Efficacy of pregabalin in post-traumatic peripheral neuropathic pain: a randomized, double-blind, placebo-controlled phase 3 trial

Efficacy of pregabalin in post-traumatic peripheral neuropathic pain: a randomized, double-blind,... The growing need for symptomatic treatment of post-traumatic neuropathic pain (PTNP) continues to be unmet. Studies evaluating the efficacy of pregabalin for reducing neuropathic pain following trauma and surgery yielded positive results over ≤ 8-week treatment. To assess the efficacy and tolerability of pregabalin over 3 months in patients with PTNP, a randomized, double-blind, placebo-controlled, parallel-group trial evaluated patients with PTNP at 101 centers in 11 countries—the long- est, largest such trial. Adults diagnosed with PTNP were randomly assigned (1:1) to 15 weeks of pregabalin (flexibly dosed 150–600 mg/day) or matching placebo. Primary efficacy analysis was by mixed-model repeated measures comparing change from baseline to week 15 in weekly mean pain scores between active and placebo groups. Evaluable patients included 274 in the pregabalin group and 265 in the placebo group. Trauma was surgical in 49.6% of patients, non-surgical in the remainder. The primary efficacy analysis showed no statistically significant difference between pregabalin and placebo groups in the change from baseline to week 15 [mean difference, − 0.22 points (95% confidence interval, 0.54–0.10); p = 0.1823]. However, comparisons for key secondary outcome measures yielded p values < 0.05 favoring pregabalin. Consistent with the known safety profile of pregabalin, the most common adverse events were dizziness and somnolence (14.6 and 9.9% of patients, respectively) with pregabalin (vs 4.2 and 3.4% with placebo). These findings demonstrate the feasibility of conducting a large, phase 3 registration trial in the heterogeneous PTNP study population. ClinicalTrials.gov NCT01701362. Keywords Neuropathic pain · Post-traumatic neuropathic pain · Post-surgical neuropathic pain · Pregabalin Introduction from acute to chronic [4, 5]. The need for symptomatic treatment of PTNP is increasing but remains inadequately Diverse types of nerve injury are recognized as triggers of addressed [6–8]. chronic post-traumatic neuropathic pain (PTNP), including Pregabalin, an alpha -delta (α δ) ligand (gabapentinoid), 2 2 post-surgical syndromes [1–3]. Tissue injury may chroni- is approved in the United States for the treatment of three cally alter peripheral nociceptive processing, shifting pain neuropathic pain (NeP) conditions: diabetic peripheral neu- ropathy (DPN), post-herpetic neuralgia (PHN), and post- spinal cord injury (SCI) [9]. An 8-week randomized clinical Electronic supplementary material The online version of this trial demonstrated the efficacy of pregabalin for the manage- article (https ://doi.org/10.1007/s0041 5-018-9063-9) contains ment of chronic post-traumatic/post-surgical pain [10]. supplementary material, which is available to authorized users. A study of longer duration was designed to meet the US regulatory standard for a chronic pain indication: 12 weeks * John Markman John_Markman@urmc.rochester.edu of maintenance or fixed dosing [11]. Methodologic fea- tures were incorporated to increase assay sensitivity for the Translational Pain Research Program, Department detection of an analgesic signal in this heterogeneous patient of Neurosurgery, University of Rochester Medical Center, population [12]. The primary objective was to compare the 601 Elmwood Avenue, Box 670, Rochester, NY 14642, USA efficacy of pregabalin (flexibly dosed, 150–600 mg/day) ver - Pfizer Inc, New York, NY, USA sus placebo in the treatment of PTNP. Secondary objectives Analgesic Solutions, Natick, MA, USA Vol.:(0123456789) 1 3 2816 Journal of Neurology (2018) 265:2815–2824 compared the efficacy of pregabalin vs placebo with respect serotonin-specific reuptake inhibitors (SSRIs), tricyclic to overall status, pain-related activity limitation, and sleep, antidepressants, and serotonin–norepinephrine reuptake in addition to safety and tolerability assessments. inhibitors (SNRIs)], tramadol and triptans, and/or sleep medications; acetaminophen ≤ 3 g/day was allowed as res- cue medication. Methods Study patients Study design and procedures Eligible patients were aged ≥ 18 years and had PTNP for Eligible patients were randomized at 101 centers in 11 ≥ 6 months after a surgical or non-surgical traumatic event countries (Bulgaria, Canada, Denmark, Germany, Hun- (e.g., history of a motor vehicle accident, fall, sports injury, gary, Poland, Romania, Sweden, South Africa, South knee or hip replacement, hernia repair, thoracotomy, mastec- Korea, and the United States). Following a single-blind tomy, focal/localized burns, or crush injury), a mean score of screening period, the 15-week double-blind treatment ≥ 4 in pain recall for the past week at screening, and a mean period comprised 3 weeks of dose titration/optimization score of ≥ 4 and ≤ 9 on a 0–10 numeric rating scale (NRS) and 12 weeks of maintenance treatment (Supplementary of average pain (0, “no pain” to 10, “worst possible pain”) Fig. S1). After randomization, clinic visits occurred every based on ≥ 4 daily diary scores from the last week of a sin- 3 weeks. gle-blind baseline screening period (5–14 days before ran- Patients were randomized (1:1) to pregabalin or matching domization). Peripheral nerve(s) implicated in the pain was placebo. The pregabalin dose was individually optimized via identified to confirm nerve trauma, and pain was categorized telephone contact to 150, 300, 450, or 600 mg/day over the as neuropathic based on prespecified criteria (i.e., neurologic titration period, with 4 days at each dose before titration to exam, study-specific PTNP assessment including use of the the next level. Dose adjustments were not allowed during the PainDETECT questionnaire to identify neuropathic compo- maintenance period, except for a single dose reduction if the nents of back pain [13]) and diagnostic tests (e.g., electro- investigator judged it necessary for tolerability. myography, nerve conduction tests, skin or nerve biopsy) if available. While PainDETECT was a screening assessment and used as part of the initial diagnostic assessment, since Outcome measures it is not specifically validated for this indication, this instru- ment itself did not determine eligibility in the study. The primary outcome was pain rated in a diary completed by Each neuropathic symptom or sign, mapped separately, telephone each evening between 7 mp and midnight. Patients was submitted to a team of independent neurologists (con- were asked to select the number that best described their tracted by Analgesic Solutions, Natick, MA, USA) who NeP during the past 24 h on an 11-point NRS ranging from determined the plausibility of matching a PTNP syndrome 0 (“no pain”) to 10 (“worst possible pain”). During this with respect to the history, anatomic distribution of reported call, patients were also asked to select the number that best pain, and associated signs identified on neurologic examina - described how NeP had interfered with their sleep during the tion in the corresponding body region. past 24 h, on an NRS from 0 (“pain does not interfere with Exclusion criteria included NeP due to PHN, DPN, sleep”) to 10 (“pain completely interferes with sleep [unable complex regional pain syndrome, and other conditions; to sleep due to pain]”). other sources of pain that might confound assessment of Secondary outcome measures at randomization and PTNP; disallowed concomitant medications; nonpharma- endpoint included the patient-reported Medical Outcomes cologic treatments for PTNP; severe or acute medical or Study-Sleep Scale (MOS-SS) [17], Brief Pain Inven- psychiatric conditions; or clinically significant laboratory tory-Short Form (BPI-sf) [18], European Quality of Life abnormalities. Patients scoring ≥ 15 on the Patient Health 5-Dimensions Questionnaire (EQ-5D) [19], Healthcare Questionnaire (PHQ-8) at screening or who were at risk Utilization Economic Assessment, and Work Productivity based on Columbia-Suicide Severity Rating (C-SSRS) and Activity Impairment Questionnaire-Specific Health responses were recommended for evaluation by a mental Problem (WPAI-SHP) [20]. Patients completed the Patient health professional prior to randomization [14–16]. Pro- Global Impression of Change (PGIC) using a 7-point scale hibited medications included opioids, local anesthetics, from “very much worse” to “very much improved”. At end- topical and intraspinal steroids, antiepileptics, and antip- point, only the BPI-sf was summarized for the pain severity sychotics. Allowed medications included stable regi- index score (average of 4 individual pain scores) and pain mens of nonsteroidal anti-inflammatory drugs (NSAIDs), interference index score (average of 7 individual interfer- non-opioid analgesics, antidepressants [including ence scores). 