Cranberry versus placebo in the prevention of urinary infections in multiple sclerosis: a multicenter,randomized,placebo-controlled,double-blind trial

Abstract

Objective:

Our aim was to assess the usefulness of cranberry extract in multiple sclerosis (MS) patients suffering from urinary disorders.

Methods:

In total, 171 adult MS outpatients with urinary disorders presenting at eight centers were randomized (stratification according to center and use of clean intermittent self-catheterization) to cranberry versus placebo in a 1-year, prospective, double-blind study that was analyzed using a sequential method on an intent-to-treat basis. An independent monitoring board analyzed the results of the analyses each time 40 patients were assessed on the main endpoint. Cranberry extract (36 mg proanthocyanidins per day) or a matching placebo was taken by participants twice daily for 1 year. The primary endpoint was the time to first symptomatic urinary tract infection (UTI), subject to validation by a validation committee.

Results:

The second sequential analyses allowed us to accept the null hypothesis (no difference between cranberry and placebo). There was no difference in time to first symptomatic UTI distribution across 1 year, with an estimated hazard ratio of 0.99, 95% CI [0.61, 1.60] (p = 0.97). Secondary endpoints and tolerance did not differ between groups.

Conclusion:

Taking cranberry extract versus placebo twice a day did not prevent UTI occurrence in MS patients with urinary disorders. Trial Registration NCT00280592.

Keywords

Multiple sclerosis urinary tract infection neurogenic bladder

Introduction

Multiple sclerosis (MS) is an inflammatory demyelinating and neurodegenerative disease of the central nervous system.¹ Lower urinary tract dysfunction is mainly the result of spinal cord disease. About 50–80% of patients with MS develop urinary disorders during the course of the disease.² Frequency, urgency, hesitancy, incomplete emptying and incontinence are the most common problems. Urinary disorders not only reduce quality of life but also lead to complications, the most frequent being recurrent urinary tract infections (UTIs). Moreover, neurological symptoms can deteriorate acutely when patients develop infections and pyrexia.³

Cranberry juice exhibits antibacterial activity⁴ mediated by proanthocyanidins, which prevent Escherichia coli from adhering to the urogenital mucosa.⁵

The use of cranberry juice for UTI prophylaxis in MS is a tempting prospect, as it appears to be a safe, herbal choice. There is no major side effect, except for gastrointestinal disorders⁶ and a possible increased risk of kidney stone formation.⁷ Overall, it could limit emerging antibiotic resistance in urinary tract pathogens by reducing the need for strategies based on antibiotic medications.⁸

Several randomized trials involving participants with either neurogenic or non-neurogenic bladders, but all with a history of recurrent UTIs, have reported conflicting results. Regarding patients with spinal cord injuries (SCIs), a recent review⁹ suggested performing more rigorous clinical research. Even in specialist centers, the prevention of UTIs in patients with SCI tends to be based on the treating physician’s personal experience, rather than on the published evidence.¹⁰ Only one randomized, placebo-controlled trial has been conducted in MS.¹¹ Although this failed to prove any prophylactic effect of cranberry supplements, not all such supplements have been found to contain proanthocyanidins. A definitive answer has therefore yet to be found.

In the current study, we tested the hypothesis that a daily dose of cranberry extract would prevent UTIs in MS patients with urinary disorders. Our objectives were to assess the efficacy and safety of this treatment in this population.

Patients and methods

To address these objectives, we designed a 1-year, prospective, multicenter, randomized, placebo-controlled, double-blind study with two parallel groups. To allow for a more rapid conclusion, the study was planned, monitored and analyzed using a sequential method.¹²

The protocol was approved by the committee for human investigation (Comité Consultatif de Protection des Personnes dans la Recherche Biomédicale) of Rennes, France, on 11 July 2005 (05/24-551). All the patients gave their written informed consent. The study was registered with ClinicalTrials.gov (no. NCT00280592) and there was no change to methods after trial commencement.

