Fibromyalgia (FM) is a common, chronic pain disorder

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1 ORIGINAL ARTICLE Long-term Maintenance of Response Across Multiple Fibromyalgia Symptom Domains in a Randomized Withdrawal Study of Pregabalin Lynne Pauer, MS,* Gary Atkinson, MSc,w T. Kevin Murphy, PhD,z Danielle Petersel, MD,z and Bernhardt Zeiher, MD* Objective: To determine the incidence and duration of response of clinically meaningful improvements with pregabalin across several key symptoms of fibromyalgia (FM). Methods: This was a post hoc analysis of data from a multicenter, double-blind, placebo-controlled, randomized, withdrawal study, originally designed to evaluate the efficacy of pregabalin monotherapy for durability of effect on FM pain based on pain and Patient Global Impression of Change (PGIC) criteria. Responder criteria for Fibromyalgia Impact Questionnaire total score (Z16- point change), Medical Outcomes Study Sleep Scale Sleep Disturbance subscale (Z15.8-point change), and the 36-item Short-Form Health Survey Vitality scale (Z10-point change) were used to evaluate the incidence and duration of improvements in function, sleep, and fatigue for pregabalin versus placebo among pain and PGIC responders. A composite responder index consisting of pain, PGIC, function, and sleep endpoints was used to explore multidimensional response. Results: Approximately 80% of patients meeting pain and PGIC improvement criteria at randomization had clinically meaningful improvement in fatigue, sleep, or function. Higher proportions of patients in the pregabalin group maintained a clinically meaningful response, and pregabalin-treated patients had a significantly longer time to loss of therapeutic response compared with the placebo group. Composite responder Kaplan-Meier analysis, performed with patients demonstrating clinically meaningful improvements in pain, PGIC, function, and sleep at randomization showed a significantly longer median time to loss of therapeutic response for pregabalintreated patients. Discussion: The results from this post hoc analysis indicate that pregabalin provides long-term effects across multiple domains of FM (ClinicalTrials.gov registry ID: NCT ). Received for publication June 8, 2011; accepted October 18, From the *Pfizer Global Research and Development, New London, CT; wpfizer Global Research and Development, Sandwich, Kent, UK; and zpfizer Inc., New York, NY. The original study and this post hoc analysis were funded by Pfizer Inc. (New York, NY). Bernhardt Zeiher, MD was an employee of Pfizer Inc. (Pfizer Global Research and Development, New London, CT) at the time the study and this analysis were conducted and the original manuscript was drafted. Gary Atkinson, MD (Pfizer Global Research and Development, Sandwich, Kent, UK), Lynne Pauer, MS (Pfizer Global Research and Development, New London, CT), T. Kevin Murphy, PhD (Pfizer Inc., New York, NY), and Danielle Petersel, MD (Pfizer Inc., New York, NY) are full-time employees of Pfizer Inc. Editorial support was provided by Dr Max Gough, PhD, at Technical Typesetters Inc., Ashford, Kent, TN24 8HL and Dr Alison Gagnon, PhD, of UBC Scientific Solutions, Southport, CT, and was funded by Pfizer Inc. All authors contributed to the editing and revision of the manuscript; and all authors have reviewed, approved, and take responsibility for the content of the manuscript. The authors declare no conflict of interest. Reprints: Lynne Pauer, MS, Pfizer Inc., 445 Eastern Point Rd., Groton, CT ( lynne.pauer@pfizer.com). Copyright r 2012 by Lippincott Williams & Wilkins Key Words: fibromyalgia, pain, fatigue, sleep, pregabalin (Clin J Pain 2012;28: ) Fibromyalgia (FM) is a common, chronic pain disorder characterized by widespread pain and tenderness and frequently accompanied by a variety of other symptoms, such as fatigue, sleep disturbance, and mood disorders. 1 4 Patients and their physicians consistently rank pain as the most important FM symptom domain. 5 Other symptom domains ranked highly by patients and physicians include fatigue, sleep disturbance, health-related quality of life, comorbid depression, and cognitive difficulty. 