http://informahealthcare.com/pgm ISSN: 0032-5481 (print), 1941-9260 (electronic) Postgrad Med, 2015; 127(2): 218–222 DOI: 10.1080/00325481.2015.1000229
ORIGINAL RESEARCH
Assessment of confirmed urinary tract infection in patients treated with dalfampridine for multiple sclerosis Daniel Kantor1, Michael B. Chancellor2, Clayton W. Snell3, Herbert R. Henney III3 & Adrian L. Rabinowicz3 Neurologique Foundation, Inc., Ponte Vedra Beach, FL, USA, 2Department of Urology, Oakland University William Beaumont School of Medicine, Royal Oak, MI, USA, and 3Acorda Therapeutics, Inc., Ardsley, NY, USA
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1
Abstract
Keywords
Urinary tract infections (UTIs) were reported frequently with dalfampridine extended-release (dalfampridine-ER) 10 mg relative to placebo in previous multiple sclerosis (MS) studies. The objective of this study was to determine whether dalfampridine-ER is associated with increased incidence of confirmed UTIs in MS patients. This post hoc analysis used UTI data from a study comparing the 4-week safety and efficacy of 5 mg (n = 144) and 10 mg (n = 142) twice-daily dalfampridine-ER versus placebo (n = 143). To confirm UTIs, three clinical assessments were used: standard urinalysis (leukocytes > 5/high-power field); urine culture (‡ 100,000 and ‡ 10,000 colony-forming units [CFUs]/mL) for those who reported UTIs as adverse events (AEs) or had positive urinalysis; and UTI symptomatology. Fisher’s exact test assessed statistical significance. The proportion of patients who reported UTIs as AEs in the placebo and dalfampridine-ER 5 mg and 10 mg groups were 5.6%, 6.3%, and 9.9%, respectively. In comparison, those with laboratoryconfirmed UTIs were lower: ‡ 100,000 CFUs/mL: 4.2%, 2.8%, and 2.8%; and ‡ 10,000 CFUs/mL: 4.2%, 3.5%, and 4.9%, respectively (no significant statistical difference across treatments). The proportion of patients with confirmed UTI was similar between dalfampridine-ER and placebo, thus suggesting that the treatment does not increase the risk of UTIs.
4-aminopyridine, dalfampridine, MS relapse, multiple sclerosis, urinary tract infection
Introduction Neurogenic bladder is a disorder of the lower urinary tract caused by damage to or diseases of the central nervous system. Neurogenic bladder and other urinary tract disorders are present in as many as 80% of people with multiple sclerosis (MS) and commonly present with symptoms of urinary urgency, frequency, nocturia, retention, and, sometimes, urinary incontinence [1]. These symptoms, as well as a need for catheterization in some patients, increase the risk for urinary tract infections (UTIs), with more frequent occurrence of symptomatic and asymptomatic UTIs than observed in the general population [2-4]. The occurrence of UTIs is of clinical relevance to MS, as an association between recurrent UTIs and MS relapse has been shown [5]. Additionally, UTIs can potentially develop into systemic infections, which may result in a relapse that is associated with more severe and sustained effects on neurological status than relapses not associated with infections [6,7]. Dalfampridine, chemically 4-aminopyridine, is a potassium channel blocker that has been shown in animal studies to promote restoration of action potential conduction in demyelinated nerve fibers [8]. Dalfampridine extended-release (dalfampridine-ER) tablets (known as prolonged-release fampridine in Europe and as fampridine modified or sustained release
History Received 18 November 2014 Accepted 16 December 2014 Published online 6 January 2015
elsewhere), 10 mg twice daily, are available in the USA to improve walking in people with MS as demonstrated by an increase in walking speed [9]. In two Phase III, randomized controlled trials, dalfampridine-ER was shown to increase walking speed in a proportion of patients with MS [10,11]. Although dalfampridine-ER was generally well tolerated in clinical trials [10,11], and subsequent postmarketing safety assessments suggested a similar safety profile in clinical practice [12,13], UTIs were reported more frequently among patients receiving dalfampridine-ER 10 mg relative to placebo across all studies [10,11,14]. However, these reports were primarily based on patient-reported symptoms consistent with a UTI with no confirmatory urine culture. Because of the clinical implications of UTIs in people with MS, an objective of this study was to examine the increased risk of confirmed UTI as part of a postmarketing commitment.
Methods Study design This was a post hoc analysis of a randomized, placebo-controlled, double-blind, three-arm, parallel-group study designed primarily to compare safety and efficacy of two doses of dalfampridine-ER, 5 mg and 10 mg, twice daily. Efficacy
Correspondence: Adrian L. Rabinowicz, MD, Acorda Therapeutics, Inc., 420 Saw Mill River Road, Ardsley, NY 10502, USA. Tel: +1 914 326 5298. Fax: +1 914 606 9553. E-mail: [email protected] 2015 Informa UK Ltd.
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DOI: 10.1080/00325481.2015.1000229
Assessment of UTI in patients treated with dalfampridine for MS
measures and the overall tolerability have previously been described [15]. Briefly, the study included a 1-week screening and 4-week treatment period (visit 1: randomization and baseline safety and efficacy assessments; visit 2: week-2 interim assessments; and visit 3: week-4 assessments and study completion). Major inclusion criteria were age between 18 and 70 years, inclusive; a diagnosis of clinically definite MS defined by the 2005 revision of the McDonald Criteria [16]; and the presence of MS-related walking impairment but with sufficient ambulatory ability to complete all evaluations of the timed 25 foot walk test. Patients who had previously taken any formulation of dalfampridine-ER were also required to have been withdrawn from the drug for at least 1 month prior to screening, and women of childbearing potential were required to use adequate contraception during the study. Pregnant or lactating women were excluded from the study, and other key exclusion criteria included a history of seizures; presence or history of moderate or severe renal impairment defined by a calculated creatinine clearance £ 50 mL/min; presence of an active UTI at screening or within the 4 weeks before screening; initiation of an MS disease-modifying therapy within 90 days prior to screening or change in regimen of these drugs within 30 days before screening; and onset of an MS exacerbation within 60 days prior to screening.
