Asma et al.

BMC Urology (2018) 18:29

https://doi.org/10.1186/s12894-018-0342-7

STUDY PROTOCOL Open Access

Standardised high dose versus low dose

cranberry Proanthocyanidin extracts for the
prevention of recurrent urinary tract
infection in healthy women [PACCANN]: a
double blind randomised controlled trial
protocol
Babar Asma1,2 , Leblanc Vicky2, Dudonne Stephanie2, Desjardins Yves2, Howell Amy3 and Dodin Sylvie1,2*

Abstract
Background: Urinary tract infections (UTIs) are amongst the most common bacterial infections affecting women.
Although antibiotics are the treatment of choice for UTI, cranberry derived products have been used for many years to
prevent UTIs, with limited evidence as to their efficacy. Our objective is to assess the efficacy of a cranberry extract
capsule standardized in A-type linkage proanthocyanidins (PACs) for the prevention of recurrent urinary tract infection.
Methods: We will perform a 1:1 randomized, controlled, double blind clinical trial in women aged 18 years or more
who present ≥2 UTIs in 6 months or ≥ 3 UTIs in 12 months. One hundred and forty-eight women will be recruited and
randomized in two groups to either receive an optimal dose of cranberry extract quantified and standardized in PACs
(2 × 18.5 mg PACs per day) or a control dose (2 × 1 mg PACs per day). The primary outcome for the trial is the mean
number of new symptomatic UTIs in women during a 6-month intervention period. Secondary outcomes are: (1) To
evaluate the mean number of new symptomatic UTIs with pyuria as demonstrated by a positive leucocyte esterase
test; (2) To detect the mean number of new symptomatic culture-confirmed UTIs; (3) To quantify urinary PACs
metabolites in women who take a daily dose of 37 mg PACs per day compared to women who take a daily dose of
2 mg per day for 6 months; (4) To characterize women who present recurrent UTI based on known risk factors for
recurrent UTI; (5) To describe the side effects of daily intake of cranberry extract containing 37 mg PACs compared to
2 mg PACs. This report provides comprehensive methodological data for this randomized controlled trial.
Discussion: The results of this trial will inform urologists, gynaecologists, family physicians and other healthcare
professionals caring for healthy women with recurrent UTI, as to the benefits of daily use of an optimal dose of
cranberry extract for the prevention of recurrent UTI.
Trial registration: Clinicaltrials.gov, identifier: NCT02572895 October 8th 2015.
Keywords: Recurrent urinary tract infection, Women’s health, Proanthocyanidins, Cranberry, Vaccinium macrocarpon,
Antioxidants, Prevention

* Correspondence: [email protected]
1
Department of Obstetrics and Gynaecology, Laval University, CHU de
Québec - Université Laval, 2705, boulevard Laurier, Local A1385, Québec,
Québec G1V 4G2, Canada
2
Institute of Nutrition and Functional Foods, Laval University, 2440 Hochelaga
Boulevard, Quebec City, Quebec G1V 0A6, Canada
Full list of author information is available at the end of the article

© The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0
International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and
reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to
the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver
(http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.
Asma et al. BMC Urology (2018) 18:29 Page 2 of 7

Background provided an optimal antibacterial effect in the urine [16].

