ORIGINAL ARTICLE
A Randomized, Double-Blind, PlaceboControlled Trial of Duloxetine for the Treatment of Pain in Patients with Multiple Sclerosis Timothy L. Vollmer, MD*; Michael J. Robinson, MD, FRCPC, FAPM†; Richard C. Risser, MS‡; Sandra K. Malcolm, BSc§ *Department of Neurology, University of Colorado Health Sciences Center, Aurora, Colorado; † Psychiatry & Pain, Lilly BioMedicines, Eli Lilly and Company and/or one of its subsidiaries, Indianapolis, Indiana; ‡US Medical Division, Eli Lilly and Company and/or one of its subsidiaries, Indianapolis, Indiana; §Chorus Resonance, Eli Lilly and Company and/or one of its subsidiaries, Indianapolis, Indiana, U.S.A.
& Abstract Background: Patients with multiple sclerosis (MS) often report neuropathic pain (NP-MS). The purpose of this study was to assess the efficacy and tolerability of duloxetine as treatment for NP-MS. Methods: In this study, 239 adults with NP-MS (duloxetine = 118, placebo = 121) were randomized to duloxetine 60 mg (30 mg for 1 week, then 60 mg for 5 weeks) or placebo once daily for a 6-week acute therapy phase, followed by a 12-week open-label extension phase (duloxetine 30 to 120 mg/day). Eligible patients had MS for ≥ 1 year
Address correspondence and reprint requests to: Sandra K. Malcolm, BSc, Clinical Research Consultant, Eli Lilly and Company, Drop Code 0821, Indianapolis, IN, U.S.A. E-mail: [email protected]. Disclosures: Dr. Robinson was a full-time employee and shareholder of Eli Lilly and Company at the time this study was conducted. Dr. Robinson is a current employee of AbbVie. Author TLV is a consultant and/or advisory board member with Lilly and has received grants from and is involved in research supported by Lilly. Authors RCR and SKM are current employees and/or stockholders of Lilly. Submitted: March 29, 2013; Revision Accepted: August 15, 2012 DOI. 10.1111/papr.12127
© 2013 World Institute of Pain, 1530-7085/13/$15.00 Pain Practice, Volume 14, Issue 8, 2014 732–744
and a score ≥ 4 on daily average pain intensity (API) ratings for ≥ 4 of 7 days immediately before randomization. Patients rated API daily on an 11-point numeric scale (0 [no pain] to 10 [worst possible pain]) in an electronic diary. The primary efficacy measure, change in weekly API ratings, was analyzed longitudinally with a mixed-model repeated-measures analysis. Completion, reasons for discontinuation, and treatmentemergent adverse event incidence were compared by Fisher’s exact test. Results: Duloxetine-treated patients had statistically greater mean improvement in API vs. placebo at Week 6 ( 1.83 vs. 1.07, P = 0.001). Treatment completion did not significantly differ between groups. Discontinuation due to adverse events was statistically greater for duloxetine vs. placebo (13.6% vs. 4.1%, P = 0.012). Decreased appetite was reported significantly more often by duloxetine-treated patients (5.9% vs. 0%, P = 0.007). Conclusions: This study found analgesic efficacy of duloxetine for NP-MS. Duloxetine is not approved for treatment of this condition. The duloxetine safety profile of this study was consistent with the known profile in other patient populations. & Key Words: duloxetine, multiple sclerosis, neuropathic pain, central neuropathic pain, randomized clinical trial
Duloxetine in Patients with NP-MS 733
INTRODUCTION Patients with multiple sclerosis (MS) often experience neuropathic pain (NP-MS); from 26% to 92% report pain in the course of their disease.1–10 NP-MS is a significant burden1,7,11 and can interfere with mood and overall mental health1,3,12,13 as well as quality of life.14 This is a major concern because patients with MS are at risk of developing major depression, with an approximate 50% lifetime prevalence rate.15 Pharmacological treatment for pain in MS is challenging due to the many underlying pathophysiologic mechanisms. Pharmacological intervention and even polypharmacy are common in the treatment for NP-MS.1,9,14 Treatments include over-the-counter pain relievers, tricyclic and selective serotonin reuptake inhibitor antidepressants, anticonvulsant agents, opioids, and cannabinoids.3,9,16 The cannabinoid nabiximols (Sativexâ, GW Pharma Ltd., Salisbury, UK) is approved in Canada as an adjunctive treatment for the symptomatic relief of neuropathic pain in adult patients with MS.17 Despite extensive therapies to treat NP-MS, there is a notable paucity of controlled studies in the literature.18 Exceptions include a study by Rog et al.,19 which demonstrated efficacy of a cannabis-based medicine over placebo in a small group of patients (n = 66) with central neuropathic pain associated with MS. In a preliminary pilot trial, Breuer et al.20 assessed lamotrigine in 12 patients with central pain associated with MS, which failed to demonstrate pain reduction compared with placebo. Duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI), is approved in the United States for the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain in patients with chronic low back pain (CLBP) or chronic pain due to osteoarthritis.21 The results of a recent preclinical study suggested that duloxetine may have some utility in treating NP-MS22; however, there are no known clinical studies of duloxetine for the treatment of this condition. The primary objective of this study was to assess the efficacy of duloxetine 60 mg once daily (QD) compared with placebo in reducing pain severity as measured by the weekly mean of daily 24-hour average pain intensity (API) ratings after 6 weeks of treatment. Secondary objectives included evaluations of efficacy as measured by a 30% reduction and a 50% reduction in the diarybased weekly API ratings as well as assessments to rate
the severity and impact of pain and health-related quality of life.
METHODS Study Design This was a randomized, double-blind, placebo-controlled trial. This study consisted of 4 phases: (I) a 7- to 30-day screening phase (beginning at Visit 1), (II) a 6-week, double-blind, fixed-dose, acute-therapy phase (beginning at Visit 2), (III) a 12-week, optional, openlabel, flexible-dose, extension phase (beginning at Visit 5), and (IV) an optional 2-week taper period (beginning at Visit 11). Patients were randomly assigned in a 1:1 ratio (stratified by investigative site) to receive either placebo or duloxetine 30 mg/day for 1 week followed by 5 weeks of 60 mg/day. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was consistent with good clinical practices and applicable local laws and regulations. The ethical review boards of each investigator’s institution approved the protocol, and informed consent was obtained from each patient prior to study participation. ClinicalTrials.gov identifier: NCT00755807. Participants Male and female outpatients were recruited from 22 sites in Belgium, Canada, Poland, and the United States from November 2008 to November 2010. Participants were at least 18 years of age and had met the McDonald23 or Poser24 criteria for MS for at least 1 year. Patients were required to be clinically stable (ie, to have no MS exacerbations or changes in therapy) and to experience NP-MS on a daily basis (as assessed by the investigator) for at least 3 months prior to randomization. Patients were required to have a score of ≥ 4 on the daily API rating for at least 4 of 7 days immediately before randomization. Patients meeting any of the following criteria were excluded: Presence of pain that cannot clearly be differentiated from NP-MS (eg, diabetic peripheral neuropathic pain, arthritis, or chronic headache); substance abuse (excluding nicotine/caffeine) within the last 6 months; current or historical DSM-IV diagnosis of mania, bipolar disorder, psychosis, or schizoaffective disorder; current (≤ 1 year) DSM-IV Axis I alcohol or eating disorder or posttraumatic stress disorder, as
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determined by patient history or using specific modules of the Mini-International Neuropsychiatric Interview; monoamine oxidase inhibitor (MAOI) treatment within the last 2 weeks; history of recurrent seizures; current pregnancy or breast-feeding; or current risk of suicide based on either the Columbia Suicide Severity Rating Scale (C-SSRS)25 or a score ≥ 2 on Item 9 (suicidal ideation) of the Beck Depression Inventory-II (BDI-II).26 Patients taking any of the following medications were instructed that such medications were excluded and if present required a minimum wash-out period of 5 halflives prior to Visit 2: cimetidine, the quinolone class of antibiotics (except levofloxacin and moxifloxacin, which were allowed), antimanics, antipsychotics, psychostimulants (except Provigilâ, Cephalon, Inc., Frazer, PA, USA), medical marijuana, nabiximols (Sativexâ, GW Pharma Ltd), dronabinol (Marinolâ, Banner Pharmacaps, Inc., High Point, NC, USA), methocarbamol (Robaxinâ, A.H. Robins Company, Richmond, VA, USA), cyclobenzaprine (Flexerilâ, McNeil Consumer Healthcare [Division of McNeil-PPC, Inc.], Fort Washington, PA, USA), metaxalone (Skelaxinâ, Mallinckrodt Inc., Hobart, NY, USA), carisoprodol (Somaâ, Meda Pharmaceuticals Inc., Somerset, NJ, USA), varenicline (Chantixâ, Pfizer, New York, NY, USA), and onabotulinumtoxinA (BOTOXâ, Allergan Pharmaceuticals Ireland, Dublin 2, Ireland) injections. MAOIs required a minimum wash-out period of 14 days and could not be used until a minimum of 5 days after discontinuation of the study medication. Restricted medications included nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (paracetamol), which were allowed if the patient was on a stable dose (defined as taking the medication for ≥ 14 days over the month prior to study entry). Patients were not allowed to adjust their doses or stop taking NSAIDs or acetaminophen during the study. The maximum allowed use of acetaminophen was 4 g/day. Episodic use of shortacting analgesics, including opioids, was allowed for management of acute conditions unrelated to NP-MS for a length of time appropriate for the condition being treated. Patients exceeding the allotted use of analgesics during the study were to be discontinued from the study. Chronic opioid analgesic use was allowed if the patient was on a stable dose prior to entering the study. Study Procedure Patients were randomized to receive duloxetine or placebo. Those randomized to duloxetine were administered