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Table 1. Post hoc criteria for evaluation of urinary tract infections. Variable
Criterion A
Criterion B
Leukocytes Colony count Contamination
> 5/HPF ‡ 105 CFUs/mL None
> 5/HPF ‡ 104 CFUs/mL None
Abbreviations: CFUs = Colony-forming units; HPF = High-power field.
used for defining significant bacteriuria [17], the latter was included to increase diagnostic sensitivity. It has been hypothesized that “low-count” bacteriuria may be an early sign of infection since 30%–50% of patients with lower urinary tract symptoms have been reported to have colony counts < 105 CFUs/mL [17,18]. To better quantify the incidence of confirmed UTIs, two evaluation criteria (A and B) were applied post hoc that included the microscopic urinalysis but differed by urine culture data (Table 1). UTI symptomatology Patient reports of UTI symptoms were recorded as AEs in the case reports. For the purpose of this analysis, a broad range of urinary symptoms was used as search terms to capture any treatment-emergent events that could be potentially interpreted as UTI symptoms (Table 2). However, the terms listed in Table 2 do not necessarily represent events that actually occurred.
Evaluation of UTI At every visit, a urine sample (clean catch urine specimen) was taken from all patients for microscopic urinalysis for detection of UTI. If patients experienced adverse events (AEs) suggestive of UTI symptoms, urine cultures were required in addition to the standard urinalysis for confirmation of UTI diagnosis. A urine culture was also performed if the urinalysis was positive, even if the patient had no symptoms of UTI. Symptoms of UTI were coded using version 13.1 of the Medical Dictionary of Regulatory Activities (MedDRA). To determine whether treatment with dalfampridine-ER increases the incidence of UTI or merely the likelihood of UTI symptoms, three types of clinical UTI assessments were applied, based on best practice [17-19]: microscopic urinalysis, urine culture for patients who reported UTI symptoms or who had a positive urinalysis, and UTI symptomatology. An incidence of UTI was confirmed only if all three clinical assessments were met at least during one visit, including the screening and any unscheduled visits. Differences among the treatment groups were evaluated using Fisher’s exact test. Microscopic urinalysis Samples were analyzed for the presence of ‡ 5 leukocytes per high-power field, since the presence of leukocytes is specific (94%–98%) and reliably sensitive (75%–96%) for detecting UTIs [19]. Urine cultures
Standard protocol approvals, registrations, and patient consents The study was approved by the appropriate institutional review boards or independent ethics committees and was performed in accordance with the revised Declaration of Helsinki. All patients provided written informed consent. The study was registered with ClinicalTrials.gov (NCT01328379). Table 2. Search terms used for UTI symptomatology analysis. Infections UTI Urinary tract infection Asymptomatic UTI Symptomatology (verbatim term/preferred terma) Worsening of urinary urgencyb/micturition urgencyb Worsening of urgeb/urinary incontinenceb Increasing polyuria/polyuria Overactive bladderc/hypertonic bladderc Burning sensation felt during urination/dysuria Nocturiab/nocturia Increased urinary frequencyb/pollakiuria Urinary discomfortb/dysuria Urinary retention/urinary retention Intermittent urinary frequencyb/pollakiuria Dark urine/chromaturia Bloody urine Left lower quadrant flank pain/flank pain Right flank pain/flank pain Clinical laboratory tests terms Increased specific gravity White blood cells present in urine Elevated urine protein Abbreviation: UTI = Urinary tract infection. Adverse events were coded as preferred terms as used in version 13.1 of the Medical Dictionary of Regulatory Activities. b Lower urinary tract symptoms that overlap with UTI. c Non-UTI diagnoses. a
Two colony counts were applied to cultures from positive uncontaminated urine samples: ‡ 105 and ‡ 104 colonyforming units (CFUs)/mL. Whereas the former is commonly
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Table 3. Demographic and clinical characteristics of the treatment groups at baselinea. Dalfampridine-ER
Gender, n (%) Men Women Age, years, mean ± SD Race, n (%) Asian White African-American Other BMI, kg/m2, mean ± SD MS diagnosis type, n (%) Relapsing-remitting Secondary-progressive Primary-progressive Progressive-relapsing Disease duration, years, mean ± SD EDSS score, mean ± SD
5 mg (n = 144)
10 mg (n = 143)
42 (29.6%) 100 (70.4%) 52.2 ± 9.9
42 (29.2%) 102 (70.8%) 52.2 ± 9.3
45 (31.5%) 98 (68.5%) 53.4 ± 9.5
1 (0.7%) 117 (82.4%) 22 (15.5%) 2 (1.4%) 28.3 ± 7.1
1 (0.7%) 113 (78.5%) 27 (18.8%) 3 (2.1%) 28.3 ± 6.6
1 (0.7%) 114 (79.7%) 24 (16.8%) 4 (2.8%) 29.1 ± 5.8
103 (72.5%) 23 (16.2%) 12 (8.5%) 4 (2.8%) 13.0 ± 9.5 4.8 ± 1.6
104 (72.2%) 19 (13.2%) 17 (11.8%) 4 (2.8%) 11.3 ± 8.5 4.8 ± 1.5
107 (74.8%) 21 (14.7%) 11 (7.7%) 4 (2.8%) 12.1 ± 9.0 4.7 ± 1.5
a
Safety population as randomized. Abbreviations: BMI = Body mass index; EDSS = Expanded disability status scale; ER = Extended release; MS = Multiple sclerosis; SD = Standard deviation.