Participants

The study was conducted in eight outpatient settings in university hospitals or rehabilitation clinics from January 2006 to November 2007. Patients with MS aged 18–70 years, with an Expanded Disability Status Scale (EDSS) score¹³ greater or equal to three, who had been clinically stable for at least 3 months and who were able to undergo evaluation were eligible for inclusion. They had to have urinary disorders (at least one of these four symptoms: pollakiuria, urgency, dysuria and urinary incontinence), and had to agree to a 1-year follow-up. Pregnant or breast-feeding women, patients with renal failure, risk of uric acid lithiasis, peptic ulcer, intolerance to cranberry and/or excipients, who were receiving UTI antibioprophylaxis, who were receiving oral anticoagulants, who had consumed cranberry in some form within the previous 3 months, or who had an indwelling catheter were excluded. Patients with UTIs at the time of randomization were also excluded.

Patients underwent a complete physical examination, together with serum creatinine and uric acid tests. Post-void urine was evaluated by bladder scan. They were each given an information letter describing the protocol and the treatment modalities. The absolute necessity of performing a urine culture in the case of a suspected UTI was fully explained before they gave their informed consent.

Interventions

Participants took the treatment (powder for oral solution of cranberry extract or matching placebo) twice a day. Each dose of cranberry extract contained 18 mg of proanthocyanidins, corresponding to 36 mg of proanthocyanidins per day.¹⁴ At each appointment, they were given enough treatment to last until the next one, 3 months later. Compliance was assessed by counting used and non-used sachets. The proportion of compliant patients (patients using more than 70% of their treatment) was calculated for each group.

Endpoints

The primary endpoint was time to first symptomatic UTI between inclusion and Month 12 (censored criterion). A symptomatic UTI was defined as an UTI with (i) at least one of the following symptoms: fever above 38°C, pain on passing urine, frequency or dysuria syndrome, and (ii) a bacterial count of more than 100,000 CFU/ml on urine culture. When a UTI was detected by the patient, its date was recorded. Each UTI had to be confirmed by a urine culture prior to antibiotic treatment.

Secondary endpoints were the 1-year UTI rate, the number of UTIs experienced by each patient, quality of life, as measured on the Qualiveen scale (lower scores indicate a better quality of life),¹⁵ the EDSS score, the symptomatology of urinary disorders, the number of MS relapses, antibiotic consumption and the percentage of patients who reported side effects. These endpoints were assessed at M3, M6, M9 and M12.

Each patient received a booklet in which they were asked to report all UTIs and the treatments they received. All the patients were assessed every 3 months by the investigator until the end of the study. Each month, they were contacted by phone. The side effects of the treatment were recorded at each follow-up visit.

Committees

A diagnosis and main endpoint validation committee was set up before the protocol was implemented. This committee met before each sequential analysis and blindly reviewed the data of all included patients. It had to validate inclusion and exclusion criteria, as well as UTI diagnoses. If necessary, this committee could ask the investigators to provide additional information to validate the patient data.

An independent data and safety monitoring board (DSMB) was also set up. This committee had to analyze the conduct of the study, scrutinize the results of the sequential analyses, and review serious adverse events.

Sample size

Based on the literature,¹⁶ we estimated that the mean UTI rate would be 35% at the 1-year follow-up. So that we could stop the study as soon as sufficient information had been gathered, we chose to use a sequential method¹² (single triangular test).¹⁷ This test was designed to allow for the detection of an expected 15% reduction in the UTI rate (i.e. a hazard ratio of 0.57), with 90% power, while the Type-I error (two-sided) was set at 5%. We chose the single triangular test in its two-sided version to allow for a two-sided conclusion while reducing the sample size, as compared with the double triangular test.¹⁸ This methodological option was acceptable because the control group received a placebo and we were not interested in demonstrating the inferiority of cranberry with a power similar to that required for demonstrating its superiority.¹⁸

Under these conditions, using PEST 3.0 statistical software (Reading University, Reading, UK), we determined that the mean number of events required to stop the study was 52 (90^th percentile: 77) under both the null and alternative hypotheses, 61 (90^th percentile: 88), right between the null and alternative hypotheses, and that the maximum number of events (corresponding to the apex of the triangle) was 134.