30 mg QD for 7 days then 60 mg QD for the remainder of the acute phase. Patients who satisfactorily completed the acute phase were offered the option to continue the study in the extension phase. During the extension phase, duloxetine was administered at 30 mg/day for 1 week then 60 mg/day for the following week. Thereafter, the daily dose could be escalated in 30 mg/day increments up to 120 mg/day based on physician discretion. Throughout the study, patients recorded API and night pain intensity (NPI) in an electronic diary on a daily basis upon awakening, using a numeric rating scale ranging from 0 (no pain) to 10 (worst possible pain). Patients with MS commonly experience concurrent multiple types of pain (due to, for example, spasticity, muscle spasms). Thus, to increase specificity of NP-MS reporting, patients recorded the loci of pain at initial electronic diary use. On each day thereafter, patients were reminded via the diary of previously recorded regions of pain. Thus, the electronic diary was designed to help patients maintain focus on specific regions of NP-MS. The Expanded Disability Status Scale (EDSS),27 consisting of 20 scores ranging from 0 (normal) to 10 (death), was administered at screening to assess disability. For example, an EDSS score of < 4 corresponds to ambulatory patients, and a score of ≥ 4 corresponds to ambulatory impaired patients. To minimize the burden on patients, data were collected either during office visits or by telephone interviews. Efficacy Measures The primary objective of this study was to evaluate the difference between treatments in change from baseline in API at Week 6 after randomization. The primary efficacy measure was change from baseline in the weekly mean of the daily API. Additional secondary measures included change from baseline in the weekly mean of diary-based NPI ratings; changes from baseline in the Clinical Global Impression of Severity (CGI-S) scale,28 Brief Pain Inventory (BPI),29 and Multiple Sclerosis Quality of Life-54 Instrument (MS-QoL-54)30; and mean endpoint rating for the Patient’s Global Impressions of Improvement (PGI-I) scale28 at office visits. The PGI-I required patient responses from “very much better” to “very much worse.” Exploratory analyses included between-group comparisons for the BDI-II and the Beck Anxiety Inventory (BAI)31 to assess changes in mood and anxiety, respectively, and the Modified Fatigue Impact Scale (MFIS)32 to assess changes in fatigue at office visits.
Duloxetine in Patients with NP-MS 735
Safety Measures Spontaneous patient-reported treatment-emergent adverse events (TEAEs), concomitant medication use, and treatment-emergent suicide-related events (by C-SSRS) were assessed at each visit (office and phone). Treatment-emergent suicide-related events (by BDI-II Item 9), vital signs, and laboratory tests were assessed at baseline and during treatment at office visits at Weeks 6, 12, and 18.
Statistical Analysis Sample Size Justification. Using a 0.05 level of significance for a 2-tailed, 2-sample Student’s t-test and equal allocation of assignment to treatment with 113 patients randomized per treatment, there was 80% power to detect a small to moderate effect size of 0.375 to address the primary objective of the study. To account for approximately 5% of randomized patients to be excluded from the efficacy analysis due to early discontinuation (prior to providing postbaseline data), a total of 238 patients were planned to be enrolled and randomized. Analytical Methods. Data were analyzed on a modified intent-to-treat basis, that is, all patients were maintained in the group to which they were randomized, but only patients with baseline and postbaseline data were included in the assessment-based results. The level of significance for 2-tailed statistical tests was 0.05 for comparison of treatments and 0.10 for tests of interaction. All analyses were performed with SASâ software, version 9.1 (Cary, NC, U.S.A.). Quantitative patient characteristics at baseline were compared between treatments using an analysis of variance (ANOVA) model containing explanatory terms for treatment and investigator, and comparisons between groups based on nominal characterizations at baseline were based on the Fisher’s exact test. Change in the weekly mean of API and NPI ratings was analyzed longitudinally using a mixed-models repeated-measures (MMRM) model. The MMRM model contained explanatory terms for week (W), treatment (T), baseline severity (B), investigator, and T 9 W and B 9 W interactions, with patient modeled as a random effect; mean pain severity reductions by week were compared between treatments using a t-test of the MMRM model. The observed effect size was derived as the difference in estimated mean reduction in API between treatments
divided by the estimated common within-patient standard deviation (SD) at Week 6. Two sensitivity analyses of the primary objective used different approaches to handling missing data. Each analysis employed a different imputation approach for analysis of baseline-to-endpoint change in mean API: last-observation-carried-forward (LOCF) imputation and baseline-observation-carried-forward (BOCF) imputation. LOCF imputation used the last available efficacy assessment if a patient discontinued for any reason at any time or failed to have an endpoint assessment. BOCF imputation used the baseline efficacy assessment if the patient did not complete the treatment period for any reason at any time and implemented LOCF imputation for study completers if necessary. With each imputation approach, change was analyzed using an analysis of covariance (ANCOVA) model containing explanatory terms for treatment, investigator, and baseline. A secondary efficacy measure, percent reduction in the weekly mean of API in response to treatment with duloxetine 60 mg QD vs. placebo, was evaluated using a priori criteria: at least 30% reduction and at least 50% reduction from baseline to the Week-6 endpoint as well as the frequency of patients achieving endpoint PGI-I ratings that were at least “much improved.” These results were based on LOCF imputation and compared between groups using Fisher’s exact test. Related to these response outcomes was the Number Needed to Treat (NNT), derived as the reciprocal of the difference in response rates between treatments. Endpoint PGI-I (LOCF) was analyzed using ANOVA with a model containing terms for treatment and investigator. Change from baseline to endpoint (LOCF) in other secondary and exploratory efficacy measures was analyzed using an ANCOVA model containing explanatory terms for treatment, investigator, and baseline. LOCF imputation was implemented as these measures were assessed only at the end of acute therapy. In general, descriptive results for analysis of change, matching tests of significance, represent model-based (least-squares) estimated means standard error (SE). Rates of completion, discontinuation, efficacy-based response, treatment and pain-diary compliance, concomitant pain-medication use, serious adverse events (SAEs), TEAEs, abnormalities among laboratory parameters, vital signs, body weight, and treatmentemergent suicidal ideation/behaviors were compared between groups using Fisher’s exact test. TEAEs were defined as adverse events (AEs) that first occurred or
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worsened after randomization based on spontaneous reports of events from patients. Terms for all AEs were based on version 13.1 of the Medical Dictionary for Regulatory Activities. Laboratory abnormalities were based on reference ranges for the single central laboratory employed during this study (Covance); only patients with baseline values within normal ranges were considered to be at risk of postrandomization abnormality in laboratory values and vital signs. Treatmentemergent suicidal ideation/behaviors were based on scale-specific ratings (C-SSRS; BDI-II Item 9) that worsened after initiation of treatment compared with baseline. Open-label extension-phase results are descriptive for completion rates, frequency of TEAEs, and final dose. Mean change in API and NPI by week was estimated for all extension patients and for groups based on acutephase treatment using an MMRM model with explanatory terms for week (W), site, baseline (Week 6) as a covariate (B), acute-phase treatment (T), and the B 9 W interactions, with patient modeled as a random effect. Use of the acute-phase treatment as an explanatory term in this model of the extension-phase data provides tests of significance that should be interpreted with caution because the patients continuing on after 6 weeks of duloxetine dosing may be characteristically different from those continuing after 6 weeks of placebo exposure. Change in other efficacy and/or safety assessments from the open-label period was compared with 0 (no change) based on the 1-sample t-test, with the exception of laboratory values for which the Wilcoxon signedrank test was used. Treatment-emergent diastolic hypertension was defined as sitting diastolic blood pressure (DBP) ≥ 90 mm Hg with coincident ≥ 10 mm Hg increase from baseline (if DBP < 90 mm Hg at baseline), systolic hypertension as sitting systolic blood pressure (SBP) ≥ 140 mm Hg with coincident ≥ 15 mm Hg increase from baseline (if SBP < 140 mm Hg at baseline), tachycardia as sitting heart rate (HR) ≥ 100 bpm with coincident ≥ 10 bpm increase (if HR < 100 bpm at baseline), and abnormal weight gain or loss as change at endpoint of ≥ 7% or ≤ 7% of baseline weight, respectively.