Results Among the 538 subjects who were screened for inclusion, 55 had an active UTI or a UTI reported within the past 4 weeks and were excluded. Based on these data, the occurrence of UTI in the screened MS population was estimated to be 10.2%. Of those randomized and treated with at least one dose of investigational product (n = 429; safety population as randomized), the demographic and clinical characteristics were balanced between treatment groups (Table 3). Subjects were primarily women (70%), the mean age was 52.6 years, the main diagnosis type was relapsing-remitting MS (73.2%), and the mean disease duration was 12.1 years. For all safety analyses including UTI reporting, patients were classified based on the actual treatment received (safety population as treated: 143 patients in the placebo group, and
144 and 142 in the dalfampridine-ER 5 mg and 10 mg, respectively; one patient who was randomized to dalfampridine-ER 10 mg received placebo). The reported renal and urinary disorders as treatment-emergent AEs, based on MedDRA System Organ Class and Preferred Terms, were low across treatment groups and did not show dose-dependent effects with dalfampridine-ER (Table 4). However, the proportion of patients who reported lower UTI symptoms as AEs appeared to be dose-related: 5.6% (8/143), 6.3% (9/144), and 9.9% (14/ 142) in the placebo and dalfampridine-ER 5 mg and 10 mg groups, respectively (Figure 1). However, these data do not distinguish whether treatment is associated with higher rates of UTI or simply an increased likelihood of symptomatic reports. Thus, to determine the number of confirmed UTI cases among those with urinary symptomatology (Table 2), the laboratory evaluation criteria were applied across treatment groups. Based on the microscopic and culture data, there were fewer patients with confirmed UTI and symptomatology
Table 4. Incidence of reported renal and urinary disorders as treatmentemergent adverse events by MedDRA System organ class and preferred terms.
Dalfampridine-ER
Renal and urinary disorders Chromaturia Dysuria Hypertonic bladder Micturition urgency Nephrolithiasis Nocturia Pollakiuria Polyuria Urinary incontinence Urinary retention
Placebo (n = 142) 5 (3.5) 0 0 0 1 (0.7) 1 0 1 (0.7) 0 1 (0.7) 1 (0.7)
5 mg (n = 144) 6 (4.2) 0 2 (1.4) 0 0 0 1 (0.7) 2 (1.4) 1 (0.7) 0 0
10 mg (n = 143) 6 (4.2) 1 (0.7) 1 (0.7) 1 (0.7) 1 (0.7) 0 0 2 (1.4) 0 0 0
Abbreviations: ER = Extended release; MedDRA = Medical Dictionary of Regulatory Activities.
Placebo (n = 143) Dalfampridine-ER 5 mg (n = 144) Dalfampridine-ER 10 mg (n = 142)
9.9%
10
Incidence, n (%)
MedDRA system organ class preferred term
12
Percent of patients
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Characteristic
Placebo (n = 142)
8 6.3% 6
5.6% 4.9% 4.2%
4
4.2% 3.5% 2.8% 2.8%
2 0 Reported UTI symptoms
Confirmed UTI with criterion A
Confirmed UTI with criterion B
Figure 1. Proportion of patients with UTI during treatment is shown. Criteria A and B included the microscopic urinalysis and culture data but differed by colony count: A: ‡ 105 CFUs/mL and B: ‡ 104 CFUs/ mL. Abbreviations: CFUs = Colony-forming units; ER = Extended release; UTI = Urinary tract infection.
Assessment of UTI in patients treated with dalfampridine for MS
DOI: 10.1080/00325481.2015.1000229
a
b
Criterion A analysis 12
6.9%
2 6
10
4
Number of patients
Number of patients
4
6
8
5
10.5%
4
10 mg (n = 142)
7 4
2 Placebo (n = 143)
5 mg (n = 144)
Criterion A with symptomatology Symptomatology only
10 mg (n = 142)
Dalfampridine-ER
Dalfampridine-ER Criterion A only
7
5
6
0 5 mg (n = 144)
11.3% 12.5%
2
2 Placebo (n = 143)
9
6
5.6%
2
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7.0%
6
9
13
10
6
8
0
Criterion B analysis 12
10
4
221
Criterion B only
Criterion B with symptomatology Symptomatology only
Figure 2. Analyses by laboratory evaluation criterion and symptomatology are shown. Symptomatology-only groups did not have confirmed UTI; criterion-only groups were asymptomatic. Criteria A and B included the urinalysis and culture data, but they differed by colony count: A: ‡ 105 CFUs/mL and B: ‡ 104 CFUs/mL. Percentages reflect the proportion of patients with confirmed UTIs, regardless of reported symptoms. Abbreviations: CFUs = Colony-forming units; ER = Extended release; UTI = Urinary tract infection.
(Figure 2): criterion A: 6 (4.2%), 4 (2.8%), and 4 (2.8%); and criterion B: 6 (4.2%), 5 (3.5%), and 7 (4.9%) for the placebo and dalfampridine-ER 5 mg and 10 mg groups, respectively. There were no statistically significant differences among the treatment groups for the number of patients who met these criteria (criterion A: P = 0.7463; criterion B: P = 0.8347). The number of asymptomatic patients who met the laboratory criteria were: criterion A: 2 (1.4%), 6 (4.2%), and 6 (4.2%); and criterion B: 9 (6.3%), 13 (9.0%), and 9 (6.3%) for the placebo and dalfampridine-ER 5 mg and 10 mg groups, respectively (Figure 2). The proportion of patients who were only symptomatic appeared to be dose-dependent when stratified by laboratory criteria and symptomatology (criterion A: 2 (1.4%), 5 (3.5%), and 10 (7.0%); and criterion B: 2 (1.4%), 4 (2.8%), and 7 (4.9%) for placebo and dalfampridine-ER 5 mg and 10 mg, respectively; Figure 2). Regardless of urinary symptomatology, the proportion of patients who had confirmed UTIs with criterion A was lower relative to criterion B (5.6%, 6.9%, and 7.0% vs 10.5%, 12.5%, and 11.3% for placebo and dalfampridine-ER 5 mg and 10 mg, respectively; Figure 2), which is likely due to the application of high stringency colony count in criterion A. There were no statistically significant differences among treatment groups for criterion A or criterion B in patients who met these criteria (P = 0.9108 and P = 0.8935, respectively). These proportions were also similar to or less than the frequency of UTIs observed in the screened MS population (10.2%).