1 3 Journal of Neurology (2018) 265:2815–2824 2817 defined as all randomized patients who received at least one Statistical analyses dose of study drug, was used for all analyses. A per-protocol population was defined as a subset of the ITT population Sample size was calculated using estimates of variance and treatment difference from a previous PTNP trial. A sample who completed the study and did not have major protocol deviations with the potential to affect the primary efficacy of 235 patients per arm would provide 90% power to detect a treatment difference from placebo of 0.6 with respect analysis. The per-protocol population was used only in a sensitivity analysis of the primary efficacy endpoint. to change from baseline to week 15 in mean pain scores (MPS), assuming standard deviation (SD) of 2.0 and type I error rate of 0.05. A preplanned, unblinded interim analy- sis to re-estimate the sample size up to a maximum of 700 Results patients was performed by an independent data and safety monitoring board when approximately 80% of 470 patients Demographic and baseline characteristics had completed or discontinued from the study. The interim analysis was not intended to stop the study early for any This study was conducted between 31 October 2012 and 4 August 2015. Of 1164 patients screened for inclusion, efficacy claim. The prespecified primary analysis compared change 622 did not meet the inclusion criteria, most often because of failure to meet eligibility criteria (n = 584; 93.9%), spe- from baseline to week 15 in the MPS. The primary analysis employed mixed-model repeated measures (MMRM), using cifically, the NeP criteria ( n = 190). A total of 542 patients were randomized, 3 of whom were not treated (pregabalin, SAS PROC MIXED with model terms of treatment, trauma type, country, week, treatment-by-week interaction, and n = 274; placebo, n = 265) (Fig. 1). Approximately half the patients were male; mean age baseline MPS as covariates. Week was used as a class vari- able. A multiple imputation (MI) method was used to impute was 53 years (range, 20–85 years). Most patients were white (79.7%). Approximately half the patients had pain from missing MPS for the primary efficacy analysis, with poor outcomes imputed for withdrawals due to adverse events surgery, and the remainder had pain from other traumatic injuries. All randomized patients had a primary diagnosis (AEs) or lack of efficacy. Secondary analyses compared the change from baseline of peripheral nerve injury, with the nerves most commonly affected (i.e., amounting to > 5% of cases) as follows: pero- in weekly MPS and weekly mean sleep interference score with an MMRM model using model terms of treatment, neal (10.1%), ulnar (6.6%), sural (6.1%), median (6.0%), sciatic (5.9%), radial (5.6%), lateral cutaneous nerve of the trauma type, center, week, treatment-by-week interaction, and baseline MPS as covariates, without use of an MI thigh (5.3%), and other (6.3%). Demographic characteris- tics were similar between treatment groups. Mean duration algorithm. For sensitivity analyses, analysis of covariance (ANCOVA) with model terms of treatment, center, trauma between symptom onset and enrollment in the trial was 8.0 years in both treatment groups. The MPS from the base- type, and baseline value analysis was applied to the change from baseline to week 15 in MPS with imputation meth- line week of the daily NRS diary was 6.41 in the pregabalin group and 6.54 in the placebo group (Table 1). ods of baseline observation carried forward (BOCF), last observation carried forward (LOCF), and modified baseline Prior exposure to gabapentinoids (40 patients in total) was higher in the placebo group (9.4%) than in the pregaba- observation carried forward (mBOCF), which applied the BOCF rule for patients discontinued due to AEs and the lin group (5.5%). Concomitant pain drug treatments (con- tinuing stable treatment at randomization) were taken by 120 LOCF rule for patients discontinued for any other reason. Other continuous secondary endpoints were also analyzed (43.8%) patients in the pregabalin group and 130 (49.1%) patients in the placebo group. The most common concomi- with this ANCOVA model. Responder analyses compared the percentage of par- tant pain drugs were ibuprofen, acetaminophen, and trama- dol. The proportions of patients taking antidepressants for ticipants who achieved a 30% and 50% reduction in MPS from baseline to weeks 1–15 using a generalized linear any reason were similar between the treatment groups, com- prising less than one-tenth of patients in either group, with a model with a logistic link function. The model included categorical effects of treatment, center, trauma type, week, smaller subset of patients taking tricyclic antidepressants or serotonin–norepinephrine reuptake inhibitors. Rescue drug and treatment-by-week interaction, as well as a continuous baseline MPS. PGIC was analyzed at the endpoint using the treatments were taken by 16 patients in the pregabalin group and by 37 patients in the placebo group. Cochran–Mantel–Haenszel (CMH) test stratified for center and trauma type. At the end of the dose optimization period, the mean maintenance dose for evaluable pregabalin-treated patients A p value < 0.05 was considered statistically significant for all analyses. Adjustments for multiple secondary analy- (n = 256) was 473.7 mg/day. The maintenance dose of prega- balin was 600 mg/day for 150 (58.6%) patients, 450 mg/day ses were not made. The intention-to-treat (ITT) population, 1 3 2818 Journal of Neurology (2018) 265:2815–2824 Fig. 1 Trial profile. Subjects may have met more than one criterion procedures; 44 had exclusionary pain conditions; 43 did not have the for exclusion. Of 584 not meeting eligibility criteria, 190 did not meet implicated peripheral nerve identified; 34 had other exclusionary NeP requirements for neuropathic pain assessment; 71 did not meet the conditions; 34 had creatinine clearance ≤ 60  mL/min; and 22 were required duration of PTNP; 69 did not meet pain diary criteria prior taking prohibited medications to randomization; 65 were unwilling/unable to comply with study for 54 (21.1%) patients, 300 mg/day for 28 (10.9%) patients, similar when missing data were imputed using sensitivity and 150 mg/day for 24 (9.4%) patients. analyses LOCF, BOCF, and mBOCF. Weekly assessments At all weeks, the pregabalin-treated group had greater improvement in weekly MPS than the Efficacy placebo-treated group, although a relative increase in pla- cebo response during the final 2 weeks, 14 and 15, was Primary analysis noted. Differences were statistically significant (p < 0.05) from week 2 to 13, except for week 5 (Fig. 2). In addition, The primary analysis did not demonstrate a significant dif- the overall mean was also statistically significant (p < 0.05), ference between groups in the mean change of pain scores with a treatment difference of − 0.31. from baseline to week 15 [pregabalin vs placebo, − 0.22; The 30 and 50% responder status was defined for each 95% confidence interval (CI) − 0.54 to 0.10; p = 0.1823]. At patient based on the percentage change in the MPS from week 15, pain scores in both groups had improved compared baseline to each week, 1–15. Overall, there were more pre- with baseline [least-squares (LS) mean change from base- gabalin 30% and 50% pain responders when compared with line: pregabalin, − 2.12; placebo, − 1.90]. The results were the placebo group. The incidence of responders generally 1 3 Journal of Neurology (2018) 265:2815–2824 2819 Table 1 Baseline characteristics Demographic characteristics Pregabalin (n = 275) Placebo (n = 267) Total (N = 542) (randomized population) Age (years)  Mean (SD) 52.8 (12.9) 53.5 (12.6) 53.1 (12.8)  Range 20–81 20–85 20–85 Age, years, no. (%) of patients  18–44 60 (21.8) 61 (22.8) 121 (22.3)  45–64 163 (59.3) 156 (58.4) 319 (58.9)  ≥ 65 52 (18.9) 50 (18.7) 102 (18.8) Race, no. (%) of patients  White 217 (78.9) 215 (80.5) 432 (79.7)  Black 47 (17.1) 46 (17.2) 93 (17.2)  Asian 7 (2.5) 3 (1.1) 10 (1.8)  Other 4 (1.5) 3 (1.1) 7 (1.3) Weight (kg) Mean (SD) 85.9 (20.0) 86.2 (19.0) 86.1 (19.5)  Range 49.1–193.7 45.4–166.0 45.4–193.7 Height (cm) Mean (SD) 170.1 (10.1) 168.6 (9.4) 169.4 (9.8)  Range 142.2–198·0 140.0–198.1 140.0–198.1 Trauma type, no. (%) of patients  Surgical 131 (47.6) 138 (51.7) 269 (49.6)  Non-surgical 144 (52.4) 129 (48.3) 273 (50.4) Baseline mean pain (daily NRS)  Mean (SD) 6.41 (1.3) 6.5 (1.3) Questionnaire: PainDETECT [13] N = 274 N = 265  Mean (SD) 23.1 (5.52) 22.6 (5.52)  Range 2–36 3–38 NRS numeric rating scale, SD standard deviation increased over the first 3 weeks of treatment for both 30 index, a statistically significant change from baseline to week and 50% responders. Responder data for weeks 1–3, 14, 15 favored pregabalin over placebo (p = 0.0050; ANCOVA). and 15 are summarized for brevity (responder percentage The LS mean (standard error) change was − 2.40 (0.13) in [week, number responders/number observed at week, p the pregabalin group and − 1.95 (0.13) in the placebo group. value pregabalin vs placebo]). Pregabalin 30% responders In the mean pain interference index, a statistically significant were 11.9% (week 1, 31/260; p = 0.0028), 27.2% (week 2, change from baseline also favored pregabalin over placebo 69/254; p = 0.0360), 38.9% (week 3, 98/252; p = 0.0235), (p = 0.0168) (Table 2). 