5 Few current FM therapies have demonstrated consistent or adequate efficacy in these domains in large controlled clinical studies. Pregabalin (Lyrica, Pfizer Inc., New York, NY) is an a 2 d ligand that has an analgesic, an anxiolytic, and an anticonvulsant activity. Its action is mediated through the a 2 d protein, an auxiliary subunit of voltage-dependent calcium channels. 6 Pregabalin reduces the synaptic release of several neurotransmitters, including glutamate, noradrenaline, and substance P, and modulates the influx of calcium ions into hyperexcited neurons. This reduction in synaptic activity may account for pregabalin actions in vivo to reduce neuronal excitability and ultimately its analgesic action The efficacy and safety of pregabalin in the treatment of FM were shown in 4 randomized controlled clinical studies (Pfizer Inc., unpublished data, April 2011) Consistent improvement in pain and patient global assessment with pregabalin dosages of 300 to 600 mg/d were demonstrated in these clinical studies lasting between 8 and 14 weeks. The long-term efficacy of pregabalin was demonstrated in a 6-month randomized withdrawal study designed to evaluate the durability of effect of pregabalin monotherapy on FM pain. 17 This clinical study included a 6-week openlabel (OL) pregabalin treatment period. Patients who had Z50% pain reduction and reported Patient Global Impression of Change (PGIC) as much improved or very much improved during the OL phase were deemed responders and were randomized to receive placebo or continue pregabalin at their optimized dose. In the ensuing 6-month double-blind (DB) phase, patients randomized to pregabalin were significantly more likely to maintain pain and PGIC responses compared with placebo. 17 The objective of the current post hoc analysis of data from the randomized withdrawal study was to determine the incidence of clinically meaningful improvements in other key symptom domains of FM, namely function, sleep, and fatigue, and whether these benefits were maintained by continued pregabalin treatment. 17 In addition, we evaluated Clin J Pain Volume 28, Number 7, September

2 Pauer et al Clin J Pain Volume 28, Number 7, September 2012 the proportion of patients responding across multiple domains (composite responder analysis) and the duration of time patients maintain response across these multiple symptom domains. MATERIAL AND METHODS Study Design The Fibromyalgia Relapse Evaluation and Efficacy for Durability of Meaningful relief (FREEDOM) study was a multicenter, DB, placebo-controlled, randomized, withdrawal study (ClinicalTrials.gov registry ID: NCT ). A complete description of the design and results of the study have been reported. 17 Briefly, this study consisted of a screening phase followed by a 6-week OL treatment phase in which all patients were titrated to their optimal dose of pregabalin (300 to 600 mg/d). Patients meeting response criteria for pain [Z50% reduction in pain 100-mm Visual Analog Scale (VAS) score from OL baseline] and PGIC (self-rating of much improved or very much improved) at the end of the OL treatment phase were eligible for the 26-week DB treatment phase, into which they were randomized to receive placebo or to remain at their optimal dosage of pregabalin. During the DB phase, patients maintaining r30% improvement in pain compared with baseline of the OL phase or those requiring additional therapy because of worsening FM symptoms were considered to have loss of therapeutic reponse (LTR) and were discontinued from the study. A 50% reduction in pain represents a substantial improvement in pain, and maintenance of Z30% pain improvement is considered clinically meaningful. 18,19 The study was conducted in compliance with the Declaration of Helsinki, the International Conference on Harmonization Good Clinical Practice Guidelines, and the Food and Drug Administration Guidelines, and was registered under NCT at Patients The FREEDOM study 17 included patients who met the 1990 American College of Rheumatology criteria for FM, 4 had an average pain score Z4 on an 11-point numerical rating scale (0 = no pain to 10 = worst possible pain), and reported a score Z40 mm on the 100-mm VAS of the Short-Form McGill Pain Questionnaire 20 at both screening and randomization visits. Pain medications with potential effects on pain and sleep, including antidepressants, must have been stopped at least 1 to 7 days before the start of the study, depending on the drug class, and fluoxetine required a