Urinary tract infections (UTIs) are one of the most com- A Cochrane systematic review published in 2012, could
mon bacterial infections affecting women [1, 2]. UTI not definitively conclude on the efficacy of cranberry
preferentially affects young, sexually active women with products for the prevention of r-UTI mainly because of
50–60% of women reporting at least one UTI during a lack of observance to the intake of cranberry supple-
their lifetime [2]. Nearly 1 in 3 women will experience at ments in juice form and also because of varying PACs
least one episode of UTI requiring antibiotic therapy be- concentrations in the different clinical trials that were
fore the age of 24 years and a quarter of these women rarely quantified or standardized [17]. A systematic re-
will present reoccurrence within 6 months [1]. view in 2013 including trials conducted in women with
Anatomical differences in male and female perineal r-UTI found a significantly decreased risk of UTI among
anatomy may explain why women are more susceptible women receiving cranberry-containing products com-
than men to the ascension of faecal bacteria in the pared to control (2 trials, Risk ratio (RR) = 0.53, 95%CI
urinary tract. More precisely, these anatomical features 0.33–0.83, I2 = 0%) [18].
include a relative shortness of the urethra [3], the Since these reviews, several well-designed trials have
urethral meatus’s proximity to the anus and a more evaluated the effects of daily cranberry capsules in women
humid surrounding environment comparatively to the with r-UTI. Most notably, an RCT compared the prevent-
male anatomy [4, 5]. Additional well-established risk fac- ive effects of a cranberry juice (UR65) containing 40 mg
tors include spermicide-based contraception, history of PACs versus placebo on the relapse of UTI in women
previous UTI, first UTI before 15 years of age and those aged 20–79 years presenting acute complicated or uncom-
with UTI history in the mother [6–10]. plicated cystitis with a history of r-UTI during a six-
Recurrent UTIs (r-UTI) are defined as more than 2 epi- month follow-up [19] The authors found no significant
sodes in the last 6 months or 3 episodes in the last year difference in the relapse rates of UTI between groups
[11]. The major symptoms of UTI include dysuria, in- (log-rank test, p = 0.4209). Similarly, a double blind RCT
creased frequency of urine, cloudy urine and occasionally evaluated the effects of a daily dose of 500 mg of a com-
hematuria [12]. In general, uncomplicated UTIs are con- mercial cranberry fruit powder (2 mg PACs) compared to
fined to the bladder, resolve quickly following antibiotic a placebo in 176 women who experienced at least 2 symp-
treatment and thus are associated with fewer severe or tomatic UTI in the twelve months preceding the study
long-term sequelae [13]. Though viewed as a benign afflic- [20]. In this trial, the proportion of women who experi-
tion, uncomplicated lower UTI symptoms can have con- enced greater than one UTI in the cranberry powder
siderable impacts on the patient’s productivity and quality group was significantly lower than in the placebo group
of life. A study of university women reported that patients during the six-month follow-up period (10.8% vs 25.8%, p
suffering from UTI experienced 2.4 days of restricted ac- = 0.04). Although well designed, these studies presented
tivity, 1.2 days of lost time and 0.4 bed bound days due to several methodological flaws such as the inclusion of
their symptoms [7]. Presently, the Canadian Urological women with complicated UTIs related to catheterization
Association and Society of Obstetricians and Gynecolo- in the former as well as the use of a sub-optimal dose of
gists of Canada recommendations for the treatment of un- cranberries in the latter.
complicated r-UTI use one of three antibiotic treatment We hypothesize that the efficacy of cranberry products
regimens: continuous antibiotic prophylaxis, post-coital for the prevention of R-UTI in women will be strongly
antibiotic prophylaxis or self-start antibiotic therapy [11, increased by the usage of an optimal dose of cranberry
12]. Empirical and preventive antibiotics for the treatment extracts in capsule form (standardized to 37 mg PACs
of r-UTI have been established as the most cost-effective per day) and by an adequate measure of participant
way to manage these infections. However, prescribing observance.
without confirmation of diagnosis and isolation of causal
bacterial contributes to the growing problem of uropatho- Methods
gen resistance in primary care [14]. Study design and objectives
Cranberries have been used for numerous years to pre- To assess the effects of a standardized cranberry extract
vent UTIs. Research suggests that proanthocyanidins in sexually active healthy women who present r-UTI, we
(PACs), a component of cranberries, inhibit the adher- will undertake a double blind, prospective RCT with 2
ence of p-fimbriated Escherichia coli on uroepithelial arms comparing the mean number of new UTIs during
cells of the bladder, preventing the adherence of bacteria a 6-month period after consumption of a standardized
to the mucosal surface of the urinary tract and thereby cranberry extract containing 37 mg PACs (2 × 18.5 mg
inhibiting bacterial proliferation [15]. A multicentre ran- PACs per day) with a control dose of 2 mg PACs (2 ×
domized clinical trial (RCT) in sexually active adult 1 mg PACs per day) in women presenting r-UTI. This
women showed that a daily dose of 36 mg PACs or more protocol was developed in accordance with the Standard
Asma et al. BMC Urology (2018) 18:29 Page 3 of 7