Discussion The results of this analysis showed that despite more frequent reports of urinary symptoms among patients treated with
dalfampridine-ER, treatment was not associated with an increased incidence of laboratory-confirmed UTIs. However, it should be noted that the study population was selected for lack of infection at screening, so patients included in the analysis do not necessarily represent the broader population that was screened. Urinary symptoms can occur with UTI, neurogenic bladder dysfunction, or both. Using criteria for identifying UTIs in clinical practice [17-19] that are based on a composite of leukocyte count and bacterial quantitation, no significant differences were observed between the proportions of patients who developed UTIs during the treatment period in the dalfampridine-ER and placebo groups. Although dalfampridine-ER 5 mg and 10 mg treatment groups had similar proportions of confirmed UTIs, the incidence of reported UTI symptoms (ie, in the absence of a confirmed UTI) was higher with the 10 mg dose, which was similar to the prevalence of UTIs observed in the screened population. Although no increased risk of UTIs was associated with dalfampridine-ER, a number of factors may have contributed to the increased incidence of urinary symptoms in the absence of an actual confirmed UTI. In the current analysis, a broad range of urinary symptoms reported as treatmentemergent AEs was used to capture UTI events. Many of the AE terms that were used overlap with UTI symptoms and can also be related to lower urinary tract symptoms; and two of the terms used, overactive bladder and detrusor overactivity, are separate non-UTI diagnoses. The use of such a broad range of urinary symptomatology may account, at least in part, for the higher incidence of symptomatic reports of UTI. Additionally, the consistently higher frequency of symptoms with dalfampridine-ER relative to placebo suggests that
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additional factors may have been involved, especially considering the dose-proportional increase in the number of symptomatic patients who did not meet the laboratory criteria for UTIs. A putative factor contributing to these symptoms could be local bladder sensory effects of dalfampridine on the urinary tract resulting from increased activation of afferent neurons. Because renal excretion of dalfampridine is the main route of elimination and it is primarily excreted as unchanged compound [20], its presence in urine may result in some local sensory effects in the urinary tract that potentially occur from increased electrical activity in afferent nerves. It is thus possible that the occurrence of these sensory effects may give rise to the report of symptoms in a proportion of patients. Although no new safety concerns were identified, further studies to more fully characterize these effects may be warranted. Nevertheless, because of the higher risk of UTIs in patients with MS and the clinical implications of UTIs, it is important in the clinical setting to verify whether urinary tract symptoms in fact represent an actual confirmed UTI. A limitation of this study is that the details of the analysis were determined post hoc, although all data captured for determining the occurrence of UTI-related symptoms and laboratory confirmation of UTIs was pre-specified. Although a broad range of urinary symptoms including some that are not specific to UTIs were used, it was thought that adopting a conservative approach to capture such events may more accurately reflect what is reported in clinical practice.
Conclusion In this analysis, no differences in UTI incidence rate could be detected between patients treated with dalfampridine-ER and what would be expected in the general MS population. The proportion of patients with confirmed UTIs by laboratory criteria was not different between dalfampridine-ER and placebo, and the frequency of these UTIs was lower than that observed in the screened MS population. There were no new safety signals, and these results suggest that dalfampridineER is not likely to increase the incidence of UTIs in patients with MS.
Acknowledgments This work was supported by Acorda Therapeutics, Inc., Ardsley, NY, USA. Kantor, Chancellor, Henney, and Rabinowicz were involved in the concept and design of the post hoc analysis, review of data, and manuscript development. Data analysis was performed by Snell. Editorial assistance was provided by E Jay Bienen, PhD, of The Curry Rockefeller Group, LLC, Tarrytown, NY, USA, and funded by Acorda Therapeutics, Inc., Ardsley, NY, USA. Trial Registration: NCT01328379.
Declaration of interest D Kantor has received honoraria or payments for consulting, advisory services, and speaking services from Acorda Therapeutics, Inc., Allergan, Avanir, Biogen Idec, Depomed, Genzyme, Novartis, Questcor, Osmotica, and Teva and has
Postgrad Med, 2015; 127(2):218–222
received research support from Acorda Therapeutics, Inc., Avanir, Biogen Idec, Genzyme, Novartis, and Teva. CW Snell and AL Rabinowicz are employees of Acorda Therapeutics, Inc., with stock options. HR Henney III was an employee of Acorda Therapeutics, Inc., at the time of the study. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
References [1] National Multiple Sclerosis Society. “About MS: bladder dysfunction”. Available from http://www.nationalmssociety.org/aboutmultiple-sclerosis/what-we-know-about-ms/symptoms/bladder-dysfunction/index.aspx. [2] Foxman B. Epidemiology of urinary tract infections: incidence, morbidity, and economic costs. Am J Med 2002;113:5S–13S. [3] Edlich RF, Westwater JJ, Lombardi SA, Watson LR, Howards SS. Multiple sclerosis and asymptomatic urinary tract infection. J Emerg Med 1990;8:25–8. [4] Sand PK, Sand RI. The diagnosis and management of lower urinary tract symptoms in multiple sclerosis patients. Dis Mon 2013;59:261–8. [5] Metz LM, McGuinness SD, Harris C. Urinary tract infections may trigger relapse in multiple sclerosis. Axone 1998;19:67–70. [6] Buljevac D, Flach HZ, Hop WC, et al. Prospective study on the relationship between infections and multiple sclerosis exacerbations. Brain 2002;125:952–60. [7] Correale J, Fiol M, Gilmore W. The risk of relapses in multiple sclerosis during systemic infections. Neurology 2006;67:652–9. [8] Shi R, Blight AR. Differential effects of low and high concentrations of 4-aminopyridine on axonal conduction in normal and