Z30-day washout period. Patients were informed of all aspects of the study, and written informed consent was obtained. Assessments and Response Criteria At each study visit, patients were administered a battery of instruments to evaluate efficacy and were assessed for adverse events (AEs). Efficacy assessments included the following: pain on the 100-mm VAS of the Short-Form McGill Pain Questionnaire (0 = no pain to 100 = worst possible pain), PGIC (1 = very much improved; 2 = much improved; 3 = minimally improved; 4 = no change; 5 = minimally worse; 6 = much worse; 7 = very much worse), Fibromyalgia Impact Questionnaire (FIQ), Medical Outcomes Study Sleep Scale (MOS-SS), and the 36-item Short- Form Health Survey (SF-36). Each of the endpoints was assessed at randomization for the DB phase, at 2 weeks subsequent to randomization, and every 4 weeks thereafter, or at early termination. The current post hoc analysis evaluated the proportions of responders and durations of response on key symptoms of FM using responder criteria for function (FIQ total score), sleep (MOS-SS Sleep Disturbance subscale), and fatigue (SF-36 Vitality scale). A composite responder analysis that included pain, PGIC, FIQ total score, and MOS-SS Sleep Disturbance subscale endpoints was also performed to determine the incidence of multidimensional response and duration of these benefits relative to placebo. Patients were retrospectively identified for inclusion in this post hoc analysis who were pain and PGIC responders and who also met the following function, sleep, or fatigue response criteria at the end of the OL treatment phase in the FREEDOM study: FIQ total score a change of 8 points was considered a clinically important difference that correlated with a 1-category change in PGIC. 19 A 16-point change corresponds to a more substantial 2-category change in PGIC. 21 MOS-SS Sleep Disturbance subscale a 7.9-point change was found to correspond to a 1-category change in PGIC, with a 15.8-point change representing a 2-category change in PGIC. 22 SF-36 Vitality scale changes of 5 to 10 points have previously been reported to represent clinically important differences. 23 As shown in Table 1, the larger of each of these values was used as the threshold criterion at randomization, with only those patients demonstrating that level of improvement included in the Kaplan-Meier analysis of time to LTR for a given endpoint. The smaller of the clinically meaningful improvements described was used as the lower limit for maintenance of response. Patients meeting the threshold response criterion at randomization were evaluated to determine whether a clinically meaningful response could be maintained during the DB phase of the study. For the multidimensional composite analysis, threshold response criteria are provided in Table 2. Patients deemed responders on pain, PGIC, FIQ, and MOS-SS TABLE 1. Response Criteria for Time to LTR Analyses Endpoint Randomization Improvement Threshold LTR Definition (Compared With OL Baseline) Original analyses* Pain Z50% <30% improvement PGIC New analyses FIQ total score MOS-SS Sleep Disturbance SF-36 Vitality scale Very much or much improved Z16 points Less than much improved r8 points Z15.8 points r7.9 points Z10 points r5 points *See Crofford et al. 17 FIQ indicates Fibromyalgia Impact Questionnaire; LTR, loss of therapeutic response; MOS-SS, Medical Outcomes Study Sleep Scale; OL, open-label; PGIC, Patient Global Impression of Change; SF-36, 36-item Short-Form Health Survey r 2012 Lippincott Williams & Wilkins

3 Clin J Pain Volume 28, Number 7, September 2012 Fibromyalgia Symptom Domains TABLE 2. Multidimensional Response Criteria for Analysis of Time to LTR Endpoint Randomization Improvement Threshold Patients Meeting Threshold LTR Definition (Vs. OL Baseline) Pain Z50% 100% <30% PGIC Very much or 100% NA* much improved FIQ total score 16 points 86% r8 points MOS-SS Sleep 15.8 points 79% r7.9 points Disturbance Overall Composite index: pain, PGIC, FIQ, MOS-SS above 75% Any pain, function, and sleep thresholds abovew *Not used in this analysis because it is an aggregate measure. wltr defined as loss of response on any one threshold. FIQ indicates Fibromyalgia Impact Questionnaire; LTR, loss of therapeutic response; MOS-SS, Medical Outcomes Study Sleep Scale; NA, not