Protocol Items: Recommendations for Interventional sexual relations, personal and familial history of UTI; (5)
Trials (SPIRIT) Statement. The SPIRIT figure is illus- To describe the side effects of daily intake of cranberry
trated in Fig. 1. extract containing 37 mg PACs compared to 2 mg PACs.
The primary objective is to evaluate, in sexually active
women who present r-UTIs, the effects of a standardized Study participants and recruitment
cranberry extract containing 37 mg type-A linkage PACs This clinical trial aims to enrol sexually active non-
per day, compared to a control dose of 2 mg PACs per pregnant non-lactating women aged 18 years and over
day during a 6-month period on the incidence rate of presenting culture-confirmed r-UTI (defined as ≥2 UTIs
newly symptomatic UTIs during a 6-month follow-up in the past 6 months or ≥ 3 UTIs in the past 12 months).
period. Secondary objectives are: (1) To evaluate the Women will be recruited in the Laval University com-
mean number of new symptomatic UTIs with pyuria as munity in Quebec City, Canada, through list serves and
demonstrated by a positive leucocyte esterase test; (2) local clinician referrals as well as posters in medical
To detect the mean number of new symptomatic clinics, social media, paid advertising and word of
culture-confirmed UTIs; (3) To quantify urinary PACs mouth. Women wishing to participate will contact the
metabolites in women who take a daily dose of 37 mg study coordinator who will explain the research project
PACs per day compared to women who take a daily dose to them and verify eligibility according to inclusion and
of 2 mg per day for 6 months; (4) To characterize exclusion criteria (Table 1). The risks and benefits of the
women who present r-UTI based on known risk factors study will be thoroughly discussed and the consent form
such as spermicidal contraception use, frequency of will be signed at the first of three visits at the Institute
on Nutrition and Functional Foods (INAF).
Potential participants will need to restrain exposure to
systemic antimicrobial agents or cranberry derivatives in
the two weeks preceding enrolment. Women with ana-
tomical abnormalities of the urinary tract, a history of
renal disease (renal failure, nephrolithiasis) or intestinal
disease causing malabsorption (Crohn’s disease, Celiac
disease), or anticoagulant therapy will be excluded. Fur-
thermore, we will exclude women with known allergy or
intolerance to cranberries.

Study randomization
Concealed randomization will be generated using com-
puter aided block randomization by blocks of 10. Eligible

Table 1 Admissibility criteria for the cranberry extract for

prevention of recurrent urinary tract infections trial
Inclusion Criteria
Sexually active healthy women
Aged 18 years and older
Recent history of recurrent urinary tract infections (UTIs)a
≥ 2 UTIs in the past 6 months and/or
≥ 3 UTIs in the past 12 months
No consumption of cranberry juice, polyphenol or antioxidant
supplements in the last 2 weeks
Exclusion Criteria
Pregnancy
History of anatomical urogenital anomalies, urogenital tract surgery
History of acute or chronic renal failure, nephrolithiasis
History of intestinal diseases causing malabsorption
Anticoagulant medication in the last month
Known allergy or intolerance to cranberry
Fig. 1 Study procedures and characteristics of study visits a
UTIs diagnosed by a clinician and treated with antibiotic therapy
Asma et al. BMC Urology (2018) 18:29 Page 4 of 7