RESULTS Patient Characteristics and Concomitant Medications A total of 239 patients were randomly assigned to duloxetine (N = 118) or placebo (N = 121), and the
majority of patients (n = 209 [87.4%]) completed the acute phase of the study (Figure 1). Frequency of completion did not differ significantly between treatment groups, but significantly more duloxetine patients than placebo patients discontinued from the acutetherapy phase due to AEs (P = 0.012). Baseline characteristics for the acute study period are presented in Table 1. Most commonly, patients were female (74.9%) and Caucasian (92.5%) and had MS of the relapse-remitting subtype (64%). Mean duration of MS was 11.2 years, and mean duration of NP-MS was 6.9 years. The median EDSS for each group was 4, indicating that most participants were ambulatory; the maximum EDSS value in each group was 8 (ie, mainly restricted to bed). Pain in the face, among the least common loci reported, was reported by more patients in the duloxetine group (22.3%) than in the placebo group (9.3%, P = 0.008). Apart from presence of pain in the face, there were no other significant treatment-group differences at baseline in demographics or illness characteristics. There was no significant difference in the percentages of duloxetine-treated and placebo-treated patients taking at least 1 concomitant pain medication (66.1% vs. 74.4%, P = 0.203) or at least 1 MS medication (48.3% vs. 42.1%, respectively, P = 0.365) during treatment. Fewer duloxetine-treated patients than placebo-treated patients were taking gabapentin (14.4% vs. 27.3%, P = 0.017). More duloxetine-treated patients than placebo-treated patients had been treated for their MS with interferon b-1A (25.4% vs. 14%, respectively, P = 0.034). Efficacy Acute Phase. The mean (SD) baseline API scores for patients in the duloxetine and placebo groups were 6.5 (1.4) and 6.3 (1.3), respectively (P = 0.277). The mean (SE) change in the weekly API ratings from baseline to Week 6 was greater for duloxetine-treated patients ( 1.83 [0.17]) than for placebo-treated patients ( 1.07 [0.16], P = 0.001) (Figure 2). The pain reduction advantage for duloxetine equated to an observed effect size of 0.44. The between-treatment difference was statistically significant as early as Week 1 of treatment (P = 0.016) and remained significant at each subsequent week of the acute-therapy phase (P < 0.01 at each week) (Figure 2). Using both the LOCF and BOCF imputation approaches for sensitivity analysis of the primary objective, greater mean (SE) pain improvement was
Duloxetine in Patients with NP-MS 737
Assessed for eligibility N=312
Screen failure, n (%) Entry criteria not met 58 (79.5) Patient decision 14 (19.2) Adverse event 1 (1.4)
Randomized N=239
Discontinued, n (%) Adverse event 5 (4.1) Protocol violation 3 (2.5) Subject decision 2 (1.7) Lack of efficacy 1 (0.8) Physician decision 1 (0.8)
Placebo N=121
Duloxetine 60 mg N=118 Discontinued, n (%) Adverse event 16 (13.6)* Subject decision 1 (0.8) Protocol violation 1 (0.8)
Completed acute phase n=109 (90.1%)
Discontinued, n (%) Adverse event 14 (6.7) Protocol violation 7 (3.3) Lack of efficacy 6 (2.9) Subject decision 4 (1.9) Lost to follow-up 2 (1.0) Sponsor decision 1 (0.5)
Completed acute phase n=100 (84.7%)
Entered extension phase n=209
Completed extension phase n=175
Figure 1. CONSORT flow diagram of patient disposition. *Statistically significantly more duloxetine-treated patients discontinued due to adverse events vs. placebo-treated patients, Fisher’s exact test, P = 0.012.
observed for the duloxetine group than for the placebo group ( 1.78 [0.17] vs. 1.09 [0.16], respectively, P = 0.002 [LOCF], and 1.66 [0.17] vs. 1.02 [0.16], P = 0.004 [BOCF]). More duloxetine patients than placebo patients met the 30% or greater reduction response criterion (41% vs. 27%, P = 0.027), which reflects an NNT estimate of 8. Thus, in treating 8 patients with duloxetine, 1 additional patient is expected to respond compared with placebo. No significant difference emerged between the groups using the 50% or greater response reduction criterion (23% vs. 16%, P = 0.246). Table 2 presents treatment-group comparisons on the secondary measures NPI, CGI-S, BPI, and MS-QoL54 and the exploratory measures BDI-II, BAI, and MFIS. Duloxetine-treated patients experienced significantly greater baseline-to-endpoint improvements compared with placebo-treated patients on the following measures: weekly mean of NPI ratings, CGI-S, BPI pain
severity ratings, and BPI rating of pain-related interference with mood. No significant between-group differences emerged on any of the MS-QoL-54 scales. Mean (SD) endpoint PGI-I ratings did not differ between treatments (3.3 [0.1] for each group, P = 0.121), nor did the frequency of PGI-I ratings of “much better” or “very much better” at the end of treatment (24.5% for duloxetine and 15.5% for placebo, P = 0.129). Exploratory comparisons revealed no between-group differences on measures of depression (BDI-II), anxiety (BAI), or fatigue (MFIS) during the acute-therapy phase. There were no significant between-group differences on compliance rates related to study drug (88.9% vs. 89.2%, respectively, P = 1) or electronic diary completion (89.7% vs. 95.8%, P = 0.081) during the 6-week acute phase. Open-Label Extension Phase. A total of 209 patients entered the open-label phase. Of these, 100 had been
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Table 1. Baseline Demographics and Illness Characteristics
Characteristic Demographics Age (years), mean (SD) [minimum to maximum] Ethnicity, n (%) African descent Caucasian Hispanic Native American Country United States Poland Belgium Canada Female, n (%) BMI, kg/m2, mean (SD) Illness characteristics Diagnosis subtype, n (%) Relapsing remitting Primary progressive Secondary progressive Progressive relapsing Duration of MS (years), mean (SD) Duration of NP-MS (years), mean (SD) Time since MS relapse (months), mean (SD) MS relapses in last 6 months, mean (SD) NP-MS loci, n (%) Lower leg Foot Thigh Hand Lower back Forearm Shoulder Arm Neck Upper back Head Face Spine Pelvis Comorbid MDD, n (%) Comorbid GAD, n (%) EDSS mean (SD) EDSS median (range)
Duloxetine 60 mg/day (N = 118)
Placebo (N = 121)
50.8 (9.7) [26.7 to 70.8]
52.7 (9.1) [28.7 to 71.2]
P value 0.092a 0.310b
9 109 0 0
(7.6) (92.4) (0) (0)
6 112 2 1
(5) (92.6) (1.7) (0.8)
87 (73.7) 20 (16.9) 7 (5.9) 4 (3.4) 86 (72.9) 29.4 (8.3)
87 20 7 7 93 28
(71.9) (16.5) (5.8) (5.8) (76.9) (6)
0.875b
0.551b 0.120a 0.455b
81 (68.6) 10 (8.5) 23 (19.5) 4 (3.4) 11.1 (7.5)
72 (59.5) 16 (13.2) 27 (22.3) 5 (5) 11.4 (8.5)
0.698a
6.2 (5.9)
7.6 (6.7)
0.058a
2.7 (2.8)
3 (3.3)
0.481a
0.3 (0.5)
0.2 (0.4)
0.185a
90 (74.4) 76 (62.8) 60 (49.6) 54 (44.6) 47 (38.8) 37 (30.6) 31 (25.6) 28 (23.1) 31 (25.6) 27 (22.3) 26 (21.5) 27 (22.3) 17 (14) 16 (13.2) 7 (5.9) 3 (2.5) 4.3 (2) 4 (0 to 8)
92 (78) 83 (70.3) 59 (50) 53 (44.9) 44 (37.3) 39 (33.1) 35 (29.7) 32 (27.1) 26 (22) 21 (17.8) 17 (14.4) 11 (9.3) 15 (12.7) 12 (10.2) 4 (3.3) 2 (1.7) 4.3 (1.8) 4 (0 to 8)
0.546b 0.273b 1b 1b 0.894b 0.781b 0.563b 0.551b 0.546b 0.422b 0.179b 0.008b 0.850b 0.548b 0.371a 0.681a 0.992a
a
ANOVA. Fisher’s exact test. BMI, body mass index; EDSS, Expanded Disability Status Score; GAD, generalized anxiety disorder; MDD, major depressive disorder; MS, multiple sclerosis; NP-MS, neuropathic pain in MS; SD, standard deviation.