available; OL, open-label; PGIC, Patient Global Impression of Change. Sleep Disturbance at the end of the OL treatment phase were evaluated for maintenance of response during the DB phase of the study. LTR was defined as loss of response on any one threshold (ie, pain, FIQ total score, or MOS-SS Sleep Disturbance) compared with OL baseline. PGIC was not used as a loss of response criterion because it is an aggregate measure. Statistical Analyses The Kaplan-Meier survival analyses were used to compare treatment groups for time to LTR, classifying each patient into 1 of the 2 groups: those who experienced LTR (also termed as failed patients), and those who did not experience LTR (also termed as censored patients) either because they completed the study before LTR was observed, or they discontinued because of AEs, withdrawal of consent, or any reasons other than LTR. The methodology is robust in that it does not assume any distributional form for time to LTR and provides a test statistic (log-rank test) to compare treatment groups. The estimated Kaplan- Meier survival function and summary statistics (median, 25th quartile, and associated confidence intervals) were calculated. FIGURE 1. Patient disposition. FM indicates fibromyalgia. Adapted from Crofford et al. 17 Because patients were randomized to their optimal dosages attained during the OL treatment phase, the primary comparison was between all pregabalin patients and all placebo patients. Events were censored at 28 days after the last dose of study medication (to ensure that while drug was still possibly present in patients systems, AEs would be reported and collected), and patients who discontinued DB treatment for reasons other than LTR were censored. RESULTS Patient Disposition In the FREEDOM study, a total of 1777 patients were screened and 1051 entered OL treatment. 17 Of these, 663 patients completed OL treatment, and 566 (placebo, n = 287; pregabalin, n = 279) met the pain and PGIC responder criteria and elected to continue in the study. Patient disposition is shown in Figure 1. Proportions of patients who completed the treatment based on dosage were 48% for pregabalin 300 mg/d, 33% for 450 mg/d, and 37% for 600 mg/d patients. Baseline Characteristics The majority of patients who entered the OL phase were female (93%) and white (88%). 17 Mean age at OL baseline was 49.5 years. There were no meaningful differences in TABLE 3. Summary of Patients Who Did and Did Not Experience LTR Endpoint/Treatment Group Total, N Responders, n (%)* % Analyzed LTR by End of Study, n (%)w Did Not Have LTR by End of Study, n (%)z FIQ total score worsening (to within 8 points of OL baseline) Placebo (82.6) (47.3) 125 (52.7) Pregabalin (90.0) 80 (31.9) 171 (68.1) MOS-SS Sleep Disturbance worsening (to within 7.9 points of OL baseline) Placebo (76.0) (52.3) 104 (47.7) Pregabalin (81.7) 55 (24.1) 173 (75.9) SF-36 Vitality scale worsening (to within 5 points of OL baseline) Placebo (79.8) (45.9) 124 (54.1) Pregabalin (82.4) 70 (30.4) 160 (69.6) *Patients meeting randomization improvement thresholds. wpatients who experienced loss of therapeutic response by the end of the study. zpatients who did not lose therapeutic response by end of the study. FIQ indicates Fibromyalgia Impact Questionnaire; LTR, loss of therapeutic response; MOS-SS, Medical Outcomes Study Sleep Scale; OL, open-label; SF-36, 36-item Short-Form Health Survey. r 2012 Lippincott Williams & Wilkins 611

4 Pauer et al Clin J Pain Volume 28, Number 7, September 2012 TABLE 4. Summary of Kaplan-Meier Estimates for Time to LTR Time to LTR (days) Endpoint/Treatment Group Total, N Responders, n (%)* 1st Quartilew 95% CI Median 95% CI Pz Time to FIQ total score worsening (to within 8 points of OL baseline) Placebo (82.6) 14 NA NA Pregabalin (90.0) NA 182-NA < Time to MOS-SS Sleep Disturbance worsening (to within 7.9 points of OL baseline) Placebo (76.0) 14 NA Pregabalin (81.7) NA NA < Time to SF-36 Vitality scale worsening (to within 5 points of OL baseline) Placebo (79.8) 14 NA Pregabalin (82.4) NA NA < Time to worsening on multidimensional composite index (pain, FIQ, MOS-SS)y Placebo (71.8) 14 NA Pregabalin (78.9) < *Patients meeting randomization improvement thresholds. wday on which one quarter of patients lost therapeutic response. zlog-rank test comparison in time to loss of therapeutic response versus placebo. yworsening on any one measure. CI indicates confidence interval; FIQ, Fibromyalgia Impact Questionnaire; LTR, loss of therapeutic response; MOS-SS, Medical Outcomes Study Sleep Scale; NA, not available, as fewer than half of patients experienced LTR; OL, open-label; SF-36, 36-item Short-Form Health Survey. demographic characteristics between those who entered OL treatment and those who were randomized to DB treatment, nor were there meaningful differences between the treatment groups. 