injured spinal cord. Neuroscience 1997;77:553–62. [9] Ampyra [dalfampridine] extended release (ER) tablets highlights of prescribing information. Acorda Therapeutics, Inc; Ardsley, NY: January 2014. [10] Goodman AD, Brown TR, Krupp LB, et al. Fampridine MS-F203 Investigators. Sustained-release oral fampridine in multiple sclerosis: a randomised, double-blind, controlled trial. Lancet 2009;373:732–8. [11] Goodman AD, Brown TR, Edwards KR, et al. MSF204 Investigators. A phase 3 trial of extended release oral dalfampridine in multiple sclerosis. Ann Neurol 2010;68:494–502. [12] Jara M, Barker G, Henney HR 3rd. Dalfampridine extended release tablets: 1 year of postmarketing safety experience in the US. Neuropsychiatr Dis Treat 2013;9:365–70. [13] Jara M, Adera M, Adedeji A, Henney H, Carrazana E. Dalfampridine extended release tablets: safety profile after 2 years of postmarketing experience in the United States [ECTRIMS abstract P1026]. Mult Scler 2012;18:476–7. [14] Goodman AD, Brown TR, Cohen JA, et al. Fampridine MS-F202 Study Group. Dose comparison trial of sustained-release fampridine in multiple sclerosis. Neurology 2008;71:1134–41. [15] Yapundich R, Applebee A, Bethoux F, et al. Evaluation of dalfampridine extended release 5 and 10 mg in multiple sclerosis: a randomized, controlled trial. Int J MS Care 2014; In press. [16] Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiple sclerosis: 2005 revisions to the “McDonald Criteria”. Ann Neurol 2005;58:840–6. [17] Kunin CM, White LV, Hua TH. A reassessment of the importance of “low-count” bacteriuria in young women with acute urinary symptoms. Ann Intern Med 1993;119:454–60. [18] Wilson ML, Gaido L. Laboratory diagnosis of urinary tract infections in adult patients. Clin Infect Dis 2004;38:1150–8. [19] Mehnert-Kay SA. Diagnosis and management of uncomplicated urinary tract infections. Am Fam Physician 2005;72:451–6. [20] Blight AR, Henney HR 3rd. Pharmacokinetics of 14C-radioactivity after oral intake of a single dose of 14C-labeled fampridine (4-aminopyridine) in healthy volunteers. Clin Ther 2009;31:328–35.
ORIGINAL RESEARCH
Assessment of confirmed urinary tract infection in patients treated with dalfampridine for multiple sclerosis Daniel Kantor1, Michael B. Chancellor2, Clayton W. Snell3, Herbert R. Henney III3 & Adrian L. Rabinowicz3 Neurologique Foundation, Inc., Ponte Vedra Beach, FL, USA, 2Department of Urology, Oakland University William Beaumont School of Medicine, Royal Oak, MI, USA, and 3Acorda Therapeutics, Inc., Ardsley, NY, USA
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1
Abstract
Keywords
Urinary tract infections (UTIs) were reported frequently with dalfampridine extended-release (dalfampridine-ER) 10 mg relative to placebo in previous multiple sclerosis (MS) studies. The objective of this study was to determine whether dalfampridine-ER is associated with increased incidence of confirmed UTIs in MS patients. This post hoc analysis used UTI data from a study comparing the 4-week safety and efficacy of 5 mg (n = 144) and 10 mg (n = 142) twice-daily dalfampridine-ER versus placebo (n = 143). To confirm UTIs, three clinical assessments were used: standard urinalysis (leukocytes > 5/high-power field); urine culture (‡ 100,000 and ‡ 10,000 colony-forming units [CFUs]/mL) for those who reported UTIs as adverse events (AEs) or had positive urinalysis; and UTI symptomatology. Fisher’s exact test assessed statistical significance. The proportion of patients who reported UTIs as AEs in the placebo and dalfampridine-ER 5 mg and 10 mg groups were 5.6%, 6.3%, and 9.9%, respectively. In comparison, those with laboratoryconfirmed UTIs were lower: ‡ 100,000 CFUs/mL: 4.2%, 2.8%, and 2.8%; and ‡ 10,000 CFUs/mL: 4.2%, 3.5%, and 4.9%, respectively (no significant statistical difference across treatments). The proportion of patients with confirmed UTI was similar between dalfampridine-ER and placebo, thus suggesting that the treatment does not increase the risk of UTIs.
4-aminopyridine, dalfampridine, MS relapse, multiple sclerosis, urinary tract infection
Introduction Neurogenic bladder is a disorder of the lower urinary tract caused by damage to or diseases of the central nervous system. Neurogenic bladder and other urinary tract disorders are present in as many as 80% of people with multiple sclerosis (MS) and commonly present with symptoms of urinary urgency, frequency, nocturia, retention, and, sometimes, urinary incontinence [1]. These symptoms, as well as a need for catheterization in some patients, increase the risk for urinary tract infections (UTIs), with more frequent occurrence of symptomatic and asymptomatic UTIs than observed in the general population [2-4]. The occurrence of UTIs is of clinical relevance to MS, as an association between recurrent UTIs and MS relapse has been shown [5]. Additionally, UTIs can potentially develop into systemic infections, which may result in a relapse that is associated with more severe and sustained effects on neurological status than relapses not associated with infections [6,7]. Dalfampridine, chemically 4-aminopyridine, is a potassium channel blocker that has been shown in animal studies to promote restoration of action potential conduction in demyelinated nerve fibers [8]. Dalfampridine extended-release (dalfampridine-ER) tablets (known as prolonged-release fampridine in Europe and as fampridine modified or sustained release
History Received 18 November 2014 Accepted 16 December 2014 Published online 6 January 2015
elsewhere), 10 mg twice daily, are available in the USA to improve walking in people with MS as demonstrated by an increase in walking speed [9]. In two Phase III, randomized controlled trials, dalfampridine-ER was shown to increase walking speed in a proportion of patients with MS [10,11]. Although dalfampridine-ER was generally well tolerated in clinical trials [10,11], and subsequent postmarketing safety assessments suggested a similar safety profile in clinical practice [12,13], UTIs were reported more frequently among patients receiving dalfampridine-ER 10 mg relative to placebo across all studies [10,11,14]. However, these reports were primarily based on patient-reported symptoms consistent with a UTI with no confirmatory urine culture. Because of the clinical implications of UTIs in people with MS, an objective of this study was to examine the increased risk of confirmed UTI as part of a postmarketing commitment.