b
treated with duloxetine and 109 with placebo during the acute phase. The distribution of the final dose showed that most patients remained on 60 mg/day (117/209 [56%]), but some patients were escalated to higher doses prior to completion of the 12-week treatment extension (90 mg/day, 60/209 [28.7%]; 120 mg/day, 29/209 [13.9%]).
Improvements in API ratings during the 12-week extension phase are presented in Figure 3. Considering all patients who entered the extension phase of treatment, the mean (SD) API was 4.9 (2.1) at the end of acute treatment, with a significant improvement in API compared with baseline (P < 0.001) at all weeks during the extension except the initial week (P = 0.413). Among patients who had received placebo during the acute phase, the mean (SD) API was 5.2 (2) at the beginning of the extension phase, and among patients who had received duloxetine, the mean (SD) API was 4.5 (2.2). Relative to the start of the extension phase, patients who had received placebo during the acute phase reported greater mean reductions in API than patients who had received duloxetine during the acute phase at Week 12 (P = 0.039), Week 13 (P = 0.015), Week 16 (P = 0.026), and Week 17 (P = 0.010) of the extension phase. Thus, during the extension phase, API improvements were reported in patients in both groups, with greater improvement reported by patients who had received placebo during the acute phase. The weekly mean of NPI ratings improved across all patients (change from baseline to endpoint, 1.04 [0.11], P < 0.001) (Table 2). Improvements were observed in the BPI pain ratings (severity items and interference items) and CGI-S (each P < 0.001) (Table 2). Improvement also was observed in PGI-I at endpoint (mean [SD], 2.7 [1.3]; P < 0.001). Safety Acute Phase. Significantly more duloxetine- vs. placebo-treated patients withdrew from the study due to AEs during the acute therapy phase (n = 16 [13.6%] vs. n = 5 [4.1%], P = 0.012). Most common causes for withdrawal among duloxetine-treated patients were dizziness (n = 3 [2.5%]) and somnolence (n = 2 [1.7%]). The TEAEs that were reported in at least 5% of duloxetine-treated patients and at a rate at least twice that of placebo-treated patients included dizziness (8% vs. 4%, P = 0.282) and dry mouth (6% vs. 3%, P = 0.212). Other TEAEs occurring in ≥ 5% of duloxetine-treated patients included fatigue (8% vs. 6%, P = 0.613), nausea (8% vs. 6%, P = 0.613), constipation (6% vs. 4%, P = 0.567), and somnolence (5% vs. 3%, P = 0.329). Decreased appetite was reported more in duloxetine-treated patients than in placebo-treated patients (5.9% vs. 0%, P = 0.007). No other significant between-group differences were observed for specific TEAEs. SAEs were reported by 4 patients (3.4%) of the
Duloxetine in Patients with NP-MS 739
Week of Treatment
Estimated mean change from baseline in weekly API rating
Improvement
1
2
3
4
5
6
0
-0.5
Duloxetine
(N=115)
*
Placebo
(N=119)
-1
***
-1.5
***
**
-2
**
***
-2.5
-3
Figure 2. Primary efficacy analysis: estimated mean change in weekly mean average pain intensity ratings (mixed-models repeatedmeasures analysis). *P < 0.05, **P ≤ 0.01, ***P ≤ 0.001.
Table 2. Change in Secondary and Exploratory Efficacy Measures Acute Phase
Extension Phase
Duloxetine (N = 118) Mean (SE)
Placebo (N = 121) Mean (SE)
Change
Change
Duloxetine (N = 118) Mean (SD)
Placebo (N = 121) Mean (SD)
Efficacy Measure
Baseline
Baseline
P valuea
NPI CGI-S BPI severity Worst pain Least pain Average pain Pain right now BPI interference General activity Mood Walking ability Normal work Relations with others Sleep Enjoyment of life MS-QoL-54 Physical health composite score Mental health composite score Exploratory measures BDI-II total score BAI total score MFIS total score
5.7 (2) 4.3 (0.8)
5.3 (2) 4.3 (0.8)
0.072 0.873
1.8 (0.2) 0.7 (0.1)
7.5 4.7 6.1 5.8
(1.4) (2.1) (1.5) (1.9)
7.5 (1.4) 4.5 (2.1) 5.9 (1.3) 5.6 (1.9)
0.858 0.346 0.261 0.401
2 1.2 1.4 1.9
5.6 5.7 5.8 5.9 4.6 5.5 5.6
(2.2) (2.3) (3) (2.4) (2.7) (2.5) (2.4)
5.7 (2) 5.3 (2.4) 5.2 (2.8) 5.5 (2.4) 4.2 (2.7) 5.4 (2.6) 5.2 (2.6)
0.934 0.129 0.133 0.157 0.235 0.570 0.223
1.8 1.9 1.5 1.5 1.7 2 1.8
42.5 (15.1)
44.3 (15.5)
62 (21.4)
14 (9.0) 16.8 (9) 50.4 (13.9)
a
All Patients (N = 209) Mean (SD) P valueb
Baseline
Change
P valuec
1.1 (0.2) 0.4 (0.1)
0.003 0.041
4.1 (2.3) 3.7 (0.9)
1 (1.6) 0.6 (1)
< 0.001 < 0.001
(0.2) (0.2) (0.2) (0.2)
1.3 (0.2) 0.7 (0.2) 0.8 (0.2) 1 (0.2)
0.016 0.043 0.030 0.001
5.8 3.6 4.9 4.1
(2.3) (2.3) (2.1) (2.4)
1.3 1 1.3 1
(2.1) (1.8) (1.8) (2.2)
< < <
A Randomized, Double-Blind, PlaceboControlled Trial of Duloxetine for the Treatment of Pain in Patients with Multiple Sclerosis Timothy L. Vollmer, MD*; Michael J. Robinson, MD, FRCPC, FAPM†; Richard C. Risser, MS‡; Sandra K. Malcolm, BSc§ *Department of Neurology, University of Colorado Health Sciences Center, Aurora, Colorado; † Psychiatry & Pain, Lilly BioMedicines, Eli Lilly and Company and/or one of its subsidiaries, Indianapolis, Indiana; ‡US Medical Division, Eli Lilly and Company and/or one of its subsidiaries, Indianapolis, Indiana; §Chorus Resonance, Eli Lilly and Company and/or one of its subsidiaries, Indianapolis, Indiana, U.S.A.