Interim analyses and stopping rules

Sequential analyses were performed on the primary endpoint after each assessment of 40 patients. Two statistics (V and Z) were computed at each sequential analysis and the corresponding points plotted a sample path in the sequential plan.

On the basis of the results of the sequential analyses, the DSMB could (i) decide to continue the study if no statistical decision could be made (sample path remained within the boundaries of the triangular test), or (ii) decide to stop the study in the case of the null hypothesis being rejected or accepted (sample path crossed one of the boundaries of the triangular test).

Randomization

Randomization was centrally performed, concealed, and stratified according to center and the use of clean intermittent self-catheterization, in blocks of four according to a computer-generated random number table with a 1:1 allocation. In each center, sequentially numbered boxes containing the whole treatment for each patient were delivered to the investigator by the pharmacist following the order of the randomization list. The randomization day was taken as D1 of the study.

Blinding

All the patients, pharmacists, medical and nursing staff remained blinded throughout the study period.

Statistical analyses

Statistical analyses were performed on an intent-to-treat basis. Reported values are expressed either as means ± SD (continuous variables) or as frequencies and their corresponding percentages (categorical variables). Sequential analyses were performed with PEST 3.0 (Reading University, Reading, UK). When the trial was stopped, the last of the sequential analyses of the primary endpoint was also performed with PEST 3.0. Final analyses were performed with SAS 9.1 statistical software (SAS Institute, Cary, NC, USA). Student’s t-test was used to compare continuous variables, while the chi-square test (or Fisher’s exact test when appropriate) was used to compare the categorical variables, and the log-rank test was used to compare the censored variables. Cumulative event curves were constructed using the Kaplan–Meier method.

Results

Recruitment and baseline data

Figure 1 shows the study’s flow diagram. A total of 171 patients with urinary disorders were recruited between 26 January 2006 and 5 November 2007. There were three protocol deviations: two patients in the placebo group and one patient in the cranberry group were not regarded as clinically stable, but were nonetheless included in the analysis.

As shown in Table 1, the two treatment groups were well balanced at baseline concerning neurological status, urinary disorders, quality of life, post-void urine, serum creatinine and uric acid at inclusion. In total, 60 out of 72 (83%, missing data = 17) patients in the placebo group and 51 out of 64 (80%, missing data = 18) patients in the cranberry group were considered as compliant.

Table 1.

Baseline demographic and clinical characteristics Note. EDSS: Expanded Disability Status Scale; CISC: clean intermittent self-catheterization.

Characteristics	Whole sample (N=171)	Cranberry (n=82)	Placebo (n=89)
Demographic
Age (years)	49 ± 10	49 ± 9	48 ± 11
Sex (men)	46 (26.9%)	19 (23.2%)	27(30.3)
Neurological status
Years since disease onset	14.7 ± 9.0	15.4 ± 9.7	14.0 ± 8.3
Type of MS
Remitting	58 (33.9%)	31 (37.8%)	27 (30.3%)
Primary progressive	33 (19.3%)	16 (19.5%)	17 (19.1%)
Secondary progressive	80 (46.8%)	35 (42.7%)	45 (50.6%)
Time since last relapse (months)	5.9 ± 5.1 (n=37)	5.0 ± 5.0 (n=16)	6.6 ± 5.2 (n=21)
EDSS score	5.32 ± 1.51	5.43 ± 1.57	5.22 ± 1.44
Total Qualiveen score	1.46 ± 0.88 (n=164)	1.37 ± 0.90 (n=79)	1.55 ± 0.85 (n=85)
Urinary disorders
CISC catheterization	58 (33.9%)	27 (32.9%)	31 (34.8%)
Time since onset of urinary disorders (years)	8.2 ± 6.5 (N=167)	8.3 ± 6.7 (N=79)	8.2 ± 6.4 (N=88)
Frequency
Nighttime	82 (48.0%)	33 (40.2%)	49 (55.1%)
Daytime	84 (49.1%)	41 (50.0%)	43 (48.3%)
Urgency	139 (81.3%)	69 (84.1%)	70 (78.7%)
Dysuria	148 (86.5%)	70 (85.4%)	78 (87.6%)
Urine leakage	106 (62.0%)	51 (62.2%)	55 (61.8%)
Pain passing urine	10 (5.8%)	7 (8.5%)	3 (3.4%)
Suprapubic pain	12 (7.0%)	6 (7.3%)	6 (6.7%)
Cloudy urine	21 (12.3%)	11 (13.4%)	10 (11.2%)
Serum creatinine (μmol/l)	72.9 ± 14.1 (N=162)	72.7 ± 14.0 (N=79)	73.0 ± 14.4 (N=83)
Acid uricemia (μmol/l)	236.2 ± 69.7 (N=157)	231.7 ± 67.7 (N=75)	240.3 ± 71.6 (N=82)
Post-void urine	109 ± 117 (N=111)	102 ± 103 (N=52)	115 ± 129 (N=59)
History of urinary tract infections	129 (75.4%)	64 (78.0%)	65 (73.0%)
History of nephrolithiasis	13 (7.6%)	8 (9.8%)	5 (5.6%)