women will be assigned 1:1 to consume a cranberry ex- for an additional 24 weeks, with follow-up visits at 36 and
tract either formulated in high PAC content capsules (2 48 weeks. This data will provide information on seasonal
capsules of 18.5 mg PAC per day) or low PAC content variations in the incidence of UTI.
capsules (2 capsules of 1 mg PAC per day) for 6 months.
The low PAC content cranberry capsule is comparable Sample size and statistical analysis
to the majority of cranberry extract products presently Statistical analyses will be performed using SAS 9.2 (SAS
approved by Health Canada [21] . The standardized cap- Institute Inc., USA). All analyses will be based on the
sules will be manufactured and provided by Diana Foods intention-to-treat principle before unmasking the treatment
and will be distributed in opaque packaging in order to groups. The baseline characteristics of both groups will be
conceal colour variations from the research team. The compared using a Student’s t test for continuous variables
PAC content of each cranberry treatment will be vali- and a generalized linear model for nominal variables. The
dated at INAF according to the standardized BL-DMAC Poisson regression model, which allows us to adjust for par-
method, using A2 procyanidin dimer as standard for the ticipants that were lost to follow up, will be used to com-
quantification [22]. All clinical investigation, laboratory pare the incidence of UTI during the 6-month follow up
analysis, data collection and assessment will be blinded period as well as side effects of the treatment. Subgroup
to the randomization allocation. analyses will be performed in order to evaluate the impact
of cranberry capsules in pre- and post-menopausal women
Clinical follow-up as well as women with certain risk factors for complicated
Each visit (0, 12 and 24 weeks) will include a short ques- UTI such as pelvic floor disorders and diabetes.
tionnaire documenting socio-demographic characteristics Based on the literature [17], we estimate that 35% of
(T = 0 only), medication and natural health product intake, patients in the control group will present at least one
quality of life (SF-12) [23], risk factors for UTIs, and a vali- UTI during the 6-month follow-up period. In total, 126
dated food frequency questionnaire (FFQ) [24] modified for women will need to be recruited in order to detect a
our study to specifically include foods containing PACs. clinically significant difference of 25% between the 2
Double data entry will be performed under the study co- groups (10% of women assigned to the experimental
ordinator supervision in order to promote data quality. Par- group will have at least 1 UTI with a power of 80%).
ticipants will be instructed to obtain a midstream urine Based on our past clinical trial experience [25], we esti-
sample according to standard methods suggested by the mate that 15% of randomized participants will be lost to
microbiological laboratory. A dipstick urinalysis using follow up, therefore 148 women will need to be recruited
Chemstrip 9 (Roche Diagnostics USA) and a pregnancy test in order to have at least 126 participants who will
(ß-hCG) will be completed. Three 10 ml tubes will be complete the 24-week intervention.
placed in a − 80 °C freezer for urinary PAC metabolites
measurements by ultra-high performance liquid chroma- End points
tography coupled with mass spectrometry, and the urine Incidence of UTI
sample for culture will be refrigerated and transported to The primary endpoint is the average number of symptom-
the microbiology laboratory at the CHU de Quebec – Uni- atic UTIs during the 6-month follow-up period. Individ-
versite Laval within 24 h after collection. uals with acute urinary symptoms such as pollakiuria,
During their participation, the women will be asked to urgency, burning, suprapubic pain, and hematuria will be
contact the study coordinator if they present symptoms of assessed by study staff and will have to provide a urine
UTI in order to schedule a visit at INAF to confirm the sample for urinalysis. Women who present both symptom
diagnosis by urinalysis and urine culture and to receive an and pyuria criteria, defined as a positive leukocyte esterase
appropriate antibiotic prescription based on their medical dipstick result, will be diagnosed as having confirmed
history and allergies. Women unable to present themselves symptomatic UTI and prescribed appropriate antibiotic
at INAF will be prescribed antibiotics waiving a confirm- treatment. If the urine culture results are positive, the epi-
ation of their UTI. Women wishing to discontinue the con- sode will be categorized as a culture-confirmed UTI.
sumption of capsules will be asked to present themselves at Women with symptomatic UTI during the study period
the 3 and 6-month visit in order to complete intention to will continue to take the cranberry capsules and remain in
treat analysis. The participants will be asked not to con- the study for the full 6 months unless they are lost to fol-
sume other products containing cranberry derivatives for low up or discontinue the intervention.
the duration of the study and to consume their cranberry
extracts 2–4 h preceding each visit. Participants will also be Urinary PAC content
asked to limit intense physical activity for 24 h preceding At the beginning of the trial, participants will be offered
each visit. After 24 weeks of participation, women will be the option to provide a 24-h urine collect for targeted
provided with the option of prolonging their participation metabolomic characterization of PAC metabolites using
Asma et al. BMC Urology (2018) 18:29 Page 5 of 7