& Abstract Background: Patients with multiple sclerosis (MS) often report neuropathic pain (NP-MS). The purpose of this study was to assess the efficacy and tolerability of duloxetine as treatment for NP-MS. Methods: In this study, 239 adults with NP-MS (duloxetine = 118, placebo = 121) were randomized to duloxetine 60 mg (30 mg for 1 week, then 60 mg for 5 weeks) or placebo once daily for a 6-week acute therapy phase, followed by a 12-week open-label extension phase (duloxetine 30 to 120 mg/day). Eligible patients had MS for ≥ 1 year
Address correspondence and reprint requests to: Sandra K. Malcolm, BSc, Clinical Research Consultant, Eli Lilly and Company, Drop Code 0821, Indianapolis, IN, U.S.A. E-mail: [email protected]. Disclosures: Dr. Robinson was a full-time employee and shareholder of Eli Lilly and Company at the time this study was conducted. Dr. Robinson is a current employee of AbbVie. Author TLV is a consultant and/or advisory board member with Lilly and has received grants from and is involved in research supported by Lilly. Authors RCR and SKM are current employees and/or stockholders of Lilly. Submitted: March 29, 2013; Revision Accepted: August 15, 2012 DOI. 10.1111/papr.12127
© 2013 World Institute of Pain, 1530-7085/13/$15.00 Pain Practice, Volume 14, Issue 8, 2014 732–744
and a score ≥ 4 on daily average pain intensity (API) ratings for ≥ 4 of 7 days immediately before randomization. Patients rated API daily on an 11-point numeric scale (0 [no pain] to 10 [worst possible pain]) in an electronic diary. The primary efficacy measure, change in weekly API ratings, was analyzed longitudinally with a mixed-model repeated-measures analysis. Completion, reasons for discontinuation, and treatmentemergent adverse event incidence were compared by Fisher’s exact test. Results: Duloxetine-treated patients had statistically greater mean improvement in API vs. placebo at Week 6 ( 1.83 vs. 1.07, P = 0.001). Treatment completion did not significantly differ between groups. Discontinuation due to adverse events was statistically greater for duloxetine vs. placebo (13.6% vs. 4.1%, P = 0.012). Decreased appetite was reported significantly more often by duloxetine-treated patients (5.9% vs. 0%, P = 0.007). Conclusions: This study found analgesic efficacy of duloxetine for NP-MS. Duloxetine is not approved for treatment of this condition. The duloxetine safety profile of this study was consistent with the known profile in other patient populations. & Key Words: duloxetine, multiple sclerosis, neuropathic pain, central neuropathic pain, randomized clinical trial
Duloxetine in Patients with NP-MS 733
INTRODUCTION Patients with multiple sclerosis (MS) often experience neuropathic pain (NP-MS); from 26% to 92% report pain in the course of their disease.1–10 NP-MS is a significant burden1,7,11 and can interfere with mood and overall mental health1,3,12,13 as well as quality of life.14 This is a major concern because patients with MS are at risk of developing major depression, with an approximate 50% lifetime prevalence rate.15 Pharmacological treatment for pain in MS is challenging due to the many underlying pathophysiologic mechanisms. Pharmacological intervention and even polypharmacy are common in the treatment for NP-MS.1,9,14 Treatments include over-the-counter pain relievers, tricyclic and selective serotonin reuptake inhibitor antidepressants, anticonvulsant agents, opioids, and cannabinoids.3,9,16 The cannabinoid nabiximols (Sativexâ, GW Pharma Ltd., Salisbury, UK) is approved in Canada as an adjunctive treatment for the symptomatic relief of neuropathic pain in adult patients with MS.17 Despite extensive therapies to treat NP-MS, there is a notable paucity of controlled studies in the literature.18 Exceptions include a study by Rog et al.,19 which demonstrated efficacy of a cannabis-based medicine over placebo in a small group of patients (n = 66) with central neuropathic pain associated with MS. In a preliminary pilot trial, Breuer et al.20 assessed lamotrigine in 12 patients with central pain associated with MS, which failed to demonstrate pain reduction compared with placebo. Duloxetine, a serotonin and norepinephrine reuptake inhibitor (SNRI), is approved in the United States for the treatment of major depressive disorder (MDD), generalized anxiety disorder (GAD), diabetic peripheral neuropathic pain, fibromyalgia, and chronic musculoskeletal pain in patients with chronic low back pain (CLBP) or chronic pain due to osteoarthritis.21 The results of a recent preclinical study suggested that duloxetine may have some utility in treating NP-MS22; however, there are no known clinical studies of duloxetine for the treatment of this condition. The primary objective of this study was to assess the efficacy of duloxetine 60 mg once daily (QD) compared with placebo in reducing pain severity as measured by the weekly mean of daily 24-hour average pain intensity (API) ratings after 6 weeks of treatment. Secondary objectives included evaluations of efficacy as measured by a 30% reduction and a 50% reduction in the diarybased weekly API ratings as well as assessments to rate
the severity and impact of pain and health-related quality of life.
METHODS Study Design This was a randomized, double-blind, placebo-controlled trial. This study consisted of 4 phases: (I) a 7- to 30-day screening phase (beginning at Visit 1), (II) a 6-week, double-blind, fixed-dose, acute-therapy phase (beginning at Visit 2), (III) a 12-week, optional, openlabel, flexible-dose, extension phase (beginning at Visit 5), and (IV) an optional 2-week taper period (beginning at Visit 11). Patients were randomly assigned in a 1:1 ratio (stratified by investigative site) to receive either placebo or duloxetine 30 mg/day for 1 week followed by 5 weeks of 60 mg/day. This study was conducted in accordance with the ethical principles of the Declaration of Helsinki and was consistent with good clinical practices and applicable local laws and regulations. The ethical review boards of each investigator’s institution approved the protocol, and informed consent was obtained from each patient prior to study participation. ClinicalTrials.gov identifier: NCT00755807. Participants Male and female outpatients were recruited from 22 sites in Belgium, Canada, Poland, and the United States from November 2008 to November 2010. Participants were at least 18 years of age and had met the McDonald23 or Poser24 criteria for MS for at least 1 year. Patients were required to be clinically stable (ie, to have no MS exacerbations or changes in therapy) and to experience NP-MS on a daily basis (as assessed by the investigator) for at least 3 months prior to randomization. Patients were required to have a score of ≥ 4 on the daily API rating for at least 4 of 7 days immediately before randomization. Patients meeting any of the following criteria were excluded: Presence of pain that cannot clearly be differentiated from NP-MS (eg, diabetic peripheral neuropathic pain, arthritis, or chronic headache); substance abuse (excluding nicotine/caffeine) within the last 6 months; current or historical DSM-IV diagnosis of mania, bipolar disorder, psychosis, or schizoaffective disorder; current (≤ 1 year) DSM-IV Axis I alcohol or eating disorder or posttraumatic stress disorder, as
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determined by patient history or using specific modules of the Mini-International Neuropsychiatric Interview; monoamine oxidase inhibitor (MAOI) treatment within the last 2 weeks; history of recurrent seizures; current pregnancy or breast-feeding; or current risk of suicide based on either the Columbia Suicide Severity Rating Scale (C-SSRS)25 or a score ≥ 2 on Item 9 (suicidal ideation) of the Beck Depression Inventory-II (BDI-II).26 Patients taking any of the following medications were instructed that such medications were excluded and if present required a minimum wash-out period of 5 halflives prior to Visit 2: cimetidine, the quinolone class of antibiotics (except levofloxacin and moxifloxacin, which were allowed), antimanics, antipsychotics, psychostimulants (except Provigilâ, Cephalon, Inc., Frazer, PA, USA), medical marijuana, nabiximols (Sativexâ, GW Pharma Ltd), dronabinol (Marinolâ, Banner Pharmacaps, Inc., High Point, NC, USA), methocarbamol (Robaxinâ, A.H. Robins Company, Richmond, VA, USA), cyclobenzaprine (Flexerilâ, McNeil Consumer Healthcare [Division of McNeil-PPC, Inc.], Fort Washington, PA, USA), metaxalone (Skelaxinâ, Mallinckrodt Inc., Hobart, NY, USA), carisoprodol (Somaâ, Meda Pharmaceuticals Inc., Somerset, NJ, USA), varenicline (Chantixâ, Pfizer, New York, NY, USA), and onabotulinumtoxinA (BOTOXâ, Allergan Pharmaceuticals Ireland, Dublin 2, Ireland) injections. MAOIs required a minimum wash-out period of 14 days and could not be used until a minimum of 5 days after discontinuation of the study medication. Restricted medications included nonsteroidal anti-inflammatory drugs (NSAIDs) and acetaminophen (paracetamol), which were allowed if the patient was on a stable dose (defined as taking the medication for ≥ 14 days over the month prior to study entry). Patients were not allowed to adjust their doses or stop taking NSAIDs or acetaminophen during the study. The maximum allowed use of acetaminophen was 4 g/day. Episodic use of shortacting analgesics, including opioids, was allowed for management of acute conditions unrelated to NP-MS for a length of time appropriate for the condition being treated. Patients exceeding the allotted use of analgesics during the study were to be discontinued from the study. Chronic opioid analgesic use was allowed if the patient was on a stable dose prior to entering the study. Study Procedure Patients were randomized to receive duloxetine or placebo. Those randomized to duloxetine were administered