Methods Study design This was a post hoc analysis of a randomized, placebo-controlled, double-blind, three-arm, parallel-group study designed primarily to compare safety and efficacy of two doses of dalfampridine-ER, 5 mg and 10 mg, twice daily. Efficacy
Correspondence: Adrian L. Rabinowicz, MD, Acorda Therapeutics, Inc., 420 Saw Mill River Road, Ardsley, NY 10502, USA. Tel: +1 914 326 5298. Fax: +1 914 606 9553. E-mail: [email protected] 2015 Informa UK Ltd.
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DOI: 10.1080/00325481.2015.1000229
Assessment of UTI in patients treated with dalfampridine for MS
measures and the overall tolerability have previously been described [15]. Briefly, the study included a 1-week screening and 4-week treatment period (visit 1: randomization and baseline safety and efficacy assessments; visit 2: week-2 interim assessments; and visit 3: week-4 assessments and study completion). Major inclusion criteria were age between 18 and 70 years, inclusive; a diagnosis of clinically definite MS defined by the 2005 revision of the McDonald Criteria [16]; and the presence of MS-related walking impairment but with sufficient ambulatory ability to complete all evaluations of the timed 25 foot walk test. Patients who had previously taken any formulation of dalfampridine-ER were also required to have been withdrawn from the drug for at least 1 month prior to screening, and women of childbearing potential were required to use adequate contraception during the study. Pregnant or lactating women were excluded from the study, and other key exclusion criteria included a history of seizures; presence or history of moderate or severe renal impairment defined by a calculated creatinine clearance £ 50 mL/min; presence of an active UTI at screening or within the 4 weeks before screening; initiation of an MS disease-modifying therapy within 90 days prior to screening or change in regimen of these drugs within 30 days before screening; and onset of an MS exacerbation within 60 days prior to screening.
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Table 1. Post hoc criteria for evaluation of urinary tract infections. Variable
Criterion A
Criterion B
Leukocytes Colony count Contamination
> 5/HPF ‡ 105 CFUs/mL None
> 5/HPF ‡ 104 CFUs/mL None
Abbreviations: CFUs = Colony-forming units; HPF = High-power field.
used for defining significant bacteriuria [17], the latter was included to increase diagnostic sensitivity. It has been hypothesized that “low-count” bacteriuria may be an early sign of infection since 30%–50% of patients with lower urinary tract symptoms have been reported to have colony counts < 105 CFUs/mL [17,18]. To better quantify the incidence of confirmed UTIs, two evaluation criteria (A and B) were applied post hoc that included the microscopic urinalysis but differed by urine culture data (Table 1). UTI symptomatology Patient reports of UTI symptoms were recorded as AEs in the case reports. For the purpose of this analysis, a broad range of urinary symptoms was used as search terms to capture any treatment-emergent events that could be potentially interpreted as UTI symptoms (Table 2). However, the terms listed in Table 2 do not necessarily represent events that actually occurred.
Evaluation of UTI At every visit, a urine sample (clean catch urine specimen) was taken from all patients for microscopic urinalysis for detection of UTI. If patients experienced adverse events (AEs) suggestive of UTI symptoms, urine cultures were required in addition to the standard urinalysis for confirmation of UTI diagnosis. A urine culture was also performed if the urinalysis was positive, even if the patient had no symptoms of UTI. Symptoms of UTI were coded using version 13.1 of the Medical Dictionary of Regulatory Activities (MedDRA). To determine whether treatment with dalfampridine-ER increases the incidence of UTI or merely the likelihood of UTI symptoms, three types of clinical UTI assessments were applied, based on best practice [17-19]: microscopic urinalysis, urine culture for patients who reported UTI symptoms or who had a positive urinalysis, and UTI symptomatology. An incidence of UTI was confirmed only if all three clinical assessments were met at least during one visit, including the screening and any unscheduled visits. Differences among the treatment groups were evaluated using Fisher’s exact test. Microscopic urinalysis Samples were analyzed for the presence of ‡ 5 leukocytes per high-power field, since the presence of leukocytes is specific (94%–98%) and reliably sensitive (75%–96%) for detecting UTIs [19]. Urine cultures
Standard protocol approvals, registrations, and patient consents The study was approved by the appropriate institutional review boards or independent ethics committees and was performed in accordance with the revised Declaration of Helsinki. All patients provided written informed consent. The study was registered with ClinicalTrials.gov (NCT01328379). Table 2. Search terms used for UTI symptomatology analysis. Infections UTI Urinary tract infection Asymptomatic UTI Symptomatology (verbatim term/preferred terma) Worsening of urinary urgencyb/micturition urgencyb Worsening of urgeb/urinary incontinenceb Increasing polyuria/polyuria Overactive bladderc/hypertonic bladderc Burning sensation felt during urination/dysuria Nocturiab/nocturia Increased urinary frequencyb/pollakiuria Urinary discomfortb/dysuria Urinary retention/urinary retention Intermittent urinary frequencyb/pollakiuria Dark urine/chromaturia Bloody urine Left lower quadrant flank pain/flank pain Right flank pain/flank pain Clinical laboratory tests terms Increased specific gravity White blood cells present in urine Elevated urine protein Abbreviation: UTI = Urinary tract infection. Adverse events were coded as preferred terms as used in version 13.1 of the Medical Dictionary of Regulatory Activities. b Lower urinary tract symptoms that overlap with UTI. c Non-UTI diagnoses. a
Two colony counts were applied to cultures from positive uncontaminated urine samples: ‡ 105 and ‡ 104 colonyforming units (CFUs)/mL. Whereas the former is commonly
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Table 3. Demographic and clinical characteristics of the treatment groups at baselinea. Dalfampridine-ER
Gender, n (%) Men Women Age, years, mean ± SD Race, n (%) Asian White African-American Other BMI, kg/m2, mean ± SD MS diagnosis type, n (%) Relapsing-remitting Secondary-progressive Primary-progressive Progressive-relapsing Disease duration, years, mean ± SD EDSS score, mean ± SD
5 mg (n = 144)
10 mg (n = 143)
42 (29.6%) 100 (70.4%) 52.2 ± 9.9
42 (29.2%) 102 (70.8%) 52.2 ± 9.3
45 (31.5%) 98 (68.5%) 53.4 ± 9.5
1 (0.7%) 117 (82.4%) 22 (15.5%) 2 (1.4%) 28.3 ± 7.1
1 (0.7%) 113 (78.5%) 27 (18.8%) 3 (2.1%) 28.3 ± 6.6
1 (0.7%) 114 (79.7%) 24 (16.8%) 4 (2.8%) 29.1 ± 5.8
103 (72.5%) 23 (16.2%) 12 (8.5%) 4 (2.8%) 13.0 ± 9.5 4.8 ± 1.6
104 (72.2%) 19 (13.2%) 17 (11.8%) 4 (2.8%) 11.3 ± 8.5 4.8 ± 1.5
107 (74.8%) 21 (14.7%) 11 (7.7%) 4 (2.8%) 12.1 ± 9.0 4.7 ± 1.5
a
Safety population as randomized. Abbreviations: BMI = Body mass index; EDSS = Expanded disability status scale; ER = Extended release; MS = Multiple sclerosis; SD = Standard deviation.