57.4% (week 14, 128/223; p = 0.4245), and 57.7% (week At week 15, the PGIC ratings of improvement were sta- 15, 113/196; p = 0.8464). Placebo 30% responders were tistically significantly higher in the pregabalin group than 5.0% (week 1, 13/258), 20.1% (week 2, 49/244), 30.2% the placebo group. More patients in the pregabalin group (week 3, 74/245), 54.3% (week 14, 113/208), and 58.3% (n = 157; 60.9%) than the placebo group (n = 120; 48.2%) (week 15, 109/187). Pregabalin 50% responders were 4.6% reported that they were very much or much improved on (week 1, 12/260; p = 0.1633), 11.4% (week 2, 29/254; the PGIC (p = 0.0029, CMH). Two additional predefined p = 0.0652), 22.6% (week 3, 57/252; p = 0.0039), 37.7% approaches for PGIC analysis, involving different groupings (week 14, 84/223; p = 0.0314), and 39.8% (week 15, 78/196; of the categories of improvement (“very much” or “much p = 0.1889). Placebo 50% responders were 2.3% (week 1, improved” vs all other groups; and categories compris- 6/258), 7.0% (week 2, 17/244), 13.5% (week 3, 33/245), ing “any improvement”, “no change”, “any worsening”), 29.8% (week 14, 62/208), and 34.2% (week 15, 64/187). also demonstrated statistically significant results favoring Differences were statistically significant for pregabalin com- pregabalin. pared with placebo (p < 0.05, generalized linear model) for Sleep The weekly mean sleep interference score at 30% responders at weeks 1–3, and for 50% responders at week 15 showed significantly greater improvement in the weeks 3–5, 7, 9, and 11–14. In the BPI-sf mean pain severity pregabalin group than in the placebo group [difference in 1 3 2820 Journal of Neurology (2018) 265:2815–2824 Fig. 2 Change from baseline in weekly mean pain score (daily pain in the 7 days. Generally, week “n” mean pain score is defined as the NRS; ITT population). *Unadjusted p < 0.05 from MMRM analysis. mean of the 7 daily diary pain ratings from day 2 + 7*(n–1) to day Changes in weekly mean pain score ± standard error were estimated 1 + 7*n. At least four entries within the last 7 days are required to cal- from mixed-model repeated measures (MMRM) model. Weekly culate a mean score. NRS ranged from 0 (“no pain”) to 10 (“worst mean pain numerical rating scale (NRS) scores are derived from the possible pain”), with higher scores indicating increased pain. ITT daily pain NRS and calculated as the mean of the available scores intention to treat Table 2 Summary of efficacy results: ITT population Outcome measure Screening/baseline (s.d.) LS mean change from baseline (s.e.) [95% LS mean difference p value CI] (s.e.) [95% CI] Pregabalin (N = 274) Placebo (N = 265) Pregabalin Placebo Primary efficacy 6.41 (1.29) 6.54 (1.31) − 2.12 (0.15) − 1.90 (0.16) [– 2.21, – 0.22 (0.16) [– 0.54, 0.1823 endpoint, week 15 [− 2.42, − 1.82] − 1.60] 0.10] mean pain Week 1–15 overall 6.41 (1.29) 6.54 (1.31) – 2.10 (0.10) [– 2.29, − 1.79 (0.10) [–1.99, − 0.31 (0.12) [– 0.55, 0.0117 mean pain effect − 1.90] − 1.60] − 0.07] Sleep interference, 4.97 (2.30) 4.99 (2.27) − 2.29 (0.11) [− 2.51, − 1.86 (0.11) [− 2.08, − 0.43 (0.15) [− 0.71, 0.0031 week 15 − 2.07] − 1.63] − 0.14] Endpoint BPI pain 5.95 (1.50) 5.90 (1.50) − 2.40 (0.13) [− 2.66, − 1.95 (0.13) [− 2.21, − 0.46 (0.16) [− 0.77, 0.0050 severity − 2.15] − 1.69] − 0.14] Endpoint BPI pain 4.07 (2.16) 4.06 (2.11) − 1.72 (0.13) − 1.33 (0.13) − 0.38 (0.16) [− 0.70, 0.0168 interference − 1.97, − 1.46] [− 1.59, − 1.07] − 0.07] BPI brief pain inventory, CI confidence interval, ITT intention to treat, LS least squares, SD standard deviation, SE standard error Primary analyses and sleep: mixed-model repeated measures, intention-to-treat population; Brief Pain Inventory-Short Form analysis of covari- ance Overall is for each subject to pool pain score for all post-baseline weeks adjusted mean change (pregabalin vs placebo) − 0.43; 95% and placebo groups was − 2.29 (0.11) and − 1.86 (− 0.11), CI, − 0.71 to − 0.14; p = 0.0031]. Adjusted mean change in respectively. Statistically significant differences favoring sleep interference from baseline to week 15 in the pregabalin 1 3 Journal of Neurology (2018) 265:2815–2824 2821 pregabalin were observed at all weeks (Supplementary Fig. group. Dizziness led to permanent discontinuation of treat- S2). ment for two patients in the pregabalin group and one in the placebo group. Discontinuation for somnolence occurred for Safety two patients in the pregabalin group. Pregabalin was well tolerated in this study, and the safety profile was consistent with or demonstrated fewer AEs when Discussion compared to the known profile of pregabalin in other NeP conditions [9]. Adverse events, most frequently dizziness This randomized, double-blind, placebo-controlled, parallel- and somnolence, occurred more frequently in the pregabalin group study of patients with PTNP did not demonstrate a group than the placebo group (Table 3). All pregabalin dose statistically significant treatment effect with pregabalin on levels used in the study were combined for reporting AEs mean pain intensity scores at the prespecified primary effi- consistent with a flexible dose design in which doses were cacy endpoint of the study, week 15. However, the primary titrated based on patients’ responses and treatment tolerabil- efficacy parameter (change in mean pain intensity scores) ity. Overall, 138 (50.4%) patients in the pregabalin group was statistically significant at most other time points, and and 106 (40.0%) in the placebo group experienced at least several secondary outcomes related to analgesic efficacy one AE. Two patients in the pregabalin group and seven and quality of life improved with pregabalin compared with in the placebo group experienced serious adverse events placebo treatment. Pregabalin was superior to placebo in (SAEs), none of which was considered related to treatment. reducing pain severity and interference with daily function One death occurred in the placebo group. There were no as measured by the BPI-sf. A significantly greater number of clinically significant findings with respect to changes in lab- patients in the pregabalin group described their overall status oratory values, vital signs, physical and neurologic examina- as very much improved or much improved when comparing tions, or electrocardiogram. their assessment on the PGIC during the last week of treat- There were 53 (19.3%) and 16 (6.0%) patients in the ment (i.e., week 15) to that at study outset. Finally, there was pregabalin and placebo groups, respectively, who had dose a consistent and significant reduction in pain interference reductions or temporary discontinuation of treatment due to with sleep over the course of the study. AEs. Treatment-emergent (all-causality) AEs led to perma- This was the first large phase 3, randomized, controlled nent discontinuation from the study for 13 (4.7%) patients in trial designed to evaluate the analgesic eca ffi cy of pregabalin the pregabalin group and 15 (5.7%) patients in the placebo in PTNP for registration purposes in the United States. The conduct of this trial indicates that a large, multinational, phase 3 trial of pregabalin in PTNP is feasible. The sig- nificant effect of pregabalin on a number of secondary end- Table 3 Adverse events (all-causality) experienced by ≥ 2% of patients in either treatment group by preferred term: safety analysis points, including second measure of pain intensity (BPI-sf) population raises the possibility that the absence of a statistically sig- nificant difference on the primary endpoint may be partly No. (%) of patients with adverse Pregabalin Placebo events (treatment related) by preferred (N = 274) No. (N = 265) attributed to additional factors individually or in aggregate term (%) No. (%) including (1) the study design, (2) dose titration, (3) ade- quacy of dose achieved, (4) duration of the fixed dose period, Dizziness 40 (14.6) 11 (4.2) (5) the number and wide geographical location of study sites Somnolence 27 (9.9) 9 (3.4) needed to conduct the study, (6) the level of refractoriness Fatigue 14 (5.1) 10 (3.8) of the study population, and (7) differential response to Nausea 14 (5.1) 8 (3.0) study treatments over time in study, particularly the placebo Headache 12 (4.4) 8 (3.0) response. A review of randomized, parallel-group, placebo- Vertigo 12 (4.4) 1 (0.4) Back pain 8 (2.9) 5 (1.9) controlled trials in neuropathic pain found that the magni- Disturbance in attention 8 (2.9) 0 tude of the placebo response accrues slowly and continually, Memory impairment 7 (2.6) 0 whereas pain reduction in response to active treatments man- Nasopharyngitis 7 (2.6) 8 (3.0) ifests more rapidly, before leveling off [21]. Such a pattern Constipation 6 (2.2) 4 (1.5) of placebo response occurred over the course of the present Sedation 6 (2.2) 0 study and possibly explains why pregabalin demonstrated a Pain in extremity 2 (0.7) 6 (2.3) Insomnia 2 (0.7) 6 (2.3) significant treatment effect on mean pain intensity in earlier weeks, but not in the primary analysis at week 15. Moreover, Includes data up to 999 days after last dose of study drug. Medical the efficacy of pregabalin observed in the earlier weeks of Dictionary for Regulatory Activities (MedDRA) v18.1) coding dic- this trial is consistent with the results from a prior, shorter tionary