ultra-high-performance liquid chromatography coupled test and a urine culture. Positive leucocytes or nitrites
to tandem mass spectrometry, performed by a chemist will indicate a positive dipstick test [26]. A positive urine
blinded to treatment allocation. culture will be designated by greater than 106 colony-
forming units, according to the microbiological labora-
Compliance and side effects tory standards of the CHUL hospital. In our study, anti-
The cranberry extract capsules will be distributed at each biotics will be prescribed in the presence of clinical
visit and participants will be asked to bring remaining cap- symptoms in combination with either a positive urine
sules the next visit in order to count remaining capsules. dipstick test and/or positive urine culture.
The participants will fill out a daily journal to record com-
pliance, transient UTI symptoms and any adverse effects
related to capsule intake. A bi-monthly email reminder Implications of findings
will be sent to encourage participation. Each participant Many Canadian women who present r-UTI commonly use
will receive an email reminder in the week preceding each over the counter cranberries-derived products with inad-
visit. Evaluation of side effects will take place at each visit equate labelling of PACs concentrations. For cranberry prod-
and participants will be asked to document symptoms ucts with quantification of PACs, these concentrations rarely
(nausea, dyspepsia, abdominal pain, bloating and head- exceed 2 mg in Canada [21]. Various trials have tested the ef-
aches) in their daily journal. In the presence of severe side fectiveness of cranberry derived products, essentially in juice
effects, participants will be allowed to discontinue the form, and their results remain discordant mainly due to the
intervention and remain in the study in order to preserve lack of standardization and low doses of PACs in tested
the intention to treat analyses. products. Hence, the intrinsic activity of cranberry PACs,
demonstrated against Escherichia coli in vitro, has never
Blinding and contamination Bias been optimized for the prevention of UTI. The results gener-
The proportion of women who will guess their group allo- ated from this trial will clarify the role of cranberry extracts
cation correctly will be documented with a short question- standardized in PACs on the decreased incidence of UTI in
naire at the last visit. To control for contamination bias, women presenting r-UTIs, will evaluate the differences in
any antibiotic therapy during the study period will be de- the incidence of UTI on the basis of different PACs concen-
clared to the study coordinator and PAC consumption will trations and will respond to the recommendations reported
be measured by FFQ for the 24 h preceding each visit. in the last Cochrane meta-analysis [17].
This report provides comprehensive methods for a clin-
Discussion ical trial on the prevention of RUTI by cranberry extract
Use of cranberry derived products in the prevention of capsule intake. The strengths of this trial include the
r-UTI remains controversial, with no definitive evidence quantification and standardisation of PACs contained in
to show superiority of the cranberry compared to anti- the cranberry extract capsule and a randomized, double
biotic therapy [17, 18]. There is some evidence that blind, controlled trial method. Our trial will add to a
cranberry products may reduce the incidence of UTIs growing body of literature regarding cranberry extract
compared to placebo, though the most effective amount capsule for the prevention of r-UTI in healthy women. In
and concentration of PACs that must be consumed and addition, the data set and specimen bank generated from
the duration for the intervention are unknown [17]. To conducting this trial will enable researchers to understand
our knowledge, this study is the first large, prospective the metabolites of type-A PACs produced after prolonged
randomized clinical trial assessing the impact of a cran- consumption of cranberry capsules.
berry extract capsule standardized to 37 mg PAC per
day compared to 2 mg PAC per day in preventing UTIs Trial status
in healthy women presenting r-UTI. Participant recruitment started on August 18th 2015
Incidence of symptomatic UTI during the 6-month and was completed in March 2017. Study follow up
follow-up period was selected as the primary end-point visits will continue into Winter 2018.
in this trial because it is the most important, clinically
relevant long-term outcome for patients. We used three Abbreviations
classifications for UTI analyses: symptomatic UTI, FFQ: Food frequency questionnaire; PAC: Proanthocyanidin; RCT: Randomized
dipstick-positive UTI and culture-confirmed UTI. Symp- controlled trial; r-UTI: Recurrent UTI; UTI: Urinary tract infection
tomatic UTI was diagnosed if a participant presented at
least one of the following symptoms: dysuria, pollakiuria, Acknowledgements
urinary urgency, suprapubic pain or hematuria. In the We thank Iseult Grenier-Ouellet and Marie-Pier Bernard-Genest for their assistance
in the clinical follow-up of participants during this clinical trial at the Institute of
presence of clinical symptoms, participants will be asked Nutrition and Functional Foods, Laval University. The authors are very grateful to
to provide a urine sample in order to perform a dipstick the laboratory and clinical staff and all participants in this study.
Asma et al. BMC Urology (2018) 18:29 Page 6 of 7

Funding 4. Yamamoto S, Tsukamoto T, Terai A, Kurazono H, Takeda Y, Yoshida O.