Primary endpoint (sequential analyses)

The DSMB met after the second wave of sequential analyses (October 2007). By that time, 80 patients had been included and assessed on the primary endpoint and a further 89 patients were still in the follow-up period. On the grounds of the analysis results, the null hypothesis was accepted and the DSMB recommended stopping inclusions. By the time this decision became known, two more patients had been enrolled in the study. A new analysis was performed (December 2007) to confirm the results of the second sequential analysis and to decide whether the follow-up should also be stopped (108 patients analyzed by that point, with a further 63 patients still being followed). Results confirmed the previous analysis and the DSMB decided to stop the study after each patient had been assessed one more time. Owing to this decision, 25 participants (14 in the cranberry group and 11 in the placebo group) did not undergo the full 1-year follow-up.

Figure 2 shows the triangular test and the corresponding sample path. Figure 3 shows the Kaplan–Meier UTI probabilities. At the end of the study, the estimated hazard ratio was 0.99, 95% CI [0.61, 1.60], p = 0.97 (unbiased estimation and significance level taking into account the sequential nature of the analysis).

Secondary endpoints (final analysis)

No significant difference was found between the two groups in 1-year UTI rates (cranberry: 31 (37.8%); placebo: 36 (40.4%); p = 0.72). Nor was there any significant difference between the groups at M12 in the number of UTIs experienced by patients who had at least one UTI (placebo: 2.2 ± 2.3; cranberry: 2.3 ± 1.8; p = 0.46). Table 2 sets out the values for these two endpoints at each assessment.

Table 2.

Number of patients with at least one urinary tract infection (UTI) and number of UTIs per patient.

	Cranberry (n=82)	Placebo (n=89)	p-value
Number of patients with at least one UTI during the period
D0 - M3	20/77 (26.0%)	21/87 (24.1%)	0.78
D0 - M6	20/69 (29.0%)	22/81 (27.2%)	0.80
D0 - M9	21/60 (35.0%)	27/70 (38.6%)	0.67
D0 - M12	21/51 (41.2%)	24/60 (40.0%)	0.90
Mean (± SD) number of UTIs per patient with at least one UTI
D0 - M3	1.6 ± 0.8 (n=20)	1.4 ± 0.8 (n=21)	0.38
D0 - M6	2.2 ± 1.5 (n=20)	2.2 ± 2.0 (n=22)	0.49
D0 - M9	2.1 ± 1.5 (n=21)	2.4 ± 2.6 (n=27)	0.28
D0 - M12	2.3 ± 1.8 (n=21)	2.2 ± 2.3 (n=24)	0.46

The only significant difference was in the Qualiveen score at M9, which was higher in the placebo group (0.91 ± 0.70 for cranberry vs. 1.27 ± 0.86 for placebo, p = 0.02). No differences were observed at the other time points.