applied 1 3 2822 Journal of Neurology (2018) 265:2815–2824 trial with an 8-week double-blind period [10]. Although surgery were not worsened by tissue manipulation, electro- subjects in this study by Van Seventer et al. had an equally cautery, and/or incisions of the required surgery. Eighteen diverse set of etiologic mechanisms associated with chronic percent of participants did not complete the study, and the neuropathic pain [10], it should also be noted that the dura- corresponding loss of data may have affected the primary tion of the syndromes was nearly 50% shorter (4.4 vs 8 years result. Treatment-emergent side effects of pregabalin had in this study) and, therefore, the studies may not be strictly the potential for partial unblinding, which may have led to comparable. bias. Finally, performing multiple analyses and basing con- In future studies designed for a post-traumatic neuro- clusions of statistical significance on p values < 0.05 may pathic pain study population, a few considerations are worth lead to false-positive inferences; however, considering that noting. For example, a retrospective analysis demonstrated the preponderance of clinically relevant secondary analyses the effect size was larger in the post-surgical vs non-surgi- yielded p values < 0.05, the totality of the data appears to cal subgroup (− 0.43 vs 0.05, respectively), and nominal support a clinical benefit for pregabalin in PTNP. unadjusted P value was 0.04 compared with placebo (data The primary analysis of this trial was not statistically sig- on file). However, this is caveated in that the surgical and nificant; however, secondary analyses of multiple outcome non-surgical subgroup analyses were not preplanned prior measures were. Statistically significant changes were rela- to unblinding, were conducted post hoc and not adjusted tively modest, and there is no consensus on the magnitude of for multiple comparisons. It may be, for example, that post- a group difference for the 0–10 NRS that is considered clini- surgical traumatic pain contrasted with non-surgical pain cally meaningful. The efficacy of pregabalin in PTNP mer - is diagnosed with greater definitiveness and/or that such its further study in light of promising findings in clinically subjects can rate their pain and change in pain better than relevant outcomes, the low rate of SAEs, the positive results non-surgical subjects. Thus, it would be premature to sug- of a previous trial, established efficacy in other chronic NeP gest meaningful significance to this finding; however, this syndromes, and the lack of evidence-based treatments for finding could be considered or explored in future research. PTNP. Fixed-dose studies in contrast to flexible dosing in registra- tion studies might help to address any potential concerns for the adequacy of dose studied. When feasible, using Key points countries with a well-established research infrastructure for neuropathic pain research may be advisable. Performing Question Is pregabalin ec ffi acious and tolerable for the treat - the final assessment 1 week prior to the end of the study ment of chronic, post-traumatic neuropathic pain? while not making this explicitly apparent to the subjects may Findings In a double-blind, randomized international potentially avoid the presumed anticipatory narrowing of the study of 542 evaluable patients (pregabalin n = 274) of treatment difference observed at the end of the current study. whom approximately half had post-surgical neuropathic The tolerability of pregabalin observed in this study was pain, the primary efficacy analysis did not demonstrate a sta- consistent with the known profile of pregabalin in the man- tistically significant difference between active treatment and agement of NeP [22, 23]. Adverse events were preponder- placebo in change from baseline to week 15 (p = 0.1823). antly dizziness, somnolence, and fatigue, which generally However, comparisons for key secondary outcome measures resolved as treatment continued. Treatment-emergent AEs yielded p values < 0.05 favoring pregabalin. Safety and toler- of all-causality resulted in permanent withdrawal from the ability were consistent with the known profile of pregabalin. study for 13 patients in the pregabalin group and 15 in the Meaning Additional studies are needed to characterize placebo group. The two SAEs that occurred among prega- the efficacy and tolerability of pregabalin for chronic, post- balin-treated patients were not ascribed to the study drug. traumatic neuropathic pain. A few limitations warrant consideration. The methodol- ogy included the most recent recommendations intended to Acknowledgements This study was sponsored by Pfizer Inc. None of enhance assay sensitivity; some of these have face valid- the authors were paid to write this article, and all authors had full ity but have yet to be empirically tested [12, 24]. A related access to all data in the study. Medical writing support was provided by limitation was the lack of capacity to determine the effect Karen Burrows and Rosemary Perkins of Engage Scientific Solutions and was funded by Pfizer. All authors gave final consent for submis- of the recommended methods on assay sensitivity. Many sion of this article. variables related to study design influence assay sensitivity making it difficult to draw conclusions from a single study. Compliance with ethical standards The acute mechanisms of nerve injury within the enrolled population were etiologically diverse, and it may be diffi- Ethical standards The protocol complied with the Declaration of Hel- cult to discern in some cases, whether a peripheral nerve sinki (1964), and was reviewed and approved by the institutional review injury and corresponding deficits characterized prior to board at each participating center. 1 3 Journal of Neurology (2018) 265:2815–2824 2823 Informed consent All participants provided written, informed consent. 7. Macrae WA (2008) Chronic post-surgical pain: 10 years on. Br J Anaesth 101(1):77–86. https ://doi.org/10.1093/bja/aen09 9 8. Wong K, Phelan R, Kalso E, Galvin I, Goldstein D, Raja S, Gilron Conflicts of interest JM has participated in advisory boards (Pfizer, I (2014) Antidepressant drugs for prevention of acute and chronic Editas Medicine, Flexion Therapeutics, Teva, Quark, Pacira, Inspiri- postsurgical pain: early evidence and recommended future direc- on Delivery Sciences, Quartet, Pacira Egalet, Biogen, Nektar, Endo, tions. Anesthesiology 121(3):591–608. https ://doi.org/10.1097/ Immune Pharma, Chromocell, Collegium, Purdue, Novartis, Sanofi, ALN.00000 00000 00030 7 Convergence, Aptinyx, Daiichi Sankyo, Allergan, Plasmasurgical, and 9. Lyrica (pregabalin) [Prescribing Information]. Pfizer Inc. NY, NY Grunenthal), received research funding (Depomed, Pfizer), and served (2016) http://label ing.pf ize r .com/ShowL abeli ng.aspx?id=561. on Data Safety Monitoring Boards (Allergan, Novartis). M Resnick, Accessed 25 Jan 2018 R Yang, J Scavone, E Whalen, G Gregorian, B Parsons, and L Knapp 10. van Seventer R, Bach FW, Toth CC, Serpell M, Temple J, Mur- are employees of Pfizer Inc. S Greenberg was an employee of Pfizer phy TK, Nimour M (2010) Pregabalin in the treatment of post- at the time of the study and development of the manuscript. N Katz is traumatic peripheral neuropathic pain: a randomized double- employed by Analgesic Solutions, which provided a central eligibility blind trial. Eur J Neurol 17(8):1082–1089. https ://doi.org/10.111 verification service to identify patients with PTNP. 1/j.1468-1331.2010.02979 .x 11. US Department of Health and Human Services FaDA, Center for Data sharing statement Upon request, and subject to certain crite- Drug Evaluation and Research (CDER) (2014) Guidance for indus- ria, conditions and exceptions (see https ://www.pfize r.com/scien ce/ try analgesic indications: developing drug and biological products. clini cal-tr ial s/tr ial -dat a-and-r esul ts for more information), Pfizer http://www.fda.gov/downloads/Dr ugs/Guida nceCo m plianceR egulat will provide access to individual de-identified participant data from or yIn f or ma tion/Guida nces/UCM38 4691.pdf. Accessed 10 Nov Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have 12. Dworkin RH, Turk DC, Peirce-Sandner S, Burke LB, Farrar JT, been approved in the US and/or EU or (2) in programs that have been Gilron I, Jensen MP, Katz NP, Raja SN, Rappaport BA, Rowbotham terminated (i.e., development for all indications has been discontinued). MC, Backonja MM, Baron R, Bellamy N, Bhagwagar Z, Costello Pfizer will also consider requests for the protocol, data dictionary, and A, Cowan P, Fang WC, Hertz S, Jay GW, Junor R, Kerns RD, Ker- statistical analysis plan. Data may be requested from Pfizer trials 24 win R, Kopecky EA, Lissin D, Malamut R, Markman JD, McDer- months after study completion. The de-identified participant data will mott MP, Munera C, Porter L, Rauschkolb C, Rice AS, Sampaio C, be made available to researchers whose proposals meet the research cri- Skljarevski V, Sommerville K, Stacey BR, Steigerwald I, Tobias teria and other conditions, and for which an exception does not apply, J, Trentacosti AM, Wasan AD, Wells GA, Williams J, Witter J, via a secure portal. To gain access, data requestors must enter into a Ziegler D (2012) Considerations for improving assay sensitivity data access agreement with Pfizer. in chronic pain clinical trials: IMMPACT recommendations. Pain 153(6):1148–1158. https ://doi.org/10.1016/j.pain.2012.03.003 13. Freynhagen R, Baron R, Gockel U, Tolle TR (2006) painDETECT: Open Access This article is distributed under the terms of the Crea- a new screening questionnaire to identify neuropathic components tive Commons Attribution 4.0 International License (http://creat iveco in patients with back pain. 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Efficacy of pregabalin in post-traumatic peripheral neuropathic pain: a randomized, double-blind, placebo-controlled phase 3 trial