30 mg QD for 7 days then 60 mg QD for the remainder of the acute phase. Patients who satisfactorily completed the acute phase were offered the option to continue the study in the extension phase. During the extension phase, duloxetine was administered at 30 mg/day for 1 week then 60 mg/day for the following week. Thereafter, the daily dose could be escalated in 30 mg/day increments up to 120 mg/day based on physician discretion. Throughout the study, patients recorded API and night pain intensity (NPI) in an electronic diary on a daily basis upon awakening, using a numeric rating scale ranging from 0 (no pain) to 10 (worst possible pain). Patients with MS commonly experience concurrent multiple types of pain (due to, for example, spasticity, muscle spasms). Thus, to increase specificity of NP-MS reporting, patients recorded the loci of pain at initial electronic diary use. On each day thereafter, patients were reminded via the diary of previously recorded regions of pain. Thus, the electronic diary was designed to help patients maintain focus on specific regions of NP-MS. The Expanded Disability Status Scale (EDSS),27 consisting of 20 scores ranging from 0 (normal) to 10 (death), was administered at screening to assess disability. For example, an EDSS score of < 4 corresponds to ambulatory patients, and a score of ≥ 4 corresponds to ambulatory impaired patients. To minimize the burden on patients, data were collected either during office visits or by telephone interviews. Efficacy Measures The primary objective of this study was to evaluate the difference between treatments in change from baseline in API at Week 6 after randomization. The primary efficacy measure was change from baseline in the weekly mean of the daily API. Additional secondary measures included change from baseline in the weekly mean of diary-based NPI ratings; changes from baseline in the Clinical Global Impression of Severity (CGI-S) scale,28 Brief Pain Inventory (BPI),29 and Multiple Sclerosis Quality of Life-54 Instrument (MS-QoL-54)30; and mean endpoint rating for the Patient’s Global Impressions of Improvement (PGI-I) scale28 at office visits. The PGI-I required patient responses from “very much better” to “very much worse.” Exploratory analyses included between-group comparisons for the BDI-II and the Beck Anxiety Inventory (BAI)31 to assess changes in mood and anxiety, respectively, and the Modified Fatigue Impact Scale (MFIS)32 to assess changes in fatigue at office visits.
Duloxetine in Patients with NP-MS 735
Safety Measures Spontaneous patient-reported treatment-emergent adverse events (TEAEs), concomitant medication use, and treatment-emergent suicide-related events (by C-SSRS) were assessed at each visit (office and phone). Treatment-emergent suicide-related events (by BDI-II Item 9), vital signs, and laboratory tests were assessed at baseline and during treatment at office visits at Weeks 6, 12, and 18.
Statistical Analysis Sample Size Justification. Using a 0.05 level of significance for a 2-tailed, 2-sample Student’s t-test and equal allocation of assignment to treatment with 113 patients randomized per treatment, there was 80% power to detect a small to moderate effect size of 0.375 to address the primary objective of the study. To account for approximately 5% of randomized patients to be excluded from the efficacy analysis due to early discontinuation (prior to providing postbaseline data), a total of 238 patients were planned to be enrolled and randomized. Analytical Methods. Data were analyzed on a modified intent-to-treat basis, that is, all patients were maintained in the group to which they were randomized, but only patients with baseline and postbaseline data were included in the assessment-based results. The level of significance for 2-tailed statistical tests was 0.05 for comparison of treatments and 0.10 for tests of interaction. All analyses were performed with SASâ software, version 9.1 (Cary, NC, U.S.A.). Quantitative patient characteristics at baseline were compared between treatments using an analysis of variance (ANOVA) model containing explanatory terms for treatment and investigator, and comparisons between groups based on nominal characterizations at baseline were based on the Fisher’s exact test. Change in the weekly mean of API and NPI ratings was analyzed longitudinally using a mixed-models repeated-measures (MMRM) model. The MMRM model contained explanatory terms for week (W), treatment (T), baseline severity (B), investigator, and T 9 W and B 9 W interactions, with patient modeled as a random effect; mean pain severity reductions by week were compared between treatments using a t-test of the MMRM model. The observed effect size was derived as the difference in estimated mean reduction in API between treatments
divided by the estimated common within-patient standard deviation (SD) at Week 6. Two sensitivity analyses of the primary objective used different approaches to handling missing data. Each analysis employed a different imputation approach for analysis of baseline-to-endpoint change in mean API: last-observation-carried-forward (LOCF) imputation and baseline-observation-carried-forward (BOCF) imputation. LOCF imputation used the last available efficacy assessment if a patient discontinued for any reason at any time or failed to have an endpoint assessment. BOCF imputation used the baseline efficacy assessment if the patient did not complete the treatment period for any reason at any time and implemented LOCF imputation for study completers if necessary. With each imputation approach, change was analyzed using an analysis of covariance (ANCOVA) model containing explanatory terms for treatment, investigator, and baseline. A secondary efficacy measure, percent reduction in the weekly mean of API in response to treatment with duloxetine 60 mg QD vs. placebo, was evaluated using a priori criteria: at least 30% reduction and at least 50% reduction from baseline to the Week-6 endpoint as well as the frequency of patients achieving endpoint PGI-I ratings that were at least “much improved.” These results were based on LOCF imputation and compared between groups using Fisher’s exact test. Related to these response outcomes was the Number Needed to Treat (NNT), derived as the reciprocal of the difference in response rates between treatments. Endpoint PGI-I (LOCF) was analyzed using ANOVA with a model containing terms for treatment and investigator. Change from baseline to endpoint (LOCF) in other secondary and exploratory efficacy measures was analyzed using an ANCOVA model containing explanatory terms for treatment, investigator, and baseline. LOCF imputation was implemented as these measures were assessed only at the end of acute therapy. In general, descriptive results for analysis of change, matching tests of significance, represent model-based (least-squares) estimated means standard error (SE). Rates of completion, discontinuation, efficacy-based response, treatment and pain-diary compliance, concomitant pain-medication use, serious adverse events (SAEs), TEAEs, abnormalities among laboratory parameters, vital signs, body weight, and treatmentemergent suicidal ideation/behaviors were compared between groups using Fisher’s exact test. TEAEs were defined as adverse events (AEs) that first occurred or
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VOLLMER ET AL.