No difference was found concerning urinary disorder symptomatology. The EDSS score also remained stable, even for patients who contracted UTIs. A total of 31 patients had MS relapses during the follow-up (cranberry: 12 (14.6%); placebo: 19 (21.3%); p = 0.25). Thirty-eight (46.3%) patients in the cranberry group and 47 (52.8%) patients in the placebo group took at least one antibiotic (p = 0.40) during their follow-up. For these patients, the mean number of days with antibiotics was 29.2 ± 25.7 in the cranberry group and 24.1± 22.9 in the placebo group (p = 0.38). Infecting organisms in the patients who developed infection are presented in e-table1 (supplementary information).

Treatment safety

There were no significant differences between the two groups in terms of adverse events. No serious adverse event that could be ascribed to the cranberry extract was observed during the study period. The most frequent adverse event reported by patients was the occurrence of UTIs. Regarding the known or expected side effects of cranberry, 14 patients (17.1%) in the cranberry group and 18 (20.5%) in the placebo group presented with gastrointestinal disorders (p = 0.32), while two patients (2.4%) in the cranberry group and two in the placebo group (2.3%) presented with noninfectious urinary disorders (p = 1).

Discussion

Main findings

No significant reduction in UTIs was observed during the 1-year follow-up. The administration of cranberry to prevent UTIs in MS therefore appears to be inefficient. Moreover, the consumption of cranberry extract failed to improve either urinary symptoms or quality of life. Then again, the occurrence of UTIs did not actually influence the course of the disease in our population.

Although one study of the usefulness of cranberry in preventing UTIs had previously been conducted in MS,¹¹ there were doubts surrounding the quality of the cranberry supplements that were administered.

Our study supports the results of a recent review of research among patients with SCIs.⁹ Regarding individual studies, neither Linsenmeyer et al.¹⁹ nor Waites et al.²⁰ found any benefits to taking cranberry extract in terms of reducing bacterial or leukocyte counts or the rate of symptomatic UTIs. In the first study, cranberry exposure lasted only 1 month. It was based up a crossover design with a 1-week washout period, even though it can be a whole month before the cranberry extract starts to take effect, and that effect may then last for up to a month. In the second study, cranberry was administered for 6 months, but there was an imbalance in the characteristics of the randomized groups, as the cranberry group was more likely to use intermittent catheterization and the control group an external collection device. The bladder drainage method is known to influence the UTI rate in the SCI population.²¹

A single-center, randomized, double-blind study with a 6-month follow-up of four groups of 75, 78, 75 and 77 SCI patients who received either methenamine hippurate, cranberry tablets, association of methenamine hippurate and cranberry tablets, or a placebo concluded that cranberry is inefficient in preventing UTIs.²² More recently, Hess et al.²³ found a significant reduction in both the incidence of UTI and the number of patients who contracted UTIs during a 6-month course of cranberry treatment. However, this was yet again a crossover study without a washout period, and included participants with heterogeneous methods of bladder management.

Our study addressed the limitations identified in the above-mentioned studies, insofar as it was a multicenter trial with a randomization stratified according (i) to center and (ii) the use of clean intermittent self-catheterization. In line with the recommendation of a previous Cochrane Review of the use of cranberries to prevent UTIs,¹⁴ our follow-up lasted more than 6 months, in order to take the natural course of the disease into account. The sample size of our study was one of the largest ever for a clinical trial involving patients with neurogenic bladders. The results on the main endpoint were scrutinized by a validation committee.

Limitations

In our study, there were a large number of withdrawals, essentially owing to the premature stoppage of the study, but also as a result of the patients’ own decision in some instances. This had a negative impact on the final analysis of our secondary endpoints. However, dropouts also signal that the patients have derived no discernible benefit.¹⁴

The study was stopped as soon as we had amassed sufficient information to reach a conclusion. Nevertheless, the primary endpoint was not reached particularly quickly and the recruitment rate was higher than we had originally forecast. Thus, although we reached a conclusion after the second analysis, a substantial number of additional patients had already been included and were still in follow-up. Although we could have arrived at our conclusion with a smaller sample size, thus exposing fewer patients to an ineffectual treatment and reducing the cost of the study, the larger sample size increased the statistical power, which was one of the strengths of our study.