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Medicine & Public Health; Neurology; Neurosciences; Neuroradiology
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Abstract

The growing need for symptomatic treatment of post-traumatic neuropathic pain (PTNP) continues to be unmet. Studies evaluating the efficacy of pregabalin for reducing neuropathic pain following trauma and surgery yielded positive results over ≤ 8-week treatment. To assess the efficacy and tolerability of pregabalin over 3 months in patients with PTNP, a randomized, double-blind, placebo-controlled, parallel-group trial evaluated patients with PTNP at 101 centers in 11 countries—the long- est, largest such trial. Adults diagnosed with PTNP were randomly assigned (1:1) to 15 weeks of pregabalin (flexibly dosed 150–600 mg/day) or matching placebo. Primary efficacy analysis was by mixed-model repeated measures comparing change from baseline to week 15 in weekly mean pain scores between active and placebo groups. Evaluable patients included 274 in the pregabalin group and 265 in the placebo group. Trauma was surgical in 49.6% of patients, non-surgical in the remainder. The primary efficacy analysis showed no statistically significant difference between pregabalin and placebo groups in the change from baseline to week 15 [mean difference, − 0.22 points (95% confidence interval, 0.54–0.10); p = 0.1823]. However, comparisons for key secondary outcome measures yielded p values < 0.05 favoring pregabalin. Consistent with the known safety profile of pregabalin, the most common adverse events were dizziness and somnolence (14.6 and 9.9% of patients, respectively) with pregabalin (vs 4.2 and 3.4% with placebo). These findings demonstrate the feasibility of conducting a large, phase 3 registration trial in the heterogeneous PTNP study population. ClinicalTrials.gov NCT01701362. Keywords Neuropathic pain · Post-traumatic neuropathic pain · Post-surgical neuropathic pain · Pregabalin Introduction from acute to chronic [4, 5]. The need for symptomatic treatment of PTNP is increasing but remains inadequately Diverse types of nerve injury are recognized as triggers of addressed [6–8]. chronic post-traumatic neuropathic pain (PTNP), including Pregabalin, an alpha -delta (α δ) ligand (gabapentinoid), 2 2 post-surgical syndromes [1–3]. Tissue injury may chroni- is approved in the United States for the treatment of three cally alter peripheral nociceptive processing, shifting pain neuropathic pain (NeP) conditions: diabetic peripheral neu- ropathy (DPN), post-herpetic neuralgia (PHN), and post- spinal cord injury (SCI) [9]. An 8-week randomized clinical Electronic supplementary material The online version of this trial demonstrated the efficacy of pregabalin for the manage- article (https ://doi.org/10.1007/s0041 5-018-9063-9) contains ment of chronic post-traumatic/post-surgical pain [10]. supplementary material, which is available to authorized users. A study of longer duration was designed to meet the US regulatory standard for a chronic pain indication: 12 weeks * John Markman John_Markman@urmc.rochester.edu of maintenance or fixed dosing [11]. Methodologic fea- tures were incorporated to increase assay sensitivity for the Translational Pain Research Program, Department detection of an analgesic signal in this heterogeneous patient of Neurosurgery, University of Rochester Medical Center, population [12]. The primary objective was to compare the 601 Elmwood Avenue, Box 670, Rochester, NY 14642, USA efficacy of pregabalin (flexibly dosed, 150–600 mg/day) ver - Pfizer Inc, New York, NY, USA sus placebo in the treatment of PTNP. Secondary objectives Analgesic Solutions, Natick, MA, USA Vol.:(0123456789) 1 3 2816 Journal of Neurology (2018) 265:2815–2824 compared the efficacy of pregabalin vs placebo with respect serotonin-specific reuptake inhibitors (SSRIs), tricyclic to overall status, pain-related activity limitation, and sleep, antidepressants, and serotonin–norepinephrine reuptake in addition to safety and tolerability assessments. inhibitors (SNRIs)], tramadol and triptans, and/or sleep medications; acetaminophen ≤ 3 g/day was allowed as res- cue medication. Methods Study patients Study design and procedures Eligible patients were aged ≥ 18 years and had PTNP for Eligible patients were randomized at 101 centers in 11 ≥ 6 months after a surgical or non-surgical traumatic event countries (Bulgaria, Canada, Denmark, Germany, Hun- (e.g., history of a motor vehicle accident, fall, sports injury, gary, Poland, Romania, Sweden, South Africa, South knee or hip replacement, hernia repair, thoracotomy, mastec- Korea, and the United States). Following a single-blind tomy, focal/localized burns, or crush injury), a mean score of screening period, the 15-week double-blind treatment ≥ 4 in pain recall for the past week at screening, and a mean period comprised 3 weeks of dose titration/optimization score of ≥ 4 and ≤ 9 on a 0–10 numeric rating scale (NRS) and 12 weeks of maintenance treatment (Supplementary of average pain (0, “no pain” to 10, “worst possible pain”) Fig. S1). After randomization, clinic visits occurred every based on ≥ 4 daily diary scores from the last week of a sin- 3 weeks. gle-blind baseline screening period (5–14 days before ran- Patients were randomized (1:1) to pregabalin or matching domization). Peripheral nerve(s) implicated in the pain was placebo. The pregabalin dose was individually optimized via identified to confirm nerve trauma, and pain was categorized telephone contact to 150, 300, 450, or 600 mg/day over the as neuropathic based on prespecified criteria (i.e., neurologic titration period, with 4 days at each dose before titration to exam, study-specific PTNP assessment including use of the the next level. Dose adjustments were not allowed during the PainDETECT questionnaire to identify neuropathic compo- maintenance period, except for a single dose reduction if the nents of back pain [13]) and diagnostic tests (e.g., electro- investigator judged it necessary for tolerability. myography, nerve conduction tests, skin or nerve biopsy) if available. While PainDETECT was a screening assessment and used as part of the initial diagnostic assessment, since Outcome measures it is not specifically validated for this indication, this instru- ment itself did not determine eligibility in the study. The primary outcome was pain rated in a diary completed by Each neuropathic symptom or sign, mapped separately, telephone each evening between 7 mp and midnight. Patients was submitted to a team of independent neurologists (con- were asked to select the number that best described their tracted by Analgesic Solutions, Natick, MA, USA) who NeP during the past 24 h on an 11-point NRS ranging from determined the plausibility of matching a PTNP syndrome 0 (“no pain”) to 10 (“worst possible pain”). During this with respect to the history, anatomic distribution of reported call, patients were also asked to select the number that best pain, and associated signs identified on neurologic examina - described how NeP had interfered with their sleep during the tion in the corresponding body region. past 24 h, on an NRS from 0 (“pain does not interfere with Exclusion criteria included NeP due to PHN, DPN, sleep”) to 10 (“pain completely interferes with sleep [unable complex regional pain syndrome, and other conditions; to sleep due to pain]”). other sources of pain that might confound assessment of Secondary outcome measures at randomization and PTNP; disallowed concomitant medications; nonpharma- endpoint included the patient-reported Medical Outcomes cologic treatments for PTNP; severe or acute medical or Study-Sleep Scale (MOS-SS) [17], Brief Pain Inven- psychiatric conditions; or clinically significant laboratory tory-Short Form (BPI-sf) [18], European Quality of Life abnormalities. Patients scoring ≥ 15 on the Patient Health 5-Dimensions Questionnaire (EQ-5D) [19], Healthcare Questionnaire (PHQ-8) at screening or who were at risk Utilization Economic Assessment, and Work Productivity based on Columbia-Suicide Severity Rating (C-SSRS) and Activity Impairment Questionnaire-Specific Health responses were recommended for evaluation by a mental Problem (WPAI-SHP) [20]. Patients completed the Patient health professional prior to randomization [14–16]. Pro- Global Impression of Change (PGIC) using a 7-point scale hibited medications included opioids, local anesthetics, from “very much worse” to “very much improved”. At end- topical and intraspinal steroids, antiepileptics, and antip- point, only the BPI-sf was summarized for the pain severity sychotics. Allowed medications included stable regi- index score (average of 4 individual pain scores) and pain mens of nonsteroidal anti-inflammatory drugs (NSAIDs), interference index score (average of 7 individual interfer- non-opioid analgesics, antidepressants [including ence scores). 