Results Among the 538 subjects who were screened for inclusion, 55 had an active UTI or a UTI reported within the past 4 weeks and were excluded. Based on these data, the occurrence of UTI in the screened MS population was estimated to be 10.2%. Of those randomized and treated with at least one dose of investigational product (n = 429; safety population as randomized), the demographic and clinical characteristics were balanced between treatment groups (Table 3). Subjects were primarily women (70%), the mean age was 52.6 years, the main diagnosis type was relapsing-remitting MS (73.2%), and the mean disease duration was 12.1 years. For all safety analyses including UTI reporting, patients were classified based on the actual treatment received (safety population as treated: 143 patients in the placebo group, and
144 and 142 in the dalfampridine-ER 5 mg and 10 mg, respectively; one patient who was randomized to dalfampridine-ER 10 mg received placebo). The reported renal and urinary disorders as treatment-emergent AEs, based on MedDRA System Organ Class and Preferred Terms, were low across treatment groups and did not show dose-dependent effects with dalfampridine-ER (Table 4). However, the proportion of patients who reported lower UTI symptoms as AEs appeared to be dose-related: 5.6% (8/143), 6.3% (9/144), and 9.9% (14/ 142) in the placebo and dalfampridine-ER 5 mg and 10 mg groups, respectively (Figure 1). However, these data do not distinguish whether treatment is associated with higher rates of UTI or simply an increased likelihood of symptomatic reports. Thus, to determine the number of confirmed UTI cases among those with urinary symptomatology (Table 2), the laboratory evaluation criteria were applied across treatment groups. Based on the microscopic and culture data, there were fewer patients with confirmed UTI and symptomatology
Table 4. Incidence of reported renal and urinary disorders as treatmentemergent adverse events by MedDRA System organ class and preferred terms.
Dalfampridine-ER
Renal and urinary disorders Chromaturia Dysuria Hypertonic bladder Micturition urgency Nephrolithiasis Nocturia Pollakiuria Polyuria Urinary incontinence Urinary retention
Placebo (n = 142) 5 (3.5) 0 0 0 1 (0.7) 1 0 1 (0.7) 0 1 (0.7) 1 (0.7)
5 mg (n = 144) 6 (4.2) 0 2 (1.4) 0 0 0 1 (0.7) 2 (1.4) 1 (0.7) 0 0
10 mg (n = 143) 6 (4.2) 1 (0.7) 1 (0.7) 1 (0.7) 1 (0.7) 0 0 2 (1.4) 0 0 0
Abbreviations: ER = Extended release; MedDRA = Medical Dictionary of Regulatory Activities.
Placebo (n = 143) Dalfampridine-ER 5 mg (n = 144) Dalfampridine-ER 10 mg (n = 142)
9.9%
10
Incidence, n (%)
MedDRA system organ class preferred term
12
Percent of patients
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Characteristic
Placebo (n = 142)
8 6.3% 6
5.6% 4.9% 4.2%
4
4.2% 3.5% 2.8% 2.8%
2 0 Reported UTI symptoms
Confirmed UTI with criterion A
Confirmed UTI with criterion B
Figure 1. Proportion of patients with UTI during treatment is shown. Criteria A and B included the microscopic urinalysis and culture data but differed by colony count: A: ‡ 105 CFUs/mL and B: ‡ 104 CFUs/ mL. Abbreviations: CFUs = Colony-forming units; ER = Extended release; UTI = Urinary tract infection.
Assessment of UTI in patients treated with dalfampridine for MS
DOI: 10.1080/00325481.2015.1000229
a
b
Criterion A analysis 12
6.9%
2 6
10
4
Number of patients
Number of patients
4
6
8
5
10.5%
4
10 mg (n = 142)
7 4
2 Placebo (n = 143)
5 mg (n = 144)
Criterion A with symptomatology Symptomatology only
10 mg (n = 142)
Dalfampridine-ER
Dalfampridine-ER Criterion A only
7
5
6
0 5 mg (n = 144)
11.3% 12.5%
2
2 Placebo (n = 143)
9
6
5.6%
2
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7.0%
6
9
13
10
6
8
0
Criterion B analysis 12
10
4
221
Criterion B only
Criterion B with symptomatology Symptomatology only
Figure 2. Analyses by laboratory evaluation criterion and symptomatology are shown. Symptomatology-only groups did not have confirmed UTI; criterion-only groups were asymptomatic. Criteria A and B included the urinalysis and culture data, but they differed by colony count: A: ‡ 105 CFUs/mL and B: ‡ 104 CFUs/mL. Percentages reflect the proportion of patients with confirmed UTIs, regardless of reported symptoms. Abbreviations: CFUs = Colony-forming units; ER = Extended release; UTI = Urinary tract infection.