This research project was funded by the Ministry of Agriculture, Fisheries and Genetic evidence supporting the fecal-perineal-urethral hypothesis in
Food of Quebec and Nutra Canada (now part of Diana Food). The funders had no cystitis caused by Escherichia coli. J Urol. 1997;157(3):1127–9.
role in the design and conduct of this clinical trial; the collection, management, 5. Hooton TM. Pathogenesis of urinary tract infections: an update. J
analysis, and interpretation of data; the preparation, review, or approval of the antimicrobial chemotherapy. 2000;46(Suppl A):1–7.
manuscript; and the decision to submit the manuscript for publication. Nutra 6. Strom BL, Collins M, West SL, Kreisberg J, Weller S. Sexual activity,
Canada manufactured and donated the cranberry capsules used in this study. contraceptive use, and other risk factors for symptomatic and asymptomatic
bacteriuria. A case-control study. Ann Intern Med. 1987;107(6):816–23.
Availability of data and materials 7. Foxman B, Frerichs RR. Epidemiology of urinary tract infection: I. Diaphragm
All data sets will be password protected and only available to project use and sexual intercourse. Am J Public Health. 1985;75(11):1308–13.
investigators. Data sets, cleaned and blinded of any identifying participant 8. McDonald AM, Knight RC, Campbell MK, Entwistle VA, Grant AM, Cook JA,
information, as well as the full protocol, will be available after the Elbourne DR, Francis D, Garcia J, Roberts I, et al. What influences recruitment to
completion of the trial on request to the contacting author. randomised controlled trials? A review of trials funded by two UK funding
agencies. Trials. 2006;7:9.
Dissemination of results 9. Foxman B, Frerichs RR. Epidemiology of urinary tract infection: II. Diet,
Trial results will be accessible to health professionals and the scientific clothing, and urination habits. Am J Public Health. 1985;75(11):1314–7.
community through articles published in peer-reviewed journals and 10. Scholes D, Hawn TR, Roberts PL, Li SS, Stapleton AE, Zhao LP, Stamm WE,
presentations at local, national and international scientific conferences in the Hooton TM. Family history and risk of recurrent cystitis and pyelonephritis
fields of gynaecology, urology, nutraceuticals and antioxidants. Results will also in women. J Urol. 2010;184(2):564–9.
be disseminated to the general public through interviews on community radio 11. Epp A, Larochelle A, Lovatsis D, Walter JE, Easton W, Farrell SA, Girouard L,
and the publication of news articles. Gupta C, Harvey MA, Robert M, et al. Recurrent urinary tract infection. J
Obstet Gynaecol Can. 2010;32(11):1082–101.
Authors’ contributions 12. Dason S, Dason JT, Kapoor A. Guidelines for the diagnosis and
AB performed recruitment, clinical follow up, interpretation of data, statistical management of recurrent urinary tract infection in women. Can Urol
analyses and writing of the manuscript; VL. contributed to the design of this Assoc J. 2011;5(5):316–22.
study, recruitment, clinical follow up, interpretation of data, statistical 13. Little P, Merriman R, Turner S, Rumsby K, Warner G, Lowes JA, Smith H, Hawke
analyses and revision of the manuscript; S. Dudonne undertook supervision C, Leydon G, Mullee M, et al. Presentation, pattern, and natural course of
of the biomarker measures and review of the manuscript, AD and YD severe symptoms, and role of antibiotics and antibiotic resistance among
contributed to the original concept and design of this study; S. Dodin patients presenting with suspected uncomplicated urinary tract infection in
contributed to the original concept and design of this study, undertook primary care: observational study. BMJ (Clinical research ed). 2010;b5633:340.
supervision of the clinical follow-up of participants, and wrote the study 14. Giesen LG, Cousins G, Dimitrov BD, van de Laar FA, Fahey T. Predicting acute