1 3 Journal of Neurology (2018) 265:2815–2824 2817 defined as all randomized patients who received at least one Statistical analyses dose of study drug, was used for all analyses. A per-protocol population was defined as a subset of the ITT population Sample size was calculated using estimates of variance and treatment difference from a previous PTNP trial. A sample who completed the study and did not have major protocol deviations with the potential to affect the primary efficacy of 235 patients per arm would provide 90% power to detect a treatment difference from placebo of 0.6 with respect analysis. The per-protocol population was used only in a sensitivity analysis of the primary efficacy endpoint. to change from baseline to week 15 in mean pain scores (MPS), assuming standard deviation (SD) of 2.0 and type I error rate of 0.05. A preplanned, unblinded interim analy- sis to re-estimate the sample size up to a maximum of 700 Results patients was performed by an independent data and safety monitoring board when approximately 80% of 470 patients Demographic and baseline characteristics had completed or discontinued from the study. The interim analysis was not intended to stop the study early for any This study was conducted between 31 October 2012 and 4 August 2015. Of 1164 patients screened for inclusion, efficacy claim. The prespecified primary analysis compared change 622 did not meet the inclusion criteria, most often because of failure to meet eligibility criteria (n = 584; 93.9%), spe- from baseline to week 15 in the MPS. The primary analysis employed mixed-model repeated measures (MMRM), using cifically, the NeP criteria ( n = 190). A total of 542 patients were randomized, 3 of whom were not treated (pregabalin, SAS PROC MIXED with model terms of treatment, trauma type, country, week, treatment-by-week interaction, and n = 274; placebo, n = 265) (Fig. 1). Approximately half the patients were male; mean age baseline MPS as covariates. Week was used as a class vari- able. A multiple imputation (MI) method was used to impute was 53 years (range, 20–85 years). Most patients were white (79.7%). Approximately half the patients had pain from missing MPS for the primary efficacy analysis, with poor outcomes imputed for withdrawals due to adverse events surgery, and the remainder had pain from other traumatic injuries. All randomized patients had a primary diagnosis (AEs) or lack of efficacy. Secondary analyses compared the change from baseline of peripheral nerve injury, with the nerves most commonly affected (i.e., amounting to > 5% of cases) as follows: pero- in weekly MPS and weekly mean sleep interference score with an MMRM model using model terms of treatment, neal (10.1%), ulnar (6.6%), sural (6.1%), median (6.0%), sciatic (5.9%), radial (5.6%), lateral cutaneous nerve of the trauma type, center, week, treatment-by-week interaction, and baseline MPS as covariates, without use of an MI thigh (5.3%), and other (6.3%). Demographic characteris- tics were similar between treatment groups. Mean duration algorithm. For sensitivity analyses, analysis of covariance (ANCOVA) with model terms of treatment, center, trauma between symptom onset and enrollment in the trial was 8.0 years in both treatment groups. The MPS from the base- type, and baseline value analysis was applied to the change from baseline to week 15 in MPS with imputation meth- line week of the daily NRS diary was 6.41 in the pregabalin group and 6.54 in the placebo group (Table 1). ods of baseline observation carried forward (BOCF), last observation carried forward (LOCF), and modified baseline Prior exposure to gabapentinoids (40 patients in total) was higher in the placebo group (9.4%) than in the pregaba- observation carried forward (mBOCF), which applied the BOCF rule for patients discontinued due to AEs and the lin group (5.5%). Concomitant pain drug treatments (con- tinuing stable treatment at randomization) were taken by 120 LOCF rule for patients discontinued for any other reason. Other continuous secondary endpoints were also analyzed (43.8%) patients in the pregabalin group and 130 (49.1%) patients in the placebo group. The most common concomi- with this ANCOVA model. Responder analyses compared the percentage of par- tant pain drugs were ibuprofen, acetaminophen, and trama- dol. The proportions of patients taking antidepressants for ticipants who achieved a 30% and 50% reduction in MPS from baseline to weeks 1–15 using a generalized linear any reason were similar between the treatment groups, com- prising less than one-tenth of patients in either group, with a model with a logistic link function. The model included categorical effects of treatment, center, trauma type, week, smaller subset of patients taking tricyclic antidepressants or serotonin–norepinephrine reuptake inhibitors. Rescue drug and treatment-by-week interaction, as well as a continuous baseline MPS. PGIC was analyzed at the endpoint using the treatments were taken by 16 patients in the pregabalin group and by 37 patients in the placebo group. Cochran–Mantel–Haenszel (CMH) test stratified for center and trauma type. At the end of the dose optimization period, the mean maintenance dose for evaluable pregabalin-treated patients A p value < 0.05 was considered statistically significant for all analyses. Adjustments for multiple secondary analy- (n = 256) was 473.7 mg/day. The maintenance dose of prega- balin was 600 mg/day for 150 (58.6%) patients, 450 mg/day ses were not made. The intention-to-treat (ITT) population, 1 3 2818 Journal of Neurology (2018) 265:2815–2824 Fig. 1 Trial profile. Subjects may have met more than one criterion procedures; 44 had exclusionary pain conditions; 43 did not have the for exclusion. Of 584 not meeting eligibility criteria, 190 did not meet implicated peripheral nerve identified; 34 had other exclusionary NeP requirements for neuropathic pain assessment; 71 did not meet the conditions; 34 had creatinine clearance ≤ 60  mL/min; and 22 were required duration of PTNP; 69 did not meet pain diary criteria prior taking prohibited medications to randomization; 65 were unwilling/unable to comply with study for 54 (21.1%) patients, 300 mg/day for 28 (10.9%) patients, similar when missing data were imputed using sensitivity and 150 mg/day for 24 (9.4%) patients. analyses LOCF, BOCF, and mBOCF. Weekly assessments At all weeks, the pregabalin-treated group had greater improvement in weekly MPS than the Efficacy placebo-treated group, although a relative increase in pla- cebo response during the final 2 weeks, 14 and 15, was Primary analysis noted. Differences were statistically significant (p < 0.05) from week 2 to 13, except for week 5 (Fig. 2). In addition, The primary analysis did not demonstrate a significant dif- the overall mean was also statistically significant (p < 0.05), ference between groups in the mean change of pain scores with a treatment difference of − 0.31. from baseline to week 15 [pregabalin vs placebo, − 0.22; The 30 and 50% responder status was defined for each 95% confidence interval (CI) − 0.54 to 0.10; p = 0.1823]. At patient based on the percentage change in the MPS from week 15, pain scores in both groups had improved compared baseline to each week, 1–15. Overall, there were more pre- with baseline [least-squares (LS) mean change from base- gabalin 30% and 50% pain responders when compared with line: pregabalin, − 2.12; placebo, − 1.90]. The results were the placebo group. The incidence of responders generally 1 3 Journal of Neurology (2018) 265:2815–2824 2819 Table 1 Baseline characteristics Demographic characteristics Pregabalin (n = 275) Placebo (n = 267) Total (N = 542) (randomized population) Age (years)  Mean (SD) 52.8 (12.9) 53.5 (12.6) 53.1 (12.8)  Range 20–81 20–85 20–85 Age, years, no. (%) of patients  18–44 60 (21.8) 61 (22.8) 121 (22.3)  45–64 163 (59.3) 156 (58.4) 319 (58.9)  ≥ 65 52 (18.9) 50 (18.7) 102 (18.8) Race, no. (%) of patients  White 217 (78.9) 215 (80.5) 432 (79.7)  Black 47 (17.1) 46 (17.2) 93 (17.2)  Asian 7 (2.5) 3 (1.1) 10 (1.8)  Other 4 (1.5) 3 (1.1) 7 (1.3) Weight (kg) Mean (SD) 85.9 (20.0) 86.2 (19.0) 86.1 (19.5)  Range 49.1–193.7 45.4–166.0 45.4–193.7 Height (cm) Mean (SD) 170.1 (10.1) 168.6 (9.4) 169.4 (9.8)  Range 142.2–198·0 140.0–198.1 140.0–198.1 Trauma type, no. (%) of patients  Surgical 131 (47.6) 138 (51.7) 269 (49.6)  Non-surgical 144 (52.4) 129 (48.3) 273 (50.4) Baseline mean pain (daily NRS)  Mean (SD) 6.41 (1.3) 6.5 (1.3) Questionnaire: PainDETECT [13] N = 274 N = 265  Mean (SD) 23.1 (5.52) 22.6 (5.52)  Range 2–36 3–38 NRS numeric rating scale, SD standard deviation increased over the first 3 weeks of treatment for both 30 index, a statistically significant change from baseline to week and 50% responders. Responder data for weeks 1–3, 14, 15 favored pregabalin over placebo (p = 0.0050; ANCOVA). and 15 are summarized for brevity (responder percentage The LS mean (standard error) change was − 2.40 (0.13) in [week, number responders/number observed at week, p the pregabalin group and − 1.95 (0.13) in the placebo group. value pregabalin vs placebo]). Pregabalin 30% responders In the mean pain interference index, a statistically significant were 11.9% (week 1, 31/260; p = 0.0028), 27.2% (week 2, change from baseline also favored pregabalin over placebo 69/254; p = 0.0360), 38.9% (week 3, 98/252; p = 0.0235), (p = 0.0168) (Table 2). 