The effect of cranberry on E. coli adherence is dose-dependent, and there are still problems with the standardization of cranberry products, making it extremely difficult to compare products or extrapolate from the results of the various studies cited earlier.²⁴ Nevertheless, our clinical trial assessed specific cranberry-derived active compounds (proanthocyanidins) that were accurately titrated, with a daily dose of 36 mg, which is thought to be an active dosage.

Other factors such as fructose and hippuric acid were proposed to contribute to cranberry antiseptic effects. Our cranberry extract contained sufficient dose of fructose but hippuric acid was not titrated. Nevertheless, its putative role is far from being consensual.²⁵

Lastly, in our study, patient compliance seemed acceptable. Our data reflects the use of the treatment in a real-life setting. Nevertheless, it is, in general, very difficult to assess compliance in the absence of a specific measure of plasmatic concentration of drugs.

Conclusion

The daily administration of cranberry extract containing 36 mg of proanthocyanidins did not prevent UTI occurrence in MS patients with neurogenic bladders.

Footnotes

Acknowledgements

Group Authorship

The “Cranberry Study Group” comprised:

- Study chairs: Philippe Gallien and Jean Michel Reymann;

- Investigators: Philippe Gallien, Benoit Nicolas, Gérard Amarenco, Marianne de Seze, Cécile Donze, Véronique Bonniaud, Pierre Denis, Jacques Kerdraon;

- Pharmacy: Catherine Hamon, Laurent Flet;

- Data monitoring: Christelle Tual;

- Pharmacovigilance: Catherine Mouchel;

- Data management: Hélène Danjou;

- Statisticians: Alain Renault, Florian Naudet;

- Diagnosis and main endpoint validation committee: Cédric Arvieux, Sophie Lasfargeas, Bruno Laviolle;

- Independent data and safety monitoring board (DSMB): Christophe Camus, Patrice Nordmann, Elisabeth Polard, Véronique Sébille, Catherine Mouchel;

- Clinical research assistants: Christelle Tual, Sophie Lasfargeas, Aurélie Veislinger.

Conflict of interest

(1) No authors had support from any company for the submitted work.

(2) P.G., B.N., V.B., J.K., M.S., P.D., A.R., J.M.R. have had no relationship with any company that might have an interest in the submitted work in the previous three years; G.A. has relationships (consultancy or board membership or travel/accommodation expenses covered/reimbursed) with Allergan, Wellspect, Pfizer, Astellas and Coloplast; C.D. has relationships (investigator or consultancy or board membership or travel/accommodation expenses covered/reimbursed) with Biogen Idec, Merck Serono, Bayer, Teva, Sanofi–Aventis, Novartis, Almiral and Coloplast; F.N. has relationships (board membership or travel/accommodation expenses covered/reimbursed) with Servier, BMS, Lundbeck and Janssen.

(3) None of the authors’ spouses, partners, or children have any financial relationships that may be relevant to the submitted work.

(4) None of the authors has any non-financial interests that may be relevant to the submitted work.

Funding

This study was carried out with financial support from the French Ministry of Health (PHRC 2005).

Author contributions

Philippe Gallien had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Philippe Gallien and Jean Michel Reymann;

Data acquisition: Philippe Gallien, Benoit Nicolas, Gérard Amarenco, Marianne de Seze, Cécile Donze, Véronique Bonniaud, Pierre Denis, Jacques Kerdraon;

Data analysis and interpretation: Philippe Gallien, Florian Naudet and Jean Michel Reymann;

Drafting of the manuscript: Philippe Gallien, Florian Naudet and Jean Michel Reymann.

Critical revision of the manuscript for important intellectual content: All authors;

Statistical analysis: Alain Renault;

Obtained funding: Philippe Gallien and Jean Michel Reymann;

Administrative, technical, or material support: Philippe Gallien and Jean Michel Reymann;

Study supervision: Philippe Gallien and Jean Michel Reymann.

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