grant. All authors read and approved the final manuscript. uncomplicated urinary tract infection in women: a systematic review of the
diagnostic accuracy of symptoms and signs. BMC Fam Pract. 2010;11:78.
Ethics approval and consent to participate 15. Gupta K, Chou MY, Howell A, Wobbe C, Grady R, Stapleton AE.
The protocol and consent form of this study were reviewed and approved by the Cranberry products inhibit adherence of p-fimbriated Escherichia coli to
institutional ethics committee of Laval University with approval number 2015–091 primary cultured bladder and vaginal epithelial cells. J Urol.
A-5/ 03–11-2016. Further changes to the study protocol will require ethics approval 2007;177(6):2357–60.
from the institutional ethics committee. The study coordinator will obtain written 16. Howell AB, Botto H, Combescure C, Blanc-Potard AB, Gausa L, Matsumoto T,
informed consent from all study participants. Women will be able to withdraw from Tenke P, Sotto A, Lavigne JP. Dosage effect on uropathogenic Escherichia
the study at any time during their participation. Data will be entered electronically coli anti-adhesion activity in urine following consumption of cranberry
and original study forms will be kept locked at the study site and maintained in powder standardized for proanthocyanidin content: a multicentric
storage for a period of 25 years after the completion of the study. This randomized randomized double blind study. BMC Infect Dis. 2010;10:94.
clinical trial is registered in ClinicalTrials.gov, identifier: NCT02572895. 17. Jepson RG, Williams G, Craig JC. Cranberries for preventing urinary tract
infections. Cochrane Database Syst Rev. 2012;10:CD001321.
Competing interests 18. Wang CH, Fang CC, Chen NC, Liu SS, Yu PH, Wu TY, Chen WT, Lee CC,
The authors report no conflicts of interest. The authors alone are responsible Chen SC. Cranberry-containing products for prevention of urinary tract
for the content and writing of the paper. infections in susceptible populations: a systematic review and meta-
analysis of randomized controlled trials. Arch Intern Med.
2012;172(13):988–96.
Publisher’s Note 19. Takahashi S, Hamasuna R, Yasuda M, Arakawa S, Tanaka K, Ishikawa K, Kiyota
Springer Nature remains neutral with regard to jurisdictional claims in H, Hayami H, Yamamoto S, Kubo T, et al. A randomized clinical trial to
published maps and institutional affiliations. evaluate the preventive effect of cranberry juice (UR65) for patients with
recurrent urinary tract infection. J Infection Chemotherapy : official journal
Author details of the Japan Society of Chemotherapy. 2013;19(1):112–7.
1
Department of Obstetrics and Gynaecology, Laval University, CHU de 20. Fromentin E, Vostalova J, Vidlar A, Galandakova A, Vrbkova J, Ulrichova J,
Québec - Université Laval, 2705, boulevard Laurier, Local A1385, Québec, Student V, Simanek V. A randomized, double-blind, placebo-controlled clinical
Québec G1V 4G2, Canada. 2Institute of Nutrition and Functional Foods, Laval trial to investigate the efficacy of cranberry fruit powder (Pacran) in the
University, 2440 Hochelaga Boulevard, Quebec City, Quebec G1V 0A6, prevention of recurrent urinary tract infection in women. FASEB J. 2014;28
Canada. 3Rutgers University, 125A Lake Oswego Rd., Chatsworth, NJ 08019, 21. Licensed Natural Health Products Database [https://www.canada.ca/en/
USA. health-canada/services/drugs-health-products/natural-non-prescription/
applications-submissions/product-licensing/licensed-natural-health-products-
Received: 16 June 2017 Accepted: 18 April 2018 database.html].
22. Prior RL, Fan E, Ji H, Howell A, Nio C, Payne MJ, Reed J. Multi-laboratory
validation of a standard method for quantifying proanthocyanidins in
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