57.4% (week 14, 128/223; p = 0.4245), and 57.7% (week At week 15, the PGIC ratings of improvement were sta- 15, 113/196; p = 0.8464). Placebo 30% responders were tistically significantly higher in the pregabalin group than 5.0% (week 1, 13/258), 20.1% (week 2, 49/244), 30.2% the placebo group. More patients in the pregabalin group (week 3, 74/245), 54.3% (week 14, 113/208), and 58.3% (n = 157; 60.9%) than the placebo group (n = 120; 48.2%) (week 15, 109/187). Pregabalin 50% responders were 4.6% reported that they were very much or much improved on (week 1, 12/260; p = 0.1633), 11.4% (week 2, 29/254; the PGIC (p = 0.0029, CMH). Two additional predefined p = 0.0652), 22.6% (week 3, 57/252; p = 0.0039), 37.7% approaches for PGIC analysis, involving different groupings (week 14, 84/223; p = 0.0314), and 39.8% (week 15, 78/196; of the categories of improvement (“very much” or “much p = 0.1889). Placebo 50% responders were 2.3% (week 1, improved” vs all other groups; and categories compris- 6/258), 7.0% (week 2, 17/244), 13.5% (week 3, 33/245), ing “any improvement”, “no change”, “any worsening”), 29.8% (week 14, 62/208), and 34.2% (week 15, 64/187). also demonstrated statistically significant results favoring Differences were statistically significant for pregabalin com- pregabalin. pared with placebo (p < 0.05, generalized linear model) for Sleep The weekly mean sleep interference score at 30% responders at weeks 1–3, and for 50% responders at week 15 showed significantly greater improvement in the weeks 3–5, 7, 9, and 11–14. In the BPI-sf mean pain severity pregabalin group than in the placebo group [difference in 1 3 2820 Journal of Neurology (2018) 265:2815–2824 Fig. 2 Change from baseline in weekly mean pain score (daily pain in the 7 days. Generally, week “n” mean pain score is defined as the NRS; ITT population). *Unadjusted p < 0.05 from MMRM analysis. mean of the 7 daily diary pain ratings from day 2 + 7*(n–1) to day Changes in weekly mean pain score ± standard error were estimated 1 + 7*n. At least four entries within the last 7 days are required to cal- from mixed-model repeated measures (MMRM) model. Weekly culate a mean score. NRS ranged from 0 (“no pain”) to 10 (“worst mean pain numerical rating scale (NRS) scores are derived from the possible pain”), with higher scores indicating increased pain. ITT daily pain NRS and calculated as the mean of the available scores intention to treat Table 2 Summary of efficacy results: ITT population Outcome measure Screening/baseline (s.d.) LS mean change from baseline (s.e.) [95% LS mean difference p value CI] (s.e.) [95% CI] Pregabalin (N = 274) Placebo (N = 265) Pregabalin Placebo Primary efficacy 6.41 (1.29) 6.54 (1.31) − 2.12 (0.15) − 1.90 (0.16) [– 2.21, – 0.22 (0.16) [– 0.54, 0.1823 endpoint, week 15 [− 2.42, − 1.82] − 1.60] 0.10] mean pain Week 1–15 overall 6.41 (1.29) 6.54 (1.31) – 2.10 (0.10) [– 2.29, − 1.79 (0.10) [–1.99, − 0.31 (0.12) [– 0.55, 0.0117 mean pain effect − 1.90] − 1.60] − 0.07] Sleep interference, 4.97 (2.30) 4.99 (2.27) − 2.29 (0.11) [− 2.51, − 1.86 (0.11) [− 2.08, − 0.43 (0.15) [− 0.71, 0.0031 week 15 − 2.07] − 1.63] − 0.14] Endpoint BPI pain 5.95 (1.50) 5.90 (1.50) − 2.40 (0.13) [− 2.66, − 1.95 (0.13) [− 2.21, − 0.46 (0.16) [− 0.77, 0.0050 severity − 2.15] − 1.69] − 0.14] Endpoint BPI pain 4.07 (2.16) 4.06 (2.11) − 1.72 (0.13) − 1.33 (0.13) − 0.38 (0.16) [− 0.70, 0.0168 interference − 1.97, − 1.46] [− 1.59, − 1.07] − 0.07] BPI brief pain inventory, CI confidence interval, ITT intention to treat, LS least squares, SD standard deviation, SE standard error Primary analyses and sleep: mixed-model repeated measures, intention-to-treat population; Brief Pain Inventory-Short Form analysis of covari- ance Overall is for each subject to pool pain score for all post-baseline weeks adjusted mean change (pregabalin vs placebo) − 0.43; 95% and placebo groups was − 2.29 (0.11) and − 1.86 (− 0.11), CI, − 0.71 to − 0.14; p = 0.0031]. Adjusted mean change in respectively. Statistically significant differences favoring sleep interference from baseline to week 15 in the pregabalin 1 3 Journal of Neurology (2018) 265:2815–2824 2821 pregabalin were observed at all weeks (Supplementary Fig. group. Dizziness led to permanent discontinuation of treat- S2). ment for two patients in the pregabalin group and one in the placebo group. Discontinuation for somnolence occurred for Safety two patients in the pregabalin group. Pregabalin was well tolerated in this study, and the safety profile was consistent with or demonstrated fewer AEs when Discussion compared to the known profile of pregabalin in other NeP conditions [9]. Adverse events, most frequently dizziness This randomized, double-blind, placebo-controlled, parallel- and somnolence, occurred more frequently in the pregabalin group study of patients with PTNP did not demonstrate a group than the placebo group (Table 3). All pregabalin dose statistically significant treatment effect with pregabalin on levels used in the study were combined for reporting AEs mean pain intensity scores at the prespecified primary effi- consistent with a flexible dose design in which doses were cacy endpoint of the study, week 15. However, the primary titrated based on patients’ responses and treatment tolerabil- efficacy parameter (change in mean pain intensity scores) ity. Overall, 138 (50.4%) patients in the pregabalin group was statistically significant at most other time points, and and 106 (40.0%) in the placebo group experienced at least several secondary outcomes related to analgesic efficacy one AE. Two patients in the pregabalin group and seven and quality of life improved with pregabalin compared with in the placebo group experienced serious adverse events placebo treatment. Pregabalin was superior to placebo in (SAEs), none of which was considered related to treatment. reducing pain severity and interference with daily function One death occurred in the placebo group. There were no as measured by the BPI-sf. A significantly greater number of clinically significant findings with respect to changes in lab- patients in the pregabalin group described their overall status oratory values, vital signs, physical and neurologic examina- as very much improved or much improved when comparing tions, or electrocardiogram. their assessment on the PGIC during the last week of treat- There were 53 (19.3%) and 16 (6.0%) patients in the ment (i.e., week 15) to that at study outset. Finally, there was pregabalin and placebo groups, respectively, who had dose a consistent and significant reduction in pain interference reductions or temporary discontinuation of treatment due to with sleep over the course of the study. AEs. Treatment-emergent (all-causality) AEs led to perma- This was the first large phase 3, randomized, controlled nent discontinuation from the study for 13 (4.7%) patients in trial designed to evaluate the analgesic eca ffi cy of pregabalin the pregabalin group and 15 (5.7%) patients in the placebo in PTNP for registration purposes in the United States. The conduct of this trial indicates that a large, multinational, phase 3 trial of pregabalin in PTNP is feasible. The sig- nificant effect of pregabalin on a number of secondary end- Table 3 Adverse events (all-causality) experienced by ≥ 2% of patients in either treatment group by preferred term: safety analysis points, including second measure of pain intensity (BPI-sf) population raises the possibility that the absence of a statistically sig- nificant difference on the primary endpoint may be partly No. (%) of patients with adverse Pregabalin Placebo events (treatment related) by preferred (N = 274) No. (N = 265) attributed to additional factors individually or in aggregate term (%) No. (%) including (1) the study design, (2) dose titration, (3) ade- quacy of dose achieved, (4) duration of the fixed dose period, Dizziness 40 (14.6) 11 (4.2) (5) the number and wide geographical location of study sites Somnolence 27 (9.9) 9 (3.4) needed to conduct the study, (6) the level of refractoriness Fatigue 14 (5.1) 10 (3.8) of the study population, and (7) differential response to Nausea 14 (5.1) 8 (3.0) study treatments over time in study, particularly the placebo Headache 12 (4.4) 8 (3.0) response. A review of randomized, parallel-group, placebo- Vertigo 12 (4.4) 1 (0.4) Back pain 8 (2.9) 5 (1.9) controlled trials in neuropathic pain found that the magni- Disturbance in attention 8 (2.9) 0 tude of the placebo response accrues slowly and continually, Memory impairment 7 (2.6) 0 whereas pain reduction in response