17 Maintenance of Effect Achieved in Key Symptom Domains Approximately 80% of patients achieved the randomization improvement threshold for sleep, fatigue, and function endpoints: 86% achieved the FIQ total score threshold of a Z16-point improvement, 79% the MOS-SS Sleep Disturbance threshold of Z15.8-point improvement, and 81% the SF-36 Vitality improvement of Z10 points (Table 3). Analyses of each of these endpoints demonstrated a highly statistically significant (P<0.0001) difference in time to LTR between patients who met these randomization improvement thresholds and were subsequently randomized to pregabalin or placebo (Table 4). Kaplan-Meier plots show a clear separation between pregabalin and placebo-treated patients for FIQ total score (Fig. 2A), MOS-SS Sleep Disturbance (Fig. 2B), and SF-36 Vitality (Fig. 2C). In all analyses, 25% of placebo-treated patients had lost therapeutic response by day 14, compared with a significantly longer time for pregabalin for each endpoint: day 53 for FIQ total score, day 98 for MOS-SS Sleep Disturbance, and day 66 for SF-36 Vitality (Table 4). The median time to LTR for function, sleep disturbance, and fatigue endpoints ranged between 41 and 47 days for placebo-treated patients, whereas median time was not estimated for pregabalin-treated patients, because fewer than 50% of patients in each case lost therapeutic response (Table 4). Across function, sleep, and fatigue endpoints, greater proportions of patients in the placebo treatment group than the pregabalin treatment group lost therapeutic response. Therapeutic response was maintained in 68.1%, 75.9%, and 69.6% of pregabalin-treated patients compared with 52.7%, 47.7%, and 54.1% of placebo-treated patients for FIQ, MOS-SS Sleep Disturbance, and SF-36 Vitality, respectively (Table 3). Long-term Efficacy Demonstrated Across FM Symptom Domains Given the multidimensional nature of FM, an additional analysis was performed using those patients who demonstrated clinically meaningful improvements in pain, PGIC, sleep disturbance, and FIQ total score at randomization. Of the 566 randomized patients, 426 patients (75.3%) met all of these improvement thresholds and were included in a Kaplan-Meier analysis in which loss of FIGURE 2. Kaplan-Meier plots of time to LTR on (A) function, (B) sleep, and (C) fatigue. Kaplan-Meier estimates of time to LTR from open-label baseline were evaluated for each of the measures based on thresholds in Table 1. FIQ indicates Fibromyalgia Impact Questionnaire; LTR, loss of therapeutic response; MOS-SS, Medical Outcomes Study Sleep Scale; SF-36, 36-item Short-Form Health Survey r 2012 Lippincott Williams & Wilkins

5 Clin J Pain Volume 28, Number 7, September 2012 Fibromyalgia Symptom Domains FIGURE 3. Multidimensional response analysis. Kaplan-Meier plot for time to LTR. Kaplan-Meier estimates of time to LTR were evaluated for worsening on either pain, FIQ, or MOS-SS from open-label baseline. Multidimensional response and LTR were determined based on thresholds in Table 2. LTR was defined as loss of response on any single endpoint. LTR indicates loss of therapeutic response. improvement on any one of these endpoints (apart from PGIC, which was considered an aggregate endpoint) was considered LTR (Table 2). Using these stringent criteria, the median time to LTR was significantly longer (P< , log-rank test: Table 4 and Fig. 3) for patients maintained on pregabalin (66 d) as compared with patients switched to placebo (14 d). In total, 136 pregabalin patients (62%) and 170 placebo patients (85%) experienced LTR on any one of the endpoints (ie, pain, sleep disturbance, or function; Table 5). Safety The overall safety profile of pregabalin in this study has been previously reported. 