. Brumfitt W, Hamilton-Miller JM.Prevention of recurrent acute cystitis by methenamine 
hippurate.Br Med J (Clin Res Ed). 1987 Aug 8;295(6594):390-1 
12. Cronberg S, Welin CO, Henriksson L, Hellsten S, Persson KM, Stenberg P. 
Prevention of recurrent acute cystitis by methenamine hippurate: double blind controlled 
crossover long term study.Br Med J (Clin Res Ed). 1987 Jun 13;294(6586):1507-8. 
13. Brumfitt W, Hamilton-Miller JM, Gargan RA, Cooper J, Smith GW.Long-term prophylaxis of 
urinary infections in women: comparative trial of trimethoprim, methenamine hippurate and 
topical povidone-iodine. J Urol. 1983 Dec;130(6):1110-4. 
14. Brumfitt W, Cooper J, Hamilton-Miller JM.Prevention of recurrent urinary infections in 
women: a comparative trial between nitrofurantoin and methenamine hippurate. 
J Urol. 1981 Jul;126(1):71-4. 
15. Kalowski S, Nanra RS, Friedman A, Radford N, Standish H, Kincaid-Smith P.Controlled trial 
comparing co-trimoxazole and methenamine hippurate in the prevention of recurrent 
urinary tract infections.Med J Aust. 1975 May 10;1(19):585-9. 
16. Harding GK, Ronald AR.A controlled study of antimicrobial prophylaxis of recurrent urinary 
infection in women.N Engl J Med. 1974 Sep 19;291(12):597-601. 
17. Nielsen, K.L., et al., Whole-genome comparison of urinary pathogenic Escherichia coli and faecal 
isolates of UTI patients and healthy controls. International journal of medical microbiology : IJMM, 
2017. 307(8): p. 497-507. 
18. Etienne, M., et al., Antibiotic treatment of acute uncomplicated cystitis based on rapid urine test and 
local epidemiology: lessons from a primary care series. BMC infectious diseases, 2014. 14: p. 137-
137. 
19. Schito, G.C., et al., The ARESC study: an international survey on the antimicrobial resistance of 
pathogens involved in uncomplicated urinary tract infections. Int J Antimicrob Agents, 2009. 34(5): p. 
407-13. 

 
Clinical Study Protocol 
Study code: 
ImpresU WP3 
(Improving rational 
prescribing for UTI in 
frail elderly Work 
Package 3) 
Version No: 
Version 11.1  
Date: 
7th July 2021 
 
35 (35) 
 
20. Schmiemann, G., et al., Resistance profiles of urinary tract infections in general practice--an 
observational study. BMC urology, 2012. 12: p. 33-33. 
21. Clermont, O., et al., The Clermont Escherichia coli phylo-typing method revisited: improvement of 
specificity and detection of new phylo-groups. 2013. 5(1): p. 58-65. 
22. Amarsy, R., et al., Determination of <em>Escherichia coli</em> phylogroups in elderly patients with 
urinary tract infection or asymptomatic bacteriuria. Clinical Microbiology and Infection, 2019. 25(7): p. 
839-844. 
23. Vila, J., et al., Escherichia coli: an old friend with new tidings. FEMS Microbiol Rev, 2016. 40(4): p. 
437-463. 
24. Barclay J et al: Non-antibiotic options for recurrent urinary tract infections in women. BMJ 2017; 359 
doi: https://doi.org/10.1136/bmj.j5193  
25. Forbes R1, Ali A2, Abouhajar A1, Brennand C1, Brown H3, Carnell S1, Chadwick T3, Eardley I4, 
Lecouturier J3, Mossop H3, Pearce I5, Pickard R6, Thiruchelvam N7, Walton K8, Wilkinson J1, Harding 
C. ALternatives To prophylactic Antibiotics for the treatment of Recurrent urinary tract infection in 
women (ALTAR): study protocol for a multicentre, pragmatic, patient-randomised, non-inferiority trial. 
Trials. 2018 Nov 9;19(1):616. doi: 10.1186/s13063-018-2998-4.