to active treatments man- Nasopharyngitis 7 (2.6) 8 (3.0) ifests more rapidly, before leveling off [21]. Such a pattern Constipation 6 (2.2) 4 (1.5) of placebo response occurred over the course of the present Sedation 6 (2.2) 0 study and possibly explains why pregabalin demonstrated a Pain in extremity 2 (0.7) 6 (2.3) Insomnia 2 (0.7) 6 (2.3) significant treatment effect on mean pain intensity in earlier weeks, but not in the primary analysis at week 15. Moreover, Includes data up to 999 days after last dose of study drug. Medical the efficacy of pregabalin observed in the earlier weeks of Dictionary for Regulatory Activities (MedDRA) v18.1) coding dic- this trial is consistent with the results from a prior, shorter tionary applied 1 3 2822 Journal of Neurology (2018) 265:2815–2824 trial with an 8-week double-blind period [10]. Although surgery were not worsened by tissue manipulation, electro- subjects in this study by Van Seventer et al. had an equally cautery, and/or incisions of the required surgery. Eighteen diverse set of etiologic mechanisms associated with chronic percent of participants did not complete the study, and the neuropathic pain [10], it should also be noted that the dura- corresponding loss of data may have affected the primary tion of the syndromes was nearly 50% shorter (4.4 vs 8 years result. Treatment-emergent side effects of pregabalin had in this study) and, therefore, the studies may not be strictly the potential for partial unblinding, which may have led to comparable. bias. Finally, performing multiple analyses and basing con- In future studies designed for a post-traumatic neuro- clusions of statistical significance on p values < 0.05 may pathic pain study population, a few considerations are worth lead to false-positive inferences; however, considering that noting. For example, a retrospective analysis demonstrated the preponderance of clinically relevant secondary analyses the effect size was larger in the post-surgical vs non-surgi- yielded p values < 0.05, the totality of the data appears to cal subgroup (− 0.43 vs 0.05, respectively), and nominal support a clinical benefit for pregabalin in PTNP. unadjusted P value was 0.04 compared with placebo (data The primary analysis of this trial was not statistically sig- on file). However, this is caveated in that the surgical and nificant; however, secondary analyses of multiple outcome non-surgical subgroup analyses were not preplanned prior measures were. Statistically significant changes were rela- to unblinding, were conducted post hoc and not adjusted tively modest, and there is no consensus on the magnitude of for multiple comparisons. It may be, for example, that post- a group difference for the 0–10 NRS that is considered clini- surgical traumatic pain contrasted with non-surgical pain cally meaningful. The efficacy of pregabalin in PTNP mer - is diagnosed with greater definitiveness and/or that such its further study in light of promising findings in clinically subjects can rate their pain and change in pain better than relevant outcomes, the low rate of SAEs, the positive results non-surgical subjects. Thus, it would be premature to sug- of a previous trial, established efficacy in other chronic NeP gest meaningful significance to this finding; however, this syndromes, and the lack of evidence-based treatments for finding could be considered or explored in future research. PTNP. Fixed-dose studies in contrast to flexible dosing in registra- tion studies might help to address any potential concerns for the adequacy of dose studied. When feasible, using Key points countries with a well-established research infrastructure for neuropathic pain research may be advisable. Performing Question Is pregabalin ec ffi acious and tolerable for the treat - the final assessment 1 week prior to the end of the study ment of chronic, post-traumatic neuropathic pain? while not making this explicitly apparent to the subjects may Findings In a double-blind, randomized international potentially avoid the presumed anticipatory narrowing of the study of 542 evaluable patients (pregabalin n = 274) of treatment difference observed at the end of the current study. whom approximately half had post-surgical neuropathic The tolerability of pregabalin observed in this study was pain, the primary efficacy analysis did not demonstrate a sta- consistent with the known profile of pregabalin in the man- tistically significant difference between active treatment and agement of NeP [22, 23]. Adverse events were preponder- placebo in change from baseline to week 15 (p = 0.1823). antly dizziness, somnolence, and fatigue, which generally However, comparisons for key secondary outcome measures resolved as treatment continued. Treatment-emergent AEs yielded p values < 0.05 favoring pregabalin. Safety and toler- of all-causality resulted in permanent withdrawal from the ability were consistent with the known profile of pregabalin. study for 13 patients in the pregabalin group and 15 in the Meaning Additional studies are needed to characterize placebo group. The two SAEs that occurred among prega- the efficacy and tolerability of pregabalin for chronic, post- balin-treated patients were not ascribed to the study drug. traumatic neuropathic pain. A few limitations warrant consideration. The methodol- ogy included the most recent recommendations intended to Acknowledgements This study was sponsored by Pfizer Inc. None of enhance assay sensitivity; some of these have face valid- the authors were paid to write this article, and all authors had full ity but have yet to be empirically tested [12, 24]. A related access to all data in the study. Medical writing support was provided by limitation was the lack of capacity to determine the effect Karen Burrows and Rosemary Perkins of Engage Scientific Solutions and was funded by Pfizer. All authors gave final consent for submis- of the recommended methods on assay sensitivity. Many sion of this article. variables related to study design influence assay sensitivity making it difficult to draw conclusions from a single study. Compliance with ethical standards The acute mechanisms of nerve injury within the enrolled population were etiologically diverse, and it may be diffi- Ethical standards The protocol complied with the Declaration of Hel- cult to discern in some cases, whether a peripheral nerve sinki (1964), and was reviewed and approved by the institutional review injury and corresponding deficits characterized prior to board at each participating center. 1 3 Journal of Neurology (2018) 265:2815–2824 2823 Informed consent All participants provided written, informed consent. 7. Macrae WA (2008) Chronic post-surgical pain: 10 years on. Br J Anaesth 101(1):77–86. https ://doi.org/10.1093/bja/aen09 9 8. Wong K, Phelan R, Kalso E, Galvin I, Goldstein D, Raja S, Gilron Conflicts of interest JM has participated in advisory boards (Pfizer, I (2014) Antidepressant drugs for prevention of acute and chronic Editas Medicine, Flexion Therapeutics, Teva, Quark, Pacira, Inspiri- postsurgical pain: early evidence and recommended future direc- on Delivery Sciences, Quartet, Pacira Egalet, Biogen, Nektar, Endo, tions. Anesthesiology 121(3):591–608. https ://doi.org/10.1097/ Immune Pharma, Chromocell, Collegium, Purdue, Novartis, Sanofi, ALN.00000 00000 00030 7 Convergence, Aptinyx, Daiichi Sankyo, Allergan, Plasmasurgical, and 9. Lyrica (pregabalin) [Prescribing Information]. Pfizer Inc. NY, NY Grunenthal), received research funding (Depomed, Pfizer), and served (2016) http://label ing.pf ize r .com/ShowL abeli ng.aspx?id=561. on Data Safety Monitoring Boards (Allergan, Novartis). M Resnick, Accessed 25 Jan 2018 R Yang, J Scavone, E Whalen, G Gregorian, B Parsons, and L Knapp 10. van Seventer R, Bach FW, Toth CC, Serpell M, Temple J, Mur- are employees of Pfizer Inc. S Greenberg was an employee of Pfizer phy TK, Nimour M (2010) Pregabalin in the treatment of post- at the time of the study and development of the manuscript. N Katz is traumatic peripheral neuropathic pain: a randomized double- employed by Analgesic Solutions, which provided a central eligibility blind trial. Eur J Neurol 17(8):1082–1089. https ://doi.org/10.111 verification service to identify patients with PTNP. 1/j.1468-1331.2010.02979 .x 11. US Department of Health and Human Services FaDA, Center for Data sharing statement Upon request, and subject to certain crite- Drug Evaluation and Research (CDER) (2014) Guidance for indus- ria, conditions and exceptions (see https ://www.pfize r.com/scien ce/ try analgesic indications: developing drug and biological products. clini cal-tr ial s/tr ial -dat a-and-r esul ts for more information), Pfizer http://www.fda.gov/downloads/Dr ugs/Guida nceCo m plianceR egulat will provide access to individual de-identified participant data from or yIn f or ma tion/Guida nces/UCM38 4691.pdf. Accessed 10 Nov Pfizer-sponsored global interventional clinical studies conducted for medicines, vaccines and medical devices (1) for indications that have 12. 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Journal of NeurologySpringer Journals

Published: Sep 21, 2018

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