worsened after randomization based on spontaneous reports of events from patients. Terms for all AEs were based on version 13.1 of the Medical Dictionary for Regulatory Activities. Laboratory abnormalities were based on reference ranges for the single central laboratory employed during this study (Covance); only patients with baseline values within normal ranges were considered to be at risk of postrandomization abnormality in laboratory values and vital signs. Treatmentemergent suicidal ideation/behaviors were based on scale-specific ratings (C-SSRS; BDI-II Item 9) that worsened after initiation of treatment compared with baseline. Open-label extension-phase results are descriptive for completion rates, frequency of TEAEs, and final dose. Mean change in API and NPI by week was estimated for all extension patients and for groups based on acutephase treatment using an MMRM model with explanatory terms for week (W), site, baseline (Week 6) as a covariate (B), acute-phase treatment (T), and the B 9 W interactions, with patient modeled as a random effect. Use of the acute-phase treatment as an explanatory term in this model of the extension-phase data provides tests of significance that should be interpreted with caution because the patients continuing on after 6 weeks of duloxetine dosing may be characteristically different from those continuing after 6 weeks of placebo exposure. Change in other efficacy and/or safety assessments from the open-label period was compared with 0 (no change) based on the 1-sample t-test, with the exception of laboratory values for which the Wilcoxon signedrank test was used. Treatment-emergent diastolic hypertension was defined as sitting diastolic blood pressure (DBP) ≥ 90 mm Hg with coincident ≥ 10 mm Hg increase from baseline (if DBP < 90 mm Hg at baseline), systolic hypertension as sitting systolic blood pressure (SBP) ≥ 140 mm Hg with coincident ≥ 15 mm Hg increase from baseline (if SBP < 140 mm Hg at baseline), tachycardia as sitting heart rate (HR) ≥ 100 bpm with coincident ≥ 10 bpm increase (if HR < 100 bpm at baseline), and abnormal weight gain or loss as change at endpoint of ≥ 7% or ≤ 7% of baseline weight, respectively.
RESULTS Patient Characteristics and Concomitant Medications A total of 239 patients were randomly assigned to duloxetine (N = 118) or placebo (N = 121), and the
majority of patients (n = 209 [87.4%]) completed the acute phase of the study (Figure 1). Frequency of completion did not differ significantly between treatment groups, but significantly more duloxetine patients than placebo patients discontinued from the acutetherapy phase due to AEs (P = 0.012). Baseline characteristics for the acute study period are presented in Table 1. Most commonly, patients were female (74.9%) and Caucasian (92.5%) and had MS of the relapse-remitting subtype (64%). Mean duration of MS was 11.2 years, and mean duration of NP-MS was 6.9 years. The median EDSS for each group was 4, indicating that most participants were ambulatory; the maximum EDSS value in each group was 8 (ie, mainly restricted to bed). Pain in the face, among the least common loci reported, was reported by more patients in the duloxetine group (22.3%) than in the placebo group (9.3%, P = 0.008). Apart from presence of pain in the face, there were no other significant treatment-group differences at baseline in demographics or illness characteristics. There was no significant difference in the percentages of duloxetine-treated and placebo-treated patients taking at least 1 concomitant pain medication (66.1% vs. 74.4%, P = 0.203) or at least 1 MS medication (48.3% vs. 42.1%, respectively, P = 0.365) during treatment. Fewer duloxetine-treated patients than placebo-treated patients were taking gabapentin (14.4% vs. 27.3%, P = 0.017). More duloxetine-treated patients than placebo-treated patients had been treated for their MS with interferon b-1A (25.4% vs. 14%, respectively, P = 0.034). Efficacy Acute Phase. The mean (SD) baseline API scores for patients in the duloxetine and placebo groups were 6.5 (1.4) and 6.3 (1.3), respectively (P = 0.277). The mean (SE) change in the weekly API ratings from baseline to Week 6 was greater for duloxetine-treated patients ( 1.83 [0.17]) than for placebo-treated patients ( 1.07 [0.16], P = 0.001) (Figure 2). The pain reduction advantage for duloxetine equated to an observed effect size of 0.44. The between-treatment difference was statistically significant as early as Week 1 of treatment (P = 0.016) and remained significant at each subsequent week of the acute-therapy phase (P < 0.01 at each week) (Figure 2). Using both the LOCF and BOCF imputation approaches for sensitivity analysis of the primary objective, greater mean (SE) pain improvement was
Duloxetine in Patients with NP-MS 737
Assessed for eligibility N=312
Screen failure, n (%) Entry criteria not met 58 (79.5) Patient decision 14 (19.2) Adverse event 1 (1.4)
Randomized N=239
Discontinued, n (%) Adverse event 5 (4.1) Protocol violation 3 (2.5) Subject decision 2 (1.7) Lack of efficacy 1 (0.8) Physician decision 1 (0.8)
Placebo N=121
Duloxetine 60 mg N=118 Discontinued, n (%) Adverse event 16 (13.6)* Subject decision 1 (0.8) Protocol violation 1 (0.8)
Completed acute phase n=109 (90.1%)
Discontinued, n (%) Adverse event 14 (6.7) Protocol violation 7 (3.3) Lack of efficacy 6 (2.9) Subject decision 4 (1.9) Lost to follow-up 2 (1.0) Sponsor decision 1 (0.5)
Completed acute phase n=100 (84.7%)
Entered extension phase n=209
Completed extension phase n=175
Figure 1. CONSORT flow diagram of patient disposition. *Statistically significantly more duloxetine-treated patients discontinued due to adverse events vs. placebo-treated patients, Fisher’s exact test, P = 0.012.
observed for the duloxetine group than for the placebo group ( 1.78 [0.17] vs. 1.09 [0.16], respectively, P = 0.002 [LOCF], and 1.66 [0.17] vs. 1.02 [0.16], P = 0.004 [BOCF]). More duloxetine patients than placebo patients met the 30% or greater reduction response criterion (41% vs. 27%, P = 0.027), which reflects an NNT estimate of 8. Thus, in treating 8 patients with duloxetine, 1 additional patient is expected to respond compared with placebo. No significant difference emerged between the groups using the 50% or greater response reduction criterion (23% vs. 16%, P = 0.246). Table 2 presents treatment-group comparisons on the secondary measures NPI, CGI-S, BPI, and MS-QoL54 and the exploratory measures BDI-II, BAI, and MFIS. Duloxetine-treated patients experienced significantly greater baseline-to-endpoint improvements compared with placebo-treated patients on the following measures: weekly mean of NPI ratings, CGI-S, BPI pain
severity ratings, and BPI rating of pain-related interference with mood. No significant between-group differences emerged on any of the MS-QoL-54 scales. Mean (SD) endpoint PGI-I ratings did not differ between treatments (3.3 [0.1] for each group, P = 0.121), nor did the frequency of PGI-I ratings of “much better” or “very much better” at the end of treatment (24.5% for duloxetine and 15.5% for placebo, P = 0.129). Exploratory comparisons revealed no between-group differences on measures of depression (BDI-II), anxiety (BAI), or fatigue (MFIS) during the acute-therapy phase. There were no significant between-group differences on compliance rates related to study drug (88.9% vs. 89.2%, respectively, P = 1) or electronic diary completion (89.7% vs. 95.8%, P = 0.081) during the 6-week acute phase. Open-Label Extension Phase. A total of 209 patients entered the open-label phase. Of these, 100 had been
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VOLLMER ET AL.