(Figure 2): criterion A: 6 (4.2%), 4 (2.8%), and 4 (2.8%); and criterion B: 6 (4.2%), 5 (3.5%), and 7 (4.9%) for the placebo and dalfampridine-ER 5 mg and 10 mg groups, respectively. There were no statistically significant differences among the treatment groups for the number of patients who met these criteria (criterion A: P = 0.7463; criterion B: P = 0.8347). The number of asymptomatic patients who met the laboratory criteria were: criterion A: 2 (1.4%), 6 (4.2%), and 6 (4.2%); and criterion B: 9 (6.3%), 13 (9.0%), and 9 (6.3%) for the placebo and dalfampridine-ER 5 mg and 10 mg groups, respectively (Figure 2). The proportion of patients who were only symptomatic appeared to be dose-dependent when stratified by laboratory criteria and symptomatology (criterion A: 2 (1.4%), 5 (3.5%), and 10 (7.0%); and criterion B: 2 (1.4%), 4 (2.8%), and 7 (4.9%) for placebo and dalfampridine-ER 5 mg and 10 mg, respectively; Figure 2). Regardless of urinary symptomatology, the proportion of patients who had confirmed UTIs with criterion A was lower relative to criterion B (5.6%, 6.9%, and 7.0% vs 10.5%, 12.5%, and 11.3% for placebo and dalfampridine-ER 5 mg and 10 mg, respectively; Figure 2), which is likely due to the application of high stringency colony count in criterion A. There were no statistically significant differences among treatment groups for criterion A or criterion B in patients who met these criteria (P = 0.9108 and P = 0.8935, respectively). These proportions were also similar to or less than the frequency of UTIs observed in the screened MS population (10.2%).
Discussion The results of this analysis showed that despite more frequent reports of urinary symptoms among patients treated with
dalfampridine-ER, treatment was not associated with an increased incidence of laboratory-confirmed UTIs. However, it should be noted that the study population was selected for lack of infection at screening, so patients included in the analysis do not necessarily represent the broader population that was screened. Urinary symptoms can occur with UTI, neurogenic bladder dysfunction, or both. Using criteria for identifying UTIs in clinical practice [17-19] that are based on a composite of leukocyte count and bacterial quantitation, no significant differences were observed between the proportions of patients who developed UTIs during the treatment period in the dalfampridine-ER and placebo groups. Although dalfampridine-ER 5 mg and 10 mg treatment groups had similar proportions of confirmed UTIs, the incidence of reported UTI symptoms (ie, in the absence of a confirmed UTI) was higher with the 10 mg dose, which was similar to the prevalence of UTIs observed in the screened population. Although no increased risk of UTIs was associated with dalfampridine-ER, a number of factors may have contributed to the increased incidence of urinary symptoms in the absence of an actual confirmed UTI. In the current analysis, a broad range of urinary symptoms reported as treatmentemergent AEs was used to capture UTI events. Many of the AE terms that were used overlap with UTI symptoms and can also be related to lower urinary tract symptoms; and two of the terms used, overactive bladder and detrusor overactivity, are separate non-UTI diagnoses. The use of such a broad range of urinary symptomatology may account, at least in part, for the higher incidence of symptomatic reports of UTI. Additionally, the consistently higher frequency of symptoms with dalfampridine-ER relative to placebo suggests that
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additional factors may have been involved, especially considering the dose-proportional increase in the number of symptomatic patients who did not meet the laboratory criteria for UTIs. A putative factor contributing to these symptoms could be local bladder sensory effects of dalfampridine on the urinary tract resulting from increased activation of afferent neurons. Because renal excretion of dalfampridine is the main route of elimination and it is primarily excreted as unchanged compound [20], its presence in urine may result in some local sensory effects in the urinary tract that potentially occur from increased electrical activity in afferent nerves. It is thus possible that the occurrence of these sensory effects may give rise to the report of symptoms in a proportion of patients. Although no new safety concerns were identified, further studies to more fully characterize these effects may be warranted. Nevertheless, because of the higher risk of UTIs in patients with MS and the clinical implications of UTIs, it is important in the clinical setting to verify whether urinary tract symptoms in fact represent an actual confirmed UTI. A limitation of this study is that the details of the analysis were determined post hoc, although all data captured for determining the occurrence of UTI-related symptoms and laboratory confirmation of UTIs was pre-specified. Although a broad range of urinary symptoms including some that are not specific to UTIs were used, it was thought that adopting a conservative approach to capture such events may more accurately reflect what is reported in clinical practice.
Conclusion In this analysis, no differences in UTI incidence rate could be detected between patients treated with dalfampridine-ER and what would be expected in the general MS population. The proportion of patients with confirmed UTIs by laboratory criteria was not different between dalfampridine-ER and placebo, and the frequency of these UTIs was lower than that observed in the screened MS population. There were no new safety signals, and these results suggest that dalfampridineER is not likely to increase the incidence of UTIs in patients with MS.
Acknowledgments This work was supported by Acorda Therapeutics, Inc., Ardsley, NY, USA. Kantor, Chancellor, Henney, and Rabinowicz were involved in the concept and design of the post hoc analysis, review of data, and manuscript development. Data analysis was performed by Snell. Editorial assistance was provided by E Jay Bienen, PhD, of The Curry Rockefeller Group, LLC, Tarrytown, NY, USA, and funded by Acorda Therapeutics, Inc., Ardsley, NY, USA. Trial Registration: NCT01328379.
Declaration of interest D Kantor has received honoraria or payments for consulting, advisory services, and speaking services from Acorda Therapeutics, Inc., Allergan, Avanir, Biogen Idec, Depomed, Genzyme, Novartis, Questcor, Osmotica, and Teva and has
Postgrad Med, 2015; 127(2):218–222
received research support from Acorda Therapeutics, Inc., Avanir, Biogen Idec, Genzyme, Novartis, and Teva. CW Snell and AL Rabinowicz are employees of Acorda Therapeutics, Inc., with stock options. HR Henney III was an employee of Acorda Therapeutics, Inc., at the time of the study. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
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