17 During the DB treatment phase, the most commonly reported AEs were insomnia, nausea, and anxiety. Serious AEs were reported in 3% and 1% of patients in the pregabalin and placebo groups, respectively. 17 DISCUSSION FM is an important cause of pain, fatigue, reduced health-related quality of life, and disability. 1 4 Arandomized withdrawal study found a higher likelihood for the durability or maintenance of response with pregabalin treatment relative to placebo based on assessment of pain and PGIC. 17 The current post hoc analysis was performed to evaluate whether improvements in other domains of FM function, sleep, and fatigue were maintained over time, utilizing responder criteria for FIQ total score, MOS-SS Sleep Disturbance subscale, and the SF-36 Vitality scale. Approximately 80% of patients meeting pain and PGIC improvement criteria at randomization also had clinically meaningful improvement of fatigue, sleep, or function. Across each of these endpoints during the 6-month DB phase, a greater proportion of patients in the pregabalin treatment group maintained a clinically meaningful response, and the time to LTR was significantly longer in the pregabalin treatment group compared with the placebo treatment group. In addition, a stringent composite responder Kaplan- Meier analysis showed that 75% of patients demonstrated clinically meaningful improvements in pain, PGIC, sleep disturbance, and FIQ total score at randomization and a significantly longer median time to LTR for patients treated with pregabalin (66 d) compared with placebo (14 d). The multidimensional composite responder analysis reflects a particularly high efficacy hurdle, given that loss of response on any one of the key efficacy endpoints was considered an overall LTR. Therefore, a higher rate of LTR would be expected in this multidimensional analysis. These results demonstrate that response across multiple symptom domains of FM pain, function, sleep, and fatigue is maintained for a significantly longer time in patients treated with pregabalin. This was a post hoc analysis and as such had certain limitations. Patients were randomized in the DB phase based on pain and PGIC responses and not across function, sleep, and fatigue response criteria, potentially biasing the results. Enrichment withdrawal trials may have carryover effects in which patients converted to placebo from the 6-week OL pregabalin treatment phase may become unblinded to the treatment they were receiving. Finally, patients in clinical studies typically represent a more homogenous population of patients than those encountered in clinical practice, and this may limit the generalizability of the results to a broad patient population. Taken together, the response on pain and PGIC was associated with response on other relevant FM symptom domains. At the end of the OL pregabalin treatment phase, approximately 80% of pain and PGIC responders also responded on other domains such as sleep disturbance, FIQ, and vitality. Overall, 75% of patients demonstrated a multidimensional response on pain, PGIC, sleep, and FIQ. Whether analyzed as a single response domain or a stringent composite responder domain, response was more likely to be maintained with pregabalin treatment when compared with placebo. These results confirm that pregabalin provides longterm effects across multiple domains of FM. TABLE 5. Multidimensional Response Analysis: Patients With and Without LTR* Treatment Group Total N Responder, n (%) LTR by End of Study, n (%) Did Not Have LTR by End of Study, n (%) Placebo (71.8) 170 (85.2) 36 (17.5) Pregabalin (78.9) 136 (61.8) 84 (28.2) *LTR was defined as loss of response on any one threshold compared with open-label baseline. LTR indicates loss of therapeutic response. REFERENCES 1. Bennett RM. Fibromyalgia. In: Wall PD, Melzack R, eds. Textbook of Pain. 4th ed. London: Harcourt Publishers Churchill Livingstone; 1999: Clauw DJ, Crofford LJ. Chronic widespread pain and fibromyalgia: what we know, and what we need to know. Best Pract Res Clin Rheumatol. 2003;17: Mease P. Fibromyalgia syndrome: review of clinical presentation, pathogenesis, outcome measures, and treatment. J Rheumatol. 2005;75(suppl): Wolfe F, Smythe HA, Yunus MB, et al. The American College of Rheumatology 1990 criteria for the classification of fibromyalgia. Report of the multicenter criteria committee. 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