Table 1. Baseline Demographics and Illness Characteristics
Characteristic Demographics Age (years), mean (SD) [minimum to maximum] Ethnicity, n (%) African descent Caucasian Hispanic Native American Country United States Poland Belgium Canada Female, n (%) BMI, kg/m2, mean (SD) Illness characteristics Diagnosis subtype, n (%) Relapsing remitting Primary progressive Secondary progressive Progressive relapsing Duration of MS (years), mean (SD) Duration of NP-MS (years), mean (SD) Time since MS relapse (months), mean (SD) MS relapses in last 6 months, mean (SD) NP-MS loci, n (%) Lower leg Foot Thigh Hand Lower back Forearm Shoulder Arm Neck Upper back Head Face Spine Pelvis Comorbid MDD, n (%) Comorbid GAD, n (%) EDSS mean (SD) EDSS median (range)
Duloxetine 60 mg/day (N = 118)
Placebo (N = 121)
50.8 (9.7) [26.7 to 70.8]
52.7 (9.1) [28.7 to 71.2]
P value 0.092a 0.310b
9 109 0 0
(7.6) (92.4) (0) (0)
6 112 2 1
(5) (92.6) (1.7) (0.8)
87 (73.7) 20 (16.9) 7 (5.9) 4 (3.4) 86 (72.9) 29.4 (8.3)
87 20 7 7 93 28
(71.9) (16.5) (5.8) (5.8) (76.9) (6)
0.875b
0.551b 0.120a 0.455b
81 (68.6) 10 (8.5) 23 (19.5) 4 (3.4) 11.1 (7.5)
72 (59.5) 16 (13.2) 27 (22.3) 5 (5) 11.4 (8.5)
0.698a
6.2 (5.9)
7.6 (6.7)
0.058a
2.7 (2.8)
3 (3.3)
0.481a
0.3 (0.5)
0.2 (0.4)
0.185a
90 (74.4) 76 (62.8) 60 (49.6) 54 (44.6) 47 (38.8) 37 (30.6) 31 (25.6) 28 (23.1) 31 (25.6) 27 (22.3) 26 (21.5) 27 (22.3) 17 (14) 16 (13.2) 7 (5.9) 3 (2.5) 4.3 (2) 4 (0 to 8)
92 (78) 83 (70.3) 59 (50) 53 (44.9) 44 (37.3) 39 (33.1) 35 (29.7) 32 (27.1) 26 (22) 21 (17.8) 17 (14.4) 11 (9.3) 15 (12.7) 12 (10.2) 4 (3.3) 2 (1.7) 4.3 (1.8) 4 (0 to 8)
0.546b 0.273b 1b 1b 0.894b 0.781b 0.563b 0.551b 0.546b 0.422b 0.179b 0.008b 0.850b 0.548b 0.371a 0.681a 0.992a
a
ANOVA. Fisher’s exact test. BMI, body mass index; EDSS, Expanded Disability Status Score; GAD, generalized anxiety disorder; MDD, major depressive disorder; MS, multiple sclerosis; NP-MS, neuropathic pain in MS; SD, standard deviation.
b
treated with duloxetine and 109 with placebo during the acute phase. The distribution of the final dose showed that most patients remained on 60 mg/day (117/209 [56%]), but some patients were escalated to higher doses prior to completion of the 12-week treatment extension (90 mg/day, 60/209 [28.7%]; 120 mg/day, 29/209 [13.9%]).
Improvements in API ratings during the 12-week extension phase are presented in Figure 3. Considering all patients who entered the extension phase of treatment, the mean (SD) API was 4.9 (2.1) at the end of acute treatment, with a significant improvement in API compared with baseline (P < 0.001) at all weeks during the extension except the initial week (P = 0.413). Among patients who had received placebo during the acute phase, the mean (SD) API was 5.2 (2) at the beginning of the extension phase, and among patients who had received duloxetine, the mean (SD) API was 4.5 (2.2). Relative to the start of the extension phase, patients who had received placebo during the acute phase reported greater mean reductions in API than patients who had received duloxetine during the acute phase at Week 12 (P = 0.039), Week 13 (P = 0.015), Week 16 (P = 0.026), and Week 17 (P = 0.010) of the extension phase. Thus, during the extension phase, API improvements were reported in patients in both groups, with greater improvement reported by patients who had received placebo during the acute phase. The weekly mean of NPI ratings improved across all patients (change from baseline to endpoint, 1.04 [0.11], P < 0.001) (Table 2). Improvements were observed in the BPI pain ratings (severity items and interference items) and CGI-S (each P < 0.001) (Table 2). Improvement also was observed in PGI-I at endpoint (mean [SD], 2.7 [1.3]; P < 0.001). Safety Acute Phase. Significantly more duloxetine- vs. placebo-treated patients withdrew from the study due to AEs during the acute therapy phase (n = 16 [13.6%] vs. n = 5 [4.1%], P = 0.012). Most common causes for withdrawal among duloxetine-treated patients were dizziness (n = 3 [2.5%]) and somnolence (n = 2 [1.7%]). The TEAEs that were reported in at least 5% of duloxetine-treated patients and at a rate at least twice that of placebo-treated patients included dizziness (8% vs. 4%, P = 0.282) and dry mouth (6% vs. 3%, P = 0.212). Other TEAEs occurring in ≥ 5% of duloxetine-treated patients included fatigue (8% vs. 6%, P = 0.613), nausea (8% vs. 6%, P = 0.613), constipation (6% vs. 4%, P = 0.567), and somnolence (5% vs. 3%, P = 0.329). Decreased appetite was reported more in duloxetine-treated patients than in placebo-treated patients (5.9% vs. 0%, P = 0.007). No other significant between-group differences were observed for specific TEAEs. SAEs were reported by 4 patients (3.4%) of the
Duloxetine in Patients with NP-MS 739
Week of Treatment
Estimated mean change from baseline in weekly API rating
Improvement
1
2
3
4
5
6
0
-0.5
Duloxetine
(N=115)
*
Placebo
(N=119)
-1
***
-1.5
***
**
-2
**
***
-2.5
-3
Figure 2. Primary efficacy analysis: estimated mean change in weekly mean average pain intensity ratings (mixed-models repeatedmeasures analysis). *P < 0.05, **P ≤ 0.01, ***P ≤ 0.001.
Table 2. Change in Secondary and Exploratory Efficacy Measures Acute Phase
Extension Phase
Duloxetine (N = 118) Mean (SE)
Placebo (N = 121) Mean (SE)
Change
Change
Duloxetine (N = 118) Mean (SD)
Placebo (N = 121) Mean (SD)
Efficacy Measure
Baseline
Baseline
P valuea
NPI CGI-S BPI severity Worst pain Least pain Average pain Pain right now BPI interference General activity Mood Walking ability Normal work Relations with others Sleep Enjoyment of life MS-QoL-54 Physical health composite score Mental health composite score Exploratory measures BDI-II total score BAI total score MFIS total score
5.7 (2) 4.3 (0.8)
5.3 (2) 4.3 (0.8)
0.072 0.873
1.8 (0.2) 0.7 (0.1)
7.5 4.7 6.1 5.8
(1.4) (2.1) (1.5) (1.9)
7.5 (1.4) 4.5 (2.1) 5.9 (1.3) 5.6 (1.9)
0.858 0.346 0.261 0.401
2 1.2 1.4 1.9
5.6 5.7 5.8 5.9 4.6 5.5 5.6
(2.2) (2.3) (3) (2.4) (2.7) (2.5) (2.4)
5.7 (2) 5.3 (2.4) 5.2 (2.8) 5.5 (2.4) 4.2 (2.7) 5.4 (2.6) 5.2 (2.6)
0.934 0.129 0.133 0.157 0.235 0.570 0.223
1.8 1.9 1.5 1.5 1.7 2 1.8
42.5 (15.1)
44.3 (15.5)
62 (21.4)
14 (9.0) 16.8 (9) 50.4 (13.9)
a
All Patients (N = 209) Mean (SD) P valueb
Baseline
Change
P valuec
1.1 (0.2) 0.4 (0.1)
0.003 0.041
4.1 (2.3) 3.7 (0.9)
1 (1.6) 0.6 (1)
< 0.001 < 0.001
(0.2) (0.2) (0.2) (0.2)
1.3 (0.2) 0.7 (0.2) 0.8 (0.2) 1 (0.2)
0.016 0.043 0.030 0.001
5.8 3.6 4.9 4.1
(2.3) (2.3) (2.1) (2.4)
1.3 1 1.3 1
(2.1) (1.8) (1.8) (2.2)
< < <
